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Symptoms of Hypothyroidism:
Feeling cold (women more so than men), fatigue, weight gain or retention, water retention, hair loss, loss of the outer third of the eyebrow, constipation, high cholesterol, dry skin, dry hair, brittle nails, depression, migraines, PMS, poor wound healing, low stomach acid, gallbladder problems, low sex drive, ringing in the ears, shortness of breath, infertility, muscle pain, low blood sugar, insomnia, narcolepsy, low blood pressure, acne, usually sweating less, etc.

Common statements include:
"I am always cold". "I am ready to fall into bed as soon as I come home from work". I just don't have the energy I used to". "My get-up-and-go got up and left". "I just feel 'blah' all of the time". "I sleep all the time".

Hypothyroidism tends to be somewhat more common in women than men, and hypothyroid men tend not to complain of being cold (men tend to run much warmer than women due to more muscle mass). In women, some symptoms may also be due to hormone imbalance, such as low progesterone (feeling cold). Symptoms of adrenal fatigue (hypoglycemia, low blood pressure) also may be present.

Symptoms of Hyperthyroidism:
Hypertension, racing heart, weight loss, anxiety, etc.

Numerous opinions exist regarding what proper thyroid testing is, especially for picking up functional hypothyroidism, which is thyroid hormone imbalance or reverse T3 dominance. This form of hypothyroidism is the most difficult to diagnose, and is most often missed by doctors. Sometimes, labs can be normal yet someone can need additional T3. Wilson's Temperature Syndrome discusses using body temperature as an assessment for thyroid hormone action - consistant body temperatures below 97.8 F or 36.5 C indicate a problem that should be treated with T3.

T4 is the inactive (storage) form of thyroid hormone. It has to be converted to T3 to be useful. T4 is converted in the body to T3 and reverse T3. T3 is the active form of thyroid hormone, while reverse T3 is inactive. If your body were a car, think of T3 as the gas, and reverse T3 as the brakes. Both have their use, but best function requires a proper balance.

Usually, most of the T4 should be converted to T3, and only some should be converted to reverse T3.

Unfortunately, for various reasons, many people convert T4 into more reverse T3 than they should. I describe this as thyroid hormone imbalance. It is also called Functional Hypothyroidism, and Reverse T3 dominance.

Why test Reverse T3?
Reverse T3 in high enough concentrations can act as a competitive inhibitor of T3, blocking its entry into cells.
[Metabolism Volume 35, Issue 1, January 1986, Pages 71–74]

Reverse T3 slows metabolism, and also suppresses T4 to T3 conversion.

High levels of reverse T3 can cause symptoms of hypothyroidism even when TSH and other thyroid labs are normal.

This condition can be called Functional Hypothyroidism, Cellular Hypothyroidism, Reverse T3 Dominance, or Thyroid Hormone Imbalance.

It is impossible to diagnose from testing TSH alone, and difficult for doctors to spot unless they know to pay attention to the ratios. Using free T3 to calculate, a normal ratio is around 20-24 or more, and the lowest ratio I have found to date is 5.6; many patients I have checked have ratios between 8 and 18.

Some causes of reduced conversion of T4 to T3:
Fatty acid deficiency, selenium deficiency, zinc deficiency, candida, gut problems, high cortisol, medications including propranolol.

Why do we have reverse T3?
It is normal for have some reverse T3. In some cases, the ability to slow down metabolism by producing reverse T3 can be a survival advantage. People of Irish descent, for example, or anyone from a culture that has historically had to survive famine, had a survival advantage from being to produce more reverse T3. Those who could slow down their metabolisms could survive better in times of famine than those who had active metabolisms and could not slow them down.

Some causes of high reverse T3:
stress (due to cortisol imbalances)
diabetes
obesity
fibromyalgia
chronic fatigue
low iron
low B12 or B6
chronic alcohol intake
selenium deficiency
zinc deficiency
magnesium deficiency
acute MI
fasting
liver disease
kidney disease
BPA, pesticides, PCB toxicity, lead and mercury toxicity.
Pregnancy and estrogen therapy can also increase reverse T3.
Low B12 is a fairly common cause of higher reverse T3. Low selenium is not found often in the US.

Sometimes, even after the initial cause of a high reverse T3 has been corrected, because reverse T3 were high enough, reverse T3 by itself continues the feedback loop of high reverse T3. This cycle can be broken with proper treatment.

Managing high reverse T3
I do not necessarily treat every low ratio with desiccated thyroid. Often, I try to find the cause of the imbalance and fix it first. If energy levels improve, then nothing further needs to be done. People with ratios below 12 are more likely to need thyroid medication than those with ratios above 14.

Depending on cause(s), the thyroid can often be helped, or at least symptoms managed.

Everyone is different, and one should not decide treatment just on the basis of a T3/RT3 ratio. The full clinical picture needs to be taken into consideration.

Basic thyroid panel:
TSH:Thyroid Stimulating Hormone. Increases production of thyroid hormones. TSH tells us how the pituitary is doing. Is not an exact measure of thyroid function. Starting iodine supplementation may cause a temporary increase in TSH, which will correct over several weeks.
Free T4 (FT4) and Free T3 (FT3): Measures what is usable
Reverse T3 (RT3): Always do together with a Free T3. Very important in spotting an abnormal ratio. A thyroid panel is not properly done unless reverse T3 is included with free T3.

The key is that FT3 should be in the upper range of the lab reference, and RT3 should be in the lower part of the lab reference range. If both are mid-range, or if RT3 is high and FT3 is low, then you know there is a problem. The ratio of reverse T3 to free T3 is an important clue.

Here is a free online reverse T3 calculator. Pay attention to enter the correct units.

Normal reference ranges (can vary between different labs):
Free Serum T3 (Free Triiodothyronine, FT3, is more accurate than total): Adults 2.0 to 4.4 pg/mL (3.5 to 6.5 pmol/L); Children 2.7 to 5.2 pg/mL
Reverse T3 (RT3): Adults 9.2 to 24.1 ng/dL ( 0.11 to 0.32 ng/ml; 0.04 to 0.29 nmol/L); Children 8.3 to 22.9 ng/dL
Free T4 (FT4, is more accurate than total): Adults 0.82 to 1.77 ng/dL (10 to 23 pmol/L); Children 0.90 to 1.67 ng/dL
TSH: Adults 0.5 to 4.70 mIU/L (0.3 - 5.0 U/mL) - however any number over 2 may be suspicious for hypothyroidism.
Total T3 (TT3, includes bound as well as free): Adults 75 -200 ng/dL
Total T4 (TT4, includes bound as well as free): 4.5 -11.5 ug/dL
Thyroglobulin:5-25 ng/mL
TRH:5 -25 mIu/mL
Resin T3 uptake:25 to 35%

But my labs were normal !:
In certain states (diabetes, dyslipidemia, chronic fatigue, inflammation, insulin resistance, etc), there can be normal levels of thyroid hormones in the serum, but a cellular deficiency. This is because energy is required to transport thyroid hormones into the cell, and in states of mitochondrial dysfunction, those transporters may not be working as well.
Therefore, in certain states, one can have absolutely normal thyroid labs and still have symptoms of hypothyroidism.

Thyroid Antibodies and other tests:
Different thyroid receptor antibodies can have either stimulating or suppressing effects.
AMA: Anti-microsomal antibodies. An older term for TPO.
TPO: Thyroid Peroxidase. This is a sensitive test for detecting autoimmune thyroid problems. These antibodies are involved in thyroid tissue destruction. A common marker for Hashimoto's and post-partum thyroiditis. Elevated levels are a risk factor for miscarriage and infertility. Elevated levels are also a risk factor for developing thyroid problems from amiodarone, interferon-alpha, interleukin-2, and lithium. TPO can also be elevated in those with other autoimmune diseases such as Type I diabetes and pernicious anemia.
TgAb: Anti-Thyroglobulin. Serum measurements of TgAb may be useful in iodine deficient areas for detecting autoimmune thyroid disease in the presence of nodular goiter.
TSAb: Thyroid stimulating antibody. Mimics the action of TSH. This stimulates cAMP production, iodide uptake, and thyroglobulin production.
TRAb: Thyroid receptor antibodies. A broad group of antibodies that can either mimic or block the action of TSH and cause either hyper or hypothyroidism. These antibodies are common in Grave's.
TBAb or TSBAb: TSH receptor blocking antibodies. These block the action of TSH, causing hypothyroidism. TGI: Thyroid growth stimulating antibodies. This stimulates thyroid cell growth.
TBII: Thyroid binding inhibiting immunoglobulins. This blocks TSH from binding to the its receptor.
TSHR-Ab: Thyroid Stimulating Hormone receptor antibody: Autoimmune response to the thyroid stimulating hormone receptor. Detects both TSI (thyroid-stimulating immunoglobulins) and TSHR-blocking autoantibodies (measure using h-TBII assay).
TS-IgG and TSHR-Ab help rule out Graves in hyperthyroidism (a low TSH may prompt this testing).
Tg:Thyroglobulin. Thyroid tissue makes Tg. Thyroglobulin is used with the thyroid to produce T4 and T3. Tg can be measured before and after thyroid surgery to assess successful removal of thyroid. TgAb should also be tested with Tg because TgAb can interfere with Tg lab analysis and cause incorrect results.
hCG: human chorionic gonadotropin. Can bind weakly to the thyroid receptor and stimulate the thyroid.

How to test for Reverse T3:
If your doctor will not order it, or if the test is not available in your country, here are some possible options (prices are approximate). If you are in Pennsylvania or Virginia you may also contact me for additional options.
Walk-in Labs US $59
Life Extension US $55-73
Private MD labs US $62.50
True Health Labs US $69
RequestATest US
Personalabs US
Direct Labs US $89
Genova Diagnostics UK Europe and maybe International
Medichecks UK
Pulse Health Screening UK
DRG Diagnostics
Dr Sundardas Singapore (not sure if he actually can order the test, but he is familiar with RT3)
Diasource International research
Alpco RT3 assay For research use only

Micronutrient and other tests:
B12: should be around 800 or more.
Urine iodine (random is ok. Does not need to be 24 hr): Should be around 100.
Iron panel (Ferritin, TIBC, serum Iron): Should not be deficient. I prefer iron to be between the lower quarter and midrange of the reference range.
Serum copper, serum zinc: both should be around 100 ug/dL and zinc should be slightly higher than copper.
RBC Magnesium (serum magnesium is meaningless): this should be in the upper quarter of the reference range, and any number below that needs to be repleted. Make sure to maintain balance of calcium and potassium as well.
Selenium (contained in 5’-deiodinase, an enzyme that converts T4 to T3): I have yet to find anyone with low selenium in the US, although other parts of the world may have selenium deficiency.
Vitamin D (25 OH D and 1,25 OH D): 25 OH D should be around 50-60. A high 1,25 OH combined with a low 25 OH can be indicative of systemic inflammation.
24 hour saliva cortisol: This checks for adrenal function. Should be higher in the morning and lower in the evening.

Treatment of Functional Hypothyroidism:
In someone with Functional Hypothyroidism, synthroid or other T4 formulations may not be the correct treatment for them. This is because they are already not converting T4 to the proper ratio of T3 and RT3, and giving them a pure T4 medication will only continue that trend.

People with Functional Hypothyroidism need to be given a formulation with some T3 in it. Desiccated thyroid medications generally work well. Armour Thyroid is a commonly used brand. Of note, however, is that Armour does contain titanium dioxide in the 60 mg formulation. This is not desired. Armour also contains corn as a filler. If using Armour, just stick with the 30 mg tab, and use as many as needed, or else use Nature Throid, which is corn and titanium free.

Some people do well with just natural desiccated thyroid, while a small number may not. Others need desiccated thyroid plus additional T3 in either a sustained release form, or cytomel (immediate-release T3). Yet others do best on only T3 without any T4. Treatment must be individualized.

The compounded sustained release T3 formulations are commonly made with a cellulose compound. The cellulose is meant to slow absorption, but I feel that it may also sometimes interfere with absorption, and this can vary between individuals. Sometimes using acidophilus as a filler instead of cellulose may be desired, especially if the cellulose is causing gut problems. Unless my patient requests otherwise, I usually use the tablet immediate release T3 formulations (such as Cytomel and generic equivalents), which have the added benefit of being chewable and available as generics, although the downside is that more frequent dosing may be required.

How to dose Armour Thyroid:
Armour thyroid is made up of 1 part T3 and 4-some parts T4. The T4 has a long half life and will stay in your body for a few days. The T3 part, however, will only last for several hours. Therefore, if taking more than 30 mg of Armour daily, it is best to split the dose into a twice or thrice daily schedule. People report that taking Armour at bedtime improves their sleep. Armour Thyroid can be chewed and swallowed without any water if desired - the taste is bland and chalky but not bad. Other desiccated thyroid medications (such as Nature Throid) can be used in a similar way.

Using just T3 only:
I do not like to do this. T3 has a very short half life, and people on just T3 only can therefore experience both the symptoms of hypo and hyperthyroidism.

Other benefits of T3:
There is some evidence that T3 can be helpful in treating non-alcoholic fatty liver.

Reviews on various specific medications:
Mylan generic T3 tastes slight sweet and is crunchy in texture. Paddock generic T3 (white round tablet) is bland, soft/crumbly, and tends not to split well.

Autoimmune Thyroid Disease:
Autoimmune thyroid problems such as Hashimoto's and Grave's require special treatment, which can include detox, low dose naltrexone, selenomethionine, and homeopathics in addition to thyroid hormone. Hashimoto's with high titers of TPO needs to be treated more aggressively, as it is associated with higher rates of relapse.
Grave's disease will tend to have elevated TSH-binding inhibiting antibodies (TBAb; these block the TSH receptor) [68.8%] and thyroid stimulating autoantibodies (TSAb; these stimulate cAMP production, iodide uptake and thyroglobulin) [77.8 to 92%], as well as Thyroid-binding inhibitor immunoglobulin (TBII) [92%]. Patients with Grave's who are negative for thyroglobulin and thyroid microsomal antibodies have a tendency to be positive for TSH-receptor antibodies. TBIAb can be used as a marker for remission in Grave's, and testing for TSH receptor antibodies (TRAb) can help detect Grave's missed by other tests, and also help differentiate Grave's from non-autoimmune hyperthyroid conditions such as toxic multinodular goiter.
[Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders.]
[Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Grave's patients and in 686 normal subjects.]
[Distinction between autoimmune and non-autoimmune hyperthyroidism by determination of TSH-receptor antibodies]

Dietary measures such as eliminating gluten and dairy can also be helpful sometimes - there is evidence that gluten sensitivity can be associated with autoimmune disease. In autoimmune disease, it may be helpful to remove all foods from the diet that are hard on your immune system. For many people, common offending foods are gluten, dairy, eggs, and soy. Sometimes nightshades can also be an issue (an estimated 10% of the population may have some sensitivity to nightshades).
Also look for chronic mercury toxicity, as mercury is one of the possibilities implicated in high antibodies. Heavy metal testing by hair analysis may not be accurate. Post provocative urine or blood testing done with a chelating agent of choice is best.
In autoimmune thyroid disease, a high iodine level without known supplementation or other cause to explain it may be due to release of iodine from thyroid tissue destruction, and can be an indicator of pending thyroid failure.

Selenium in the form of selenomethionine 200 micrograms daily for 6 to 9 months can help bring down high TPO levels due to immunomodulating effects. Yeast selenium, which is about 90% selenomethionine, can also be used. Doses of 200 micrograms daily are considered safe, or 5 microgram per kg of body weight. Selenium is also protective against thyroid and other cancers.

Autoimmune hypopituitarism:
The pituitary is a tiny gland in the middle of the head that secretes TSH, the hormone which controls the thyroid. In persons genetically predisposed to developing autoimmunity, the pituitary can also be affected. Autoimmune hypopituitary disease should be suspected in someone with low T3, low to normal TSH, and low T4. Pregnancy can be a trigger for this. Symptoms can include low blood pressure, fatigue, and symptoms of hypothyroidism. This condition is difficult to diagnose. Relevant tests may include growth hormone (decreased), prolactin (increased), ACTH, anti-growth hormone antibodies, anti-PGSF1a and anti-PGSF2 antibodies; however, there is no definitive test except for tissue biopsy (which for obvious reasons is not done). And yes, there is a link between this and celiac disease.

Thyroid and Pregnancy:
Increased production of thyroid hormone is normal and expected during pregnancy due to stimulation of the thyroid by increased circulating hCG (human chorionic gonadotropin). A K183R mutation in the TSH receptor increases the effect of hCG.
Free T4 levels should increase and peak around 12 weeks, and normal fetal brain development needs T4. Free T4 then decreases in the third trimester.
TSH may rise a little during the first trimester, but a TSH of over 2.5 mIU/liter during first trimester of pregnancy should be considered suspicious and prompt further testing for hypothyroidism. Women who are on thyroid medication prior to pregnancy should have their doses increased by 30 to 50%. Untreated and undiagnosed hypothyroidism during pregnancy can have significant detrimental long term effects on the fetus.
Hypothyroidism can contribute to increased risk of fetal death, impaired child brain development, and increased risk of very pre-term delivery.
There is also evidence that thyroid antibodies can be a marker for impaired child IQ. Studies regarding thyroid antibodies and miscarriage are conflicting, but a link is suggested. There is suggestion that the presence of thyroid antibodies in combination with a higher TSH and lower free T4 is linked to increased spontaneous abortion.
There also seems to be associations between infertility, autoimmune thyroid disease, and endometriosis. It is recommended that all women who are pregnant or trying to get pregnant have adequate iodine. Thyroid nodules may have a tendency to increase in size or form during pregnancy.
Gestational transient thyrotoxicosis is a short-term syndrome caused by stimulation of the matermal thyroid by increased levels of human chorionic gonadotropin (hCG), usually toward the end of the first trimester, and nausea and vomiting (morning sickness) can be associated symptoms. Mild vomiting can be treated supportively and usually does not require thyroid intervention, but very severe vomiting should prompt thyroid testing. Post Partum Hypothyroidism is associated with a higher CD4+/CD8+ ratio, activation of T-cells in the postpartum period, and thyroid antibodies. Thyroid Peroxidase antibodies (TPO) in early pregnancy can be a warning sign. Hyperthyroidism due to Grave's during pregnancy is better treated medically instead of surgically. Surgical removal of a mother's thyroid during pregnancy can contribute to development of fetal hyperthyroidism. Antithyroid drug therapy also tends to block the fetal thyroid more than the maternal, and needs to be very carefully balanced.

Thyroid and Breast Cancer:
TSH receptor antibodies (TSHRAb) and thyroglobulin antibodies are found more frequently in breast cancer. TSHRAb has predictive value for breast cancer. Anyone with nodular breast disease should be screened for autoimmune thyroid disorders.

Thyroid and MTHFR:
In hypothyroidism with low thyroxin levels and low riboflavin, MTHFR enzyme function can be slowed. This is independent of any MTHFR mutations/defects. Thyroid hormone is important in synthesis of FAD (active B2), and FAD is a cofactor of MTHFR. Thus, optimizing thyroid hormone levels also helps MTHFR.

Adrenals and Hypothyroidism:
Hypothyroidism can often co-exist with adrenal fatigue, and if so, both need to be treated at the same time for best results. The adrenal glands have thyroid hormone receptors, and the thyroid gland has receptors for adrenal hormones, so the two are closely linked. Details are beyond the scope of this post, but an adrenal work-up is also part of what I do for many of my thyroid patients.

Thyroid and Digestion:
Hypothyroidism is associated with reduced bile flow and higher incidence of gallstones. T4 relaxes the sphincter of Oddi (a muscle which controls the flow of bile), thus a lack of T4 can lead to sluggish bile flow. There is increased prevalence of subclinical hypothyroidism in patients with common bile duct stones, so anyone with a gallstones or a sluggish gallbladder should get a full thyroid panel including a calculated FT3/RT3 ratio. Bile acids also promote intracellular thyroid hormone activation, and so there seems to be a complex interaction between the thyroid and the gallbladder. In fatty liver caused by a dietary deficiency of choline/methionine, T3 administration has been found to reverse the fatty changes in rats.

Thyroid and the Brain:
Elevated reverse T3 has been reported in depression. T3 and T4 in low concentrations enhanced the binding of GABA-A, while higher concentrations inhibited it. There is also evidence that GABA inhibits TSH stimulated thyroid hormone secretion. T3 is known to enhance the onset of antidepressant drugs. There is also an association of hypothyroidism with bipolar disorder. Individuals with schizophrenia, affective psychosis, and amphetamine abuse, may show a transient increase in TSH.

Congenital Hypothyroidism:
Deficiency of T3 and T4 can cause a number of symptoms including mental retardation. Incidence is roughly 1:3000-4000 newborns. There are two main causes of congenital hypothyroidism, with about 90% being due to defects in thyroid development causing a small or missing thyroid, and about 10% due to defects in thyroid hormone synthesis. A third less common cause is defects of thyroxine binding globulins (TBG) or resistence to TBG. Genetic factors include TSH receptor genes and thyroid transcription factors: PAX 8, TTF 1 (thyroid transcription factor), TTF 2, Pit 1, Prop 1.
Defects in thyroid hormone syntheses are autosomal recessive, and there 4 main defects of thyroid hormone biosynthesis:
Iodide transport (hNIS mutation)
Iodine oxygenation (TPO, THOX, PDS gene mutation)
Thyroglobulin iodination and conjugation (TPO TG, PDS mutation)
Hydrolysis and deiodination of T3 and T4.
In really high TSH, ruling out a TSH secreting pituitary tumor may be considered if clinically warranted. A head CT or MRI will accomplish this. If such a tumor is found, it may respond to long acting somatostatin analogues. If free T3 is normal but free T4 is low, the cause may be familial dysalbuminemic hyperthyroxinemia, where a defect in albumin results in increased bound and decreased free T4.

Genetic Differences in Thyroid Hormone Receptors:
Thyroid Hormone Receptor alpha is coded for by erbA-alpha, and Thyroid Hormone Receptor beta is coded for by erbA-beta.
Mutations in thyroid hormone receptor genes can be a cause of generalized thyroid hormone resistance (GTHR). People with GTHR can have goiter and high levels of T3 and T4, with TSH minimally to mildly elevated.


Su Fairchild, MD
Integrative and Orthomolecular Medicine
Environmental Medicine

Medical services available in PA, VA and TN: I can order labs for you as well as prescribe medication.
Worldwide (English only) Health and Wellness Coaching available by email arrangement.

Other resources:
National Academy of Hypothyroidism
www.stopthethyroidmadness.com
Tired Thyroid
Understanding Thyroid Metabolism
Thyroid Function
Hypothyroidism
http://www.iccidd.org/cm_data/2001_Dayan_Interpretation_of_thyroid_function_tests_Lancet.pdf

Further Information:

Reverse triiodothyronine (3,3',5'-Triiodothyronine, reverse T3, or rT3) increases in conditions such as sick euthyroid syndrome. rT3 is an inactive form of thyroid hormone. It increases in euthyroid syndrome because its clearance decreases while its production stays the same. The decreased clearance is possibly from lower 5'-deiodinase activity in the peripheral tissue or decreased liver uptake of rT3. There is evidence that reverse T3 can bind to the Thyroid Hormone Receptor, although it binds more weakly than T3.

Studies and references:

Thyroid Autoantibodies
Thyroid 2003;13(1)

http://www.sciencedirect.com/science/article/pii/0303720786901140
Endocrine-dependent regulation of tetrahydrobiopterin levels and guanosine triphosphate cyclohydrolase activity "The role of endocrine organs in the regulation of tetrahydrobiopterin (BH4) levels and guanosine triphosphate cyclohydrolase (GTP-CH) activity was studied in the spleen, bone marrow and brain of rats and mice. Following hypophysectomy, BH4 levels and GTP-CH activity were significantly decreased in both spleen and bone marrow. Fourteen days after hypophysectomy GTP-CH activity and BH4 levels were approximately 25% of control levels in both tissues. In contrast, BH4 levels and GTP-CH activity in brain were not significantly different from control values. The decrease in GTP-CH activity and BH4 levels in spleen and marrow could not be reversed by high doses of ACTH or by a pituitary extract. Removal of the thyroid gland resulted in significant decreases in BH4 levels and GTP-CH activity in spleen; marrow and brain levels were not affected. BH4 levels in spleens of thyroidectomized rats returned to control values following treatment with either triiodothyronine or thyroxine. Adrenalectomy and castration had no effect on biopterin metabolism in bone marrow, spleen or brain. Tissue levels of BH4 and GTP-CH were also studied in mutant mouse strains having mutations in either pituitary or thyroid functions in order to examine further the role of these tissues in the regulation of the biosynthesis of this cofactor. The results of this study indicate that factors secreted from the pituitary are important in the regulation of BH4 levels and GTP-CH activity in spleen and bone marrow and that the thyroid gland also plays a role in regulation in the spleen. Levels of BH4 and GTP-CH in the brain, if regulated, appear to be independent of the endocrine tissues studied."

http://link.springer.com/article/10.1007/BF01249135 Effects of apomorphine on behavioural activity and brain catecholamine synthesis in normal and L-triiodothyronine-treated rats "Neonatal hyperthyroidism was accompanied by an increase in spontaneous locomotor activity as well as by enhanced synthesis and release of dopamine as evidenced by increased catecholamine synthesis in crude synaptosomal preparation (P2 pellet), elevated tyrosine hydroxylase activity and higher concentrations of homovanillic acid and 3, 4-dihydroxyphenylacetic acid in striatum of rats. Repeated apomorphine treatment (1 mg/kg/day s.c.) for 15 days, beginning from the 15th day of age, produced hypermobility and stereotyped behaviour (consisting of sniffing, gnawing, rearing) which appeared to be more pronounced in neonatally hyperthyroid rats than in normal controls. In addition, apomorphine-treated hyperthyroid animals marched in a row with straub tail, and displayed increased aggressiveness and bizarre social behaviour consisting of “mock fighting” when left in pairs. In contrast to normal rats, apomorphine-treated hyperthyroid animals displayed marked hyperactivity which was evident even at 24 hours after the last injection of apomorphine. Administration of apomorphine resulted in significant decreases in striatal tyrosine hydroxylase, catecholamine synthesis in crude synaptosomal preparation (P2 pellet) as well as dopamine metabolite levels in brains of both normal and hyperthyroid animals. Our present data showing that apomorphine potentiates behavioural activity in hyperthyroid rats suggest that L-triiodothyronine and apomorphine probably share certain features common to activating dopaminergic neurons in the brain."

http://www.ncbi.nlm.nih.gov/pubmed/443685 Misleadingly low free thyroxine index and usefulness of reverse triiodothyronine measurement in nonthyroidal illnesses. "Nonthyroidal illness is frequently associated with subnormal serum thyroxine (T4) and free T4 index. To unravel the resultant diagnostic problems, we have studied several variables of thyroid function in the sera of 47 patients hospitalized with nonthyroidal illnesses and seven hypothyroid patients encountered during the same period. Of the 47 euthyroid sick patients, 18 had low T4. Among these 18, free T4 index was normal in only five, whereas free T4 concentration measured by equilibrium dialysis was normal or high in 15 and 3,3',5'-triiodothyronine (reverse T3) normal or high in all 18. Reverse T3, free T4 concentration, and free T4 index were subnormal in all seven hypothyroid patients. Thus, measurement of free T4 index may be misleading in evaluation of thyroid function in patients with nonthyroidal illnesses, whereas measurement of serum concentration of reverse T3 and free T4 is quite discriminating."

http://www.ncbi.nlm.nih.gov/pubmed/932209 An assessment of daily production and significance of thyroidal secretion of 3, 3', 5'-triiodothyronine (reverse T3) in man. "The various data suggest that: (a) just as in the case of T3, the thyroid gland is a relatively minor source of rT3; peripheral metabolism of T4 is apparently its major source; (b) the bulk of T4 metabolized daily is monodeiodinated to T3 or to rT3; (c) monodeiodination may be an obligatory step in metabolism of T4; (d) monodeiodination of T4 to rT3 is maintained normal or is increased in hepatic cirrhosis at a time when monodeiodination of T4 to T3 is decreased."

http://www.ncbi.nlm.nih.gov/pubmed/1133163 Circulating 3,3', 5'-triiodothyronine (reverse T3) in the human newborn. "The mean serum rT3 level in 5-7-day-old infants was higher than that in normal adults, but in 9-11 day and 20-30-day-old infants, mean rT3 values were statistically similar to the adult value. The mean serum T3 concentrations in neonates between 1-30 days old were either higher than or comparable to the values of normal adults. The mean serum T4 concentrations in neonates between birth and 30 days of age were significantly higher than the mean adult level. The mean serum rT3 to T4 ratios (rT3/T4) were elevated in 1-4-day-old neonates; the values in older neonates were similar to those in adults. These results suggest that (a) factors other than TSH are important modulators of serum rT3 in man; (b) high serum rT3 concentration in the newborn becomes comparable to that in the normal adult by 9-11 days of neonatal life."

http://www.ncbi.nlm.nih.gov/pubmed/6312037 Specific 3,3',5'-triiodothyronine (reverse T3) binding sites on rat liver plasma membranes: comparison with thyroxine (T4) binding sites. "The binding characteristics of thyroxine (T4), triiodothyronine (T3), and reverse T3 (rT3) to rat liver plasma membranes (RLPM) were examined to explore the interactions of thyroid hormones with cell surface receptors. Scatchard analysis suggested that all three ligands bound to two classes of binding sites. The high affinity rT3 binding sites appeared to be distinct from the high affinity T4 sites..Moreover, comparatively higher concentrations of T3 were needed to displace either radiolabeled T4 or rT3, suggesting that T3 was binding to both the T4 and rT3 sites with lower affinity"

http://www.ncbi.nlm.nih.gov/pubmed/7075548 Specific nuclear binding sites of triiodothyronine and reverse triiodothyronine in rat and pork liver: similarities and discrepancies. "The amount of nonradioactive T4 required to cause a 50% displacement of [125I]T3 from the nuclear binding sites was, on a molar basis, 27 times greater than that of T3 in the case of pork liver and 110 times greater than that of T3 in the case of rat liver. Similarly, rT3-binding sites were highly specific....Reduced glutathione and other sulfhydryl (SH)-reducing agents increased, whereas oxidized glutathione and SH-oxidizing or -binding agents decreased the binding of [125I]T3 and [125I]rT3 to nuclear extracts, with one exception. Dithiothreitol, a potent SH-reducing agent, reduced the binding of rT3 whereas it increased the binding of T3 to the nuclear binding sites...The data suggest that 1) there exist specific high affinity, low capacity nuclear rT3-binding sites in rat and pork liver which are distinct from the nuclear T3 receptors, and 2) rT3- and T3-binding sites are reduced in parallel during starvation."

http://www.jci.org/articles/view/107795/files/pdf A Radioimmunoassay for Measurement of 3,3',5'-Triiodothyronine (Reverse T3)

http://www.ncbi.nlm.nih.gov/gene/7068 THRB thyroid hormone receptor, beta

http://mcb.asm.org/content/15/5/2341 Functional regulation of thyroid hormone receptor variant TR alpha 2 by phosphorylation. "The thyroid hormone (T3) receptor (TR) variant TR alpha 2 is abundant in brain but does not bind T3 because of its unique C terminus. The only known function of TR alpha 2, inhibition of TR-dependent transactivation, involves competition for T3 response elements...The increased dominant negative activity of a nonphosphorylatable form of TR alpha 2 suggests that phosphorylation may provide a rapid, T3-independent mechanism for cell-specific modulation of the expression of T3-responsive genes."

