Thyroid Supplement Increases Estrogen

[Vida]

Could someone plz explain why supplementing thyroid would increase estrogen/cause estrogenic symptoms?

 

[meatbag]

Could someone plz explain why supplementing thyroid would increase estrogen/cause estrogenic symptoms?

I'm not sure what kind of thyroid supplemtnet you're refering to; if your talking about dessicated thyroid (70% T4), levothyroxine (pure T4), pure T3?

“There’s almost no context in which I would speak of “an appropriate dose of T4,” since thyroxin is so effective as an antithyroid substance. It’s appropriate if you are also taking T3, or if you want to shrink your thyroid. Thyroid will dependably correct your pregnenolone production, if you have enough cholesterol, vitamin A, and protein. The cholesterol will be consumed to make pregnenolone and progesterone and bile acids. If cholesterol is below 160, fruit sugar helps to raise it. The protein is needed to detoxify estrogen, unsaturated oils, etc, and to maintain the T3. Protein deficiency gives antithyroid signals, and T4 will be used to make reverse T3 to inhibit T3’s effects. About 3 mcg of T3 especially if it’s taken with milk or gelatine-rich salty soup is effective for stopping the nocturnal alarm reaction.” - Ray Peat, excerpt from this article on quotes on using thyroid from Functional Performance Systems:
Ray Peat, PhD on Thyroid, Temperature, Pulse, and TSH

It's a really helpful read and answers a lot of questions about Ray Peat's views on Thyroid. That said if it is elevating estrogen too much T4 could be the culprit since it would inhibit the own glands secretion of T4 AND T3 and cause the liver to produce Reverse T3 which opposes T3's effects, one of which is "opposing estrogen".

 

[Vida]

I'm not sure what kind of thyroid supplemtnet you're refering to; if your talking about dessicated thyroid (70% T4), levothyroxine (pure T4), pure T3?

“There’s almost no context in which I would speak of “an appropriate dose of T4,” since thyroxin is so effective as an antithyroid substance. It’s appropriate if you are also taking T3, or if you want to shrink your thyroid. Thyroid will dependably correct your pregnenolone production, if you have enough cholesterol, vitamin A, and protein. The cholesterol will be consumed to make pregnenolone and progesterone and bile acids. If cholesterol is below 160, fruit sugar helps to raise it. The protein is needed to detoxify estrogen, unsaturated oils, etc, and to maintain the T3. Protein deficiency gives antithyroid signals, and T4 will be used to make reverse T3 to inhibit T3’s effects. About 3 mcg of T3 especially if it’s taken with milk or gelatine-rich salty soup is effective for stopping the nocturnal alarm reaction.” - Ray Peat, excerpt from this article on quotes on using thyroid from Functional Performance Systems:
Ray Peat, PhD on Thyroid, Temperature, Pulse, and TSH

It's a really helpful read and answers a lot of questions about Ray Peat's views on Thyroid. That said if it is elevating estrogen too much T4 could be the culprit since it would inhibit the own glands secretion of T4 AND T3 and cause the liver to produce Reverse T3 which opposes T3's effects, one of which is "opposing estrogen".

Nice, thank you for this! I'm talking about pure T4 and NDT. Also low dose pure T3 gives estrogenic symptoms. I find this is really hard to get right. What seems logical and right in theory often fails in practice.

 

[RKIII]

Elevated T3 levels can increase E2. An increase in thyroid hormone increases Sexual Hormone-Binding Globule. SHBG attaches itself to sex hormones rendering them inactive. That could be throwing the balance of sex hormones out of balance resulting in estrogenic symptoms. You would need to confirm this with a blood test. I experienced this with high T3 and high out of range E2.

 

[Vida]

Elevated T3 levels can increase E2. An increase in thyroid hormone increases Sexual Hormone-Binding Globule. SHBG attaches itself to sex hormones rendering them inactive. That could be throwing the balance of sex hormones out of balance resulting in estrogenic symptoms. You would need to confirm this with a blood test. I experienced this with high T3 and high out of range E2.

How did you correct this issue, what did you do to lower the estrogen/get the sex hormones in balance? Is/was your SHBG in the higher range?

 

[meatbag]

Elevated T3 levels can increase E2. An increase in thyroid hormone increases Sexual Hormone-Binding Globule. SHBG attaches itself to sex hormones rendering them inactive. That could be throwing the balance of sex hormones out of balance resulting in estrogenic symptoms. You would need to confirm this with a blood test. I experienced this with high T3 and high out of range E2.