Nuclear Receptors: Current Concepts and Future Challenges "Effects of T3Ra1 and T3Ra2 gene deletion on T and B lymphocyte development. ...Thyroid hormone T3 acting through the thyroid hormone {alpha} receptor is ..."

http://www.jci.org/articles/view/6397/files/pdf Divergent roles for thyroid hormone receptor ß isoforms in the endocrine axis and auditory system

http://joe.endocrinology-journals.org/content/182/2/295.full.pdf Expression of thyroid hormone receptor in 3T3-L1 adipocytes; triiodothyronine increases the expression of lipogenic enzyme and triglyceride accumulation

http://www.hotthyroidology.com/editorial_pdf/Weiss_HT09_09.pdf Resistance to Thyroid Hormone (RTH) in the Absence of Abnormal Thyroid Hormone Receptor (TR) (nonTR-RTH)

http://onlinelibrary.wiley.com/doi/10.1093/emboj/18.3.623/pdf Different functions for the thyroid hormone receptors TRa and TRß in the control of thyroid hormone production and post-natal development"TRß receptors are the most potent regulators of the production of thyroid stimulating hormone (TSH). However, in the absence of TRß, the products of the TRa gene can ful?ll this function as, in the absence of any receptors, TSH and thyroid hormone concentrations reach very high levels."

http://www.karger.com/Article/PDF/244145 Differential Expression of a- and ß-Thyroid Hormone Receptor Genes in the Developing Rat Brain under Hypothyroidism "One of the most alarming observations of iodine deficiency disorders (IDD) is neurological cretinism which is caused due to lack of T3 during the crucial stages of brain development. We have developed an iodine-deficient rat model to study the pattern of T3 receptor genes expression in the brain during postnatal development under iodine deficiency. We observed increased expression of c-erbA-a2 and –ß1 T3 receptor transcripts while c-erbA-a1 remains unchanged in the brain of the iodine-deficient neonates compared with their euthyroid counterparts. Up-regulation of the ß1 form in the developing brain under iodine deficiency is suggestive of an adaptive process coming into play to protect it from the damages that are inflicted due to hypothyroidism. Though the significance of the increased a2 form in the iodine-deficient rat brain has not yet been ascertained, it can be conjectured that it acts as a homeostatic control over ‘functional receptor’ (namely ß1) under developmental hypothyroidism."

Subcutaneous Fat Shows Higher Thyroid Hormone Receptor-a1 Gene Expression Than Omental Fat Obesity (2009) 17, 2134–2141. doi:10.1038/oby.2009.110. Ortega et al. "Our findings suggest that TRa1 could contribute to SC adipose tissue expandability in obese subjects."

http://jcb.rupress.org/content/204/1/2.3 Thyroid hormones speed cellular aging "Thyroid hormones fire up metabolism by binding to either of two receptors, thyroid hormone receptor a (THRA) or thyroid hormone receptor ß (THRB) and can induce opposing impacts on health. On the one hand, people with hyperthyroidism accumulate liver damage and have shortened life spans. On the other hand, thyroid hormone receptor blocks cancer growth and metastasis...They found that one thyroid hormone, T3, spurs cultured cells to senesce. T3 only triggered this effect through THRB, not THRA...T3 turned up mitochondrial activity, increasing production of noxious reactive oxygen species (ROS). This surge of ROS resulted in increased numbers of DNA double-strand breaks, thereby precipitating cellular senescence...Although triggering senescence prevents damaged cells from becoming cancerous, it also might contribute to aging by curtailing the replacement of worn-out cells"

http://www.biomed.cas.cz/physiolres/pdf/47/47_41.pdf Thyroid Hormone Receptor occupancy and biological effects

BINDING OF REVERSE T3 TO HEPATIC NUCLEAR PROTEIN Australian Journal of Experimental Biology & Medical Science . Apr1980, Vol. 58 Issue 2, p207-212. 6p. Smith, Howard C.; Robinson, Shirley E.; Eastman, Creswell J. "The study was undertaken to examine the potential intrinsic biological activity of reverse T3 by comparing its binding to nuclear protein in vitro with that of other iodothyronines. Nuclear protein was extracted from normal pig liver using methods described for rat tissues. At 25° 30% of the added 125I rT3, was specifically bound to the nuclear protein. The order of potency in displacing 125 rT3 was rT3 > 3:5'T2 >T4 > T3 > 3,3'T1 > 3,5T2. This contrasted with the order of potency in displacing 125I T3, which was T11 > T4 > 3.3'T2 > 3,5T2 > rT1 > 3'.5'T2. This difference in the hierarchy of iodothyronine binding is consistent with binding of these radioligands to different components of the nuclear protein extract. These experiments demonstrate separate binding components of nuclear protein for T3 and rT3 in a thyroid hormone responsive tissue and may be relevant to the mechanism of action of thyroid hormones."

http://www.ncbi.nlm.nih.gov/pubmed/12055988 Effect of obesity and starvation on thyroid hormone, growth hormone, and cortisol secretion. "Obesity and starvation have opposing affects on normal physiology and are associated with adaptive changes in hormone secretion. The effects of obesity and starvation on thyroid hormone, GH, and cortisol secretion are summarized in Table 1. Although hypothyroidism is associated with some weight gain, surveys of obese individuals show that less than 10% are hypothyroid. Discrepancies have been reported in some studies, but in untreated obesity, total and free T4, total and freeT3, TSH levels, and the TSH response to TRH are normal. Some reports suggest an increase in total T3 and decrease in rT3 induced by overfeeding. Treatment of obesity with hypocaloric diets causes changes in thyroid function that resemble sick euthyroid syndrome. Changes consist of a decrease in total T4 and total and free T3 with a corresponding increase in rT3. untreated obesity is also associated with low GH levels; however, levels of IGF-1 are normal. GH-binding protein levels are increased and the GH response to GHRH is decreased. These changes are reversed by drastic weight reduction. Cortisol levels are abnormal in people with abdominal obesity who exhibit an increase in urinary free cortisol but exhibit normal or decreased serum cortisol and normal ACTH levels. These changes are explained by an increase in cortisol clearance. There is also an increased response to CRH. Treatment of obesity with very low calorie diets causes a decrease in serum cortisol explained by a decrease in cortisol-binding proteins. The increase in cortisol secretion seen in patients with abdominal obesity may contribute to the metabolic syndrome (insulin resistance, glucose intolerance, dyslipidemia, and hypertension). States of chronic starvation such as seen in anorexia nervosa are also associated with changes in thyroid hormone, GH, and cortisol secretion. There is a decrease in total and free T4 and T3, and an increase in rT3 similar to findings in sick euthyroid syndrome. The TSH response to TRH is diminished and, in severe cases, thyroid-binding protein levels are decreased. In regards to GH, there is an increase in GH secretion with a decrease in IGF-1 levels. GH responses to GHRH are increased. The [table: see text] changes in cortisol secretion in patients with anorexia nervosa resemble depression. They present with increased urinary free cortisol and serum cortisol levels but without changes in ACTH levels. In contrast to the findings observed in obesity, the ACTH response to CRH is suppressed, suggesting an increased secretion of CRH. The endocrine changes observed in obesity and starvation may complicate the diagnosis of primary endocrine diseases. The increase in cortisol secretion in obesity needs to be distinguished from Cushing's syndrome, the decrease in thyroid hormone levels in anorexia nervosa needs to be distinguished from secondary hypothyroidism, and the increase in cortisol secretion observed in anorexia nervosa requires a differential diagnosis with primary depressive disorder."

http://www.ncbi.nlm.nih.gov/pubmed/115194 Effects of obesity, total fasting and re-alimentation on L-thyroxine (T4), 3,5,3'-L-triiodothyronine (T3), 3,3',5'-L-triiodothyronine (rT3), thyroxine binding globulin (TBG), cortisol, thyrotrophin, cortisol binding globulin (CBG), transferrin, alpha 2-haptoglobin and complement C'3 in serum. "The rapid decrease of T3 and increase of RT3U after initiation of fasting are not fully explained by the observed slower decreases in TBG...Re-alimentation reverses rapidly all observed changes."

http://www.ncbi.nlm.nih.gov/pubmed/7227325 Effects of total fasting in obese women. IV. Response of serum triiodothyronine (T3) andreverse triiodothyronine (rT3) to administered T3. "These results suggest that in addition to an enhanced synthesis of rT3 to the detriment of a decreased production of T3 from T4, an increased catabolism of administered T3 and of endogenous rT3 is involved in a strict calorie restriction."

http://www.sciencedirect.com/science/article/pii/S0021915002003726 Elevated C-reactive protein and homocysteine values: cardiovascular risk factors in hypothyroidism? A cross-sectional and a double-blind, placebo-controlled trial "This is the first paper to show that CRP values increase with progressive thyroid failure and may count as an additional risk factor for the development of coronary heart disease in hypothyroid patients. In contrast to overt disease, only CRP, but not tHcy values, are affected in SCH, yet without significant improvement after l-thyroxine therapy."

http://www.ncbi.nlm.nih.gov/pubmed/8701059 [Hashimoto toxicosis: diagnostic criteria and a 10-year follow up]. "An study was carried out of the association of Basedow disease (B) and Hashimoto toxicosis (H), the response to the usual therapeutic regimens and prognostic factors for the clinical course. Seventy-one patients with the diagnosis of autoimmune hyperthyroidism were included. Sixty-one of them were prospectively followed for 8.4 +/- 2.2 years (range: 5-10 years). All patients were treated following the same criteria with antithyroid drugs and aggressive therapy (radioiodine or surgery). Two groups were differentiated: group H (62%), with titers of antimicrosomal antibodies (AMSA) > or = 1/6,400 and a positive perchlorate discharge test (PDT), and group B, with AMSA titers < 1/6,400 and negative PDT. During follow-up a three-fold number of relapses was observed in group H compared with group B, a higher frequency towards spontaneous hypothyroidism in the evolution (23% in H versus 0% in B), and higher requirements of radioiodine in H than in B. In our experience, H makes up and important percentage of autoimmune hyperthyroidism (62%) with a clinical course characterized by a higher number of relapses, higher requirements of radioiodine and a higher rate towards spontaneous hypothyroidism."

http://www.ncbi.nlm.nih.gov/pubmed/3823018 [Functional state of the hepato-biliary system in patients with thyroid diseases studied with radiopharmaceuticals]. Function of the hepatobiliary system was studied in 33 patients with thyroid diseases (11 with diffuse euthyroid goiter, 15 with diffuse toxic goiter, of them 7 with thyrotoxicosis of a mild degree and 8 with thyrotoxicosis of an average severity, and 7 patients with primary hypothyrosis) and in 14 healthy persons of the control group by a radionuclide method using a gamma-chamber and 99mTc-HIDA, a hepatotropic radiopharmaceutical. It was established that absorptive-excretory liver function and the concentration ability of the gall bladder decreased in noticeable thyrotoxicosis and moderate hypothyrosis. Hypermotor dyskinesia of the gall bladder and hypertension of the biliary tract sphincters were revealed in more than half of the patients. Similar changes though quantitatively less pronounced were noted in the patients with euthyroid goiter. Thyrotoxicosis of a mild degree was characterized by the affection of motor function of the gall bladder (hypermotor dyskinesia) and frequent hypertension of Oddi's sphincter. Possible mechanisms of the development of the above changes were discussed.

http://www.sciencedirect.com/science/article/pii/S0039606002216827 Is bile flow reduced in patients with hypothyroidism? "Disturbances in the sphincter of Oddi (SO) function may prevent normal bile flow and thus enhance the probability of common bile duct stone (CBDS) formation. We have previously shown increased prevalence of diagnosed hypothyroidism in CBDS patients, thyroxine (T4) -induced inhibition of the SO contractility both in animal and in human experiments ex vivo, and reduced bile flow to duodenum in hypothyroid rats. The aim of the present study was to investigate human biliary dynamics in relation to altered thyroid gland function. Methods. Eight female patients, 1 with diagnosed untreated hypothyroidism and 7 with total thyroidectomy performed due to thyroid cancer, were studied in hypothyroid stage and again after thyroxine replacement therapy in euthyroid stage, with quantitative 99mTc HIDA cholescintigraphy (QC), biliary ultrasonography, and serum determinations. Each patient served as her own control in the 2 stages of the study. Results. In QC, maximal uptake of 99mTc HIDA was not changed in hypothyroidism compared to euthyroidism. The first appearance of radioactivity to large bile ducts at the hepatic hilum remained unchanged in the 2 stages of the study. Hepatic clearance of 99mTc HIDA was decreased at 45 minutes (28% [11-38] vs 50% [33-54]; P =.028; median and range) and at 60 minutes (55% [28-80] vs 69% [61-79]; P=.028; median and range) and hilum-duodenal transit time increased by 31% compared to euthyroid stage. In US no changes were seen in gall bladder or bile ducts in the 2 stages of the study. Serum hypercholesterolemia was observed in the hypothyroid stage. Conclusions. We conclude that hypothyroidism may result in delayed emptying of the biliary tract, as studied with QC. In addition to the changes in bile composition and excretion rate suggested before to take place in hypothyroidism, according to the present study changes in biliary emptying also may be included in the probable causes for the increased prevalence of CBDS in hypothyroidism. This may be due to the absence of the prorelaxing effect of thyroxine on SO, which we have shown before to exist ex vivo. (Surgery 2003;133:288-93)"

http://jcem.endojournals.org/content/92/11/4260.short Increased Prevalence of Subclinical Hypothyroidism in Common Bile Duct Stone Patients Context: Earlier, we have shown an increased prevalence of previously diagnosed hypothyroidism in common bile duct (CBD) stone patients and a delayed emptying of the biliary tract in hypothyroidism, explained partly by the missing prorelaxing effect of T4 on the sphincter of Oddi contractility. Conclusion: Subclinical hypothyroidism is more common in the CBD stone patients, compared with nongallstone controls, supporting our hypothesis that hypothyroidism might play a role in the forming of CBD stones. At minimum, women older than 60 yr with CBD stones should be screened for borderline or overt subclinical hypothyroidism.

http://tampub.uta.fi/bitstream/handle/10024/67171/951-44-5266-6.pdf?sequence=1 Effect of Thyroxine (T4) on Biliary Motility.

http://journals.lww.com/theendocrinologist/Abstract/1993/09000/Reverse_T3.9.aspx Reverse T3 Hurd, Robert E. M.D.; Chopra, Inder J. M.D. "Reverse triiodothyronine (rT3) is an iodothyronine produced mainly by enzymatic inner ring [5-]monodeiodination of thyroxine (T4). The 5-monodeiodinase (5-MD) enzyme is most abundant in skin, cerebral cortex, and placenta. In contrast to triiodothyronine (T3), which is the most active thyroid hormone, rT3 has little or no calorigenic or thyroid stimulating horomone suppressive activity. However, rT3 may exert other important functions, e.g., regulation of T3 production (from T4), by its ability to interact with and inhibit both type I and type II 5'-monodeiodinases. Some suggest that rT3 may influence brain development in the fetus. On the other hand, elevated rT3 levels may interfere with recovery from hemorrhagic shock. Serum rT3 levels are increased in systemic non-thyroidal illnesses except chronic renal failure. This increase is related to decreased type I 5'-MD activity and decreased metabolic clearance rate of rT3 in non-thyroidal illnesses. Serum rT3 levels is also increased in patients taking drugs such as amiodarone, propylthiouracil, dexamethasone, propranolol, and ipodate. This too is related to decreased activity of type I 5'-MD caused by the drug. High serum rT3, low T3, and low T4 are correlated with bad prognosis in systemic illness."

http://www.sciencemag.org/content/244/4900/76.short Identification of a thyroid hormone receptor that is pituitary-specific "Three cellular homologs of the v-erbA oncogene were previously identified in the rat; two of them encode high affinity receptors for the thyroid hormone triiodothyronine (T3). A rat complementary DNA clone encoding a T3 receptor form of the ErbA protein, called r-ErbA beta-2, was isolated. The r-ErbA beta-2 protein differs at its amino terminus from the previously described rat protein encoded by c-erbA beta and referred to as r-ErbA beta-1. Unlike the other members of the c-erbA proto-oncogene family, which have a wide tissue distribution, r-erbA beta-2 appears to be expressed only in the anterior pituitary gland. In addition, thyroid hormone downregulates r-erbA beta-2 messenger RNA but not r-erbA beta-1 messenger RNA in a pituitary tumor-derived cell line. The presence of a pituitary-specific form of the thyroid hormone receptor that may be selectively regulated by thyroid hormone could be important for the differential regulation of gene expression by T3 in the pituitary gland."

http://online.liebertpub.com/doi/abs/10.1089/thy.1996.6.505 Acute Effects of Thyroid Hormone on Vascular Smooth Muscle "The enhanced cardiovascular hemodynamics associated with triiodo-L-thyronine (T3) treatment is in part mediated by a decrease in systemic vascular resistance."

http://www.sciencedirect.com/science/article/pii/0026049586900983 Nuclear thyroid hormone receptors in cultured bone cells Metabolism Volume 35, Issue 1, January 1986, Pages 71–74 "Thyroid hormones influence bone metabolism, but a direct interaction of triiodothyronine with nuclear T3 receptors in bone cells has not yet been reported....Thyroxine (T4) and 3,3',5'triiodothyronine (reverse T3) competed with 125I-T3 with a 20-fold and 400-fold lower affinity than T3, respectively."

http://www.ncbi.nlm.nih.gov/pubmed/17532181 A new bioluminescent cellular assay to measure the transcriptional effects of chemicals that modulate the alpha-1 thyroid hormone receptor. "Interactions of environmental pollutants with the thyroid endocrine axis have received much attention especially because thyroid hormones (THs) play a major role in mammalian brain development. In order to screen for compounds that act on the triiodothyronine (T3) signaling pathway, we developed a new reporter gene assay expressing luciferase under the control of the TH receptor (TR). PC12 cells expressing the alpha1-isoform of TR of avian origin were stably transfected with a luciferase gene controlled by the SV40 promoter, and enhanced by a four-spaced direct repeat (DR4) thyroid response element (TRE). The resulting PC-DR-LUC cells were used to optimize a T3 assay in multi well microplates. This assay was highly sensitive (30 pM T3) and reproducible, and responded as expected to TH analogues. Several halogenated phenolic (3,3',5,5'-tetrabromobisphenol A, 3,3',5,5'-tetrachlorobisphenol A, 4-hydroxy-2',3,4',5,6'-pentachlorobiphenyl) and phenol (pentachlorophenol, 2,4,6-triiodophenol) compounds suspected of being thyroid-disrupting environmental chemicals induced partial agonistic and/or complex competitive/uncompetitive antagonistic responses in PC-DR-LUC cells at micromolar concentrations. A cell viability test indicated that these effects were not related to cytotoxicity of the chemicals. These results suggest that the PC-DR-LUC assay could be a valuable tool for the large-scale screening for thyroid receptor agonists and antagonists in vitro, and for detecting thyroid disruptors in the environment."

http://www.ncbi.nlm.nih.gov/pubmed/19457453 Anti-thyroid hormone activity of bisphenol A, tetrabromobisphenol A and tetrachlorobisphenol A in an improved reporter gene assay. "Previously, we transiently transfected Gal4-fused thyroid hormone receptor (TR) expressing vector and the Gal4 response reporter structure pUAS-tk-luc into HepG2 cell, developed a TR beta-1 mediated reporter gene assay to screen for compounds that acted on the TR signaling pathway. In this study, we improved the test efficiency by changing the transfected cell line into CV-1 cell. Triiodothyronine (T3) and thyroxine (T4) induced higher luciferase expression, with the median effective concentration (EC(50)) of 1.16 x 10(-8) and 1.36 x 10(-7)M, respectively. Bisphenol A (BPA) was selected as a positive antagonist, exhibiting weak anti-thyroid hormone activity with the median inhibitory concentration (IC(50)) of 1.64 x 10(-5)M. The assay showed acceptable repeatability to T3 with inter coefficient of variability (CV) of 27.5% and intra CV of 18.6%. Two flame retardants, tetrabromobisphenol A (TBBPA) and tetrachlorobisphenol A (TCBPA), were tested for their agonist and antagonist activities. As a result, we found that both of them possessed TR antagonist activity and neither of them showed agonist activity. These results suggested that TBBPA and TCBPA could act as TH antagonists. This assay provided a useful tool for the assessment of environmental chemicals as thyroid system disruptors."

http://www.ncbi.nlm.nih.gov/pubmed/17956155 Environmental chemicals impacting the thyroid: targets and consequences. "Thyroid hormone (TH) is essential for normal brain development, but the specific actions of TH differ across developmental time and brain region. These actions of TH are mediated largely by a combination of thyroid hormone receptor (TR) isoforms that exhibit specific temporal and spatial patterns of expression during animal and human brain development. In addition, TR action is influenced by different cofactors, proteins that directly link the TR protein to functional changes in gene expression. Considering the importance of TH signaling in development, it is important to consider environmental chemicals that may interfere with this signaling. Recent research indicates that environmental chemicals can interfere with thyroid function and with TH signaling. The key issues are to understand the mechanism by which these chemicals act and the dose at which they act, and whether adaptive responses intrinsic to the thyroid system can ameliorate potential adverse consequences (i.e., compensate). In addition, several recent studies show that TRs may be unintended targets of chemicals manufactured for industrial purposes to which humans and wildlife are routinely exposed. Polychlorinated biphenyls, polybrominated diphenyl ethers, bisphenol-A, and specific halogenated derivatives and metabolites of these compounds have been shown to bind to TRs and perhaps have selective effects on TR functions. A number of common chemicals, including polybrominated biphenyls and phthalates, may also exert such effects. When we consider the importance of TH in brain development, it will be important to pursue the possibilities that these chemicals-or interactions among chemical classes-are affecting children's health by influencing TH signaling in the developing brain."

http://toxsci.oxfordjournals.org/content/56/1/95.short Potent Competitive Interactions of Some Brominated Flame Retardants and Related Compounds with Human Transthyretin in Vitro "Brominated flame retardants such as polybrominated diphenyl ethers (PBDEs), pentabromophenol (PBP), and tetrabromobisphenol A (TBBPA) are produced in large quantities for use in electronic equipment, plastics, and building materials. Because these compounds have some structural resemblance to the thyroid hormone thyroxine (T4), it was suggested that they may interfere with thyroid hormone metabolism and transport, e.g., by competition with T4 on transthyretin (TTR)...These results indicate that brominated flame retardants, especially the brominated phenols and tetrabromobisphenol A, are very potent competitors for T4 binding to human transthyretin in vitro and may have effects on thyroid hormone homeostasis in vivo comparable to the thyroid-disrupting effects of PCBs." Desethylamiodarone is a competitive inhibitor of the binding of thyroid hormone to the thyroid hormone a1-receptor protein

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1566512/ Potential mechanisms of thyroid disruption in humans: interaction of organochlorine compounds with thyroid receptor, transthyretin, and thyroid-binding globulin. "Hydroxylated PCBs in vivo are more likely to compete for binding to serum transport proteins than for binding to the thyroid receptor."

http://www.jbc.org/content/267/18/13014.short Thyroid hormone receptor mutants that cause resistance to thyroid hormone. Evidence for receptor competition for DNA sequences in target genes. "Several distinct mutations in the ligand-binding domain of the beta form of the thyroid hormone receptor have been reported in kindreds with the autosomal dominant syndrome of generalized resistance to thyroid hormone (GRTH). GRTH receptor mutants are functionally inactive but capable of inhibiting normal receptor function in transient expression studies. We examined the possibility that this dominant negative activity of the GRTH mutants involves competition for receptor binding to DNA...These results indicate that the thyroid hormone receptor mutations that occur in GRTH compete with normal receptors at DNA-binding sites in target genes to block normal receptor function."

http://www.ncbi.nlm.nih.gov/pubmed/6417704 Reverse T3 levels in affective disorders. "Serum levels of 3,3',5' triidothyronine (reverse T3) were investigated in 32 patients with acute major depressive disorder. Twenty-six of these patients were also studied during a state of clinical improvement. Comparison subjects were 22 healthy controls, and 16 currently euthymic patients with histories of affective disorders (8 unipolar, 8 bipolar). The laboratory investigation included the determination of triiodothyronine (T3), thyroxine (T4), thyroid-stimulating hormone (TSH), and thyroxin-binding globuline (TBG) levels in serum. The clinical symptoms were rated by the Comprehensive Psychopathological Rating Scale (CPRS) for depressive illness (CPRS global score), as well as the sum of 10 items (CPRS 10) and 22 items (CPRS 22) measuring depression. The patients were also divided into those having a normal or abnormal response to the dexamethasone suppression test; those having melancholia or not having melancholia; and those having primary or secondary depression. No significant difference in reverse T3 levels emerged among the patients with acute major depressive disorders, the euthymic unipolar or bipolar affective disorders, and the healthy controls. There were also no significant differences between those having an abnormal or normal DST test; those having primary or secondary depression; or those having melancholia or not having melancholia. In the group of patients with acute major depressive disorder, however, a significant increase in reverse T3 levels and a significant decrease in T3 levels, but no significant difference in T4 or TSH levels, were seen in the patients with the most pronounced clinical symptoms as measured by the CPRS. The implications of these findings are discussed."

http://www.ncbi.nlm.nih.gov/pubmed/3160737 The TRH stimulation test and reverse T3 in depression. "Blunted TSH response to TRH and elevation of reverse T3 (rT3) have been reported in depression, though the relationship between these two abnormalities has not been clear. The authors measured basal levels of T4, T3, rT3 and the TSH response to TRH in a group of 28 depressed men and women, unipolar and bipolar subtypes. No significant difference was found between these two subtypes of depression with respect to mean basal hormonal levels or magnitude of the TSH response to TRH. Two males had slight, but significant elevations of rT3 though only one of them had a blunted TSH response to TRH levels and the TSH response to TRH. Finally no significant correlation was found between rT3 levels and the TSH response to TRH."

http://www.ncbi.nlm.nih.gov/pubmed/20410193 High-fat diet increases thyrotropin and oxygen consumption without altering circulating 3,5,3'-triiodothyronine (T3) and thyroxine in rats: the role of iodothyronine deiodinases,reverse T3 production, and whole-body fat oxidation. "This study investigated the effects of obesity induced by high-fat (HF) diet on thyroid function and whole-body energy balance. To accomplish that, we assessed the effects of 8 wk of HF diet on several parameters of hypothalamus-pituitary-thyroid axis function. Serum total T(4) and T(3), rT(3), and TSH, the activity of type 1 and type 2 deiodinases in central and peripheral tissues were determined. Also, we measured in vivo energy balance, substrate partitioning, and markers of leptin resistance. Here we provide novel evidence that prolonged positive energy balance acquired by feeding a HF diet induced hyperactivation of the hypothalamus-pituitary-thyroid axis, which was characterized by 2.24-, 1.6-, and 3.7-fold elevations in hypothalamic TRH expression, thyroid iodide uptake, and serum TSH, respectively. Serum T(4) and T(3) were normal together with augmented deiodinase type 1 activity in liver (1.3-fold) and kidney (1.2-fold) and increased (1.5-fold) serum rT3 in HF rats. Despite no increase in circulating levels of T(3) and T(4), whole-body oxygen consumption was increased, and substrate metabolism was shifted toward fat oxidation in HF rats. These in vivo metabolic adjustments were mainly driven by the fat content of the diet. Furthermore, spontaneous dark cycle physical activity was reduced by 30% in rats fed a HF diet, which limited energy expenditure and favored the development of obesity. Our findings provide new insight into the endocrine and physiological mechanisms that underlie the alterations in thyroid hormone availability, energy balance, and metabolic partitioning in HF diet-induced obesity."

http://www.ncbi.nlm.nih.gov/pubmed/21249435 Bioenergetic impact of tissue-specific regulation of iodothyronine deiodinases during nutritional imbalance. "The regulation of energy homeostasis by thyroid hormones is unquestionable, and iodothyronine deiodinases are enzymes involved in the metabolic activation or inactivation of these hormones at the cellular level. T3 is produced through the outer ring deiodination of the prohormone T4, which is catalyzed by types 1 and 2 iodothyronine deiodinases, D1 and D2. Conversely, type 3 iodothyronine deiodinase (D3) catalyzes the inner ring deiodination, leading to the inactivation of T4 into reverse triiodothyronine (rT3). Leptin acts as an important modulator of central and peripheral iodothyronine deiodinases, thus regulating cellular availability of T3. Decreased serum leptin during negative energy balance is involved in the down regulation of liver and kidney D1 and BAT D2 activities. Moreover, in high fat diet induced obesity, instead of increased serum T(3) and T(4) secondary to higher circulating leptin and thyrotropin levels, elevated serum rT3 is found, a mechanism that might impair the further increase in oxygen consumption."

http://www.ncbi.nlm.nih.gov/pubmed/8767511 Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action. "Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5'-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5'-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5'-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5'-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if selenium supplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, or cytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membrane or the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before a development of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5'-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove that retinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action."

http://www.ncbi.nlm.nih.gov/pubmed/10411325 Local activation and inactivation of thyroid hormones: the deiodinase family. "Tissue-specific activation and inactivation of ligands of nuclear receptors which belong to the steroid retinoid-thyroid hormone superfamily of transcription factors represents an important principle of development- and tissue-specific local modulation of hormone action. Recently, several enzyme families have been identified which act as 'guardians of the gate' of ligand-activated transcription modulation. Three monodeiodinase isoenzymes which are involved in activation the 'prohormone' L-thyroxine (T4), the main secretory product of the thyroid gland, have been identified, characterized, and cloned. Both, type I and type II 5'-deiodinase generate the thyromimetically active hormone 3,3',5-triiodothyronine (T3) by reductive deiodination of the phenolic ring of T4. Inactivation of T4 and its product T3 occurs by deiodination of iodothyronines at the tyrosyl ring. This reaction is catalyzed both the type III 5-deiodinase and also by the type I enzyme, which has a broader substrate specificity. The three deiodinases appear to constitute a newly discovered family of selenocysteine-containing proteins and the presence of selenocysteine in the protein is critical for enzyme activity. Whereas the selenoenzyme characteristics of the type I and type III deiodinases are definitively established some controversy still exists for the type II 5'-deiodinase in mammals. The mRNA probably encoding the type II 5'-deiodinase subunit is markedly longer than those of the two other deiodinases and its selenocysteine-insertion element is located more than 5 kB downstream of the UGA-codon in the 3'-untranslated region. The three deiodinase isoenzymes show a distinct development- and tissue-specific pattern of expression, operate at individual optimal substrate levels, are differently regulated and modulated by hormones, cytokines, signaling pathways, natural factors, and pharmaceuticals. Whereas circulating T3 mainly originates from hepatic production via the type I 5'-deiodinase, the local cellular thyroid hormone concentration in various tissues including the central nervous system is controlled by complex para-, auto-, and intracrine interactions of all three deiodinases. Local thyroid hormone availability is further modulated by conjugation reactions of the phenolic 4'-OH-group of iodothyronines, which also inactivate the thyroid hormones."

http://www.ncbi.nlm.nih.gov/pubmed/8767510 Pathways of thyroid hormone metabolism. "T4 is the main product secreted by the thyroid follicular cells and is regarded as a precursor of the bioactive hormone T3, most of which is produced by outer ring deiodination of T4 in peripheral tissues. Both T4 and T3 are inactivated by inner ring deiodination. Three deiodinases have been identified with outer and/or inner ring deiodinase activities, which play an important role in the tissue-specific regulation of thyroid hormone bioactivity. All three enzymes have recently been shown to contain selenocysteine residues. The second important pathway of thyroid hormone metabolism involves the conjugation of the phenolic hydroxyl group with sulfate or glucuronic acid. The glucuronides are excreted in bile, acting as intermediates in the enterohepatic cycle and fecal excretion of thyroid hormone. Sulfation accelerates the deiodination of different iodothyronines by the type I deiodinase and, thus, initiates the irreversible degradation of the hormone. If type I deiodinases activity is low, e.g. in the fetus, T3 sulfate may function as a reservoir from which active T3 is recovered by tissue sulfatase activity."

http://www.ncbi.nlm.nih.gov/pubmed/8033262 Role of sulfation in thyroid hormone metabolism. "The type I iodothyronine deiodinase (ID-I) in liver and kidney converts the prohormone thyroxine (T4) by outer ring deiodination (ORD) to bioactive 3,3',5-triiodothyronine (T3) or by inner ring deiodination (IRD) to inactive 3,3',5-triiodothronine (rT3), while it also catalyzes the IRD of T3 and the ORD of rT3, with the latter as the preferred substrate. Sulfation of the phenolic hydroxyl group blocks the ORD of T4, while it strongly stimulates the IRD of both T4 and T3, indicating that sulfation is an important step in the irreversible inactivation of thyroid hormone. This review summarizes recent studies concerning this interaction between sulfation and deiodination of iodothyronines, the characterization of iodothyronine sulfotransferase activities, the measurement of iodothyronine sulfates in humans and animals, and the possible physiological importance of iodothyronine sulfation."

http://www.ncbi.nlm.nih.gov/pubmed/12724022 Thyroid function and postmenopause. "There is an increasing prevalence of high levels of thyroid stimulating hormone (TSH) with age - particularly in postmenopausal women - which are higher than in men. The incidence of thyroid disease in a population of postmenopausal women is as follows: clinical thyroid disease, about 2.4%; subclinical thyroid disease, about 23.2%. Among the group with subclinical thyroid disease, 73.8% are hypothyroid and 26.2% are hyperthyroid. The rate of thyroid cancer increases with age. The symptoms of thyroid disease can be similar to postmenopausal complaints and are clinically difficult to differentiate. There can also be an absence of clinical symptoms. It is of importance that even mild thyroid failure can have a number of clinical effects such as depression, memory loss, cognitive impairment and a variety of neuromuscular complaints. Myocardial function has been found to be subtly impaired. There is also an increased cardiovascular risk, caused by increased serum total cholesterol and low-density lipoprotein cholesterol as well as reduced levels of high-density lipoprotein. These adverse effects can be improved or corrected by L-thyroxine replacement therapy. Such treatment has been found to be cost-effective. With time, overt hypothyroidism can develop. Therefore, routine screening of thyroid function in the climacteric period to determine subclinical thyroid disease is recommended. Hormone replacement therapy (HRT) in women with hypothyroidism treated with thyroxine causes changes in free thyroxine and TSH. Increased binding of thyroxine to elevated thyroxine-binding globulin causes an elevation of TSH by feedback. Since adaptation is insufficient, there is an increased need for thyroxine in these women taking HRT. TSH levels should be controlled at 12 weeks after the beginning of therapy. At higher age the need for iodine and thyroxine is decreased. Therefore, therapy has to be controlled. For bone metabolism thyroid hormones play a dominant role. While there are only marginal differences between hypothyroid patients and euthyroid controls, there are large differences for hyperthyroid patients. Previous thyrotoxicosis and subsequent long-lasting L-thyroxine treatment are together associated with reduction in femoral and vertebral bone density in postmenopausal women. In these cases HRT is important for the control of bone loss."

http://www.ncbi.nlm.nih.gov/pubmed/24162265 The Pattern of Expression and Role of Triiodothyronine (T3) Receptors and Type I 5'-Deiodinase in Breast Carcinomas, Benign Breast Diseases, Lactational Change, and Normal Breast Epithelium. "Our study revealed substantial reduction in the protein expression profile of THRs in malignant versus nonmalignant mammary epithelium suggesting a possible role in breast cancer development. The presence of THRs in mammary epithelium seems to be protective against the development of breast cancer. This could serve as a potential prognostic and therapeutic target for breast cancer."

http://www.ncbi.nlm.nih.gov/pubmed/23680448 Thyroid Res. 2013 May 16;6(1):8. doi: 10.1186/1756-6614-6-8. TSH receptor antibodies have predictive value for breast cancer - retrospective analysis. "Relationships between thyroperoxidase antibodies (TPOAb), thyroglobulin antibodies (TgAb) and breast cancer have been previously demonstrated....The coexistence of Graves' disease and breast cancer was statistically significant. We observed TSHRAb and TgAb more frequently in patients with breast cancer. We found that TSHRAb is the only variable possessing predictive value for breast cancer...screening for autoimmune thyroid disorders should be performed in patients with nodular breast disease."

http://www.ncbi.nlm.nih.gov/pubmed/2577491 Assays of TSH-receptor antibodies in 576 patients with various thyroid disorders: their incidence, significance and clinical usefulness. "The incidence and the significance of TSH-receptor antibodies in Graves' disease and in various thyroid disorders have been evaluated. TSH-binding inhibiting antibodies (TBIAb) and thyroid stimulating antibodies (TSAb) were detected in a large proportion of Graves' disease patients (TBIAb in 68.8% and TSAb in 77.8%), in a small number of patients with idiopathic myxoedema or Hashimoto's thyroiditis, and were not detected in patients with endemic euthyroid goitre, differentiated thyroid carcinoma and toxic adenoma. Furthermore, TSH-receptor antibodies were present in some patients with toxic multinodular goitre (TBIAb in 12.7% and TSAb in 15.9%). When TSH-receptor and other thyroid autoantibodies were compared, it was found that 13 of the 15 Graves' patients with negative tests for thyroglobulin and thyroid microsomal antibodies were positive for TSH-receptor antibodies. On the other hand, 9 of the 11 patients with toxic multinodular goitre who had positive TSH-receptor antibody tests, also had serum thyroglobulin and/or thyroid microsomal antibodies. No significant differences in the prevalence of TSH-receptor antibodies were found in Graves' patients irrespective of the presence of ophthalmopathy or pretibial myxoedema. Elevated TBIAb activity at the end of anti-thyroid drug treatment was found in 52.9% of Graves' patients who subsequently relapsed, while in Graves' patients in remission TBIAb was always negative. TSH-receptor antibody results were not predictive of the outcome of radioiodine treatment in Graves' disease. Finally no correlation could be found between TBIAb and TSAb in Graves' disease and Hashimoto's thyroiditis. In conclusion: the high incidence of TSH-receptor antibodies in Graves' disease confirms their pathogenetic role in the development of hyperthyroidism; TSH-receptor antibodies in Graves' disease are not significantly associated with the presence of ophthalmopathy or pretibial myxoedema; TSH-receptor antibody assays may be useful for the diagnosis of Graves' disease in the absence of other signs of autoimmunity. TBIAb seems to be a good predictor of relapse in Graves' patients treated with anti-thyroid drugs; a fraction of toxic multinodular goitre could be a nodular variant of Graves' disease."

http://www.ncbi.nlm.nih.gov/pubmed/15127319 TSH-receptor autoantibodies - differentiation of hyperthyroidism between Graves' disease and toxic multinodular goitre. "Previous studies indicate pre-existing subclinical Graves' disease in many patients with the scintigraphic diagnosis of toxic multinodular goitre type A, equivalent to the in Germany so-called disseminated thyroid autonomy. Furthermore, after radioiodine treatment an increase or the induction of TSH-receptor antibodies (TRAb) in patients with Graves' disease or toxic multinodular goitre has been repeatedly reported. The distinction between both hyperthyroid conditions, Graves' disease and toxic multinodular goitre type A, depends on the diagnostic power of the TSH-receptor antibody determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay based on competitive binding to recombinant human TSH-receptor showed a higher sensitivity for the detection of TSH-receptor antibodies in patients with Graves' disease than previous assays using solubilized porcine epithelial cell membranes. In up to 50 % of patients with toxic multinodular goitre A without antithyroid drug pretreatment TSH-receptor antibodies were detectable with a high correlation between thyroid-stimulating antibodies in the bioassay and the h-TBII assay. Moreover, in a recent study the development of TSH-receptor antibodies after radioiodine treatment was detectable in 36 % of patients with toxic multinodular goitre type A, whereas TSH-receptor antibodies were not detectable in patients with toxic multinodular goitre type B or in patients with toxic adenoma. In conclusion, thyroid-stimulating antibodies in a bioassay or TSH-receptor antibodies detected with the h-TBII assay have the highest diagnostic power to differentiate Graves' disease from toxic multinodular goitre. Because of its less cumbersome assay technique the h-TBII should be performed in all patients with hyperthyroidism to differentiate Graves' disease from non-autoimmune hyperthyroidism such as toxic multinodular goitre to select the appropriate therapy for these patients."

http://www.ncbi.nlm.nih.gov/pubmed/11544566 Distinction between autoimmune and non-autoimmune hyperthyroidism by determination of TSH-receptor antibodies in patients with the initial diagnosis of toxic multinodular goiter. "Distinguishing Graves' disease (GD) from a toxic multinodular goiter (TMG) subgroup with a diffuse but uneven Tc-distribution depends on the diagnostic power of the TSH-receptor antibody (TRAb) determination. Bioassays using CHO cell lines expressing the hTSH-receptor or a new TBII assay, which uses the hTSH-receptor as an antigen (DYNOTEST TRAK human, Brahms, Germany), showed a higher sensitivity for the detection of TRAbs in patients with GD than assays using solubilized porcine epithelial cell membranes. The aim of this study was to investigate whether the new Dynotest TRAK human assay has an increased sensitivity to distinguish GD from non-autoimmune hyperthyroidism. Therefore, we examined 21 consecutive patients with the initial diagnosis of TMG for thyroid-stimulating antibodies (TSAbs, JP26 cell assay) and TBII with the new highly sensitive Dynotest TRAK human (Brahms, Germany). The initial diagnosis of TMG was based on suppressed TSH and a patchy Tc-uptake of more than 1 % and less than 7 % or TSH of more than 0.3 mIE/l with a patchy Tc-uptake of more than 1.5 % and less than 7 % and negative TBII values in a displacement assay using solubilized porcine epithelial cell membranes (TRAK, Brahms, Germany). 11 sera from these 21 patients showed TSAb activity. Furthermore, 10 of these 11 TSAb-positive sera were also positive in the Dynotest TRAK human assay, whereas one serum sample was borderline positive. TSAb activity and inhibition of (125)I-bTSH binding in the Dynotest TRAK human assay correlated well (r = 0.7). Therefore, 11 of the 21 investigated patients initially classified as TMG actually had GD, which was undetectable using the porcine TBII assay. In conclusion, TSAbs or TRAbs detected with the Dynotest TRAK human have the highest diagnostic power to differentiate GD from TMG. Because of the less cumbersome assay technique, the Dynotest TRAK human measurements should be obtained for all patients with non-typical TMG to differentiate GD from non-autoimmune hyperthyroidism in order to select the appropriate therapy for these patients."

http://www.ncbi.nlm.nih.gov/pubmed/1358483 Evaluation of serum basal thyrotrophin levels and thyrotrophin receptor antibody activities as prognostic markers for discontinuation of antithyroid drug treatment in patients with Graves' disease. "The present study suggests that antithyroid drugs treatment can be terminated more appropriately when both the serum TSH level and TBII activity are made normal, thus avoiding prolonged and unnecessary drug treatment."

http://www.ncbi.nlm.nih.gov/pubmed/17199435 Continued suppression of serum TSH level may be attributed to TSH receptor antibody activity as well as the severity of thyrotoxicosis and the time to recovery of thyroid hormone in treated euthyroid Graves' patients. "The cause of continued suppression of serum thyroid-stimulating hormone (TSH) levels during antithyroid drug therapy in some Graves' patients is unclear. Recently, there has been a notable explanation involving the direct inhibition of TSH receptor antibody (TRAb) on TSH secretion in the pituitary gland. The purpose of this study is to verify the relation between TRAb or other clinical parameters and the continued suppression of serum TSH level during antithyroid drug therapy in patients with Graves' disease. We reviewed the medical records of patients with Graves' disease between 1995 and 2002 at Samsung Medical Center. We selected 167 Graves' patients who had been euthyroid for at least 12 months after recovery of serum T3 and T4 levels during the antithyroid drug therapy. We analyzed the correlation of the interval until recovery of serum TSH with the pretreatment clinical parameters. We compared the recovery rates of suppressed TSH levels between pretreatment thyrotrophin-binding inhibitory immunoglobulin (TBII)-positive (>15%) and TBII-negative patients. We also compared the clinical parameters between two groups at the time of diagnosis and after recovery of thyroid hormone. Pretreatment serum T3 level, (131)I uptake, TBII activity, and the time to recovery of T3 or T4/free T4 level showed significant positive correlations with the interval until recovery of serum TSH level ( p < 0.05). Recovery rates of serum TSH levels at 3 months after recovery of thyroid hormone were significantly lower in pretreatment TBII-positive patients than those in TBII-negative patients ( p < 0.01). Serum TSH levels were significantly lower in TBII-positive patients at 3 months after recovery of thyroid hormone ( p < 0.05). TBII activities inversely correlated only with serum TSH levels at 3months after recovery of thyroid hormone ( p < 0.001). In conclusion, continued suppression of serum TSH level may be attributed to TRAb activity as well as the pretreatment severity of thyrotoxicosis and the time to recovery of thyroid hormone in patients with Graves' disease during antithyroid drug therapy."

http://www.ncbi.nlm.nih.gov/pubmed/9364248 Thyroid-stimulating antibody and TSH-binding inhibitor immunoglobulin in 277 Graves' patients and in 686 normal subjects. "TSH receptor antibodies (TRAb) are believed to cause hyperthyroidism of Graves' disease. Thyroid-stimulating antibody (TSAb) and TSH-binding inhibitor immunoglobulin (TBII) have been measured as TRAb to diagnose Graves' disease and to follow Graves' patients. We intended to evaluate the clinical value of TRAb (TSAb and TBII) assay in establishing the diagnosis of Graves' disease and in predicting its clinical course. TSAb and TBII were studied in 686 normal subjects and in 277 Graves' patients before antithyroid drug therapy. We followed serial changes of TSAb and TBII in 30 Graves' patients before, during and after antithyroid drug therapy over 3.5-9 yr. We measured TSAb as a stimulator assay and TBII as a receptor assay. Both TSAb and TBII were distributed normally in 686 normal subjects. ROC curves demonstrated that both TSAb and TBII had high sensitivity and specificity for the diagnosis of Graves' disease, and were equally sensitive and specific; 150% was chosen as cut-off value for TSAb and 10% for TBII. Of the 277 untreated Graves' patients, 254 (92%) had positive TSAb and positive TBII. All of the 277 untreated Graves' patients had positive TRAb (TSAb and/or TBII). We followed the serial changes of TSAb and TBII in 30 Graves' patients over 3.5-9 yr. During antithyroid drug therapy, TSAb and TBII activities decreased and disappeared in 27 patients (Group A), but continued to be high in the other 3 (Group B). The former 27 Group A patients achieved remission, but the latter 3 Group B patients continued to have hyperthyroidism. Of the 27 Group A patients, 16 (59%) had parallel decreases of TSAb and TBII activities; in 6, the changes were predominantly observed in either TSAb or TBII, and in 4, complex changes in TSAb and TBII activities were observed. Disappearance of TSAb and appearance of TSBAb was seen in one. The other 3 Group B patients continued to have high TSAb and TBII activities and to have hyperthyroidism. In conclusion, TSAb and TBII are of clinical value in establishing the diagnosis of Graves' disease and in predicting its clinical course. We clearly demonstrated its diagnostic usefulness. Both TSAb and TBII have high sensitivity and specificity. All of the 277 untreated Graves' patients had TRAb (TSAb and/or TBII). Serial changes of TSAb and TBII during therapy differ from one patient to another, and can be classified into several groups. Changes in TSAb and TBII activities reflect the clinical courses of Graves' patients. The simultaneous measurement of both TSAb and TBII is clinically useful, since TSAb and TBII reflect two different aspects of TRAb. TSAb and TBII are different."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3181966/pdf/DialoguesClinNeurosci-13-127.pdf Hormone treatment of depression

http://online.liebertpub.com/doi/abs/10.1089/105072504323024552 The Interrelationships Between Thyroid Dysfunction and Hypogonadism in Men and Boys "Thyroid hormone deficiency affects all tissues of the body, including multiple endocrine changes that alter growth hormone, corticotrophin, glucocorticoids, and gonadal function. Primary hypothyroidism is associated with hypogonadotropic hypogonadism, which is reversible with thyroid hormone replacement therapy. In male children follicle-stimulating hormone (FSH) is elevated and associated with testicular enlargement without virilization. Men with primary hypothyroidism have subnormal responses of luteinizing hormone (LH) to gonadotropin-releasing hormone (GnRH) administration and normal response to human chorionic gonadotropin (hCG). Free testosterone concentrations are reduced in men with primary hypothyroidism and thyroid hormone replacement normalizes free testosterone concentrations. In men with primary hypothyroidism, prolactin is not consistently elevated (except in men and children with longstanding severe primary hypothyroidism), but prolactin declines following thyroid hormone replacement therapy. Thyroid hormone is known to affect sex hormone-binding hormonal globulin (SHBG) concentrations. Men with hyperthyroidism have elevated concentrations of testosterone and SHBG. Thyroid hormone therapy in normal men may also duplicate this elevation. In addition estradiol elevations are observed in men with hyperthyroidism, and gynecomastia is common in them as well. In contrast to patients with primary hypothyroidism, men with hyperthyroidism exhibit hyperresponsiveness of LH to GnRH administration and subnormal responses to hCG. Radioactive iodine therapy (RAI) of men treated for thyroid cancer produces a dose-dependent impairment of spermatogenesis and elevation of FSH up to approximately 2 years. Permanent testicular germ cell damage may occur in men treated with high doses of RAI. RAI commonly increases serum concentrations of FSH and LH while reducing inhibin B levels without affecting serum concentrations of testosterone. Thus, radioiodine therapy transiently impairs both germinal and Leydig cell function that usually recover by 18 months posttherapy."

http://press.endocrine.org/doi/abs/10.1210/jcem.86.8.7747 Usefulness of l-Carnitine, A Naturally Occurring Peripheral Antagonist of Thyroid Hormone Action, in Iatrogenic Hyperthyroidism: A Randomized, Double-Blind, Placebo-Controlled Clinical Trial "Old studies in animals and unblinded studies in a few hyperthyroid patients suggested that l -carnitine is a periferal antagonist of thyroid hormone action at least in some tissues. This conclusion was substantiated by our recent observation that carnitine inhibits thyroid hormone entry into the nucleus of hepatocytes, neurons, and fibroblasts... In conclusion, l-carnitine is effective in both reversing and preventing symptoms of hyperthyroidism and has a benefical effect on bone mineralization. Because hyperthyroidism depletes the body deposits of carnitine and since carnitine has no toxicity, teratogenicity, contraindications and interactions with drugs, carnitine can be of clinical use."

http://www.sciencedirect.com/science/article/pii/0026049577901019 Urinary excretion of carnitine in patients with hyperthyroidism and hypothyroidism: Augmentation by thyroid hormone "Urinary excretion of carnitine and serum concentrations of carnitine, triglyceride, and free fatty acids were measured in 54 hyperthyroid and 13 hypothyroid patients, and the results were compared with those of normal subjects. In hyperthyroid patients urinary excretion of carnitine was highly increased above that of the control subjects. On adequate treatment with antithyroid drug, carnitine excretion was reduced to the normal range, and serum lipids changed in parallel. In contrast, carnitine excretion was markedly reduced in hypothyroid patients. After substitution therapy with thyroid hormones the excretion increased in these patients. This change was associated with a marked reduction of serum triglyceride. There was an inverse correlation between urinary excretion of carnitine and serum triglyceride concentration. Carnitine excretion was significantly correlated with serum thyroxine concentration in hyper- and hypothyroid patients. The results suggest that thyroid hormones play an important role in carnitine metabolism, which in turn influences serum triglyceride metabolism."

http://www.sciencedirect.com/science/article/pii/0005276083900255 The outer carnitine palmitoyltransferase and regulation of fatty acid metabolism in rat liver in different thyroid states "The activity of the outer carnitine palmitoyltransferase (EC 2.3.1.21) and the carnitine-dependent oxidation of palmitoyl-CoA was increased 3–4-fold in liver mitochondria from hyperthyroid rats as compared with hypothyroid rats. The inhibitory effect of malonyl-CoA on carnitine-dependent fatty acid oxidation was preserved in all thyroid states, but decreased in hyperthyroid mitochondria. Fasting for 24 h increased the activity of the outer carnitine palmitoyltransferase about 50% in hypothyroid liver mitochondria, whereas it had no significant effect in hyperthyroid mitochondria. The thyroid state had no significant effect on total carnitine palmitoyltransferase in liver mitochondria. Fasting stimulated fatty acid oxidation 3–4-fold in isolated hepatocytes from hypothyroid rats, whereas it had no effect in hyperthyroid rats. Feeding 0.3% clofibrate to euthyroid rats about doubled the activity of the total carnitine palmitoyltransferase, whereas it had no effect on the outer transferase. The regulation of fatty acid oxidation in the liver is discussed."

Effects of Carnitine on Thyroid Hormone Action "By experiments on cells (neurons, hepatocytes, and fibroblasts) that are targets for thyroid hormones and a randomized clinical trial on iatrogenic hyperthyroidism, we validated the concept that l-carnitine is a peripheral antagonist of thyroid hormone action. In particular, l-carnitine inhibits both triiodothyronine (T3) and thyroxine (T4) entry into the cell nuclei. This is relevant because thyroid hormone action is mainly mediated by specific nuclear receptors. In the randomized trial, we showed that 2 and 4 grams per day of oral l-carnitine are capable of reversing hyperthyroid symptoms (and biochemical changes in the hyperthyroid direction) as well as preventing (or minimizing) the appearance of hyperthyroid symptoms (or biochemical changes in the hyperthyroid direction). It is noteworthy that some biochemical parameters (thyrotropin and urine hydroxyproline) were refractory to the l-carnitine inhibition of thyroid hormone action, while osteocalcin changed in the hyperthyroid direction, but with a beneficial end result on bone. A very recent clinical observation proved the usefulness of l-carnitine in the most serious form of hyperthyroidism: thyroid storm. Since hyperthyroidism impoverishes the tissue deposits of carnitine, there is a rationale for using l-carnitine at least in certain clinical settings."

http://www.jbc.org/content/275/45/34989.short Thyroid Hormone Regulates Carnitine Palmitoyltransferase Ia Gene Expression through Elements in the Promoter and First Intron "Carnitine palmitoyltransferase I (CPT-I) catalyzes the transfer of long chain fatty acyl groups from CoA to carnitine for translocation across the mitochondrial inner membrane. CPT-Ia is a key regulatory enzyme in the oxidation of fatty acids in the liver. CPT-Ia is expressed in all tissues except skeletal muscle and adipose tissue, which express CPT-Iß. Expression of CPT-Ia mRNA and enzyme activity are elevated in the liver in hyperthyroidism, fasting, and diabetes. CPT-Ia mRNA abundance is increased 40-fold in the liver of hyperthyroid compared with hypothyroid rats. Here, we examine the mechanisms by which thyroid hormone (T3) stimulates CPT-Ia gene expression. Four potential T3 response elements (TRE), which contain direct repeats separated by four nucleotides, are located 3000–4000 base pairs 5' to the start site of transcription in the CPT-Ia gene. However, only one of these elements functions as a TRE. This TRE binds the T3 receptor as well as other nuclear proteins. Surprisingly, the first intron of the CPT-Ia gene is required for the T3 induction of CPT-Ia expression, but this region of the gene does not contain a TRE. In addition, we show that CPT-Ia is induced by T3 in cell lines of hepatic origin but not in nonhepatic cell lines."

http://www.jbc.org/content/279/52/53963.short Peroxisomal Proliferator-activated Receptor-? Coactivator-1a (PGC-1a) Enhances the Thyroid Hormone Induction of Carnitine Palmitoyltransferase I (CPT-Ia) "Carnitine palmitoyltransferase I (CPT-I) catalyzes the rate-controlling step in the pathway of mitochondrial fatty acid oxidation. Thyroid hormone will stimulate the expression of the liver isoform of CPT-I (CPT-Ia). This induction of CPT-Ia gene expression requires the thyroid hormone response element in the promoter and sequences within the first intron. The peroxisomal proliferator-activated receptor-? coactivator-1a (PGC-1a) is a coactivator that promotes mitochondrial biogenesis, mitochondrial fatty acid oxidation, and hepatic gluconeogenesis. In addition, PGC-1a will stimulate the expression of CPT-Ia in primary rat hepatocytes. Here we report that thyroid hormone will increase PGC-1a mRNA and protein levels in rat hepatocytes. In addition, overexpression of PGC-1a will enhance the thyroid hormone induction of CPT-Ia indicating that PGC-1a is a coactivator for thyroid hormone. By using chromatin immunoprecipitation assays, we show that PGC-1a is associated with both the thyroid hormone response element in the CPT-Ia gene promoter and the first intron of the CPT-Ia gene. Our data demonstrate that PGC-1a participates in the stimulation of CPT-Ia gene expression by thyroid hormone and suggest that PGC-1a is a coactivator for thyroid hormone."

http://www.jbc.org/content/278/10/7964.short A Thyroid Hormone Response Unit Formed between the Promoter and First Intron of the Carnitine Palmitoyltransferase-Ia Gene Mediates the Liver-specific Induction by Thyroid Hormone "Carnitine palmitoyltransferase-I (CPT-I) catalyzes the rate-controlling step of fatty acid oxidation. CPT-I converts long-chain fatty acyl-CoAs to acylcarnitines for translocation across the mitochondrial membrane. The mRNA levels and enzyme activity of the liver isoform, CPT-Ia, are greatly increased in the liver of hyperthyroid animals. Thyroid hormone (T3) stimulates CPT-Ia transcription far more robustly in the liver than in non-hepatic tissues. We have shown that the thyroid hormone receptor (TR) binds to a thyroid hormone response element (TRE) located in the CPT-Ia promoter. In addition, elements in the first intron participate in the T3 induction of CPT-Ia gene expression, but the CPT-Ia intron alone cannot confer a T3 response. We found that deletion of sequences in the first intron between +653 and +744 decreased the T3 induction of CPT-Ia. Upstream stimulatory factor (USF) and CCAAT enhancer binding proteins (C/EBPs) bind to elements within this region, and these factors are required for the T3 response. The binding of TR and C/EBP to the CPT-Ia gene in vivo was shown by the chromatin immunoprecipitation assay. We determined that TR can physically interact with USF-1, USF-2, and C/EBPa. Transgenic mice were created that carry CPT-Ia-luciferase transgenes with or without the first intron of the CPT-Ia gene. In these mouse lines, the first intron is required for T3 induction as well as high levels of hepatic expression. Our data indicate that the T3 stimulates CPT-Ia gene expression in the liver through a T3 response unit consisting of the TRE in the promoter and additional factors, C/EBP and USF, bound in the first intron."

http://link.springer.com/article/10.1007/s00018-002-8445-3 Thyroid hormone controls carnitine status through modifications of ?-butyrobetaine hydroxylase activity and gene expression "The carnitine system plays a key role in ß-oxidation of long-chain fatty acids by permitting their transport into the mitochondrial matrix. The effects of hypothyroidism and hyperthyroidism were studied on ?-butyrobetaine hydroxylase (BBH), the enzyme responsible for carnitine biosynthesis in the rat. In rat liver, BBH activity was decreased in the hypothyroid state and increased in hyperthyroid animals. The modifications in BBH activity correlated with changes in the enzyme Vmax values. These changes were shown to be related to hepatic BBH mRNA abundance. Thyroid hormones are known to interact with lipid metabolism, in particular by increasing long-chain fatty acid oxidation through activation of carnitine-dependent fatty acid import into mitochondria. Our study showed that thyroid hormones also increased carnitine bioavailability."

http://www.sciencedirect.com/science/article/pii/S0006291X84717918 Changes in Carnitine Palmitoyltransferase-I mRNA Abundance Produced by Hyperthyroidism and Hypothyroidism Parallel Changes in Activity "To study the regulation of carnitine palmitoyltransferase-I by thyroid hormone, a cDNA was obtained by PCR amplification of DNA obtained by reverse transcription of rat liver RNA. CPT-I mRNA abundance was measured in livers of hyperthyroid, euthyroid and hypothyroid rats. In hypothyroid rats, the CPT-I mRNA levels decreased 40-fold relative to that of the hyperthyroid animals. These changes paralleled alterations in enzyme activity. These data suggest that CPT-I is regulated at the transcriptonal level by thyroid hormone."