In the case of thyroid increasing SHBG, the protein would pick up the estrogen out of the serum for excretion via the liver;

"While the competition by PUFA for protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen, it is able to enter cells, and in that estrogen-free state it probably serves a similar protective function, capturing estrogen molecules that enter cells before they can act on other proteins or chromosomes"
Fats, functions, and malfunctions - Ray Peat

Also check out this quote from @haidut and Ray Peat, in many cases it is the "bound" hormones that exert the effects on the cell.

I think the hormones that have an effect are the ones bound to albumin and other proteins like SHBG that can carry them inside the cell. The so-called free testosterone can't do much while in the blood stream. Here is an article from Peat where he talks about progesterone and thyroid, and "free" vs. bound hormones. The discussion applies just as well to testosterone. Bottom line is that while blood tests are unreliable, you probably want as high total testosterone and as low free testosterone as possible.
Thyroid: Therapies, Confusion, and Fraud
"...The idea that the "free hormone" is the active form has been tested in a few situations, and in the case of the thyroid hormone, it is clearly not true for the brain, and some other organs. The protein-bound hormone is, in these cases, the active form; the associations between the "free hormone" and the biological processes and diseases will be completely false, if they are ignoring the active forms of the hormone in favor of the less active forms. The conclusions will be false, as they are when T4 is measured, and T3 ignored. Thyroid-dependent processes will appear to be independent of the level of thyroid hormone; hypothyroidism could be caller hyperthyroidism.

Although progesterone is more fat soluble than cortisol and the thyroid hormones, the behavior of progesterone in the blood illustrates some of the problems that have to be considered for interpreting thyroid physiology. When red cells are broken up, they are found to contain progesterone at about twice the concentration of the serum. In the serum, 40 to 80% of the progesterone is probably carried on albumin. (Albumin easily delivers its progesterone load into tissues.) Progesterone, like cholesterol, can be carried on/in the lipoproteins, in moderate quantities. This leaves a very small fraction to be bound to the "steroid binding globulin." Anyone who has tried to dissolve progesterone in various solvents and mixtures knows that it takes just a tiny amount of water in a solvent to make progesterone precipitate from solution as crystals; its solubility in water is essentially zero. "Free" progesterone would seem to mean progesterone not attached to proteins or dissolved in red blood cells or lipoproteins, and this would be zero. The tests that purport to measure free progesterone are measuring something, but not the progesterone in the watery fraction of the serum.

The thyroid hormones associate with three types of simple proteins in the serum: Transthyretin (prealbumin), thyroid binding globulin, and albumin. A very significant amount is also associated with various serum lipoproteins, including HDL, LDL, and VLDL (very low density lipoproteins). A very large portion of the thyroid in the blood is associated with the red blood cells. When red cells were incubated in a medium containing serum albumin, with the cells at roughly the concentration found in the blood, they retained T3 at a concentration 13.5 times higher than that of the medium. In a larger amount of medium, their concentration of T3 was 50 times higher than the medium's. When laboratories measure the hormones in the serum only, they have already thrown out about 95% of the thyroid hormone that the blood contained.

The T3 was found to be strongly associated with the cells' cytoplasmic proteins, but to move rapidly between the proteins inside the cells and other proteins outside the cells.

When people speak of hormones travelling "on" the red blood cells, rather than "in" them, it is a concession to the doctrine of the impenetrable membrane barrier.

Much more T3 bound to albumin is taken up by the liver than the small amount identified in vitro as free T3 (Terasaki, et al., 1987). The specific binding of T3 to albumin alters the protein's electrical properties, changing the way the albumin interacts with cells and other proteins. (Albumin becomes electrically more positive when it binds the hormone; this would make the albumin enter cells more easily. Giving up its T3 to the cell, it would become more negative, making it tend to leave the cell.) This active role of albumin in helping cells take up T3 might account for its increased uptake by the red cells when there were fewer cells in proportion to the albumin medium. This could also account for the favorable prognosis associated with higher levels of serum albumin in various sicknesses.

When T3 is attached chemically (covalently, permanently) to the outside of red blood cells, apparently preventing its entry into other cells, the presence of these red cells produces reactions in other cells that are the same as some of those produced by the supposedly "free hormone." If T3 attached to whole cells can exert its hormonal action, why should we think of the hormone bound to proteins as being unable to affect cells? The idea of measuring the "free hormone" is that it supposedly represents the biologically active hormone, but in fact it is easier to measure the biological effects than it is to measure this hypothetical entity. Who cares how many angels might be dancing on the head of a pin, if the pin is effective in keeping your shirt closed? "

 

[RKIII]

I never got it SHBG tested. I was too concerned about getting gyno and the weight I was gaining.