Muscle carnitine in hypo- and hyperthyroidism "Weakness is common in both hyper- and hypothyroidism, and skeletal muscle l-carnitine may play a role in this regard, as suggested by studies indicating abnormal levels of carnitine in serum and urine of patients with thyroid dysfunction. Skeletal muscle samples were obtained for carnitine analysis from control subjects, and from hyperthyroid and hypothyroid patients before and after treatment. There was a significant reduction in carnitine, especially the esterified portion, in hyperthyroid individuals, with a return to normal as euthyroid status was regained. In hypothyroid patients, there was a trend for carnitine to be lower than normal and for improvement once euthyroid status was attained. Our data indicate that muscle carnitine levels are affected by both hypo- and hyperthyroidism. A decrease in muscle carnitine in both conditions may contribute to thyroid myopathy." Muscle Nerve, 2005

http://www.biochemj.org/bj/208/bj2080667.htm Effects of thyroidectomy and starvation on the activity and properties of hepatic carnitine palmitoyltransferase. "Hepatic carnitine palmitoyltransferase activity was measured over a range of concentrations of palmitoyl-CoA and in the presence of several concentrations of the inhibitor malonyl-CoA. These measurements were made in mitochondria obtained from the livers of fed and starved (24 h) normal rats and of fed and starved thyroidectomized rats. 2. In the fed state thyroidectomy substantially decreased overt carnitine palmitoyltransferase activity and also decreased both the Hill coefficient and the s0.5 when palmitoyl-CoA concentration was varied as substrate. Thyroidectomy did not appreciably alter the inhibitory effect of malonyl-CoA on the enzyme. 3. Starvation increased overt carnitine palmitoyltransferase activity in both the fed and the thyroidectomized state. In percentage terms this response to starvation was substantially greater after thyroidectomy. In both the hypothyroid and normal states starvation decreased sensitivity to inhibition by malonyl-CoA."

http://www.sciencedirect.com/science/article/pii/000527608190309X Effect of thyroid state on ketogenic capacity of the isolated perfused liver of starved rats "The effect of different thyroid states on the oxidation of free fatty acids was investigated in the isolated perfused liver of 24-h-starved rats. 1. Compared with the euthyroid control the oxidation of oleate to ketone bodies as well as to CO2 was increased in hyper-, while it was unchanged in hypothyroid livers. 2. The addition of camitine stimulated oleate oxidation in livers from eu- and hyperthyroid rats, but was without effect in hypothyroid livers. 3. Glucose did not affect the thyroid hormone-mediated effect of oleate conversion to ketone bodies. 4. Hepatic oxidation of octanoate was similar in all thyroid states. 5. Re-esterification of oleate was enhanced in hypo-, but reduced in hyperthyroidism. 6. The concentration of hepatic malonyl-CoA was decreased in hypo- and unchanged in hyperthyroid livers. 7. The concentration of cyclic AMP was elevated in the liver of hyperthyroid rats, no differences were observed between eu- and hypothyroid livers. However, increasing the hepatic cyclic AMP content by the addition of glucagon did not stimulate ketogenesis in eu- and hypothyroid livers. 8. The results indicate that thyroid hormones stimulate oleate oxidation by an accelerated transport of its CoA derivative into the mitochondrial compartment."

Effect of Thyroxine Treatment on Carnitine Levels in Mice "The effect in mice of 8 subcutaneous injections of 20 µg of L-thyroxine at 12 hr-intervals on the carnitine concentration in the heart and skeletal muscle tissue was studied. In skeletal muscle tissue, the thyroxine treatment resulted in a depressed carnitine concentration. The mean values were 1.59 ± 0.034(S.E.M.) and 2.03 ± 0.046 µmol/g noncollagen protein and 1.11 ± 0.035 and 1.45 ± 0.037 µmol/g dry weight for the thyroxine treated and the control animals, respectively. Thyroxine produced myocardial hypertrophy. The thyroxine treated animals had lower cardiac values when dry weight was used as reference base, 4.17 ± 0.10 µmol/g dry weight than the control group, 4.69 ± 0.18 µmol/g dry weight. No statistically significant difference was found between the two groups when the cardiac carnitine concentration was expressed per g noncollagen protein or as carnitine content in the entire hearts. Thus, thyroxine has been showed to influence the metabolism of carnitine in mice."

http://www.nature.com/nature/journal/v439/n7075/abs/nature04330.html Bile acids induce energy expenditure by promoting intracellular thyroid hormone activation "While bile acids (BAs) have long been known to be essential in dietary lipid absorption and cholesterol catabolism, in recent years an important role for BAs as signalling molecules has emerged. BAs activate mitogen-activated protein kinase pathways, are ligands for the G-protein-coupled receptor (GPCR) TGR5 and activate nuclear hormone receptors such as farnesoid X receptor (FXR-; NR1H4). FXR-regulates the enterohepatic recycling and biosynthesis of BAs by controlling the expression of genes such as the short heterodimer partner (SHP; NR0B2) that inhibits the activity of other nuclear receptors. The FXR--mediated SHP induction also underlies the downregulation of the hepatic fatty acid and triglyceride biosynthesis and very-low-density lipoprotein production mediated by sterol-regulatory-element-binding protein 1c. This indicates that BAs might be able to function beyond the control of BA homeostasis as general metabolic integrators. Here we show that the administration of BAs to mice increases energy expenditure in brown adipose tissue, preventing obesity and resistance to insulin. This novel metabolic effect of BAs is critically dependent on induction of the cyclic-AMP-dependent thyroid hormone activating enzyme type 2 iodothyronine deiodinase (D2) because it is lost in D2-/-mice. Treatment of brown adipocytes and human skeletal myocytes with BA increases D2 activity and oxygen consumption. These effects are independent of FXR-, and instead are mediated by increased cAMP production that stems from the binding of BAs with the G-protein-coupled receptor TGR5. In both rodents and humans, the most thermogenically important tissues are specifically targeted by this mechanism because they coexpress D2 and TGR5. The BA–TGR5–cAMP–D2 signalling pathway is therefore a crucial mechanism for fine-tuning energy homeostasis that can be targeted to improve metabolic control."

http://www.sciencedirect.com/science/article/pii/S0304416512002255 The syndromes of reduced sensitivity to thyroid hormone "Six known steps are required for the circulating thyroid hormone (TH) to exert its action on target tissues. For three of these steps, human mutations and distinct phenotypes have been identified. The clinical, laboratory, genetic and molecular characteristics of these three defects of TH action are the subject of this review. The first defect, recognized 45 years ago, produces resistance to TH and carries the acronym, RTH. In the majority of cases it is caused by TH receptor ß gene mutations. It has been found in over 3000 individuals belonging to approximately 1000 families. Two relatively novel syndromes presenting reduced sensitivity to TH involve membrane transport and metabolism of TH. One of them, caused by mutations in the TH cell-membrane transporter MCT8, produces severe psychomotor defects. It has been identified in more than 170 males from 90 families. A defect of the intracellular metabolism of TH in 10 individuals from 8 families is caused by mutations in the SECISBP2 gene required for the synthesis of selenoproteins, including TH deiodinases."

http://press.endocrine.org/doi/abs/10.1210/edrv-14-3-348 The Syndromes of Resistance to Thyroid Hormone "THE syndromes of resistance to thyroid hormone are characterized by reduced clinical and biochemical manifestations of thyroid hormone action relative to the circulating hormone levels. In practice, most patients are identified by the persistent elevation of serum levels of T4 and T3 with “inappropriately” nonsuppressed TSH, in the absence of intercurrent acute illness, drugs, or alterations of thyroid hormone binding to serum proteins. More importantly, administration of supraphysiological doses of thyroid hormone fail to produce the expected suppressive effect on the secretion of pituitary TSH and/or to induce the expected metabolic responses in the peripheral tissues. Since the publication of the index cases in 1967 (1), 347 subjects have been reported who exhibit the characteristics of the syndrome (Refs. 1–129 and our personal communications and observations). In this review, we summarize all cases known to us, present their common features as well as unusual manifestations, and attempt to analyze and relate both clinical and laboratory findings. Special emphasis is given to recent advances in diagnostic procedures and in genetic studies which, in addition to identifying the etiology of the resistance, have contributed to the understanding of the molecular mechanisms of thyroid hormone action. The ultimate goal is to provide more accurate means of establishing the diagnosis, earlier recognition of the disorder, and more effective approaches to therapy."

http://jme.endocrinology-journals.org/content/43/1/19.short Thyroid hormones act indirectly to increase sex hormone-binding globulin production by liver via hepatocyte nuclear factor-4a " Thyroid hormones (triiodothyronine (T3) and thyroxine (T4)) increase SHBG accumulation in HepG2 cell culture medium over 5 days, and increase cellular SHBG mRNA levels. In addition, T4 treatment of HepG2 cells for 5 days increased HNF-4a mRNA and HNF-4a levels in concert with decreased cellular palmitate levels. Plasma SHBG levels were also increased in mice expressing a human SHBG transgene after 5 days treatment with T3 along with increased hepatic HNF-4a levels. In HepG2 cells, the human SHBG promoter failed to respond acutely (within 24?h) to T4 treatment, but a 4-day pre-treatment with T4 resulted in a robust response that was prevented by co-treatment with HNF-4a siRNA, or by blocking the ß-oxidation of palmitate through co-treatment with the carnitine palmitoyltransferase I inhibitor, etomoxir. These data lead us to conclude that thyroid hormones increase SHBG production indirectly by increasing HNF-4agene expression, and by reducing cellular palmitate levels that further contribute to increased HNF-4a levels in hepatocytes."

http://www.fasebj.org/content/22/8/2981.short Thyroid hormone (T3) and TRß agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats "Nonalcoholic fatty liver disease is the most common noninfectious liver disease in clinical practice, and there is an increasing need for new therapeutic approaches for the treatment of this liver disease. Here, we examined the effect of the thyroid hormone triiodothyronine (T3) and the agonist of the thyroid hormone receptor ß isoform (TRß), GC-1, on fatty liver and steatohepatitis induced in rodents by a choline-methionine deficient (CMD) diet. Male Fischer 344 rats fed a CMD diet for 1 wk developed a marked fatty liver and mild hepatitis. Concurrent administration of T3 resulted in a complete prevention of the fatty change associated with increased fatty acid mitochondrial and peroxisomal ß-oxidation. To investigate whether T3 could also reverse fully established fatty liver, rats were fed a CMD diet for 10 wk and then cofed T3 for 1 wk. Coadministration of T3 resulted in a complete regression of liver steatosis associated with a decrease of lipid peroxidation, cyclooxygenase-2 expression, and activation of phospho-STAT3 and phospho-SAPK/JNK. Finally, additional experiments showed that GC-1, which has no significant side effects on heart rate, prevented and reverted CMD-induced fat accumulation, and ameliorated steatohepatitis. These results indicate that TR agonists have the potential to inhibit or reverse hepatic steatosis induced by a nutritional model.—Perra, A., Simbula, G., Simbula, M., Pibiri, M., Kowalik, M. A., Sulas, P., Cocco, M. T., Ledda-Columbano, G. M., Columbano, A. Thyroid hormone (T3) and TRß agonist GC-1 inhibit/reverse nonalcoholic fatty liver in rats."

http://link.springer.com/article/10.1007/BF02867868 Altered maternal thyroid function: Effect of L-carnitine supplementation on fetal and neonatal myocardial free fatty acid oxidation,in vitro "Effect of L-carnitine supplementation on myocardial free fatty acid oxidation,in vitro, in offsprings born of hypothyroid and hyperthyroid mothers was studied in rats. L-carnitine supplementation stimulated myocardial fatty acid oxidation during gestational period in offspring born of control and hyperthyroid mothers. In contrast L-carnitine supplementation induced stimulation in myocardial fatty acid oxidation was very less in fetuses born of hypothyroid mothers. However, in neonates born of hypothyroid mothers L-carnitine stimulated myocardial fatty acid oxidation to a great extent. The results suggested that during maternal hypothyroidism low availability of thyroid hormones to fetuses through maternal circulation and availability of less carnitine to neonates due to hypolactation might be responsible for decreased myocardial free fatty acid utilization. In neonates born of hypothyroid mothers and with cardiac energy insufficiency parenteral carnitine supplementation might be of great help to prevent mortality and morbidity of such offsprings."

http://www.sciencedirect.com/science/article/pii/0306452296000528 Thyroid hormonal modulation of the binding and activity of the GABA-A receptor complex of brain "Thyroid hormones, which are known to act by genomic mechanisms in peripheral tissues, were found to influence the binding and function of the GABA-A receptor complex in brain membranes. Submicromolar concentrations of triiodothyronine and thyroxine stereospecifically stimulated the binding of [35S]t-butylbicyclophosphorothionate (a convulsant ligand for the GABA-A receptor complex) to highly washed rat brain membranes, while higher concentrations of the hormones inhibited radioligand binding. GABA-stimulated36Cl- flux in isolated brain membrane sacs was inhibited byl-triiodothyronine with a half-maximally inhibitory concentration (ic50) of 10-7 M. Patch-clamp analysis of recombinant GABAA receptor subunits expressed in human embryonic kidney-293 cells showed an inhibition of chloride currents by thyroid hormones. This effect required only thea1ß2 subunits, and was not blocked by the benzodiazepine antagonist flumazenil. Since thyroid hormones are known to be concentrated in nerve terminal preparations and subsequently released, the hormones may have non-genomic mechanisms of action as putative neurotransmitters or neuromodulators in brain and act through GABA-A receptors."

http://europepmc.org/abstract/MED/3509068 Modulation of gamma-aminobutyric acid uptake of rat brain synaptosomes by thyroid hormones. "The effects of thyroid hormones on gamma-aminobutyric acid (GABA) uptake were compared in homogenates and purified synaptosomes from rat cerebral cortex. L-triiodothyronine (T3) and L-thyroxine (T4), but not reverse T3(rT3), blocked GABA uptake in homogenates when hormone and labeled GABA were added to the system simultaneously. Similar effects were obtained when homogenates were preincubated with hormone and washed to remove free hormone before addition of GABA. A competitive inhibitor of neuronal GABA uptake, diaminobutyric acid (DABA), blocked GABA uptake when added with GABA, but not after preincubation and washing. In purified synaptosomes, T3,T4, and rT3 blocked GABA uptake when added simultaneously with GABA and also after preincubation and washing before addition of GABA, thus indicating that binding of hormones had occurred. Other experiments suggested that hormone binding was not at the GABA recognition site and that the effect of T4 was not dependent on conversion to T3."

http://link.springer.com/article/10.1007/s12253-009-9165-x GABA Receptor Expression in Benign and Malignant Thyroid Tumors "Neurotransmitter systems have recently been shown to be involved in multiple malignancies including breast, colon and prostate cancers. The role of neurotransmitters and neurotrophic factors has not yet been examined in thyroid cancer. To determine the possible involvement of neurotransmitter systems in thyroid carcinogenesis we characterized the patterns of gamma-aminobutyric acid (GABA) receptor expression in normal thyroid and thyroid tumors. We examined the expression patterns of the GABAergic system in 70 human thyroid tumor samples (13 follicular adenomas, 14 follicular carcinomas, 43 papillary carcinomas) and adjacent normal thyroid by immunohistochemistry. GABAergic system mRNA expression in thyroid cancer cell lines derived from primary (FTC133) and metastatic tumors (FTC236 and FTC238) was examined by real time PCR. Overall, GABA receptor expression is increased in tumors compared to normal thyroid tissue. Expression of GABAA receptor ß2 was detected in the vasculature of normal thyroid and thyroid tumors but not in thyroid cancer cells. GABAA a2 was detected in metastatic-derived but not in primary-tumor derived cell lines. Expression levels of GABAB R2 and GABA receptor associated protein (GABARAP) are increased in adenomas and thyroid cancer suggesting their role in early stages of thyroid tumorigenesis. This study represents the first demonstration of GABA receptor expression in human thyroid tissue and suggests that the GABAergic system is involved in thyroid carcinogenesis."

http://press.endocrine.org/doi/abs/10.1210/en.2006-0164 Thyroid Hormone Insufficiency during Brain Development Reduces Parvalbumin Immunoreactivity and Inhibitory Function in the Hippocampus "Thyroid hormones are necessary for brain development. ?-Amino-butyric acid (GABA)ergic interneurons comprise the bulk of local inhibitory circuitry in brain, many of which contain the calcium binding protein, parvalbumin (PV). A previous report indicated that severe postnatal hypothyroidism reduces PV immunoreactivity (IR) in rat neocortex. We examined PV-IR and GABA-mediated synaptic inhibition in the hippocampus of rats deprived of thyroid hormone from gestational d 6 until weaning on postnatal d 30. Pregnant dams were exposed to propylthiouracil (0, 3, 10 ppm) via the drinking water, which decreased maternal serum T4 by approximately 50–75% and increased TSH. At weaning, T4 was reduced by approximately 70% in offspring in the low-dose group and fell below detectable levels in high-dose animals. PV-IR was diminished in the hippocampus and neocortex of offspring killed on postnatal d 21, an effect that could be reversed by postnatal administration of T4. Dose-dependent decreases in the density of PV-IR neurons were observed in neocortex and hippocampus, with the dentate gyrus showing the most severe reductions (50–75% below control counts). Altered staining persisted to adulthood despite the return of thyroid hormones to control levels. Developmental cross-fostering and adult-onset deprivation studies revealed that early postnatal hormone insufficiency was required for an alteration in PV-IR. Synaptic inhibition of the perforant path-dentate gyrus synapse evaluated in adult offspring, in vivo, revealed dose-dependent reductions in paired pulse depression indicative of a suppression of GABA-mediated inhibition. These data demonstrate that moderate degrees of thyroid hormone insufficiency during the early postnatal period permanently alters interneuron expression of PV and compromises inhibitory function in the hippocampus."

http://genesdev.cshlp.org/content/19/18/2152.short Anxiety, memory impairment, and locomotor dysfunction caused by a mutant thyroid hormone receptor a1 can be ameliorated by T3 treatment "The transcriptional properties of unliganded thyroid hormone receptors are thought to cause the misdevelopment during hypothyroidism of several functions essential for adult life. To specifically determine the role of unliganded thyroid hormone receptor a1 (TRa1) in neuronal tissues, we introduced a mutation into the mouse TRa1 gene that lowers affinity to thyroid hormone (TH) 10-fold. The resulting heterozygous mice exhibit several distinct neurological abnormalities: extreme anxiety, reduced recognition memory, and locomotor dysfunction. The anxiety and memory deficiencies were relieved by treatment with high levels of TH in adulthood, an effect that correlated with a normalization of GABAergic inhibitory interneurons in the hippocampal CA1 region. In contrast, a post-natal TH treatment was necessary and sufficient for ameliorating the adult locomotor dysfunction. Here, the hormone treatment normalized the otherwise delayed cerebellar development. The data thus identify two novel and distinct functions of an unliganded TRa1 during development and adulthood, respectively."

http://www.sciencedirect.com/science/article/pii/0006899387905567 Selective persistent reduction in choline acetyltransferase activity in basal forebrain of the rat after thyroid deficiency during early life "The effect of thyroid deficiency on the activity of choline acetyltransferase (ChAT; the marker for cholinergic neurons) was studied in different parts of the rat brain at ages 5, 10, 15 and 25 days, and at day 130 following 102 days of rehabilitation. During normal development, the activity of ChAT increased in the cerebral cortex, hippocampus and basal forebrain, and decreased in the cerebellum. Neonatal thyroid deficiency resulted in a marked retardation of the developmental patterns of the enzyme activity. In the hippocampus the effect diminished with age even during the period of thyroid hormone deprivation, while in the cerebral cortex and cerebellum the enzyme activity was restored to normal only after rehabilitation. In contrast, ChAT activity in the basal forebrain remained persistently reduced in comparison with controls. The results indicate that neonatal thyroid deficiency causes selective irreversible biological damage to subcortical cholinergic neurons."

http://europepmc.org/abstract/MED/2484871 GABA inhibits thyroid hormone secretion in the mouse. "The enzymes responsible for both the formation and degradation of gamma-aminobutyric acid (GABA) are known to exist in the thyroid gland. The thyroid is also equipped with high- and low-affinity uptake mechanisms for GABA. We therefore investigated the effects of GABA on basal and TSH-stimulated thyroid hormone secretion in the mouse according to the McKenzie technique. Iodine-deficient mice were pretreated with Na125I and thyroxine. GABA (1-100 nmol/kg iv) did not affect basal radioiodine levels. However, the neurotransmitter inhibited the TSH-induced increase in blood radioiodine levels. Thus, the increase after iv injection of TSH at 70 microU/animal (205 +/- 15%) was inhibited by GABA at 10 nmol/kg (to 155 +/- 14%; P less than 0.05). In contrast, a dose as high as 100 nmol/kg was necessary to inhibit the effect of TSH at its high dose of 350 microU/animal. The GABAA-receptor antagonist bicuculline counteracted this inhibitory action of GABA. Furthermore, pretreatment with the inhibitor of GABA-degrading enzyme GABA transaminase (gamma-vinyl GABA) impaired the stimulatory effect of TSH on blood radioiodine levels. Thus, at 350 microU/animal, TSH increased blood radioiodine levels by 363 +/- 34% in controls vs by only 246 +/- 32% in animals pretreated with gamma-vinyl-GABA (P less than 0.05). We conclude that GABA is an inhibitor of TSH-stimulated thyroid hormone secretion."

http://www.sciencedirect.com/science/article/pii/S0014299998001824 Direct channel-gating and modulatory effects of triiodothyronine on recombinant GABA-A receptors "We have previously shown that triiodothyronine (T3) inhibits ?-aminobutyric acid type A (GABAA) receptors in synaptoneurosomes and transfected cells. To further characterize this phenomenon, the effect of T3 on recombinant GABAA receptors expressed in Xenopus oocytes was investigated using the two-electrode voltage-clamp method. T3 inhibited GABA-gated chloride currents in a non-competitive manner and yielded an IC50 of 7.3±0.8 µM in oocytes coexpressing a1ß2?2L receptor subunits. T3 had no inhibitory effect ona6ß2?2L or ß2?2L receptor constructs, indicating that the a1 subunit imparts T3 sensitivity to the receptor. In addition to the inhibitory effect of T3 on GABA responses, T3 alone induced a current in oocytes expressinga1ß2?2L, a6ß2?2L and ß2?2L constructs. This current displayed a reversal potential identical to that of GABA-gated chloride currents, and was blocked by picrotoxin (10 µM), but not by bicuculline (50 µM), indicating that T3 gates the chloride channel by binding to a site other than the GABA-binding site. The direct channel-gating action of T3 was concentration-dependent, with an EC50 of 23±5 µM. The actions of T3 are unique in that T3 acts as a noncompetitive antagonist in the presence of GABA but can directly gate the chloride channel in the absence of GABA."

http://www.karger.com/Article/Abstract/179884 Gaba-Ergic and Dopaminergic Regulation of Thyroid Stimulating Hormone "The effects of the GABA analogue, baclofen, and the dopamine antagonist, metoclopramide, on basal and TRH-stimulated TSH release were studied in 6 normal male volunteers. Basal TSH secretion was not influenced by baclofen (10 mg orally three times daily for 3 days) or metoclopramide (10 mg i.v.), given alone or together. Baclofen produced a blunting of the TRH-stimulated TSH release (p < 0.05), which persisted after metoclopramide administration. It is speculated that GABA and its analogues exert an inhibitory effect on TSH secretion, presumably at the level of the pituitary, and this effect is not mediated by dopamine."

http://online.liebertpub.com/doi/abs/10.1089/thy.1996.6.537 Novel Uses of Thyroid Hormones in Patients with Affective Disorders "Hormones of the thyroid axis have been used to treat patients with any of several mental illnesses. However, in recent decades interest has focused almost exclusively on depression, though thyroid hormones, mainly thyroxine (T4), are used with lithium in rapid cycling bipolar disorder, a condition in which depression and mania rapidly alternate. In depression L-triiodothyronine (T3) has been used in preference to T4 because of its rapid onset and offset of action. In women starting treatment, T3 hastens the onset of therapeutic action of standard antidepressant drugs. It fails to do so in depressed men, who anyway respond faster than women to standard antidepressants. Standard drugs fail to produce satisfactory improvement in one-quarter to one-third of depressed patients. Then, in both men and women, T3 converts about two-thirds of drug failures to successes in rapid fashion. Lithium, which has antithyroid properties, produces a similar conversion rate. The majority of depressed patients are grossly euthyroid, but many show one or another subtle change in thyroid axis activity. However, the thyroid state of patients has not been matched systematically with their response to thyroid hormone augmentation. It seems likely that a tendency toward hypothyroidism can predispose to depression, but when depression occurs in a euthyroid patient, the thyroid axis is often invoked in the process of restitution."

http://www.hindawi.com/journals/jtr/2011/306367/ Thyroid Functions and Bipolar Affective Disorder "Accumulating evidence suggests that hypothalamo-pituitary-thyroid (HPT) axis dysfunction is relevant to the pathophysiology and clinical course of bipolar affective disorder. Hypothyroidism, either overt or more commonly subclinical, appears to the commonest abnormality found in bipolar disorder."

http://onlinelibrary.wiley.com/doi/10.1111/j.1528-1157.1992.tb02297.x/ Thyroid Function with Antiepileptic Drugs "Serum thyroid hormone balance was assessed in 108 patients receiving chronic antiepileptic drug (AED) therapy. Forty-five patients were receiving carbamazepine (CBZ), 26 phenytoin (PHT), 16 CBZ-PHT, 11 valproate (VPA), and 10 CBZ-VPA. Serum thyroxine (T4) and free thyroxine (FT4) concentrations were low in patient groups receiving CBZ and/or PHT. Serum T4 concentrations were below the normal range in 24 (53.3%) CBZ patients, II (42.3%) PHT patients, 12 (75%) CBZ-PHT patients, and in all 10 patients (100%) receiving CBZ-VPA. Furthermore, serum levels of FT4 were below the normal range in 13 (28.9%) CBZ patients, 6 PHT (23.1%) patients, 5 (31.3%) CBZ-PHT patients, and 5 (50%) CBZ-VPA patients. Despite the decreased serum T4 and FT4 levels in these patients, serum basal and stimulated thyrotropin (TSH) concentrations were normal, except for the slightly increased basal TSH in the CBZ-VPA group. In the VPA group, the findings were different from those in other patients: T4 serum levels were unchanged and FT4, T3, and basal TSH levels increased, but stimulated TSH levels did not differ from those of the control group. The decrease in serum thyroid hormone levels during CBZ and/or PHT medication probably is caused by an accelerated hepatic plasma clearance of these hormones due to induction of hepatic microsomal enzyme systems by these AEDs. VPA, an AED with no liver enzyme-inducing properties, does not cause similar changes. The feedback mechanism is not activated, possibly because of a hypothalamic interference by CBZ and PHT. The effects of VPA on serum thyroid hormone and TSH levels may be mediated by effects on TSH secretion and on the protein binding of thyroid hormones."

http://www.sciencedirect.com/science/article/pii/0197018694900213 Effects of thyroxine and its related compounds on cerebral gaba receptors: Inhibitory action of benzodiazepine recognition site in GABA-A receptor complex "The effects of thyroxine and its related derivatives on ?-aminobutyric acid (GABA) receptors in the rat brain were examined. d-Thyroxine strongly inhibited [3H]flunitrazepam binding to benzodiazepine receptor in crude synaptic membrane from the rat brain. The Scatchard analysis of the [3H]flunitrazepam binding in the presence of d-thyroxine indicated the decreases in the affinity and maximum number of binding site. Furthermore, d-thyroxine inhibited the enhancing effect of flunitrazepam on GABA-stimulated 36Cl- influx into membrane vesicles, although GABA-stimulated 36Cl- influx alone was not affected by d-thyroxine. On the other hand, the effects of thyroxine and its related derivatives on cerebral GABAB receptor binding were not noted. These results suggest that d-thyroxine may be a drug which is able to modulate the function of GABAA receptor complex via the inhibitory action on benzodiazepine recognition site."

http://press.endocrine.org/doi/pdf/10.1210/jcem.77.4.8408456 Amelioration of some pregnancy-associated variations in thyroid function by iodine supplementation. "Knowledge of the effect of differences in iodine intake levels on public health in areas with no endemic goiter is limited. Groups at risk when iodine intake is relatively low are pregnant and lactating women and their newborns. A prospective randomized study was performed to evaluate the effect of iodine supplementation in an area where the median daily iodine excretion in urine is around 50 micrograms. Fifty-four normal pregnant women were randomized to be controls or to receive 200 micrograms iodine/day from weeks 17-18 of pregnancy until 12 months after delivery. In the control group, serum TSH, serum thyroglobulin (Tg), and thyroid size showed significant increases during pregnancy. These variations were ameliorated by iodine supplementation. Iodine did not induce significant variations in serum T4, T3, or free T4. Cord blood Tg was much lower when the mother had received iodine, whereas TSH, T4, T3, and free T4 levels were unaltered. The results suggest that a relatively low iodine intake during pregnancy leads to thyroidal stress, with increases in Tg release and thyroid size. However, the thyroid gland is able to adapt and keep thyroid hormones in the mother and the child normal, at least under normal circumstances, as evaluated in the present study. It is not known whether this stress is sufficient to be of importance for late development of autonomous thyroid growth and function."

http://press.endocrine.org/doi/abs/10.1210/jcem-71-2-276 Regulation of Maternal Thyroid during Pregnancy "A prospective study was undertaken in 606 healthy women during pregnancy to evaluate the changes occurring in maternal thyroid economy as a result of 1) the increased thyroid hormone-binding capacity of serum, 2) the effects of increased levels of hCG on TSH and on the thyroid, and 3) a marginally low iodine intake in the population (50–75 µg/day). Four main features were observed. First, thyroidal activity adjusted to the marked increase in serum T4-binding globulin: pregnancy was accompanied by an overall reduction in the T4/T4-binding globulin ratio, with lower free T4 and T3 levels, although in most cases free hormone levels remained within the normal range. The adjustment of thyroidal output of T4 and T3 did not occur similarly in all subjects. In approximately one third of the women, there was relative hypothyroxinemia, higher T3/T4ratios (presumably indicating preferential T3 secretion), and higher, although normal, serum TSH concentrations. Second, high hCG levels were associated with thyroid stimulation, both functionally (lower serum TSH) and anatomically (increased thyroid size). The data are consistent with a TSH-like effect of hCG on the thyroid. Hence, regulation of the maternal thyroid is complex, resulting from both elevated hCG (mainly in the first half of gestation) and increasing TSH (mainly in the second half of gestation). Third, a significant increase in serum thyroglobulin levels was observed throughout gestation, especially during the last trimester. Fourth, increased thyroid volume was common, and goiter formation not uncommon (goiter was found in 9% of women at delivery). In conclusion, the alterations in maternal thyroid function during gestation are intricate and far from fully understood. In areas of marginally low iodine intake, gestation is associated in a significant number of women with relative hypothyroxinemia, increased thyroglobulin, and enlarged thyroid."

http://press.endocrine.org/doi/abs/10.1210/jc.2006-1748 Detection of Thyroid Dysfunction in Early Pregnancy: Universal Screening or Targeted High-Risk Case Finding? "Maternal subclinical hypothyroidism during pregnancy is associated with various adverse outcomes. Recent consensus guidelines do not advocate universal thyroid function screening during pregnancy but recommend testing high-risk pregnant women with a personal history of thyroid or other autoimmune disorders or with a family history of thyroid disorders... Targeted thyroid function testing of only the high-risk group would miss about one third of pregnant women with overt/subclinical hypothyroidism."

http://jama.jamanetwork.com/article.aspx?articleid=383249 Detection of At-Risk Pregnancy by Means of Highly Sensitive Assays for Thyroid Autoantibodies "We screened 552 women who presented to their obstetrician in the first trimester of pregnancy using highly sensitive enzyme-linked immunosorbent assays for the presence of thyroglobulin and thyroidperoxidase autoantibodies and found an incidence of positivity of 19.6%. The tendency to secrete detectable levels of thyroid autoantibodies was significantly correlated with an increased rate of miscarriage. Thyroid autoantibody—positive women miscarried at a rate of 17%, compared with 8.4% for the autoantibody-negative women. Individual levels of thyroglobulin and thyroidperoxidase autoantibodies were similarly related to this increased miscarriage rate, with no evidence of autoantibody specificity in the relationship. Furthermore, the increase in miscarriages could not be explained by differences in thyroid hormone levels, the presence of cardiolipin autoantibodies, maternal age, gestational age at the time of maternal entry into the study, or previous obstetric history. We conclude that thyroid autoantibodies are an independent marker of "at-risk" pregnancy."

http://msc.sagepub.com/content/7/3/127.short Maternal thyroid deficiency and pregnancy complications: implications for population screening "Objective: To examine the relation between certain pregnancy complications and thyroid stimulating hormone (TSH) measurements in a cohort of pregnant women. Methods: TSH was measured in sera obtained from women during the second trimester as part of routine prenatal care. Information was then collected about vaginal bleeding, premature delivery, low birthweight, abruptio placentae, pregnancy induced hypertension, need for cesarean section, low Apgar scores, and fetal and neonatal death. Results: Among 9403 women with singleton pregnancies, TSH measurements were 6 mU/l or greater in 209 (2.2%). The rate of fetal death was significantly higher in those pregnancies (3.8%) than in the women with TSH less than 6 mU/l (0.9%, odds ratio 4.4, 95% confidence interval 1.9–9.5). Other pregnancy complications did not occur more frequently Conclusion: From the second trimester onward, the major adverse obstetrical outcome associated with raised TSH in the general population is an increased rate of fetal death. If thyroid replacement treatment avoided this problem this would be another reason to consider population screening."

http://online.liebertpub.com/doi/abs/10.1089/thy.2005.15.44 Are Detection and Treatment of Thyroid Insufficiency in Pregnancy Feasible? "A workshop entitled, "The Impact of Maternal Thyroid Diseases on the Developing Fetus: Implications for Diagnosis, Treatment, and Screening," was held in Atlanta, Georgia, January 12–13, 2004. The workshop was sponsored jointly by The National Center on Birth Defects and Developmental Disabilities of The Centers for Disease Control and Prevention (CDC) and The American Thyroid Association. This paper reports on the individual session that examined the ability to detect and treat thyroid dysfunction during pregnancy. For this session, presented papers included: "Laboratory Reference Values in Pregnancy" and "Criteria for Diagnosis and Treatment of Hypothyroidism in Pregnancy." These presentations were formally discussed by invited respondents and by others in attendance. Salient points from this session about which there was agreement include the following: thyrotropin (TSH) can be used as marker for hypothyroidism in pregnancy, except when there is iodine deficiency usually evidenced by elevated serum thyroglobulin (Tg). We need more longitudinal studies of TSH during pregnancy in iodine-sufficient populations without evidence of autoimmune thyroid disease to develop trimester-specific TSH reference ranges. Current free thyroxine (FT4) estimate methods are sensitive to abnormal binding-protein states such as pregnancy. There is no absolute FT4 value that will define hypothyroxinemia across methods. Total thyroxine (TT4) changes in pregnancy are predictable and not method-specific. TT4 below 100 nmol/L (7.8 µg/dL) is a reasonable indicator of hypothyroxinemia in pregnancy. Women with known hypothyroidism and receiving levothyroxine (LT4) before pregnancy should plan to increase their dosage by 30% to 60% early in pregnancy. Women with autoimmune thyroid disease prior to pregnancy are at increased risk for thyroid insufficiency during pregnancy and postpartum thyroiditis and should be monitored with TSH during pregnancy."

http://press.endocrine.org/doi/abs/10.1210/jcem.80.12.8530599 Maternal thyroid peroxidase antibodies during pregnancy: a marker of impaired child development? "Women with antibodies against the enzyme thyroid peroxidase [TPO-Ab; formerly microsomal antibodies (MsAb)] are at particular risk for developing postpartum thyroid dysfunction; the latter is significantly associated with postpartum depression. Although the negative effect of postpartum maternal depression on child development is well documented, the consequences of elevated titers of TPO-Ab during pregnancy and subsequent postpartum thyroid dysfunction on child development are not known. In a prospective study of a cohort of 293 pregnant women, the occurrence of TPO-Ab during gestation, thyroid dysfunction, and depression was investigated. Five years after delivery, child development was assessed in 230 children of the original cohort using the Dutch translation of the McCarthy Scales of Children's Abilities. Children of women with TPO-Ab during late gestation (n = 19, with normal thyroid function) had significantly lower scores (by t test) on the McCarthy Scales of Children's Abilities than antibody-negative women. The difference on the General Cognitive Scale, which reflects IQ scores, was substantial (10.5 points; t = 2.8; P = 0.005). After correction for possibly confounding variables, maternal TPO-Ab during gestation was found to be the most important factor related to the scores on the General Cognitive Scale (odds ratio = 10.5; 95% confidence interval = 3-34; P = 0.003). We conclude that children of pregnant women who had elevated titers of TPO-Ab but normal thyroid function are at risk for impaired development."

http://humupd.oxfordjournals.org/content/9/2/149.short Thyroid autoimmunity and hypothyroidism before and during pregnancy "In the present review, an attempt was made to describe current knowledge and concepts concerning the complex relationships that link thyroid autoimmunity (TAI) and hypothyroidism with female and male infertility, as well as abnormalities occurring during pregnancy, such as pregnancy loss and maternal and fetal repercussions associated with hypothyroidism. In the case of infertility, although the clinical relevance of TAI is somewhat controversial, when all available information is considered the results strongly suggest that when infertility is due to well-defined female causes, autoimmunity is involved and TAI constitutes a useful marker of the underlying immune abnormality, independently of thyroid function disorders. In the case of pregnancy loss, the vast majority of available studies clearly establish that TAI (even with no overt thyroid dysfunction) is associated with a significant increase in miscarriage risk. To find an association, however, does not imply a causal relationship, and the aetiology of increased pregnancy loss associated with TAI remains presently not completely understood. With regard to maternal repercussions during gestation, the main risk associated with TAI is the occurrence of hypothyroidism and obstetric complications (premature birth, pre-eclampsia, etc.). Thus, systematic screening of TAI and hypothyroidism during early pregnancy, monitoring of thyroid function with/without L-thyroxine treatment and follow-up during post-partum have proved helpful and important in order to manage these patients adequately. Finally, with regard to potential repercussions affecting the offspring, recent evidence suggests that thyroid maternal underfunction, even when considered mild (or subclinical), may be associated with an impairment of fetal brain development. When present only during the first half of gestation, maternal hypothyroxinaemia is a risk factor for impaired fetal brain development, due to insufficient transfer of maternal thyroid hormones to the feto-placental unit. When hypothyroidism is not restricted to the first trimester and worsens as gestation progresses (as in untreated hypothyroidism), the fetus may also be deprived of adequate amounts of thyroid hormones during later neurological maturation and development, leading to poorer school performance and lower IQ."

http://europepmc.org/abstract/MED/1992688 The effects of iodoprophylaxis on thyroid size during pregnancy. "Thyroid gland size was ultrasonographically determined in 35 pregnant women who live in an area with moderate iodine deficiency. Iodide salt was administered to group A (n = 17), whereas group B (n = 18) was used as a control. Each group was tested for thyroid-stimulating hormone serum levels, iodine excretion, and thyroid volume. In both groups thyroid-stimulating hormone levels were similar and did not change throughout pregnancy. The iodine excretion at the third trimester in the treated group was significantly (p less than 0.01) higher than that of group B (100.0 +/- 39.0 versus 50.0 +/- 37.0 micrograms iodine per 24 hours, respectively). Initially, thyroid volume did not differ between the two groups. At the end of pregnancy, no difference was found in thyroid size in group A, whereas in the untreated women it increased significantly (p less than 0.0001) with a mean increase of 1.6 +/- 0.6 ml (16.2% +/- 6.0%). These results show that the increased thyroid size in the control group was mainly a result of relative iodine deficiency and that iodoprophylaxis should be warranted even in areas with moderate iodine deficiency to prevent the increase in thyroid size and, probably, to avoid the risk of maternal and fetal hypothyroidism."

http://press.endocrine.org/doi/abs/10.1210/jcem.74.3.1740500 A prospective study of lymphocyte-initiated immunosuppression in normal pregnancy: evidence of a T-cell etiology for postpartum thyroid dysfunction. "Immune function in normal pregnancy and the postpartum period remains poorly defined. We hypothesized that a comparative study between pregnant women with normal and abnormal immune function would further our understanding of the immune mechanisms of pregnancy. We chose to study a cohort of pregnant women at risk for the development of postpartum thyroid dysfunction (PPTD) as well as a group of normal controls. We chose PPTD as the model for abnormal immune function because of the relative ease of monitoring disease development and the relatively high prevalence for PPTD reported in earlier studies. Five hundred and fifty-two women were screened for the presence of thyroid autoantibodies in the first trimester of pregnancy. Thirty-three thyroid autoantibody-positive women and 28 thyroid autoantibody-negative women were followed prospectively throughout pregnancy and 6 months into the postpartum period. Lymphocyte subset analyses, thyroid function tests, and thyroid autoantibodies (antihuman thyroglobulin and antithyroid peroxidase) were performed at defined intervals. All patients were HLA serotyped. Normal pregnancy was principally characterized by decreased CD4+ T-cells and increasing CD8+ T-cells, causing a significant fall in the CD4+/CD8+ ratio in late pregnancy and into the postpartum period. Women who developed PPTD had 1) a higher CD4+/CD8+ ratio (P = 0.04), 2) activation of T-cells in the postpartum period (P = 0.02), and 3) significantly higher thyroid autoantibody titers (antihuman thyroglobulin, P = 0.02; antithyroid peroxidase, P = 0.0018). We found an overall incidence for PPTD of 8.8%. These data demonstrated that women who were thyroid autoantibody positive in the first trimester of pregnancy had a one in three chance of developing PPTD. We observed a significant fall in the T-cell helper/suppressor ratio in normal pregnant women, which was associated with distinct T-cell subset changes. This pregnancy-initiated T-cell regulation reflected an overall suppression of immune function. The development of PPTD was a frequent postpartum event in our population and was associated with a triad of immune markers: a reduction in the normal immune suppression of pregnancy (as indicated by higher T-cell helper/suppressor ratios), enhanced postpartum T-cell activation, and elevated thyroid autoantibodies. The reduction in the degree of immune suppression was, therefore, a major factor in the development of PPTD. Our results define immunological changes that occur in normal pregnancy and distinct immunological abnormalities necessary for the development of PPTD."

http://press.endocrine.org/doi/abs/10.1210/jc.2004-2555 Management of Graves’ Disease during Pregnancy: The Key Role of Fetal Thyroid Gland Monitoring "Background: Fetuses from mothers with Graves’ disease may experience hypothyroidism or hyperthyroidism due to transplacental transfer of antithyroid drugs (ATD) or anti-TSH receptor antibodies, respectively. Little is known about the fetal consequences. Early diagnosis is essential to successful management. We investigated a new approach to the fetal diagnosis of thyroid dysfunction and validated the usefulness of fetal thyroid ultrasonograms. Methods: Seventy-two mothers with past or present Graves’ disease and their fetuses were monitored monthly from 22 wk gestation. Fetal thyroid size and Doppler signals, and fetal bone maturation were determined on ultrasonograms, and thyroid function was evaluated at birth. Thyroid function and ATD dosage were monitored in the mothers. Results: The 31 fetuses whose mothers were anti-TSH receptor antibody negative and took no ATDs during late pregnancy had normal test results. Of the 41 other fetuses, 30 had normal test results at 32 wk, 29 were euthyroid at birth, and one had moderate hypothyroidism on cord blood tests. In the remaining 11 fetuses, goiter was visualized by ultrasonography at 32 wk, and fetal thyroid dysfunction was diagnosed and treated; there was one death, in a late referral, and 10 good outcomes with normal or slightly altered thyroid function at birth. The sensitivity and specificity of fetal thyroid ultrasound at 32 wk for the diagnosis of clinically relevant fetal thyroid dysfunction were 92 and 100%, respectively. Conclusion: In pregnant women with past or current Graves’ disease, ultrasonography of the fetal thyroid gland by an experienced ultrasonographer is an excellent diagnostic tool. This tool in conjunction with close teamwork among internists, endocrinologists, obstetricians, echographists, and pediatricians can ensure normal fetal thyroid function."

http://press.endocrine.org/doi/abs/10.1210/jc.2010-0340 Increased Pregnancy Loss Rate in Thyroid Antibody Negative Women with TSH Levels between 2.5 and 5.0 in the First Trimester of Pregnancy "The increased incidence of pregnancy loss in pregnant women with TSH levels between 2.5 and 5.0 mIU/liter provides strong physiological evidence to support redefining the TSH upper limit of normal in the first trimester to 2.5 mIU/liter."

Abnormalities of maternal thyroid function during pregnancy affect neuropsychological development of their children at 25–30 months "Results: Children of women with subclinical hypothyroidism, hypothyroxinemia and elevated TPOAb titres had mean intelligence scores 8·88, 9·30 and 10·56 points lower than those of the control group (P = 0·008, P = 0·004 and P = 0·001, respectively); mean motor scores were 9·98, 7·57 and 9·03 points lower than those of the controls [P < 0·001, P = 0·007 and P < 0·001, respectively (t-test)]. Unconditional multivariate logistic regression analysis showed that increased maternal serum TSH, decreased maternal serum tT4, and elevated maternal TPOAb titres were separately associated with lower intelligence scores (ORs 15·63, 12·98, and 6·69, respectively) and poorer motor scores (ORs 9·23, 5·52, and 8·25, respectively). Conclusions: Intellectual and motor development of children at 25–30 months of age is separately associated with abnormalities of maternal thyroid at 16–20 weeks gestation. Maternal subclinical hypothyroidism, hypothyroxinaemia or euthyroidism with elevated TPOAb titres were all statistically significant predictors of lower motor and intellectual development at 25–30 months."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2002082/ Thyroid cancer among young women related to prior thyroid disease and pregnancy history. "We conducted an epidemiologic case-control study of thyroid cancer in women aged 40 and under to test the hypothesis that endogenous hormones may relate to the development of this disease, since the only known cause of thyroid cancer, ionizing radiation, does not account for the striking female over male excess. When compared to neighbour controls women with thyroid cancer more often had a history of benign hyperplastic thyroid disease (Relative Risk (RR) = 14.5; P less than 0.01) and more often had ever been pregnant (RR = 2.1; P = 0.04). Both these findings were consistent with findings of previous studies. After eliminating women with a history of hyperplastic thyroid disease from the analysis we found a strong association with miscarriage as the outcome of the first pregnancy (RR = 11.5; P less than 0.01), and we suspect that this factor may be another indicator of thyroid abnormality. An independent and increasing risk was observed with an increase in the total number of pregnancies after excluding women with prior thyroid disease and those whose first pregnancy ended in a miscarriage. The RR for 4 or more pregnancies was 6.3 (P = 0.03). Prior exposure to radiation therapy was not an important factor in our study of young women; this suggests that the emphasis in future studies of thyroid cancer must shift to study other types of risk factors."

http://www.ncbi.nlm.nih.gov/pubmed/12649931 Thyroid and infertility. "Infertility is defined as the inability to conceive after one year of regular intercourse without contraception. The prevalence of infertility is estimated between 12 and 14% and remains stable in recent years. It thus represents a common condition, with important medical, economic and psychological implications. According to a standard protocol infertility evaluation usually identifies different causes, including, male infertility (30%), female infertility (35%), the combination of both (20%), and finally unexplained or "idiopathic" infertility (15%). Female causes of infertility comprise endometriosis, tubal damage and ovulatory dysfunction (OD). Thyroid dysfunction is a condition known to reduce the likelihood of pregnancy and to adversely affect pregnancy outcome. Data on the relationship between thyroid disorders and infertility remain scarce and the association with a particular cause of infertility has not thoroughly been analyzed. In a case-control study we have shown that the relative risk of positive TPO-Abs in infertility due to a female cause and in particular related to endometriosis is significantly increased. Thyroid dysfunction itself is a condition interfering with normal ovarian function and was more frequent in women with positive anti-TPO Abs. We therefore propose that a systematic screening of TSH, free T4 and TPO-Ab could be considered in all women with a female cause of infertility. Prospective follow-up of a cohort of infertile women undergoing assisted reproduction shows a significant increased risk of miscarriage in women with positive anti-TPO Abs compared to women without thyroid auto-immunity after clinical pregnancy is established by the ART procedure. The frequent association of the presence of anti-TPO-Abs and miscarriage is hypothetical explained by the fact that organ specific autoimmune diseases may be secondary to some basic cellular abnormality that directly affects pregnancy outcome. Alternatively, women with thyroid autoimmunity, may experience greater changes in free thyroxine levels during ART and subsequent pregnancy interfering with genital tract physiology and fetal development. Determining the presence of thyroid antibodies before ART procedure is thus useful in identifying women at risk for subsequent clinical miscarriage."

http://www.ncbi.nlm.nih.gov/pubmed/12490077 Thyroid dysfunction and autoimmunity in infertile women. "A prospective study was undertaken in 438 women (ages, 32 +/- 5 years) with various causes of infertility, and in 100 age-matched (33 +/- 5 years) healthy parous controls with the aim of assessing the prevalence of autoimmune thyroid disease (AITD) and hitherto undisclosed alterations of thyroid function. Female origin of the infertility was diagnosed in 45% of the couples, with specific causes including endometriosis (11%), tubal disease (30%), and ovarian dysfunction (59%). Male infertility represented 38% and idiopathic infertility 17% of the couples. Overall, median thyrotropin (TSH) was significantly higher in patients with infertility compared to controls: 1.3 (0.9) versus 1.1 (0.8) mIU/L. Serum TSH above normal (>4.2 mIU/L) or suppressed TSH (<0.27 mIU/L) levels were not more prevalent in the infertile women than in controls. The prevalence of positive thyroid peroxidase antibody (TPO-Ab) was higher in all investigated women of infertile couples, compared to controls (14% vs. 8%), but the difference was not significant. However, in infertility of female origin, a significant higher prevalence of positive TPO-Ab was present, compared to controls: 18% versus 8%. Furthermore, among the female causes, the highest prevalence of positive antibodies was observed in women with endometriosis (29%). When thyroid antibodies were positive, both hypothyroidism and hyperthyroidism were more frequent in all women of infertile couples and in the women with a female infertility cause, compared to women in the same groups but without positive TPO-Ab. The present study shows that in infertile women, thyroid autoimmunity features are significantly more frequent than in healthy fertile controls and this was especially the case for the endometriosis subgroup."

http://www.ncbi.nlm.nih.gov/pubmed/24678319 High Prevalence of Infertility among Women with Graves' Disease and Hashimoto's Thyroiditis. "Objectives. To evaluate the prevalence of infertility in women with Graves' disease (GD) or Hashimoto's thyroiditis (HT) and associated factors. Material and Methods. This cross-sectional study was conducted at the Endocrinology Clinic for Thyroid Autoimmune Diseases, with 193 women aged 18-50 years with GD and 66 women aged 18-60 years with HT. The women were interviewed to obtain data on their gynecological and obstetric history and family history of autoimmune diseases. Their medical records were reviewed to determine the characteristics of the disease and to confirm association with other autoimmune diseases. Infertility was defined as 12 months of unprotected sexual intercourse without conception. Results. The prevalence of infertility was 52.3% in GD and 47.0% in HT. Mean age at diagnosis was 36.5 years and 39.2 years, in GD and HT, respectively. The mean number of pregnancies was lower in women who were 35 years old or younger at diagnosis and was always lower following diagnosis of the disease, irrespective of age. The only variable associated with infertility was a shorter time of the disease in HT. Conclusions. The prevalence of infertility was high in women with GD and HT and affected the number of pregnancies in young women."

http://www.sciencedirect.com/science/article/pii/S1521690X04000119 The regulation of thyroid function during normal pregnancy: importance of the iodine nutrition status "The main change in thyroid function associated with the pregnant state is the requirement of an increased production of thyroid hormone that depends directly upon the adequate availability of dietary iodine and integrity of the glandular machinery. Physiologic adaptation takes place when the iodine intake is adequate, while this is replaced by pathologic alterations when there is a deficient iodine intake. Pregnancy acts typically, therefore, as a revelator of underlying iodine restriction. Iodine deficiency (ID) has important repercussions for both the mother and the fetus, leading to sustained glandular stimulation, hypothyroxinemia and goitrogenesis. Furthermore, because severe ID may be associated with an impairment in the psycho-neuro-intellectual outcome in the progeny—because both mother and offspring are exposed to ID during gestation (and the postnatal period), and because ID is still prevalent today in several European countries—it has been proposed already in the early 1990s that iodine supplements be given systematically to pregnant and breast-feeding women. Particular attention is required to ensure that pregnant women receive an adequate iodine supply, by administering multivitamin tablets containing iodine supplements, in order to achieve the ideal recommended dietary allowance of 200–250 µg iodine/day."

http://online.liebertpub.com/doi/abs/10.1089/thy.2005.15.351 The Thyroid and Pregnancy: A Novel Risk Factor for Very Preterm Delivery "Gravidas with high thyrotropin (TSH) levels had a greater than threefold increase in risk of very preterm delivery. In some analyses, gravidas who tested positive for thyroglobulin antibody at entry to prenatal care also had a better than twofold increased risk of very preterm delivery. There were no significant associations between TSH level or thyroglobulin antibody positivity and the risk of moderately preterm delivery."

Antithyroid antibodies underlying thyroid abnormalities and miscarriage or pregnancy induced hypertension "Results: Elevated antithyroperoxidase (TPO-Ab) and antithyroglobuline (TG-Ab) antibody titres are associated with an increased miscarriage rate. Also, asymptomatic thyroid abnormalities, mainly abnormal echostructure but not antithyroid antibodies, are associated with pregnancy induced hypertension. Conclusion: The presence of thyroid auto-antibodies during pregnancy constitutes a marker of increased risk of miscarriage and poor obstetric prognosis."

http://online.liebertpub.com/doi/abs/10.1089/thy.1998.8.859 Thyroid Hyperfunction During Pregnancy "The present report focuses on the two main causes of hyperthyroidism observed in the pregnant state: Graves' disease (GD) and gestational transient thyrotoxicosis. Together, the prevalence of hyperthyroidism may represent 3% to 4% of all pregnancies, and therefore constitutes an important clinical issue. Concerning GD, the variable presentations of the disease (women under treatment, in remission, or considered cured) and specific alterations occurring in pregnancy are discussed: changes in thyrotropin (TSH) receptor antibody titers, the risk of fetal and neonatal thyrotoxicosis, the outcome of pregnancy in relation to the control of hyperthyroidism, and the treatment of active GD during and after pregnancy with antithyroid drugs. Gestational transient thyrotoxicosis is associated with a direct stimulation of the maternal thyroid gland by human chorionic gonadotropin (hCG), and has been shown to be directly related to both the amplitude and duration of peak hCG values. The syndrome is usually transient, observed at the end of the first trimester, and is frequently associated with emesis. Finally, we propose a global strategy for the systematic screening of hyperthyroidism during pregnancy, based on an algorithm that allows for the diagnosis of both autoimmune and nonautoimmune forms of hyperthyroidism in the pregnant state."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1280346/ Thyroid Hormones in Pregnancy in Relation to Environmental Exposure to Organochlorine Compounds and Mercury "Experimental studies have shown that polychlorinated biphenyls (PCBs) and related chemicals decrease circulating THs during development (Donahue et al. 2004;Ulbrich and Stahlmann 2004; Zoeller et al. 2000). Prenatal or postnatal exposition of humans or animals to PCBs can result in hormonal changes and neurodevelopmental deficits (Jacobson and Jacobson 2002, 2003; Vreugdenhil et al. 2002a, 2002b, 2004). "

http://journals.lww.com/greenjournal/Abstract/1988/09000/Morning_Sickness_and_Thyroid_Function_in_Normal.14.aspx Morning Sickness and Thyroid Function in Normal Pregnancy. "Thyroid function in early normal pregnancy was evaluated with reference to morning sickness using a newly developed free thyroxine (T4) radioimmunoassay and a highly sensitive TSH immunoradiometric assay. A significant increase in serum free T4 and a decrease in serum TSH were observed in early pregnancy relative to the levels in nonpregnant controls. The increased free T4 and hCG and decreased TSH correlated with the severity of morning sickness, and these changes were especially marked in subjects with nausea and vomiting. The individual serum levels of hCG in the pregnant group correlated significantly, directly with the levels of free T4 and inversely with those of TSH. The increased free T4 and decreased TSH in subjects with einesis returned to the normal ranges of nonpregnant controls after improvement of emesis. These data indicate that the thyroid gland is physiologically activated in early pregnancy, possibly by hCG or a related substance, which may induce gestational emesis. On the other hand, an increased level of free T4 and a reduced level of TSH in early normal pregnancy are not indications of thyrotoxicosis and may not necessitate antithyroid drug treatment."

http://press.endocrine.org/doi/abs/10.1210/jcem.87.3.8285 The Effect of Pregnancy on Thyroid Nodule Formation "In conclusion, pregnancy is associated with an increase in the size of preexisting thyroid nodules as well as new thyroid nodule formation. This may predispose to multinodular goiter in later life."

http://acb.sagepub.com/content/38/4/329.short Reference intervals for thyroid hormones in pregnant Chinese women "Free T3 decreased during pregnancy, whereas free T4 initially increased, peaking between 9-13 weeks and then decreased, the decline becoming significant by week 21. TSH mirrored changes in free T4. Conclusion : The gestation-related reference intervals for thyroid hormones should alleviate the misinterpretation of thyroid function in pregnancy."

http://europepmc.org/abstract/MED/15988403 Thyroid disease in pregnancy and childhood."Thyroid function in pregnancy is characterised by a T4 surge at 12 weeks declining thereafter. Serum thyroid hormone concentrations fall in the second half of pregnancy but there are few data on normal reference ranges. Fetal brain development depends on T4 transport into the fetus which in turn depends on sufficient maternal iodine supply..There is increasing evidence that thyroid autoimmunity is associated with fetal loss but the mechanism is unclear and therapy requires carefully conducted studies. While hyperthyroidism in pregnancy is uncommon, effects on both mother and child are critical if untreated. The use of propylthiouracil is recommended together with measurement of TSH receptor antibodies at 36 weeks gestation. Women receiving thyroxine therapy for hypothyroidism or as suppressive therapy should have their dose increased by up to 50% during pregnancy. There are now substantial data to show deleterious effects on child IQ resulting from low maternal T4 (or high TSH) during gestation. Major advances in molecular biology have contributed to elucidation of many genetic causes of congenital hypothyroidism. However, the aetiology of the majority of cases is still unclear and further research is required. The presence of TPO antibodies in about 10% of pregnant women in early gestation is a predictor of an increased incidence of subclinical hypothyroidism during pregnancy and also of postpartum thyroid dysfunction. The latter condition occurs in 5-9% of women and 25-30% progress to permanent hypothyroidism. This review suggests that screening for thyroid function in early pregnancy and levothyroxine intervention therapy for maternal subclinical hypothyroidism should be considered but evidence is awaited. Screening for both thyroid dysfunction and thyroid antibodies ideally at a preconception clinic but certainly in early gestation is recommended."

http://link.springer.com/article/10.2165/00024677-200504010-00004 Thyroid Disorders Associated with Pregnancy "Pregnancy has an effect on thyroid economy with significant changes in iodine metabolism, serum thyroid binding proteins, and the development of maternal goiter especially in iodine-deficient areas. Pregnancy is also accompanied by immunologic changes, mainly characterized by a shift from a T helper-1 (Th1) lymphocyte to a Th 2 lymphocyte state. Thyroid peroxidase antibodies are present in 10% of women at 14 weeks’ gestation, and are associated with (i) an increased pregnancy failure (i.e. abortion), (ii) an increased incidence of gestational thyroid dysfunction, and (iii) a predisposition to postpartum thyroiditis. Thyroid function should be measured in women with severe hyperemesis gravidarum but not in every patient with nausea and vomiting during pregnancy. Graves hyperthyroidism during pregnancy is best managed with propylthiouracil administered throughout gestation. Thyroid-stimulating hormone-receptor antibody measurements at 36 weeks’ gestation are predictive of transient neonatal hyperthyroidism, and should be checked even in previously treated patients receiving thyroxine. Postpartum exacerbation of hyperthyroidism is common, and should be evaluated in women with Graves disease not on treatment. Radioiodine therapy in pregnancy is absolutely contraindicated. Hypothyroidism (including subclinical hypothyroidism) occurs in about 2.5% of pregnancies, and may lead to obstetric and neonatal complications as well as being a cause of infertility. During the last few decades, evidence has been presented to underpin the critical importance of adequate fetal thyroid hormone levels in order to ensure normal central and peripheral nervous system maturation. In iodine-deficient and iodine-sufficient areas, low maternal circulating thyroxine levels have been associated with a significant decrement in child IQ and development. These data suggest the advisability of further evaluation for a screening program early in pregnancy to identify women with hypothyroxinemia, and the initiation of prompt treatment for its correction. Hypothyroidism in pregnancy is treated with a larger dose of thyroxine than in the nonpregnant state. Postpartum thyroid dysfunction (PPTD) occurs in 50% of women found to have thyroid peroxidase antibodies in early pregnancy. The hypothyroid phase of PPTD is symptomatic and requires thyroxine therapy. A high incidence (25–30%) of permanent hypothyroidism has been noted in these women. Women having transient PPTD with hypothyroidism should be monitored frequently, as there is a 50% chance of these patients developing hypothyroidism during the next 7 years."