I tried to supplement my liver with vitamins and antioxidants to help with estrogen clearance and used lisuride ( metergoline was OOS) 11 keto dht to fight prolactin/estrogen and took an OTC aromatase inhibitor which work rather well. I lost a lot of water weight and am now able to supplement T3 to try to clear my rT3 levels.

The things that I read about that could lower SHBG were boron and nettle root. But I didn't find anything convincing which is why I went the way I did.

You really won't know if it is SHBG unless you get a test.

Have you tried supplementing progesterone to offset the estrogen?

 

[meatbag]

Nice, thank you for this! I'm talking about pure T4 and NDT. Also low dose pure T3 gives estrogenic symptoms. I find this is really hard to get right. What seems logical and right in theory often fails in practice.

Which product are you using?

 

[RKIII]

In the case of thyroid increasing SHBG, the protein would pick up the estrogen out of the serum for excretion via the liver;

"While the competition by PUFA for protein binding sites blocks the effects of thyroid hormone and vitamin A, the action of PUFA on the sex steroid binding protein (SBP, or SSBG, for sex steroid binding globulin) increases the activity of estrogen. That's because the SSBG neutralizes estrogen by binding it, keeping it out of cells; free PUFA keep it from binding estrogen (Reed, et al., 1986). People with low SSBG/estrogen ratio have an increased risk of cancer. When the SSBG protein is free of estrogen, it is able to enter cells, and in that estrogen-free state it probably serves a similar protective function, capturing estrogen molecules that enter cells before they can act on other proteins or chromosomes"
Fats, functions, and malfunctions - Ray Peat

Also check out this quote from @haidut and Ray Peat, in many cases it is the "bound" hormones that exert the effects on the cell.

SSBG/SHBG does not always bind to estrogen. It is when it does not bind to estrogen in excess that estrogen dominance can occur.

I believe it has a slightly greater affinity for testosterone than it does estrogen.

Elevated T3 can also raise levels of the aromatase enzyme further increasing estrogen levels.

It's nice to know that I have an increased cancer risk.

 

[beachbum]

Elevated T3 levels can increase E2. An increase in thyroid hormone increases Sexual Hormone-Binding Globule. SHBG attaches itself to sex hormones rendering them inactive. That could be throwing the balance of sex hormones out of balance resulting in estrogenic symptoms. You would need to confirm this with a blood test. I experienced this with high T3 and high out of range E2.

Well that makes sense from what I just read about low or high levels of SHBG, see below:

SHBG levels are decreased by androgens, administration of anabolic steroids,[21] polycystic ovary syndrome, hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[22] SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction of more than 50 percent increases SHBG, while lowering free and total testosterone and estradiol. DHEA-S, which lacks affinity for SHBG, is not affected by calorie restriction.[23] Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[24]

In the womb the human fetus has a low level of SHBG allowing increased activity of sex hormones. After birth, the SHBG level rises and remains at a high level throughout childhood. At puberty the SHBG level halves in girls and goes down to a quarter in boys.[3] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In pregnant women in the last two thirds of pregnancy the SHBG level escalates to five to ten times the usual level for a woman. A hypothesis is that this protects against the effect of hormone produced by the fetus.[3]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[3] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[3]

Now see another I read below, so basically low SHBG increase in weight --high decrease,:

Sex Hormone-Binding Globulin (SHBG), Serum

• Overview
• Specimen
• Clinical and Interpretive
• Performance
• Fees and Coding

LIS Resources

• Setup Information:
  Excel | PDF
• Sample Report
• Abnormal Report
• Setup Reference Guide

Useful For

Diagnosis and follow-up of women with symptoms or signs of androgen excess (eg, polycystic ovarian syndrome and idiopathic hirsutism)

An adjunct in monitoring sex-steroid and anti-androgen therapy

An adjunct in the diagnosis of disorders of puberty

An adjunct in the diagnosis and follow-up of anorexia nervosa

An adjunct in the diagnosis of thyrotoxicosis (tissue marker of thyroid hormone excess)

A possible adjunct in diagnosis and follow-up of insulin resistance and cardiovascular and type 2 diabetes risk assessment, particularly in women

In laboratories without access to bioavailable testosterone or equilibrium dialysis-based "true" free testosterone assays, sex hormone-binding globulin measurement is crucial in cases when assessment of the free testosterone fraction (aka free androgen index or calculated free testosterone) is required. At Mayo Medical Laboratories, both bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) and free testosterone (TGRP / Testosterone, Total and Free, Serum) measurements are available. Free testosterone (TGRP) is measured by equilibrium dialysis, obviating the need for sex hormone-binding globulin measurements to calculate free androgen fractions.