http://online.liebertpub.com/doi/abs/10.1089/1050725041692828 Thyroid Peroxidase Antibodies in Early Pregnancy: Utility for Prediction of Postpartum Thyroid Dysfunction and Implications for Screening "Thyroid peroxidase antibodies (TPOAb) in pregnancy are a marker for postpartum (PPTD) and long-term thyroid dysfunction, with variable sensitivity and specificity in PPTD prediction. To test its utility in prediction, we recruited 308 TPOAb-positive (147 developed PPTD (PPTD group) and 161 remained euthyroid [PPTE group]) and 102 TPOAb-negative women (none developed PPTD), in early pregnancy (median, 18; range, 9–19 weeks' gestation). TPOAb levels were higher in the PPTD group (median) (125.2 kIU/L; p < 0.001), and in its hypothyroid (162.4 kIU.; p < 0.0001), hyperthyroid (114.2 kIU/L; p < 0.007), and biphasic (105.1 kIU/L; p < 0.02) variants, compared to the PPTE group (66.7 kIU/L) The incidence of PPTD was significantly higher with TPOAb levels above 58.2 kIU/L (early pregnancy versus postpartum; relative risk, 1.37 [95% confidence interval {CI} 1.17–1.61] versus 0.78 [95% CI 0.5–1.2]) compared to levels below. The integrated postpartum TPOAb response was higher in the PPTD group (median) (159 kIU/L per week) and its variants (hypothyroid; 199 kIU/L per week; biphasic, 180 kIU/L per week; hyperthyroid, 120 kIU/L per week), compared to the PPTE group (86 kIU/L per week p < 0.004). Median early pregnancy TPOAb levels in the PPTD and PPTE groups correlated well with the postpartum antibody response (r = 0.58, p < 0.001). The sensitivity of TPOAb in PPTD prediction was 100% (early pregnancy and postpartum), specificity 62% (early pregnancy) versus 41% (postpartum) and positive predictive value 48% (early pregnancy and postpartum). The timing of TPOAb testing, the sensitive assay used and the absence of PPTD in TPOAb-negative subjects contributed to this high sensitivity. We recommend TPOAb in early pregnancy as a useful predictor of PPTD, particularly in populations where PPTD does not occur in TPOAb-negative women."

http://online.liebertpub.com/doi/abs/10.1089/105072501753271743 Autoimmune Thyroid Disease in Pregnancy and the Postpartum Period: Relationship to Spontaneous Abortion "The aim of this study was to determine the prevalence of autoimmune thyroid disease and the risk of miscarriage in autoimmune thyroid antibody (ATA)-positive women. Eight hundred seventy-six subjects completed the study, and 12.3% were thyroid antibody-positive (4.5% tested positive for both thyroid peroxidase antibody [TPO-Ab] and thyroglobulin autoantibody [Tg-Ab], 4.79% were TPO-Ab-positive only, and 3.1% were Tg-Ab-positive only). Fifty percent of the ATA-positive women and 14.1% of the ATA-negative group had a history of spontaneous abortion. Forty-eight of the ATA-positive women developed postpartum autoimmune thyroid dysfunction (PATD). Of these, 50% had hypothyroidism alone, 31.3% had transient hyperthyroidism followed by hypothyroidism, and 18.8% had transient thyrotoxicosis alone. Of the 48 PATD subjects, 12.5% developed persistent hypothyroidism. None of the ATA-negative women developed any form of thyroid dysfunction. The thyroid-stimulating hormone (TSH) levels in the ATA-positive group were significantly higher than those in the ATA-negative group, and only the ATA-positive women with a history of abortion had significantly higher TSH and lower free thyroxine (FT4) concentrations than the other subgroups. The results revealed a 5.5% prevalence rate for PATD in the study population. In addition to TPO-Ab, Tg-Ab is a useful marker for autoimmune thyroiditis."

http://europepmc.org/abstract/MED/3323500 Thyroid gland size in pregnancy. An ultrasound and clinical study. "We estimated the size of the thyroid gland by palpation and measured thyroid gland volume with ultrasound in the immediate postpartum period and six months after delivery in 16 women. The 13% reduction in the mean thyroid gland volume detected six months after delivery implied that the thyroid gland enlarges slightly during pregnancy. Physical examination, however, did not detect any goiters during the immediate postpartum period and did not identify a change in thyroid gland size six months after delivery. The thyroid gland enlargement that occurs during pregnancy is not large enough to be detected by physical examination. We urge physicians to discard the commonly held notion that goiter frequently develops during pregnancy."

http://press.endocrine.org/doi/abs/10.1210/jcem-60-4-678 Components of the Total Serum Thyroid Hormone Concentrations during Pregnancy: HighFree Thyroxine and Blunted Thyrotropin (TSH) Response to TSH Releasing Hormone in the First Trimester "The distribution of thyroid hormones between free solution and their several protein-binding sites during pregnancy was studied under physiological conditions of temperature and pH. Single serum specimens were obtained from individual women at different stages of pregnancy. Duringthe first 5 weeks of pregnancy, mean serum free T4 and free T3 concentrations were 50% higher than in nonpregnant women or women during (the third trimester. Free T4 was increased significantly through- (out the first trimester, but because of wide variance, free T3 wassignificantly above control values only during the first 5 weeks. Free T4 and free T3 concentrations decreased to control levels in the third trimester. These changes in free T4 concentrations are consistent with a weak thyrotropic action of hCG, which attained maximal concentrations early in the first trimester and then decreased markedly in the second and third trimesters. TRH testing of women scheduled for abortion in the first and second trimesters revealed marked inhibition of TSH response o t TRH in those first trimester women who had elevated free T4 concentrations. (The percent free T4 did not decrease during the first 5 weeks, but then declined progressively to term as T4-binding globulin)(TBG) affinity, defined as the product of the capacity and affinity constant, progressively increased. T4 bound to TBG T4 TBG increased from early in the first trimester to term, and (then decreased in postterm pregnancy and postpartum. T4 bound to prealbumin T4-PA) and to albumin T4-Alb) decreased significantly in the third trimester compared with either control or first trimester concentrations. The concentration of free T3 was positively correlated with T4-PA (r = 0.25) and T4-Alb (r = 0.31), but not with free T4 (r= 0.18) or T4-TBG (r = -0.30) concentrations. These results suggest that 1) only the high concentrations of hCG present in the first trimester of pregnancy have a thyro-tropic effect in excess of normal levels of TSH, and this can be sufficient to suppress the TSH response to TRH; 2) hepatic TBG secretion continues to respond to the continuously rising (estrogen levels throughout pregnancy; and 3) T4-PA and T4-Alb,)but not freeT4 of T4-TBG, are possible precursors for the) extrathyroidal generation of T3. {J Clin Endocrinol Metab 60: 678,1985)"

http://www.eje-online.org/content/160/1/1.short Management of Graves' hyperthyroidism in pregnancy: focus on both maternal and foetal thyroid function, and caution against surgical thyroidectomy in pregnancy"Major threats to optimal foetal thyroid function are inadequate or over aggressive antithyroid drug therapy of the mother. It should be taken into account that antithyroid drugs tend to block the foetal thyroid function more effectively than the maternal thyroid function, and that levothyroxin (L-T4) given to the mother will have only a limited effect in the foetus.

Surgical thyroidectomy of patients with Graves' hyperthyroidism does not lead to immediate remission of the autoimmune abnormality, and the combination thyroidectomy+withdrawal of antithyroid medication+L-T4 replacement of the mother involves a high risk of foetal hyperthyroidism. Conclusion: Antithyroid drug therapy of pregnant women with Graves' hyperthyroidism should be balanced to control both maternal and foetal thyroid function. Surgical thyroidectomy of a pregnant woman with active disease may lead to isolated foetal hyperthyroidism."

http://europepmc.org/abstract/MED/16284437 Maternal thyroid function during pregnancy and puerperal period. "It has been noted that hypothyroidism in pregnant women can adversely affect the children's subsequent psychoneurotic development. Also, transient elevation of serum free thyroxine is occasionally seen in the first trimester of normal pregnancy. However, normal thyroid function during pregnancy and the puerperal period has not been clearly defined in Japan. The aim of this study was to assess maternal thyroid function during pregnancy and puerperal period in Japan. The concentrations of thyroid stimulating hormone (TSH), free triiodo-thyronine (free T(3)), free thyroxine (free T(4)) and thyroid binding capacity (TBC) of 522 normal pregnant and puerperal women (119 in the first trimester; 132 in the second trimester; 135 in the third trimester and 136 in the early puerperium) were measured by electrochemiluminescence immunoassay. We compared the measured data with those of healthy nonpregnant control. Twenty-six (21.8%) of 119 women in the first trimester had lower TSH levels and 23 (16.9%) of 136 women in the early puerperium had higher TSH levels than the normal range of healthy nonpregnant controls. Free T(3) gradually decreased during pregnancy, although it remained within the normal control range. Eight (6.7%) of 119 women in the first trimester had high free T(4) levels, which gradually decreased during pregnancy. Sixty (44.4%) of 135 women in the third trimester had low free T(4) levels. The values of TBC in the second trimester increased compared with the first trimester and did not change in the third trimester and decreased after delivery. There were no correlations between maternal TSH and levels of thyroid hormones (free T(3) or free T(4)), except for TSH and free T(4) in the first trimester. In conclusion, we showed that maternal thyroid function, especially TSH and free T(4), changed during the course of pregnancy. In assessing the thyroid function associated with pregnancy, one needs to keep in mind the tendency toward low free T(4) levels in the third trimester and high TSH levels in the early puerperal period."

http://journals.lww.com/greenjournal/Abstract/1990/05000/Physiologic_Thyroid_Activation_in_Normal_Early.10.aspx Physiologic Thyroid Activation in Normal Early Pregnancy is Induced by Circulating hCG. "In normal early pregnancy, serum free thyroxine (T4) increases and serum TSH decreases, indicating that the thyroid gland is activated physiologically. To identify the factor responsible for this thyroid activation, we measured the serum thyroid-stimulating activity in comparison with the serum level of hCG in 39 normal women in early pregnancy. Serum thyroid-stimulating activity was measured by a sensitive cyclic adenosine 3'5'-monophosphate (cAMP) accumulation assay using a rat thyroid cell line (FRTL-5). Thyroid- stimulating activity was detected in 37 women (95%), and the activities of individuals correlated positively with their serum free T4 levels (r=0.474; P<.01) and negatively with their serum TSH levels (r=-0.376; P<.02). Moreover, serum thyroid-stimulating activity correlated closely with the serum hCG level (r=0.741; P<.001), but was completely abolished by pre-treatment of the sera with hCG antibodies. These data indicate that in normal early pregnancy, the thyroid gland is physiologically activated by serum hCG, which has intrinsic thyroid-stimulating activity."

http://press.endocrine.org/doi/abs/10.1210/jcem.85.2.6391 Opposite Variations in Maternal and Neonatal Thyroid Function Induced by Iodine Supplementation during Pregnancy "Whereas the consequences of extremes in iodine intake are well described, much less is known about the effect of more moderate variations in maternal iodine intake on fetal thyroid function. The present study performed in Denmark with mild to moderate iodine deficiency dealt with the effect of maternal iodine supplementation on thyroid function in the mother at term and in the fetus/neonate. Serum was collected consecutively from pregnant women at term (n = 144) and from cord blood (n = 139). Forty-nine women had a regular intake of vitamin and mineral tablets with iodine (150 µg/day) during pregnancy, and 95 took no artificial iodine supplementation. Iodine supplementation (+I) induced opposite variations in thyroid function in the mother and the fetus. In +I mothers, TSH was 7.6% lower than in mothers with no supplementation (P < 0.05). In cord blood, on the contrary, TSH was 27.3% higher in the +I group (P < 0.05). The variations were caused by opposite shifts in TSH frequency distribution in mothers and neonates. The association between iodine supplementation and high serum TSH in the neonates was further substantiated by an inverse correlation between thyroglobulin and TSH in cord blood (P < 0.001), whereas no specific pattern was observed in the mothers. High serum thyroglobulin was a marker of low iodine intake in both mothers and neonates. The results suggest that the fetal thyroid, at least in areas of mild iodine deficiency, is more sensitive to the inhibitory effect of iodine than hitherto anticipated."

http://press.endocrine.org/doi/abs/10.1210/jcem.87.4.8421 Selenium Supplementation in Patients with Autoimmune Thyroiditis Decreases Thyroid Peroxidase Antibodies Concentrations "In areas with severe selenium deficiency there is a higher incidence of thyroiditis due to a decreased activity of selenium-dependent glutathione peroxidase activity within thyroid cells. Selenium-dependent enzymes also have several modifying effects on the immune system. Therefore, even mild selenium deficiency may contribute to the development and maintenance of autoimmune thyroid diseases. We performed a blinded, placebo-controlled, prospective study in female patients (n = 70; mean age, 47.5 ± 0.7 yr) with autoimmune thyroiditis and thyroid peroxidase antibodies (TPOAb) and/or Tg antibodies (TgAb) above 350 IU/ml. The primary end point of the study was the change in TPOAb concentrations. Secondary end points were changes in TgAb, TSH, and free thyroid hormone levels as well as ultrasound pattern of the thyroid and quality of life estimation. Patients were randomized into 2 age- and antibody (TPOAb)-matched groups; 36 patients received 200 µg (2.53 µmol) sodium selenite/d, orally, for 3months, and 34 patients received placebo. All patients were substituted with l-T4 to maintain TSH within the normal range. TPOAb, TgAb, TSH, and free thyroid hormones were determined by commercial assays. The echogenicity of the thyroid was monitored with high resolution ultrasound. The mean TPOAb concentration decreased significantly to 63.6% (P = 0.013) in the selenium group vs. 88% (P = 0.95) in the placebo group. A subgroup analysis of those patients with TPOAb greater than 1200 IU/ml revealed a mean 40% reduction in the selenium-treated patients compared with a 10% increase in TPOAb in the placebo group. TgAb concentrations were lower in the placebo group at the beginning of the study and significantly further decreased (P = 0.018), but were unchanged in the selenium group. Nine patients in the selenium-treated group had completely normalized antibody concentrations, in contrast to two patients in the placebo group (by ?2 test, P = 0.01). Ultrasound of the thyroid showed normalized echogenicity in these patients. The mean TSH, free T4, and free T3 levels were unchanged in both groups. We conclude that selenium substitution may improve the inflammatory activity in patients with autoimmune thyroiditis, especially in those with high activity. Whether this effect is specific for autoimmune thyroiditis or may also be effective in other endocrine autoimmune diseases has yet to be investigated."

http://www.journalofanimalscience.org/content/76/4/1204.short Effect of level and source of dietary selenium on concentrations of thyroid hormones and immunoglobulins in beef cows and calves. "Our objective was to determine the effect of level and chemical form of dietary selenium on productivity of beef cows, concentrations of triiodothyronine (T3), and thyroxine (T4) in plasma, and immunoglobulins (IgG and IgM) in plasma and colostrum of cows. Pregnant cows (n = 60) were randomly allocated among four dietary treatments of 20, 60, or 120 ppm Se as selenite and 60 ppm as selenomethionine from selenized yeast (SeY) in salts offered free-choice. Treatments began 90 d prepartum and continued through the second parturition. Treatments did not affect the final body weights of cows or birth weights or weaning weights of calves. At parturition, cows given salt with 20 ppm Se as selenite had lower (P < . 05) concentrations of Se in blood than cows with access to higher-Se salts. Treatments affected (P < .01) the concentration of T3 and the ratio of T3:T4 in plasma of cows. The concentration of T3 in plasma of cows with access to salt with 20 ppm Se was 14% lower than that in cows supplemented with 60 ppm Se as selenite or SeY. Plasma IgG in cows and calves, colostrum, and Se concentrations in colostrum, casein, and whey were lowest (P < .01) for cows given salt with only 20 ppm Se. Thus, salts with concentrations of 60 and 120 ppm Se improved measures of Se status in cows and calves. Consideration should be given to the concentrations of T3 and IgG when determining the nutritional requirements for Se in cattle."

http://www.nrcresearchpress.com/doi/abs/10.1139/y91-243#.U4d3C_ldW9R The role of selenium in thyroid hormone metabolism "In animals, decreases in selenium-containing glutathione peroxidase activity and the resultant impairment of peroxide metabolism can account for many, but not all of the biochemical and clinical changes caused by selenium deficiency. Recently, however, type I iodothyronine 5'-deiodinase has also been shown to be a selenium-containing enzyme. This explains the impairment of thyroid hormone metabolism caused by selenium deficiency in animals with a normal vitamin E status. Since iodothyronine 5'-deiodinases are essential for the production of the active thyroid hormone 3,5,3'-triiodothyronine, some of the consequences of selenium deficiency may result from thyroid changes rather than inability to metabolise peroxides. In particular, the impaired thyroid hormone metabolism may be responsible for decreased growth and resistance to cold stress in selenium-deficient animals. A further consequence of the role of selenium in thyroid hormone metabolism is the exacerbation of some of the thyroid changes in iodine deficiency by a concurrent selenium deficiency. Selenium status may therefore have a major influence on the outcome of iodine deficiency in both human and animal populations"

http://link.springer.com/article/10.1007/BF02917202 Selenium concentrations in the human thyroid gland "Recently, we found that prediagnostic serum selenium concentration was significantly lower for cases developing thyroid cancer (n=43) than for controls. We assumed that redistribution of serum selenium into the affected tissue took place in the prediagnostic period. The present study was carried out to determine the physiological concentration of selenium in the thyroid, since very few data are available in the literature. The concentrations of selenium in the thyroid (n=45) and liver samples from Norwegians who had died because of acute illness or accidents were determined by hydride generation atomic absorption spectrometry. The mean selenium concentration was found to be 0.72±0.44 µg/g in the thyroid and 0.45±0.11 µg/g in the liver tissue. The surprisingly high concentration of selenium in apparently normal thyroids indicates that selenium has important functions in this organ. The remarkably broad range, together with the observation that no significant correlation exists between thyroid and liver concentrations, suggest that factors other than the selenium status are important determinants for the selenium concentration in the thyroid gland. This observation is consistent with our hypothesis that in carcinogenesis, prediagnostic processes influence the serum-/thyroid-ratio of selenium."

http://europepmc.org/abstract/MED/8767511 Thyroid hormone deiodinases--a selenoenzyme family acting as gate keepers to thyroid hormone action. "Development and tissue-specific deiodination of thyroid hormone leads to both activation of the prohormone thyroxine to the thyromimetically active T3 as well as to inactivation of T3 and its conjugates or inactivation of T4 to yield potential regulatory active rT3. At least three deiodinase isoenzymes have so far been characterized and cloned, and the deiodinase isozymes represent a new family of eukaryotic selenoproteins for which an enzyme function could be assigned. Selenium status apparently regulates the expression of these deiodinase isozymes to different extent indicating that a hierarchy of selenium incorporation exists for those enzymes. Currently, it appears that selenium deficiency does not affect expression of type II 5'-deiodinase or 5-deiodinase to a marked extent in vivo whereas type I 5'-deiodinase at least in liver and kidney is reduced in severe selenium deficiency. However, daily selenium intake in normal mideuropeans already saturates the requirement for the expression of the deiodinase isoenzymes. So far, only reduced expression of 5'-D I and decreased T 3 production has been observed in specific diets such as for PKU or in cystic fibrosis, where transport of ions (iodide, selenite?) might be affected. Further alterations of T3 production by 5'-D I activity are observed under the conditions of the low T3 syndrome, which comprise a broad spectrum of clinical disorders from carbohydrate withdrawal to intensive care patients. It is not yet clear if seleniumsupplementation or T3 treatment is beneficial to these patients. The marked tissue-specificity of expression of the deiodinases requires more detailed examinations on the relation between these enzymes and the expression of thyroid hormone action, which is mediated by the nuclear T3 receptor family or receptors and signal transduction molecules in the mitochondria, plasma membrane, orcytoskeleton. The location of the deiodinase enzymes either at the inner side of the plasma membraneor the cytosolic side of the endoplasmic reticulum positions these enzymes to a strategically important location enabling them to act as gate-keepers to the nuclear receptors. Similar to other enzymes involved in the activation or inactivation of compounds with hormone or signalling function, the deiodinases are key elements in the intracrine regulation of hormone activation in target tissues or inactivation in non-target tissues. Therefore, a detailed molecular, cell biological and physiological analysis of the function, regulation and gene structure of these enzymes is required before adevelopment of tissue- or enzyme-specific pharmacological intervention is possible. Nevertheless, first data indicate that reduced 5'-deiodinase type I expression in tumor tissues can be re-induced by treatment with retinoids at least in follicular thyroid carcinoma. Further studies are needed to prove thatretinoids might be a useful therapeutic tool for re-differentiation therapy of thyroid carcinoma which are inaccessible to surgical intervention or lack radio-iodide uptake and storage. The important function and regio- and cell-specific expression of deiodinase isozymes in the central nervous system is far from being understood. Current first evidence suggests a close interaction between thyroid hormone deiodination, thyroid hormone concentration, and expression of thyroid hormone responsive genes in the adult brain as well as tight regulation and interaction between thyroid hormone metabolism and neurotransmitter synthesis release and action."

http://press.endocrine.org/doi/abs/10.1210/jc.2006-1821 The Influence of Selenium Supplementation on Postpartum Thyroid Status in Pregnant Women with Thyroid Peroxidase Autoantibodies "Context: Pregnant women who are positive for thyroid peroxidase antibodies [TPOAb(+)] are prone to develop postpartum thyroid dysfunction (PPTD) and permanent hypothyroidism. Selenium (Se) decreases thyroid inflammatory activity in patients with autoimmune thyroiditis. Objective: We examined whether Se supplementation, during and after pregnancy, influences the thyroidal autoimmune pattern and function. Design: This was a prospective, randomized, placebo-controlled study. Setting: The study was conducted in the Department of Obstetrics and Gynecology and Department of Endocrinology. Patients: A total of 2143 euthyroid pregnant women participated in the study; 7.9% were TPOAb(+). Interventions: During pregnancy and the postpartum period, 77 TPOAb(+) women received selenomethionine 200 µg/d (group S1), 74 TPOAb(+) women received placebo (group S0), and 81 TPOAb(-) age-matched women were the control group (group C). Main Outcome Measures: We measured the prevalence of PPTD and hypothyroidism. Results: PPTD and permanent hypothyroidism were significantly lower in group S1 compared with S0 (28.6 vs. 48.6%, P < 0.01; and 11.7 vs. 20.3%, P < 0.01). Conclusion: Se supplementation during pregnancy and in the postpartum period reduced thyroid inflammatory activity and the incidence of hypothyroidism."

http://online.liebertpub.com/doi/abs/10.1089/thy.2006.16.455 The Role of Selenium in Thyroid Autoimmunity and Cancer "The essential micronutrient selenium (Se) occurs in the form of the amino acid selenocysteine in selenoproteins which exert various effects, while maintaining the cell reduction-oxidation balance. The discovery that all three deiodinases that convert thyroxine (T4) into triiodothyronine (T3) contain selenocysteine illustrates how the production of the active thyroid hormone is dependent on Se status. The selenoenzyme families of glutathione peroxidases (GPx) and thioredoxin reductases (TRx) possess powerful antioxidant properties and form a complex defense system that protects thyrocytes from oxidative damage. Se supplementation in patients with autoimmune thyroiditis seems to modify the immune response, probably by enhancing plasma GPx activity and decreasing excess levels of hydrogen peroxide. However, the enhancement of immunocompetence may also be the result of the synergistic action of various selenoproteins and not exclusively of GPx. There is evidence supporting considerable oxidative stress in Graves' disease where Se supplementation, because of its free radical scavenging properties, may increase the enzymatic antioxidant activity. TRx has been found significantly elevated in GD revealing its involvement in the pathogenesis of this condition and representing a potential future target for therapeutical intervention. Low Se serum levels have also been associated with increased risk of thyroid cancer and may play a role in carcinogenesis. It is noteworthy, that the Food and Drug Administration has recently determined that there is sufficient evidence to warrant a qualified health claim for Se and cancer. Furthermore, the recent discovery that defects in the SECIS-binding protein 2 (SBP2), which is an indispensable protein for the incorporation of Se into the selenoproteins, result in thyroid dysfunction, together with the recognition of the many roles of selenoprotein P in Se distribution and storage in the human body, reveal not only the indispensability of Se and the selenoproteins as essential factors in thyroid metabolism and pathogenesis, but open up new prospects for enhanced treatment."

http://ajcn.nutrition.org/content/57/2/244S.short Selenium and the thyroid: how the relationship was established. "Several hypotheses concerning consequences of selenium deficiency on iodine metabolism can be proposed on the basis of experimental studies in rats and from epidemiological and experimental studies in humans. By decreasing intracellular GSH peroxidase activity, selenium deficiency may increase hydrogen peroxide (H2O2) supply and lead over several weeks to the thyroid atrophy observed in myxoedematous cretins. By improving thyroid hormone synthesis and by decreasing peripheral thyroxin (T4) deiodination, selenium deficiency could protect fetal brain T4 supply and thus prevent neurologic cretinism. Selenium deficiency may protect against iodine deficiency by decreasing T4 metabolism--and thus iodide leakage and--perhaps also by increasing H2O2 supply and thyroid hormone synthesis and thus thyroid efficiency."

http://ije.oxfordjournals.org/content/18/1/45.short Prediagnostic Serum Selenium in a Case-Control Study of Thyroid Cancer "Sera from 43 persons who developed thyroid cancer on an average 4.8 years after blood sampling were compared with sera from controls. Three controls per case matched for sex, age, place of residence and year of blood sampling, with regard to serum selenium and serum copper. Cases were significantly lower in serum selenium than controls, and the estimated odds ratio of thyroid cancer increased from 1 for levels=1.65 µmol/l, to 6.1 for levels 1.26–1.64 µmol/l, to 7.7 for levels =1.25 µmol/l. When time from blood sampling to diagnosis of the case was considered, it could be shown that the protective effect of high serum selenium concentrations was restricted to the last (<7) years prior to the diagnosis of thyroid cancer. The serum selenium concentration of cases tended to decrease relative to controls the shorter time was from blood sampling to the diagnosis. There was no difference between cases and controls with regard to serum copper."

http://ajcn.nutrition.org/content/40/1/26.short Zinc, copper, manganese, and selenium metabolism in thyroid disease. "This study was designed to evaluate trace metal metabolism in adults with thyroid diseases. Erythrocyte zinc values were significantly lower than normal in hyperthyroidism and higher in hypothyroidism. A significantly higher than normal urinary excretion of zinc was observed in hyperthyroidism. The mean concentrations of plasma and erythrocyte copper were significantly above normal in hyperthyroidism. Plasma selenium levels were significantly lower than normal in hyperthyroidism. No statistically significant difference was found in plasma zinc, erythrocyte manganese, or urine copper values between patients with thyroid diseases and healthy controls. The erythrocyte manganese content correlated well with thyroxine and triiodothyronine levels. Plasma prealbumin and retinol-binding protein correlated well with the erythrocyte zinc content but not with plasma zinc levels. There was no correlation between erythrocyte superoxide dismutase activity and erythrocyte copper or zinc concentrations. The results of this study suggest that the metabolism of zinc, copper, manganese, and selenium is abnormal in thyroid diseases." http://mefanet.upol.cz/BP/2005/2/329.pdf EFFECT OF LONG-TERM ADMINISTRATION OF ARSENIC(III) AND BROMINE WITH AND WITHOUT SELENIUM AND IODINE SUPPLEMENTATION ON THE ELEMENT LEVEL IN THE THYROID OF RAT "The exposition of rat to arsenic or bromine causes the accumulation of these elements in the thyroid gland (~18 ppm of As, ~90 ppm of Br) and signi?cantly a?ects iodine and selenium concentration in the thyroid. In iodine and/or selenium supplemented rats the bromine intake into the thyroid was lowered to ~50% of the level in unsupplemented animals. Also selenium thyroid level elevated due to KBr administration was lowered by iodine supplementation in the diet. The accumulation of arsenic in the thyroid was not in?uenced by selenium or iodine supplementation; however, As(III) administration increased iodine thyroid level and suppressed selenium thyroid level in selenium or iodine supplemented group of animals."

http://link.springer.com/article/10.1385/BTER:88:1:25 Concentration of selenium in the whole blood and the thyroid tissue of patients with various thyroid diseases "We investigated the possible differences between the concentrations of selenium in the whole blood and thyroid tissue of patients with thyroid disease. The study comprises 41 women with nodular goiter, 19 women and 2 men with thyroid cancer, 18 women with Graves’ disease, and 7 women with thyroiditis. The concentration of selenium was determined by the TRXRF method. The lowest mean selenium level was achieved in the whole blood of women with Graves’ disease and the highest in the whole blood of healthy people. In the thyroid cancer tissue, we found the lowest concentration of selenium and the highest in the thyroid gland of women with nodular goiter and Graves’ disease. The low selenium levles in the thyroid tissue may increase thyroid cancer risk."

http://www.ncbi.nlm.nih.gov/pubmed/3222543 Thyroid hormone concentrations in selenium deficient and selenium sufficient cattle. "Selenium deficient calves when compared to selenium supplemented calves had increased plasma thyroxine concentrations and decreased plasma tri-iodothyronine concentrations. These changes in the selenium deficient calves were accompanied by significant increases in plasma urea and creatinine concentrations and decreased plasma alkaline phosphatase activity. The demonstration that low selenium status can cause imbalances in thyroid hormone metabolism may provide an explanation for some of the effects of the deficiency."

http://link.springer.com/article/10.1007/BF02790145 Selenium, zinc, and thyroid hormones in healthy subjects "Iodothyronine 5' deiodinase, which is mainly responsible for peripheral T3 production, has recently been demonstrated to be a selenium (Se)-containing enzyme. The structure of nuclear thyroid hormone receptors contains Zinc (Zn) ions, crucial for the functional properties of the protein. In the elderly, reduced peripheral conversion of T4 to T3 with a lower T3/T4 ratio and overt hypothyroidism are frequently observed. We measured serum Se and RBC GSH-Px (as indices of Se status), circulating and RBC Zinc (as indices of Zn status), thyroid hormones and TSH in 109 healthy euthyroid subjects (52 women, 57 men), carefully selected to avoid abnormally low thyroid hormone levels induced by acute or chronic diseases or calorie restriction. The subjects were subdivided into three age groups. To avoid under- or malnutrition conditions, dietary records were obtained for a sample of 24 subjects, randomly selected and representative of the whole population for age and sex. Low T3/T4 ratios and reduced Se and RBC GSH-Px activity were observed only in the older group. A highly significant linear correlation between the T3/T4 ratio and indices of Se status was observed in the older group of subjects (r=0.54;p<0.002, for Se;r=0.50;p<0.002, for RBC GSH-Px). Indices of Zn status did not correlate with thyroid hormones, but RBC Zn was decreased in older as compared with younger subjects. We concluded that reduced peripheral T4 conversion is related to impaired Se status in the elderly."

http://www.tandfonline.com/doi/abs/10.1080/00039896.1995.9940394#.U4d8O_ldW9Q Age Dependency of Selenium and Cadmium Content in Human Liver, Kidney, and Thyroid "Selenium and cadmium concentrations were investigated in 60 autopsy tissue samples obtained from fetal life up to adulthood (defined in this study as 25–87 y of age) in Styria, a moderately industrialized region in Austria that has a low selenium supply. During the first 2 y after birth, median liver selenium concentrations were slightly lower (i.e., 1.5 nmol/g wet weight) than concentrations found in fetal life (i.e., 2.9 nmol/g) and adulthood (2.1 nmol/g). Whereas in the fetal period median selenium content in the kidney cortex (2.1 nmol/g) and the thyroid gland (1.6 nmol/g) was lower than that found in the liver, the reverse was true for adults (i.e., kidney, 5.5 nmol/g; thyroid, 4.3 nmol/g). Tissue cadmium concentrations approached 0 during gestation. Accumulation in the kidney and liver commenced immediately after birth. In the thyroid gland of adults, significantly higher concentrations of cadmium were found. Median concentrations in adults showed no statistical significant age dependency (i.e., liver, 7.6 nmol/g; kidney, 59.8 nmol/g; thyroid, 11.2 nmol/g). In summary, the data revealed very low tissue selenium concentrations and low cadmium burdens for the Styrian population that was not exposed occupationally."

http://ajcn.nutrition.org/content/89/6/1808.short Effects of selenomethionine supplementation on selenium status and thyroid hormone concentrations in healthy adults "Background: Selenium, a potential cancer prevention agent currently being tested against prostate cancer in the Selenium and Vitamin E Cancer Prevention Trial (SELECT), plays an integral role in thyroid metabolism. The effects of long-term selenium supplementation on thyroid hormone concentrations are unknown. Objective: The objective was to investigate the effects of long-term selenium supplementation on thyroid hormone concentrations. Design: Twenty-eight healthy adults took 200 µg selenomethionine/d for 28 mo. The thyroid hormones triiodothyronine (T3), thyroxine (T4), and thyrotropin (TSH) were measured in plasma for 4 mo before supplementation and quarterly during supplementation. The assay methods were changed midstudy; the results of the 2 methods were not comparable. Therefore, one analysis was conducted based on the results of the first method, and a second analysis was based on all of the data, adjusted for the change. Serial data collection permitted a test for trends rather than simply a difference between initial and final values. Results: By 9 mo, mean (±SEM) plasma selenium concentrations had increased from 1.78 ± 0.07 µmol/L at baseline to 2.85 ± 0.11 µmol/L for men and from 1.64 ± 0.04 to 3.32 ± 0.1.2 µmol/L for women. T3 concentrations in men increased 5% per year (P = 0.01). T4 and TSH concentrations were unchanged. Conclusions: Selenium supplementation produced no clinically significant changes in thyroid hormone concentrations. A small but statistically significant increase in T3 concentrations was noted in men, with no corresponding decreases in TSH. A subset of SELECT subjects might be monitored periodically for changes during long-term selenium supplementation."

http://online.liebertpub.com/doi/abs/10.1089/thy.2007.0040 Effects of 12 Months Treatment with l-Selenomethionine on Serum Anti-TPO Levels in Patients with Hashimoto's Thyroiditis "Objective: We studied the effects of selenium (Se) treatment on serum anti–thyroid peroxidase (TPO) levels in Greek patients with Hashimoto's thyroiditis (HT). Design: We prospectively studied 80 women with HT, median age 37 (range 24–52) years, for 1 year. All patients received 200 µg Se in the form of l-selenomethionine orally for 6 months. At the end of the 6-month period, 40 patients continued taking 200 µg Se (Group A) and 40 patients stopped (Group B). Serum thyrotropin (TSH), free triiodothyronine (FT3), free thyroxine (FT4), anti-TPO, and anti-thyroglobulin (Tg) levels were measured at baseline and at the end of each 3-month period. Main outcome: There was a significant reduction of serum anti-TPO levels during the first 6 months (by 5.6% and 9.9% at 3 and 6 months, respectively). An overall reduction of 21% (p < 0.0001) compared with the basal values was noted in Group A. In Group B, serum anti-TPO levels were increased by 4.8% (p < 0.0001) during the second 6-month period. Conclusions: Our study showed that in HT patients 6 months of Se treatment caused a significant decrease in serum anti-TPO levels, which was more profound in the second trimester. The extension of Se supplementation for 6 more months resulted in an additional 8% decrease, while the cessation caused a 4.8% increase, in the anti-TPO concentrations."

http://www.eje.org/content/148/4/389.short Effects of a six month treatment with selenomethionine in patients with autoimmune thyroiditis "OBJECTIVE: Selenium (Se) in the form of selenocysteine is an essential component of the family of the detoxifying enzymes glutathione peroxidase (Gpx) and of the iodothyronine selenodeiodinases that catalyse the extrathyroidal production of tri-iodothyronine (T(3)). Thus, Se deficiency may seriously influence the generation of free radicals, the conversion of thyroxine (T(4)) to T(3) and the autoimmune process. Therefore, we performed a randomised, placebo-controlled prospective study to investigate the effects of Se treatment on patients with autoimmune thyroiditis (AIT). DESIGN AND METHODS: Sixty five patients aged 22-61 years (median age 48 years) with AIT were recruited into two groups. Group I (Gr I) (n=34) was treated with selenomethionine (Seme) 200 microg, plus L-thyroxine (LT(4)) to maintain TSH levels between 0.3-2.0 mU/l, whereas group II (Gr II) (n=31) received LT(4) plus placebo over a period of 6 months. Moreover, the pharmacokinetics of Seme were studied in 10 patients and eight volunteers at baseline and 2 h, 4 h, 6 h and 24 h after oral administration of a 200 microg tablet of Seme. Finally, Se levels were measured at the end of the study in some patients of both groups and their results were correlated with thyroid hormone levels. RESULTS: In the pharmacokinetics study, basal serum concentration of Se (75+/-6 microg/l) was within the reference range (70-125 microg/l), it promptly increased at 2 h, peaked at 4 h (147+/-17 microg/l; P<0.0001) and it was abundant in serum at 24 h. In Gr I, antibodies against thyroid peroxidase (anti-TPO) levels showed an overall decrease of 46% at 3 months (from 1875+/-1039 U/l to 1013+/-382 U/l; P<0.0001) and of 55.5% at 6 months. In Gr II the overall decrease of anti-TPO amounted to 21% at 3 months and to 27% at 6 months (from 1758+/-917 U/l to 1284+/-410 U/l; P<0.005). There were no significant changes of antibodies against thyroglobulin levels between the groups. At the end of this study Se levels were found to be statistically significantly increased in Gr I (n = 9/34) compared with Gr II (n=11/31) (97+/-8.4 vs 79+/-8; P<0.01) but no correlation with thyroid hormone was found. CONCLUSIONS: Seme is proven to be rapidly absorbed by the gastrointestinal tract. It appears to be useful as adjunctive therapy with LT(4) in the treatment of AIT. The exact mechanism(s) is not very well determined, it might enhance the activity of detoxifying enzymes and enforce the defense against oxidative stress."

http://www.spandidos-publications.com/or/16/3/569 L-selenomethionine modulates high LET radiation-induced alterations of gene expression in cultured human thyroid cells "L-selenomethionine (SeM) is emerging as a highly effective protective agent against radiation-induced biological effects. We have shown its protective effect on space radiation-induced death of MCF-10 cells as well as on space radiation-induced transformation of HTori-3 cells. The present study was aimed at elucidation of molecular mechanisms and cellular pathways involved in SeM-mediated radioprotection. Human thyroid epithelial cells (HTori-3 cells), in the presence or absence of SeM, were exposed to a non-toxic or a slightly toxic radiation dose from 1 GeV/n iron ions (10 cGy and 20 cGy, respectively). Total RNA was prepared and changes in gene expression were analyzed using microarray technology. Our analysis has revealed a dramatic effect of SeM on alterations of gene expression caused by space radiation. This study provides a basis for furthering our knowledge about radiation-induced molecular and cellular changes that lead to cellular transformation and death."

http://archinte.jamanetwork.com/article.aspx?articleid=415585 Acute Selenium Toxicity Associated With a Dietary Supplement "Selenium is an element necessary for normal cellular function, but it can have toxic effects at high doses. We investigated an outbreak of acute selenium poisoning... The product was labeled as containing 200 µg of selenium per fluid ounce (30 mL) in the form of sodium selenite, an inorganic form of selenium. The FDA subsequently tested the product and determined the selenium concentration to be 40 800 µg/1 oz, approximately 200 times the labeled concentration. Chromium was also identified as being elevated at 17 times the labeled concentration of 200 µg/1 oz."

http://jn.nutrition.org/content/130/7/1653.short Selenomethionine: A Review of Its Nutritional Significance, Metabolism and Toxicity "Although the need for selenium in human and animal nutrition is well recognized, the question concerning the proper form of selenium for supplemental use is still being debated. Ideally, selenium should be supplemented in the form in which it occurs naturally in foods. Because the L-isomer of selenomethionine (Se-met) is a major natural food-form of selenium, synthetic L-Se-met or enriched food sources thereof such as selenium yeast are appropriate supplemental forms of Se for humans; for animals, DL-Se-met is acceptable. Ingested Se-met is either metabolized directly to reactive forms of selenium or stored in place of methionine in body proteins. Se-met metabolism is closely linked to protein turnover. At constant intakes in the nutritional range, tissue Se levels increase until a steady state is established, preventing the build-up to toxic levels."

http://www.sciencedirect.com/science/article/pii/S0891584907001219 Elemental selenium at nano size possesses lower toxicity without compromising the fundamental effect on selenoenzymes: Comparison with selenomethionine in mice "Glutathione peroxidase and thioredoxin reductase are major selenoenzymes through which selenium exerts powerful antioxidant effects. Selenium also elicits pro-oxidant effects at toxic levels. The antioxidant and pro-oxidant effects, or bioavailability and toxicity, of selenium depend on its chemical form. Selenomethionine is considered to be the most appropriate supplemental form due to its excellent bioavailability and lower toxicity compared to various selenium compounds. The present studies reveal that, compared with selenomethionine, elemental selenium at nano size (Nano-Se) possesses equal efficacy in increasing the activities of glutathione peroxidase and thioredoxin reductase but has much lower toxicity as indicated by median lethal dose, acute liver injury, and short-term toxicity. Our results suggest that Nano-Se can serve as an antioxidant with reduced risk of selenium toxicity."

http://www.sciencedirect.com/science/article/pii/S0271531787800532 Chronic toxicity and retention of dietary selenium fed to rats as D- or L-selenomethionine, selenite, or selenate "Groups of 8 male weanling Sprague-Dawley rats were fed for 6 weeks Torula yeast-based purified diets containing 2.5, 5.0, or 10.0 µg Se/g added as D-selenomethionine (D-SeMet), L-selenomethionine (L-SeMet), sodium selenite, or sodium selenate. All rats consuming diets containing 10.0 µg Se/g experienced severe growth depression and diet within 29 days, regardless of the form of Se fed, whereas rats fed 2.5 µg Se/g diet gave no evidence of depressed growth and survived the entire experimental period. Selenium fed as D-SeMet was retained in the tissues as strongly as L-SeMet. Skeletal muscle and heart Se concentrations were markedly greater when D- or L-SeMet were consumed than when selenite or selenate were consumed. Lesser differences due to the form of dietary Se fed were seen in the retention of Se in red blood cells, plasma, or liver. The increased deposition of Se in muscle tissues was not reflected by proportionate increases in either plasma or RBC Se, so monitoring plasma or whole blood Se may not indicate the degree of increased total Se body burden."

http://europepmc.org/abstract/MED/7198759 Acute toxicity of sodium selenite and selenomethionine in mice after ICV or IV administration. "The acute intracerebroventricular administration of sodium selenite and selenomethionine in conscious mice produced neurotoxicity manifested by hyperreflexia, convulsions and dealth. Selenite was 43-fold more toxic than selenomethionine on the basis of LD50 determination. The intravenous administration of the selenium compounds resulted in predominantly cardio-respiratory effects, hind limb paralysis and death. Selenite was 4-fold more toxic than selenomethionine. A comparison of relative toxicity after icv or iv administration revealed that selenite is more toxic than selenomethionine and greater relative toxicity was noted via the icv route. This toxicity difference may be attributed to the lack or low level of biotransformation of selenite by the CNS."

http://jhs.pharm.or.jp/data/46(6)/46(6)p418.pdf Metabolism of Selenoamino Acids and Contribution of Selenium Methylation to Their Toxicity "Selenium (Se) is an essential trace element and a toxicant for animals. Selenocystine (CySeSeCy) and selenomethionine (SeMet), selenoamino acids, are one of the chemical forms in which selenium exists in foods. This review summarized recent studies on the relation of toxicity and metabolism of selenite, CySeSeCy and SeMet in experimental animals. Hepatotoxicity is caused by repeated oral administration of CySeSeCy. CySeSeCy is metabolized by reduced glutathione (GSH) and/or glutathione reductase to hydrogen selenide (H2Se) via selenocysteine-glutathione selenenyl sulfide (CySeSG). The H2Se is a key intermediate in the methylation process of inorganic and organic selenium compounds. Accumulation of H2Se resulting from inhibition of the Semethylation metabolism, the detoxification pathway of selenium, is found in animals following repeated oral administration of a toxic dose of CySeSeCy. The Se-methylation inhibition is caused by a reduction in the Sadenosylmethionine (SAM) level due to the repression of methionine adenosyltransferase activity. The excess of H2Se produced by inhibition of methionine adenosyltransferase contributes to the hepatotoxicity caused by CySeSeCy. Moreover, SeMet is now known to be directly metabolized to monomethylselenol (MMSe) as selenide by ?-elimination enzyme in mouse liver. The disturbances in detoxification pathway of Se compounds such as methylation process may be involved in the development of selenosis."

http://onlinelibrary.wiley.com/doi/10.1111/j.2042-7158.1998.tb06906.x/abstract Protective Effects of Selenomethionine against Cisplatin-induced Renal Toxicity in Mice and Rats "When selenomethionine (0.5–4 mg kg-1) was administered intraperitoneally to mice 1 h before intraperitoneal cisplatin (6 mg kg-1), the toxicity of cisplatin, as measured by loss of body weight and blood urea nitrogen and serum creatinine levels, was reduced significantly. The protection was dose-dependent but less when given orally. Similar results were obtained with rats. Deterioration of renal function was characterized by reduced creatinine clearance, and increased excretion of urinary protein was significantly reversed. Partial but significant protection was also observed against capsulation-induced reduction of white blood-cell count. Protective properties were further demonstrated by increased survival of mice pretreated with selenomethionine compared with the lethality observed for animals given cisplatin only. These results suggested that selenomethionine protects against cisplatin-induced renal and other toxicity. The study has many clinical implications in cancer chemotherapy and needs further investigation."

http://link.springer.com/article/10.1007/BF02990463 Metabolism, cellular actions, and cytotoxicity of selenomethionine in cultured cells "Selenomethionine metabolism and the biochemical basis for its cytotoxicity were analyzed in cultured human and murine lymphoid cells. The metabolic pathways were also addressed, using purified mammalian enzymes and crude tissue extracts. Selenomethionine was found to be effectively metabolized toS-adenosylmethionine analog, and that analog was further metabolized in transmethylation reactions and in polyamine synthesis, similarly to the corresponding sulphur metabolites of methionine. Selenomethionine did not block these pathways, nor was there a specific block on the synthesis of DNA, RNA, or proteins when added to the culture medium. Selenomethionine showed cytotoxicity at above 40 µM levels. Yet, low selenomethionine levels (10 µM) could replace methionine and support cell growth in the absence of methionine. Selenomethionine toxicity took place concomitantly with changes inS-adenosylmethionine pools. D-form was less cytotoxic than L-form. Methionine concentration modified the cytotoxicity. Together, this indicates that selenomethionine uptake and enzymic metabolism are involved in the cytotoxicity in a yet unknown way."

http://www.sciencedirect.com/science/article/pii/S0891584998001476 Selenium compounds have disparate abilities to impose oxidative stress and induce apoptosis "The cancer chemopreventive effect of selenium cannot be fully accounted for by the role of selenium as a component of the antioxidant enzyme glutathione peroxidase, which suggests that chemoprevention occurs by another mechanism. Several studies have shown that thiol oxidation and free radical generation occur as a consequence of selenium catalysis and toxicity. In the present study, we evaluated three different selenium compounds; selenite, selenocystamine, and selenomethionine to determine the relative importance of the prooxidative effects of these compounds with regard to their ability to induce apoptosis. The experimental results suggest that, in addition to supporting an increased activity of glutathione peroxidase, an antioxidant function that the three selenium compounds did with equal efficacy, catalytic selenite, and selenocystamine generated 8-hydroxydeoxyguanosine DNA adducts, induced apoptosis and were found to be cytotoxic in mouse keratinocytes. The noncatalytic selenomethionine was not cytotoxic, did not generate 8-hydroxydeoxyguanosine adducts and did not induce cellular apoptosis at any of the selenium concentrations studied. In keratinocytes, apoptosis may be initiated by superoxide (O2•-) and oxidative free radicals that are generated by selenite and selenocystamine, but not by selenomethionine."

http://www.sciencedirect.com/science/article/pii/S0006295203007330 Methioninase and selenomethionine but not Se-methylselenocysteine generate methylselenol and superoxide in an in vitro chemiluminescent assay: implications for the nutritional carcinostatic activity of selenoamino acids "Methylselenol from selenium metabolism is postulated to be and most experimental evidence now indicates that it is the selenium metabolite responsible for the dietary chemoprevention of cancers. Using the recombinant enzyme methioninase, methylselenol-generating chemiluminesence by superoxide (O2-) is shown to be catalytically produced from l-selenomethionine and d,l-selenoethionine, but not from methionine or l-Se-methylselenocysteine (SeMC). Methylselenol enzymaticaly generated by methioninase activity from the substrate selenomethionine arises from an initial putative selenium radical as measured by chemiluminesence in the absence of glutathione (GSH). In the presence of GSH, superoxide was generated as measured by chemiluminesence and superoxide dismutase inhibition of chemiluminescence. Ascorbic acid also quenched the chemiluminesence from the activity of methioninase with selenomethionine. Methylselenol and other redox cycling selenium compounds are almost assuredly accountable for inducing cell-cycle arrest and apoptosis in cancer cells in vitro and in vivo. Methylselenol generated from selenomethionine by methioninase is catalytic alone in oxidizing thiols, i.e. GSH, generating superoxide and inducing oxidative stress in direct proportion to its concentration. Se-methylselenocysteine in vivo is very likely carcinostatic in like manner to selenomethionine by generating methylselenol from other enzymatic activity, i.e. beta-lyase or amino acid oxidases."

http://www.tandfonline.com/doi/abs/10.1207/S15327914NC401_8#.U4eE5vldW9Q Dimethyldiselenide and Methylseleninic Acid Generate Superoxide in an In Vitro Chemiluminescence Assay in the Presence of Glutathione: Implications for the Anticarcinogenic Activity of L-Selenomethionine and L-Se-Methylselenocysteine "The reduction of cancer incidence by dietary supplementation with L-selenomethionine, L-Se-methylselenocysteine, and other methylated selenium compounds and metabolites is believed to be due to the metabolic generation of the monomethylated selenium species methylselenol. Dimethyldiselenide and methylseleninic acid were reduced by glutathione in an in vitro chemiluminescent assay in the presence of lucigenin for the detection of superoxide (O2 - ). The methylselenol produced on reduction of dimethyldiselenide and methylseleninic acid was found to be highly catalytic, continuously generating a steady state of O2 - . The O2 - detected by the chemiluminescence generated by methylselenol was fully quenched by superoxide dismutase, causing a complete cessation of chemiluminescence. In contrast, dimethyldisulfide in the presence of glutathione was not catalytic to any measurable extent and did not generate any superoxide. These in vitro results suggest that methylselenol catalysis is possible in vivo, and if metabolism generates sufficient concentrations of methlylselenol from L-selenomethionine or L-Se-methylselenocysteine in vivo, it could change the redox status of cells and oxidatively induce cellular apoptosis."

http://europepmc.org/abstract/MED/2313384 Comparative toxicity and tissue retention of selenium in methionine-deficient rats fed sodium selenate or L-selenomethionine. "Selenium (Se) toxicity is known to be affected by level of intake of the mineral, but there are conflicting reports on the relative toxicities of the various chemical forms of Se. We monitored Se toxicity in ratsfed Torula yeast-based diets containing 0.1, 0.5 or 2.5 micrograms Se/g of diet as either sodiumselenate (Na2SeO4) or L-selenomethionine (SeMet). Half the diets were supplemented to contain adequate dietary methionine (Met). Weights were monitored weekly for 6 (Met-adequate) or 7 (Met-deficient) wk, at which time the rats were killed. There were no significant differences in final weight among Met-adequate rats, regardless of level or form of dietary Se. Methionine-deficient rats all gained significantly less weight than their Met-adequate counterparts. Selenosis was most severe in the Met-deficient rats fed 2.5 micrograms Se/g of diet as Na2SeO4, as indicated by significantly impaired weight gains. Nonetheless, Se retention in serum, heart, brain, bone, testes, colon, skin, lungs and pancreas was greater in rats fed SeMet than in those fed Na2SeO4, and Met deficiency further intensified this trend. The kidney was the only organ in which Se levels were markedly higher in the severely poisoned Met-deficient rats fed Na2SeO4. Further research is needed to determine whether elevated kidney Se levels are related to the greater toxicity observed in the Met-deficient rats fed Na2SeO4."

http://www.sciencedirect.com/science/article/pii/S0031938407003617 Selenomethionine reduces visual deficits due to developmental methylmercury exposures "Developmental exposures to methylmercury (MeHg) have life-long behavioral effects. Many micronutrients, including selenium, are involved in cellular defenses against oxidative stress and may reduce the severity of MeHg-induced deficits. Zebrafish embryos (< 4 h post fertilization, hpf) were exposed to combinations of 0.0–0.30 µM MeHg and/or selenomethionine (SeMet) until 24 hpf then placed in clean medium. Fish were tested as adults under low light conditions (~ 60 µW/m2) for visual responses to a rotating black bar. Dose-dependent responses to MeHg exposure were evident (ANOVA, P < 0.001) as evidenced by reduced responsiveness, whereas SeMet did not induce deficits except at 0.3 µM. Ratios of SeMet:MeHg of 1:1 or 1:3 resulted in responses that were indistinguishable from controls (ANOVA, P < 0.001). No gross histopathologies were observed (H&E stain) in the retina or optic tectum at any MeHg concentration. Whole-cell, voltage-gated, depolarization-elicited outward K+ currents of bipolar cells in intact retina of slices adult zebrafish were recorded and outward K+ current amplitude was larger in bipolar cells of MeHg-treated fish. This was due to the intense response of cells expressing the delayed rectifying IK current; cells expressing the transient IA current displayed a slight trend for smaller amplitude among MeHg-treated fish. Developmental co-exposure to SeMet reduced but did not eliminate the increase in the MeHg-induced IKresponse, however, IA responses increased significantly over MeHg-treated fish to match control levels. Electrophysiological deficits parallel behavioral patterns in MeHg-treated fish, i.e., initial reactions to the rotating bar were followed by periods of inactivity and then a resumption of responses."

http://cancerres.aacrjournals.org/content/44/7/2803.short Effect of an Inorganic and Organic Form of Dietary Selenium on the Promotional Stage of Mammary Carcinogenesis in the Rat "The relative effectiveness of either sodium selenite or selenomethionine in the inhibition of mammary carcinogenesis was studied in virgin female Sprague-Dawley rats. In one experiment, rats were given 50 mg of 1-methyl-1-nitrosourea per kg of body weight s.c. at 50 days of age. Beginning 7 days post-1-methyl-1-nitrosourea, they were assigned to a basal diet containing 0.1 ppm of selenium or basal diet supplemented to contain either 4, 5, or 6 ppm of selenium as sodium selenite or 5 or 6 ppm of selenium as selenomethionine. Selenium treatment was continued until termination of the study 135 days after 1-methyl-1-nitrosourea treatment. Sodium selenite, at the 5-ppm level, was the most effective chemopreventive agent. The highest level of selenomethionine (6 ppm) caused grossly apparent liver damage. No liver damage was noted in sodium selenite-treated rats. In a second experiment, rats were given 5 mg of 7,12-dimethylbenz(a)anthracene at 50 days of age. Beginning 7 days after 7,12-dimethylbenz(a)anthracene treatment, rats were assigned randomly to the control group or to one of two selenium treatment groups receiving either 3.4 ppm of selenium as sodium selenite or 3.4 ppm as selenomethionine in their drinking water. Selenium supplementation was continued throughout the study until its termination at 111 days postcarcinogen. Sodium selenite significantly reduced cancer incidence and the average number of cancers per rat. Treatment with selenomethionine was less effective and caused severe liver damage. Although both sodium selenite and selenomethionine can inhibit some aspect of the postinitiation stage(s) of mammary carcinogenesis, selenium provided as sodium selenite was the more effective and less toxic of the two chemicals. Increasing the dose of sodium selenite above 5 ppm did not enhance the inhibitory activity of selenium."

http://www.sciencedirect.com/science/article/pii/S0946672X04000112 A report of high-dose selenium supplementation: response and toxicities "Concerns about the toxicity of selenium has limited the doses used in chemoprevention. Based on previous studies, intakes of 400 µg/day and plasma selenium of 1000 ng/ml (Dietary Reference Intakes, Academy Press, New York, 2000, p. 384) were established as the no observed adverse effect level (NOAEL). This investigation summarizes the plasma response and toxicity reports from 24 men with biopsy-proven prostate cancer who were randomized to either 1600 or 3200 µg/day of selenized yeast as part of a controlled clinical trial testing selenium as a chemopreventive agent for prostate cancer progression. Subjects were on these doses for averages of almost 12 months. Plasma selenium levels were monitored throughout the course of follow-up. Symptoms of selenium toxicity were assessed by patient interview with specific questions regarding breath, hair and nail changes. Several liver and kidney function tests and hematology were measured at 6-month intervals. 8 subjects were randomized to the 1600 µg/day and 16 to the 3200 µg/day group. The mean plasma selenium levels achieved with supplementation were 492.2 ng/ml (SD=188.3) and 639.7 ng/ml (SD=490.7) for the 1600 and 3200 µg/day doses, respectively. The 3200 µg/day group reported more selenium-related side effects. Blood chemistry and hematology results were all within normal limits for both treatment groups. More subjects on 3200 µg/day reported symptoms of selenium toxicity; however, these reports did not correspond to peaks in plasma selenium levels. We observed no obvious selenium-related serious toxicities. As selenium is used in more chemoprevention and therapeutic settings, additional information on selenium species, sequestration of selenium in specific organs, excretion, and toxicities is needed."

http://clincancerres.aacrjournals.org/content/12/4/1237.short A phase I and pharmacokinetic study of fixed-dose selenomethionine and irinotecan in solid tumors. "PURPOSE: We conducted a phase I study to determine the maximum tolerated dose (MTD) of irinotecan with fixed, nontoxic high dose of selenomethionine. EXPERIMENTAL DESIGN: Selenomethionine was given orally as a single daily dose containing 2,200 mug of elemental selenium (Se) starting 1 week before the first dose of irinotecan. Irinotecan was given i.v. once weekly x 4 every 6 weeks (one cycle). The starting dose of irinotecan was 125 mg/m(2)/wk. Escalation occurred in cohorts of three patients until the MTD was defined. Pharmacokinetic studies were done for selenium and irinotecan and its metabolites. RESULTS: Three of four evaluable patients at dose level 2 of irinotecan (160 mg/m(2)/wk) had a dose-limiting diarrhea. None of the six evaluable patients at dose level 1 (125 mg/m(2)/wk irinotecan) had a dose-limiting toxicity. One patient with history of irinotecan-refractory colon cancer achieved a partial response. The long half-life of selenium resulted in a prolonged accumulation towards steady-state concentrations. No significant changes in the pharmacokinetics of CPT-11, SN-38, or SN-38G were identified; however, the coadministration of selenomethionine significantly reduced the irinotecan biliary index, which has been associated with gastrointestinal toxicity. CONCLUSIONS: Selenomethionine at 2,200 mug/d did not allow the safe escalation of irinotecan beyond the previously defined MTD of 125 mg/m(2). None of the patients receiving 125 mg/m(2) of irinotecan had grade >2 diarrhea. Unexpected responses and disease stabilizations were noted in a highly refractory population. Further escalation of selenomethionine is recommended in future trials to achieve defined protective serum concentrations of selenium."