Clinical Information

Sex hormone-binding globulin (SHBG), a homodimeric 90,000 to 100,000 molecular weight glycoprotein, is synthesized in the liver. Metabolic clearance of SHBG is biphasic, with a fast initial distribution from vascular compartment into extracellular space (half-life of a few hours), followed by a slower degradation phase (half-life of several days).

SHBG binds sex steroids with high affinity (KD approximately 10[-10]M), dihydrotestosterone (DHT) ->testosterone (T) ->estrone/estradiol (E). Although each monomeric subunit contains 1 steroid binding site, the dimer tends to bind only a single sex-steroid molecule. The main function of SHBG is sex-steroid transport within the blood stream and to extravascular target tissues. SHBG also plays a key role in regulating bioavailable sex-steroid concentrations through competition of sex steroids for available binding sites and fluctuations in SHBG concentrations. Because of the higher affinity of SHBG for DHT and T, compared to E, SHBG also has profound effects on the balance between bioavailable androgens and estrogens. Increased SHBG levels may be associated with symptoms and signs of hypogonadism in men, while decreased levels can result in androgenization in women.

SHBG levels in prepubertal children are higher than in adults. With the increase in fat mass during early puberty they begin to fall, a process that accelerates as androgen levels rise. Men have lower levels compared with women and nutritional status is inversely correlated with SHBG levels throughout life, possibly mediated by insulin resistance. Insulin resistance, even without obesity, results in lower SHBG levels. This is associated with increased intra-abdominal fat deposition and an unfavorable cardiovascular risk profile. In postmenopausal women, it may also predict the future development of type 2 diabetes mellitus. Androgens and norethisterone-related synthetic progesterones also decrease SHBG in women.

Endogenous or exogenous thyroid hormones or estrogens increase SHBG levels. In men, there is also an age-related gradual rise, possibly secondary to the mild age-related fall in testosterone production. This process can result in bioavailable testosterone levels that are much lower than would be expected based on total testosterone measurements alone.

Reference Values

CHILDREN

Males

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

31-167

Stage II

11.5

49-179

Stage III

13.6

5.8-182

Stage IV

15.1

14-98

Stage V

18.0

10-57

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for boys at a median age of 11.5 (+/-2) years. For boys, there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.


Females

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

43-197

Stage II

10.5

7.7-119

Stage III

11.6

31-191

Stage IV

12.3

31-166

Stage V

14.5

18-144

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for girls at a median age of 10.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African American girls. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.

ADULTS
Males: 10-57 nmol/L
Females (non-pregnant): 18-144 nmol/L

Interpretation

Many conditions of mild-to-moderate androgen excess in women, particularly polycystic ovarian syndrome, are associated with low sex hormone-binding globulin (SHBG) levels. Most of these women are also insulin resistant and many are obese. A defect in SHBG production could lead to bioavailable androgen excess, in turn causing insulin resistance that depresses SHBG levels further. There are rare cases of SHBG mutations that clearly follow this pattern. SHBG levels are typically very low in these individuals. However, in most patients, SHBG levels are mildly depressed or even within the lower part of the normal range. In these patients, the primary problem may be androgen overproduction, insulin resistance, or both. A definitive cause cannot be usually established. Any therapy that either increases SHBG levels (eg, estrogens or weight loss), reduces bioactivity of androgens (eg, androgen receptor antagonists, alpha-reductase inhibitors), or reduces insulin resistance (eg, weight loss, metformin, peroxisome proliferator-activated receptor [PPAR] gamma agonists), can be effective. Improvement is usually associated with a rise in SHBG levels, but bioavailable or free testosterone levels should also be monitored.

The primary method of monitoring sex-steroid or antiandrogen therapy is direct measurement of the relevant sex-steroids and gonadotropins. However, for many synthetic androgens and estrogens (eg, ethinyl-estradiol) clinical assays are not available. In those instances, rises in SHBG levels indicate successful anti-androgen or estrogen therapy, while falls indicate successful androgen treatment.