http://www.sciencedirect.com/science/article/pii/S0378427406013889 Biomarkers of exposure and effect as indicators of the interference of selenomethionine on methylmercury toxicity "The present study was conducted to clarify the interference of selenomethionine (SeMet) on methylmercury (MeHg) toxicity through the evaluation of changes in biomarkers of exposure and effect in rats exposed to MeHg and co-exposed to MeHg and SeMet. Male Wistar rats received two intraperitoneally (i.p.) administrations, either MeHg (1.5 mg/kg body weight), SeMet alone (1 mg/kg body weight) or combined MeHg and SeMet, followed by 3 weeks of rat urine collection and neurobehavioural assays. The effects of different administrations were investigated by the quantification of total mercury in kidney and brain, analysis of urinary porphyrins, determination of hepatic GSH and evaluation of motor activity functions (rearing and ambulation). MeHg exposure resulted in a significant increase of urinary porphyrins during the 3 weeks of rat urine collection, where as it caused a significant decrease in motor activity only at the first day after cessation of rat exposure. Additionally, SeMet co-exposure was able to normalize the porphyrins excretion, and a tendency to restore rat motor activity was observed, on the first day after cessation of exposure. Brain and kidney mercury levels increased significantly in rats exposed to MeHg; however, in co-exposed rats to SeMet no significant changes in Hg levels were found as compared to rats exposed to MeHg alone. Hence, the present study shows that urinary porphyrins are sensitive and persistent indicators of MeHg toxicity and demonstrates for the first time that SeMet reduces its formation. Finally, these results confirm that the mechanism of interaction between SeMet and MeHg cannot be explained by the reduction of Hg levels in target organs and suggestions are made to clarify the interference of SeMet on MeHg toxicity."

http://www.sciencedirect.com/science/article/pii/S0140673600024909 The importance of selenium to human health "The essential trace mineral, selenium, is of fundamental importance to human health. As a constituent of selenoproteins, selenium has structural and enzymic roles, in the latter context being best-known as an antioxidant and catalyst for the production of active thyroid hormone. Selenium is needed for the proper functioning of the immune system, and appears to be a key nutrient in counteracting the development of virulence and inhibiting HIV progression to AIDS. It is required for sperm motility and may reduce the risk of miscarriage. Deficiency has been linked to adverse mood states. Findings have been equivocal in linking selenium to cardiovascular disease risk although other conditions involving oxidative stress and inflammation have shown benefits of a higher selenium status. An elevated selenium intake may be associated with reduced cancer risk. Large clinical trials are now planned to confirm or refute this hypothesis. In the context of these health effects, low or diminishing selenium status in some parts of the world, notably in some European countries, is giving cause for concern."

http://www.sciencedirect.com/science/article/pii/095528639290028H Intestinal absorption of selenite, selenate, and selenomethionine in the rat "Regional characteristics of intestinal absorption of selenocompounds under conditions of dietary selenium deficiency, intraluminal glutathione (GSH), and GSH depletion by buthionine [S,R] sulfoximine (BSO) treatment were studied. Absorption of 75Se from selenite, selenate, and selenomethionine (SeMet) was determined in ligated loops from duodena, jejuna, and ilea of selenium-deficient rats (0.009 ppm Se) or rats fed selenite-supplemented diets (0.20 ppm Se). Selenium deficiency had no effect on absorption of any selenocompound in any intestinal segment. SeMet was absorbed most rapidly from all segments. Selenate and selenite were most efficiently absorbed from the ileum. Substantial 75Se was retained within ileal tissue during selenite and SeMet absorption but was readily transferred to the body during ileal selenate uptake. Luminal GSH (50 µmol/L) had no effect on mucosal GSH levels nor on selenite uptake. BSO treatment decreased tissue GSH levels to 37%–54% of controls depressing 75Se-selenite uptake to 55%–64% and transfer to 29%–34% of controls. 75Se-SeMet absorption was not altered by 1 mmol/L intraluminal GSH or by mucosal GSH depletion. No evidence for homeostatic regulation of selenium absorption was obtained. Intracellular GSH appears to be involved in transepithelial transport of 75Se-selenite but not 75Se-SeMet."

http://www.pnas.org/content/99/25/15932.short Selenosugars are key and urinary metabolites for selenium excretion within the required to low-toxic range "Essential micronutrient selenium is excreted into the urine and/or expired after being transformed to methylated metabolites. Monomethylated selenium is excreted into the urine in response to a supply within the required to low-toxic range, whereas tri- and dimethylated selenium increase with excessive supply at a toxic dose. Here we show that the major urinary selenium metabolite within the required to low-toxic range is a selenosugar. The structure of 1ß-methylseleno-N-acetyl-D-galactosamine was deduced from the spectroscopic data and confirmed by chemical synthesis. This metabolite was also detected in the liver, and an additional metabolite increased with inhibition of methylation. The latter metabolite was again a selenosugar conjugated with glutathione instead of a methyl group and was assumed to be a precursor for methylation to the former metabolite. A metabolic pathway for the urinary excretion of selenium, i.e., from the glutathione-S-conjugated selenosugar to the methylated one, was proposed. Urinary monomethylated (selenosugar) and trimethylated selenium can be used as specific indices that increase within the required to low-toxic range and with a distinct toxic dose, respectively."

http://vdi.sagepub.com/content/18/1/61.short Comparative Toxicosis of Sodium Selenite and Selenomethionine in Lambs "Excess consumption of selenium (Se) accumulator plants can result in selenium intoxication. The objective of the study reported here was to compare the acute toxicosis caused by organic selenium (selenomethionine) found in plants with that caused by the supplemental, inorganic form of selenium (sodium selenite). Lambs were orally administered a single dose of selenium as either sodium selenite or selenomethionine and were monitored for 7 days, after which they were euthanized and necropsied. Twelve randomly assigned treatment groups consisted of animals given 0, 1, 2, 3, or 4 mg of Se/kg of body weight as sodium selenite, or 0, 1, 2, 3, 4, 6, or 8 mg of Se/kg as selenomethionine. Sodium selenite at dosages of 2, 3, and 4 mg/kg, as well as selenomethionine at dosages of 4, 6, and 8 mg/kg resulted in tachypnea and/or respiratory distress following minimal exercise. Severity and time to recovery varied, and were dose dependent. Major histopathologic findings in animals of the high-dose groups included multifocal myocardial necrosis and pulmonary alveolar vasculitis with pulmonary edema and hemorrhage. Analysis of liver, kidney cortex, heart, blood, and serum revealed linear, dose-dependent increases in selenium concentration. However, tissue selenium concentration in selenomethionine-treated lambs were significantly greater than that in lambs treated with equivalent doses of sodium selenite. To estimate the oxidative effects of these selenium compounds in vivo, liver vitamin E concentration also was measured. Sodium selenite, but not selenomethionine administration resulted in decreased liver vitamin E concentration. Results of this study indicate that the chemical form of the ingested Se must be known to adequately interpret tissue, blood, and serum Se concentrations."

http://www.sciencedirect.com/science/article/pii/S1382668901000783 The biochemistry of selenium and the glutathione system "In the context of defense against pro-oxidants, selenium and the glutathione (GSH) system play key functions. Major roles of GSH include direct interception of pro-oxidants, as well as a reduction of other antioxidants from their oxidized forms. Furthermore, GSH has ancillary functions, such as metabolism, cell signaling, and protein interactions, that can also mediate defense against oxidants. Protection by selenium in the mammalian cell is mediated by selenol-aminoacids, either as selenocysteine or selenomethionine. The active site of the potent glutathione peroxidases (GPx) contains selenocysteine residues. Furthermore, other selenoproteins (e.g. selenoprotein P and thioredoxin reductase) also have been shown to possess antioxidant properties. Synthetic organoselenium compounds (e.g. ebselen) have also shown promise as pharmacologic antioxidants in in vivo models of tissue damage due to oxidative stress. The specific function of selenoproteins and organoselenium compounds in defense against peroxynitrite, by reduction of this potent oxidizing and nitrating species to nitrite, is also discussed."

http://www.biochemj.org/bj/332/bj3320231.htm Differential expression of selenoproteins by human skin cells and protection by selenium from UVB-radiation-induced cell death "The generation of reactive oxygen species has been implicated as part of the mechanism responsible for UVB-radiation-induced skin damage. In mice, evidence suggests that increased dietary selenium intake may protect skin from many of the harmful effects of UVB radiation. We sought to determine the selenoprotein profile of cultured human skin cells and whether selenium supplementation could protect keratinocytes and melanocytes from the lethal effects of UVB radiation. Labelling experiments using [75Se]selenite showed qualitative and quantitative differences in selenoprotein expression by human fibroblasts, keratinocytes and melanocytes. This was most noticeable for thioredoxin reductase (60 kDa) and phospholipid glutathione peroxidase (21 kDa); these proteins were identified by Western blotting. Despite these differences, we found that a 24 h preincubation with sodium selenite or selenomethionine protected both cultured human keratinocytes and melanocytes from UVB-induced cell death. With primary keratinocytes, the greatest reduction in cell death was found with 10 nM sodium selenite (79% cell death reduced to 21.7%; P < 0.01) and with 50 nM selenomethionine (79% cell death reduced to 13.2%; P < 0.01). Protection could be obtained with concentrations as low as 1 nM with sodium selenite and 10 nM with selenomethionine. When selenium was added after UVB radiation, little protection could be achieved, with cell death only being reduced from 88.5% to about 50% with both compounds. In all of the experiments sodium selenite was more potent than selenomethionine at providing protection from UVB radiation."

http://www.tandfonline.com/doi/abs/10.1080/03086647608073336#.U4eL5fldW9Q TISSUE SELENIUM LEVELS AND GROWTH RESPONSES OF MICE FED SELENOMETHIONINE, SE-METHYLSELENOCYSTEINE OR SODIUM SELENITE "Mice fed diets containing selenomethionine at a level of 20 ppm selenium and raised to 30 ppm selenium at 3 weeks on experiment showed (1) delayed response to selenium toxicity, (2) slow recovery from the toxicity after removal of selenium from the diet and (3) relatively high deposition and retention of tissue selenium. These data suggest that selenomethonine initially becomes incorporated in to the primary structure of proteins and as such is not particularly toxic. However, upon its slow removal from protein, selenomethionine becomes toxic by forming selenium IV compounds through a pathway similar to that followed by methionine. Mice fed diets containing sodium selenite or Se-methylselenocysteine at the same level of selenium as the selenomethionine diet showed (1) immediate response to selenium toxicity (2) rapid recovery from the toxicity after removal of selenium from the diet and (3) relatively low deposition and relatively rapid depletion of tissue selenium. These data suggest that sodium selenite and Se-methylselenocysteine ultimately follow similar metabolic pathways and do not become part of the primary structure of proteins. A possible metabolic route for Se-methylselenocysteine is that it is oxidized to toxic selenium IV compounds through an oxidative pathway similar to that followed by S-methylcysteine."

Toxicity of Selenium in Brazil Nuts to Rats "Nuts from Bertholletia excelsa, commonly known as Brazil nuts, were analyzed for selenium. Of 529 nuts from one commercial source, 6% were found to contain 100 ppm selenium or more. The mean value for all nuts was 29.6 ppm and the median value was 13.4 ppm. Hexane extracted high-selenium Brazil nut meal in a corn-based diet fed to rats produced toxicity similar to that obtained from seleniferous corn, selenomethionine or sodium selenite as assessed by weight gain, visually scored liver damage, and liver, kidney, and spleen weights. Selenium contents of liver, kidney, spleen, and blood were also determined. It is suggested that the selenium in Brazil nuts is as biologically potent as that from other sources."

http://link.springer.com/article/10.1007/s00216-005-0007-8 Selenium metabolites in human urine after ingestion of selenite, L-selenomethionine, or DL-selenomethionine: a quantitative case study by HPLC/ICPMS "To obtain quantitative information on human metabolism of selenium, we have performed selenium speciation analysis by HPLC/ICPMS on samples of human urine from one volunteer over a 48-hour period after ingestion of selenium (1.0 mg) as sodium selenite, L-selenomethionine, or DL-selenomethionine. The three separate experiments were performed in duplicate. Normal background urine from the volunteer contained total selenium concentrations of 8–30 µg Se/L (n=22) but, depending on the chromatographic conditions, only about 30–70% could be quantified by HPLC/ICPMS. The major species in background urine were two selenosugars, namely methyl-2-acetamido-2-deoxy-1-seleno-ß-D-galactopyranoside (selenosugar 1) and its deacylated analog methyl-2-amino-2-deoxy-1-seleno-ß-D-galactopyranoside (selenosugar 3). Selenium was rapidly excreted after ingestion of the selenium compounds: the peak concentrations (~250–400 µg Se/L, normalized concentrations) were recorded within 5–9 hours, and concentrations had returned to close to background levels within 48 hours, by which time 25–40% of the ingested selenium, depending on the species ingested, had been accounted for in the urine. In all experiments, the major metabolite was selenosugar 1, constituting either ~80% of the total selenium excreted over the first 24 hours after ingestion of selenite or L-selenomethionine or ~65% after ingestion of DL-selenomethionine. Selenite was not present at significant levels (<1 µg Se/L) in any of the samples; selenomethionine was present in only trace amounts (~1 µg/L, equivalent to less than 0.5% of the total Se) following ingestion of L-selenomethionine, but it constituted about 20% of the excreted selenium (first 24 hours) after ingestion of DL-selenomethionine, presumably because the D form was not efficiently metabolized. Trimethylselenonium ion, a commonly reported urine metabolite, could not be detected (<1 µg/L) in the urine samples after ingestion of selenite or selenomethionine. Cytotoxicity studies on selenosugar 1 and its glucosamine isomer (selenosugar 2, methyl-2-acetamido-2-deoxy-1-seleno-ß-D-glucosopyranoside) were performed with HepG2 cells derived from human hepatocarcinoma, and these showed that both compounds had low toxicity (about 1000-fold less toxic than sodium selenite). The results support earlier studies showing that selenosugar 1 is the major urinary metabolite after increased selenium intake, and they suggest that previously accepted pathways for human metabolism of selenium involving trimethylselenonium ion as the excretionary end product may need to be re-evaluated."

http://www.tandfonline.com/doi/abs/10.1080/07315724.2001.10719007#.U4eNbPldW9Q Nutritional Selenium Supplements: Product Types, Quality, and Safety "Selenium supplements contain selenium in different chemical forms. In the majority of supplements, the selenium is present as selenomethionine. However, in multivitamin preparations, infant formulas, protein mixes, weight-loss products and animal feed, sodium selenite and sodium selenate are predominantly used. In some products, selenium is present in protein- or amino acid chelated forms; in still others, the form of selenium is not disclosed. Current evidence favors selenomethionine over the other forms of selenium. Extradietary supplementation of selenium at the dosage of 200 micrograms per day is generally consideredsafe and adequate for an adult of average weight subsisting on the typical American diet."

http://cebp.aacrjournals.org/content/15/4/804.short Effects of Chemical Form of Selenium on Plasma Biomarkers in a High-Dose Human Supplementation Trial "Intervention trials with different forms of selenium are under way to assess the effects of selenium supplements on the incidence of cancer and other diseases. Plasma selenium biomarkers respond to selenium administration and might be useful for assessing compliance and safety in these trials. The present study characterized the effects of selenium supplementation on plasma selenium biomarkers and urinary selenium excretion in selenium-replete subjects. Moderate (~200 µg/d) to large (~600 µg/d) selenium supplements in the forms sodium selenite, high-selenium yeast (yeast), and L-selenomethionine (selenomethionine) were administered. Subjects were randomized into 10 groups (placebo and three dose levels of each form of selenium). Plasma biomarkers (selenium concentration, selenoprotein P concentration, and glutathione peroxidase activity) were determined before supplementation and every 4 weeks for 16 weeks. Urinary selenium excretion was determined at 16 weeks. Supplementation with selenomethionine and yeast raised the plasma selenium concentration in a dose-dependent manner. Selenite did not. The increased selenium concentration correlated with the amount of selenomethionine administered. Neither glutathione peroxidase activity nor selenoprotein P concentration responded to selenium supplementation. Urinary selenium excretion was greater after selenomethionine than after selenite, with excretion after yeast being intermediate and not significantly different from either of the other two. We conclude that plasma selenium concentration is useful in monitoring compliance and safety of selenium supplementation as selenomethionine but not as selenite. Plasma selenium seems to reflect the selenomethionine content of yeast but not the other yeast selenium forms. As judged by urinary selenium excretion, selenium in the form of selenomethionine is better absorbed than selenite. (Cancer Epidemiol Biomarkers Prev 2006;15(4):804–10)"

http://www.iupac.org/publications/pac/78/1/0105/ Selenium yeast: Composition, quality, analysis, and safety "Selenium yeast, produced by growing select strains of Saccharomyces cerevisiae in Se-rich media, is a recognized source of organic food-form Se, but the determination of its exact composition with respect to the Se species present produced conflicting results. Improved methods of analysis have since revealed it to contain 90+ % of its Se in the form of selenomethionine, the principal organic nutritional form of Se for higher animals and humans. The safety record of Se yeast is excellent: During the three decades of its world-wide use as a source of supplemental Se, no cases of Se poisoning have occurred due to dosage or formulation errors."

http://www.sciencedirect.com/science/article/pii/S0278691507000099 Non-optimal levels of dietary selenomethionine alter splenocyte response and modify oxidative stress markers in female mice "Many studies evaluating the effects of selenium (Se) status on immunity utilize inorganic Se, although selenomethionine (Se-Met) has been suggested to be more bioavailable and less toxic. In the current study, we investigated the effects of dietary Se-Met on immune system function and cellular redox status in C57BL/6N female mice fed with low (0.02 ppm), sufficient (0.2 ppm, control group), or excess Se-Met (2 ppm) in the diet for 50 days. Low Se-Met intake reduced glutathione peroxidase (GPx) activity and glutathione concentration without modifying lipoperoxidation. While low Se-Met intake also reduced the number of B cells in the spleen, it increased mitogen-induced proliferation, IL-4 and IL-12 secretion when compared to the sufficient Se-Met intake group. In comparison to controls, excess Se-Met intake increased splenocyte proliferation and reduced B cell numbers, IL-4, and IL-12 secretion without affecting oxidative stress markers. These data suggest that Se-Met supplementation should be carefully evaluated as it many influence immune function."

http://mutage.oxfordjournals.org/content/24/3/225.short The effect of selenium, as selenomethionine, on genome stability and cytotoxicity in human lymphocytes measured using the cytokinesis-block micronucleus cytome assay "A supranutritional intake of selenium (Se) may be required for cancer prevention, but an excessively high dose could be toxic. Therefore, the effect on genome stability of seleno-L-methionine (Se-met), the most important dietary form of Se, was measured to determine its bioefficacy and safety limit. Peripheral blood lymphocytes were isolated from six volunteers and cultured with medium supplemented with Se-met in a series of Se concentrations (3, 31, 125, 430, 1880 and 3850 µg Se/litre) while keeping the total methionine (i.e. Se-met + L-methionine) concentration constant at 50 µM. Baseline genome stability of lymphocytes and the extent of DNA damage induced by 1.5-Gy ?-ray were investigated using the cytokinesis-block micronucleus cytome assay after 9 days of culture in 96-microwell plates. High Se concentrations (=1880 µg Se/litre) caused strong inhibition of cell division and increased cell death (P < 0.0001). Baseline frequency of nucleoplasmic bridges and nuclear buds, however, declined significantly (P trend < 0.05) as Se concentration increased from 3 to 430 µg Se/litre. Se concentration (=430 µg Se/litre) had no significant effect on baseline frequency of micronuclei and had no protective effect against genome damage induced by exposure to 1.5-Gy ?-ray irradiation. In conclusion, Se, as Se-met, may improve genome stability at concentrations up to 430 µg Se/litre, but higher doses may be cytotoxic. Therefore, a cautious approach to supplementation with Se-met is required to ensure that optimal genome health is achieved without cytotoxic effects."

http://www.sciencedirect.com/science/article/pii/S0899900706002292 Selenium supplementation, soluble tumor necrosis factor-a receptor type 1, and C-reactive protein during psoriasis therapy with narrowband ultraviolet B "Methods:Thirty-seven patients had narrowband ultraviolet B therapy five times a week and received 200 µg of selenium daily as selenomethionine (group 1, n = 19) or placebo (group 2, n = 18) for 4 wk. Assessment, performed at baseline, after 2 and 4 wk, and 4 wk after the end of treatment included measurement of the Psoriasis Area and Severity Index (PASI) and serum concentrations of selenium (micrograms per liter), sTNF-R1 (nanograms per milliliter), and CRP (milligrams per liter). Control sera were obtained from 20 healthy volunteers. Results:Baseline PASI was 12.70 ± 5.48 (13.02 ± 6.25 in group 1 and 12.37 ± 4.71 in group 2), selenium concentration was 50.55 ± 9.54 (49.05 ± 10.38 and 52.13 ± 8.61, respectively), sTNF-R1 concentration was 1.91 ± 0.38 (1.96 ± 0.37 and 1.87 ± 0.40, respectively), and CRP concentration was 25.34 ± 8.27 (26.12 ± 8.42 and 24.57 ± 7.72). In controls, selenium concentration was 48.71 ± 9.39 (P > 0.05 versus patients), sTNF-R1 concentration was 1.48 ± 0.30 (P < 0.05), CRP concentration was <6. The baseline sTNF-R1 level correlated to PASI value (r = 0.40, P < 0.05) and CRP concentration (r = 0.36, P > 0.05). The treatment resulted in an almost parallel decrease in PASI in both groups. At 4 wk after the end of treatment, selenium concentrations were 83.77 ± 5.13 in group 1 and 52.12 ± 7.54 in group 2 (P < 0.05), sTNF-R1 concentrations were 1.72 ± 0.27 and 1.47 ± 0.26 (P < 0.05), and CRP concentrations were 7.72 ± 4.23 and 8.15 ± 3.32, respectively (P > 0.05). Selenium concentration correlated inversely with CRP in group 1. Conclusion:The results confirm that sTNF-R1 and CRP concentrations are increased in active psoriasis and that supplementation with selenomethionine for 4 wk in safe doses is ineffacious as adjuvant therapy in patients with psoriasis."

http://onlinelibrary.wiley.com/doi/10.1002/biof.5520140115/abstract Plasma selenium in specific and non-specific forms "Selenium is present in plasma and tissues in specific and non-specific forms. The experiments reported here were carried out to clarify some factors that affect these forms of the element in plasma. A selenium-replete human subject was given 400 µg of selenium daily for 28 days as selenomethionine and, in a separate experiment, as selenate. The selenomethionine raised plasma and albumin selenium concentrations. Selenate did neither. The molar ratio of methionine to selenium in albumin was approximately 8000 under basal and selenate-supplemented conditions but 2800 after selenomethionine supplementation. This demonstrates that selenium from selenomethionine, but not selenium from selenate, can be incorporated into albumin, presumably as selenomethionine in the methionine pool. Selenocysteine incorporation into albumin was studied in rats using 75Se-selenocysteine. No evidence was obtained for incorporation of 75Se into albumin after exogenous administration or endogenous synthesis of 75Se-selenocysteine. Thus, selenocysteine does not appear to be incorporated non-specifically into proteins as is selenomethionine. These findings are in support of selenomethionine being a non-specific form of selenium that is metabolized as a constituent of the methionine pool and is unaffected by specific selenium metabolic processes. No evidence was found for non-specific incorporation of selenium into plasma proteins when it was administered as selenate or as selenocysteine. These forms of the element appear to be metabolized by specific selenium metabolic processes."

http://www.ingentaconnect.com/content/cog/or/2009/00000018/00000001/art00001 The Anticancer Effects of Sodium Selenite and Selenomethionine on Human Colorectal Carcinoma Cell Lines in Nude Mice "The studies were carried out on nude mice bearing human colorectal carcinoma SW480 cell line xenografts to evaluate the chemotherapeutic potential of selenium containing compounds such as sodium selenite (SSe) and selenomethionine (SeMet). Three doses of anticancer drugs were used, including 0.1 mg/kg/day SSe (LSSe), 2 mg/kg/day SSe (HSSe), and 2 mg/kg/day SeMet. We explored the anticancer effect of SSe and SeMet administered by IP injection for 21 days. We observed the pathologic changes and the cell apoptosis in tumor tissue by HE staining and TUNNEL assay after HSSe and SeMet treatment. GSH level and antioxidant enzyme GPX activity in tumor tissues were assessed. In addition, Western blotting was used to detect the expression of apoptosis-related proteins. The results suggested that HSSe and SeMet had significantly inhibited tumor growth in vivo. We also observed the pathologic changes and cell apoptosis in tumor tissues after HSSe and SeMet treatment. GSH level was a bit increased but the GPX activity was reduced. Moreover, SSe and SeMet treatment downregulated the expression of the protein Bcl-xL, increased the expression of Bax, Bad, and Bim, and activated caspase-9. SSe and SeMet may be the selective, low-toxic anticancer agents to treat human colorectal carcinoma cancer."

http://ijt.sagepub.com/content/5/1/45.short Selenium Toxicity in Animals with Emphasis on Man "This review was undertaken to establish what might be the maximum safe dose of selenium that could be administered to man in studies on the use of the element in cancer prevention. The early history of selenium poisoning is briefly summarized. The literature on clinical signs and toxicity data for acute and for chronic selenosis in farm and experimental animals is discussed. Several cases of acute selenosis in man are reviewed, and a number of reports on chronic selenosis in man are reviewed and evaluated. Based on these, the maximum safe single oral dose of selenite, selenate, DL-selenocysteine, or DL-selenomethionine is suggested as 0.05 mg Se/kg body weight (milligrams of selenium per kilogram of body weight). The maximum safe multiple oral dose is suggested as 5 µg Se/kg body weight."

http://online.liebertpub.com/doi/abs/10.1089/105072503770867237 Biologic Variation is Important for Interpretation of Thyroid Function Tests "Large variations exist in thyrotropin (TSH) and thyroid hormones in serum. The components of variation include preanalytical, analytical, and biologic variation. This is divided into between- and within-individual variation. The latter consists of circadian and seasonal differences although there are indicators of a genetically determined starting point. The ratio of within- to between-individual variation describes the reliability of population-based reference ranges. This ratio is low for serum TSH, thyroxine (T4) and triiodothyronine (T3) indicating that laboratory reference ranges are relatively insensitive to aberrations from normality in the individual. Solutions are considered but reducing the analytical variation below the calculated analytical goals of 7%, 5% and 12% for serum T3, T4, and TSH does not improve diagnostic performance. Neither does determination of the individual set-point and reference range. In practice this means that population-based reference ranges are necessary but that it is important to recognize their limitations for use in individuals. Serum TSH responds with amplification to minor alterations in T4 and T3. A consistently abnormal TSH probably indicates that T4 and T3 are not normal for the individual even when inside the laboratory reference range. This underlines the importance of TSH in diagnosis and monitoring of thyroid dysfunctions. Also, it implies that subclinical thyroid disease may be defined in purely biochemical terms. Under critical circumstances such as pregnancy where normal thyroid function is of importance for fetal brain development, subclinical thyroid disease should be treated. Even TSH within the reference range may be associated with slightly abnormal thyroid function of the individual. The clinical importance of such small abnormalities in thyroid function in small children and pregnant women for brain development remains to be elucidated."

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2957929/ Childhood Exposure to Phthalates: Associations with Thyroid Function, Insulin-like Growth Factor I, and Growth "Phthalates are widely used chemicals, and human exposure is extensive. Recent studies have indicated that phthalates may have thyroid-disrupting properties. Methods: In 845 children 4–9 years of age, we determined urinary concentrations of 12 phthalate metabolites and serum levels of thyroid-stimulating hormone, thyroid hormones, and IGF-I. Results: Phthalate metabolites were detected in all urine samples, of which monobutyl phthalate was present in highest concentration. Phthalate metabolites were negatively associated with serum levels of free and total triiodothyronine, although statistically significant primarily in girls. Metabolites of di(2-ethylhexyl) phthalate and diisononyl phthalate were negatively associated with IGF-I in boys. Most phthalate metabolites were negatively associated with height, weight, body surface, and height gain in both sexes. Conclusions: Our study showed negative associations between urinary phthalate concentrations and thyroid hormones, IGF-I, and growth in children. Although our study was not designed to reveal the mechanism of action, the overall coherent negative associations between urine phthalate and thyroid and growth parameters may suggest causative negative roles of phthalate exposures for child health."

http://medcontent.metapress.com/content/q26mu18227312384/ The Relation Between Serum Ferritin and Goiter, Urinary Iodine and Thyroid Hormone Concentration "Objective: Many children are at high risk of both goiter and iron deficiency in Iran. Because iron deficiency may impair the efficacy of iodine supplementation, the aim of this study was to determine the relation between serum ferritin and goiter, urinary iodine, and thyroid hormones following iodized salt supplementation. Design: A cross-sectional study of schoolchildren in 26 Iranian provinces. Methods: In a national iodine deficiency disorders (IDD) monitoring program, 36178 schoolchildren, approximately 1200 from each province, received goiter grading by WHO criteria. Urine and serum samples were collected from 2917 children and assayed for urinary iodine and serum ferritin, T4, T3, and thyroid-stimulating hormone (TSH) concentrations. Results: Total goiter rates were 80 and 20% in children with ferritin concentrations < 10 mg/dL and _ 10 mg/dL, respectively (p < 0.001). Increased serum T3 and decreased resin T3 uptake was present in those with lower serum ferritin levels; however, free T3 and T4 index, serum T4, and TSH were not significantly different between those with low and normal ferritin. Conclusion: Iron deficiency is associated with a high prevalence of goiter in Iranian schoolchildren."

http://www.eje.org/content/158/2/209.short
Serum TSH and serum thyroid peroxidase antibody fluctuate in parallel and high urinary iodine excretion predicts subsequent thyroid failure in a 1-year study of patients with untreated subclinical hypothyroidism "Results: Over the study year, s-TSH increased significantly in 5 patients, 16 had unchanged s-TSH, whereas none improved. From clinical and biochemical inclusion data, it was not possible to predict who would later increase in s-TSH. In individual patients, a highly significant correlation between s-TSH and s-TPO-Ab was found (r=0.37, P<0.0001) and also between s-TSH and urinary iodine excretion (r=0.14, P=0.034). No correlation between s-TSH and clinical symptoms and signs was observed. Time shift showed best correlation between s-TSH and s-TPO-Ab measured at the same time point, whereas urinary iodine excretion correlated best to s-TSH and s-TPO-Ab obtained 1 month later. Conclusion: At the time of inclusion, it was not possible to identify the 24% of SH patients who would show deterioration in thyroid function over the following year. Impairment in thyroid function varied in parallel with thyroid autoimmunity, whereas high urinary iodine excretion predicted high s-TSH and s-TPO-Ab 1 month later." -->

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