Adult SHBG levels in boys with signs of precocious puberty support that the condition is testosterone driven, rather than representing premature adrenarche.

Patients with anorexia nervosa have high SHBG levels. With successful treatment, levels start to fall as nutritional status improves. Normalization of SHBG precedes, and may be predictive of, future normalization of reproductive function.

Thyrotoxicosis increases SHBG levels. In situations when assessment of true functional thyroid status may be difficult (eg, patients receiving amiodarone treatment, individuals with thyroid hormone transport-protein abnormalities, patients with suspected thyroid hormone resistance or suspected inappropriate thyroid-stimulating hormone [TSH] secretion such as a TSH-secreting pituitary adenoma), an elevated SHBG level suggests tissue thyrotoxicosis, while a normal level indicates euthyroidism or near-euthyroidism. In patients with gradual worsening of thyrotoxicosis (eg, toxic nodular goiter), serial SHBG measurement, in addition to clinical assessment, thyroid hormone, and TSH measurement, may assist in the timing of treatment decisions. Similarly, SHBG measurement may be of value in fine-tuning suppressive TSH therapy for patients with nodular thyroid disease or treated thyroid cancer. Results are not definitive in the short-term in patients receiving drugs that displace total thyroxine (T4) from albumin.

SHBG is also produced by placental tissue and therefore values will be elevated during pregnancy. Reference ranges for pregnant females have not been established in our institution.

In patients with known insulin resistance, "metabolic syndrome," or high risk of type 2 diabetes (eg, women with a history of gestational diabetes), low SHBG levels may predict progressive insulin resistance, cardiovascular complications, and progression to type 2 diabetes. An increase in SHBG levels may indicate successful therapeutic intervention.

A genetic variant of SHBG (Asp327->Asn) introduces an additional glycosylation site in 10% to 20% of the population, resulting in significantly slower degradation. These individuals tend to have higher SHBG levels for any given level of other factors influencing SHBG.

Cautions

Human antimouse antibodies may be present in specimens from patients who have received immunotherapy utilizing monoclonal antibodies. Other heterophile antibodies may also be present in patient specimens. This assay has been specifically formulated to minimize the effects of these antibodies on the assay. However, results from patients known to have such antibodies must be carefully evaluated.

Clinical Reference

1. Pugeat M, Crave JC, Tourniare J, Forest MG: Clinical utility of sex hormone-binding globulin measurement. Horm Res 1996;45:148-155

2. Tehernof A, Despres JP: Sex steroid hormone, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000;32:526-536

3. Kahn SM, Hryb DJ, Nakhle AM, Romas NA: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 2002;175:113-120

4. Hammond GL: Access of reproductive steroids to target issues. Obstet Gynecol Clin North Am 2002;29:411-423

5. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), cortisol and ferritin in neonates, children, and young adults. Clin Chem Lab Med 2002;40(11):1151-1160

SHBG - Clinical: Sex Hormone-Binding Globulin (SHBG), Serum

This is very interesting...hmmmm..more reading on how to incesae SHBG.

 

[beachbum]

Well that makes sense from what I just read about low or high levels of SHBG, see below:

SHBG levels are decreased by androgens, administration of anabolic steroids,[21] polycystic ovary syndrome, hypothyroidism, obesity, Cushing's syndrome, and acromegaly. Low SHBG levels increase the probability of Type 2 Diabetes.[22] SHBG levels increase with estrogenic states (oral contraceptives), pregnancy, hyperthyroidism, cirrhosis, anorexia nervosa, and certain drugs. Long-term calorie restriction of more than 50 percent increases SHBG, while lowering free and total testosterone and estradiol. DHEA-S, which lacks affinity for SHBG, is not affected by calorie restriction.[23] Polycystic Ovarian Syndrome is associated with insulin resistance and excess insulin lowers SHBG, which increases free testosterone levels.[24]

In the womb the human fetus has a low level of SHBG allowing increased activity of sex hormones. After birth, the SHBG level rises and remains at a high level throughout childhood. At puberty the SHBG level halves in girls and goes down to a quarter in boys.[3] The change at puberty is triggered by growth hormone, and its pulsatility differs in boys and girls. In pregnant women in the last two thirds of pregnancy the SHBG level escalates to five to ten times the usual level for a woman. A hypothesis is that this protects against the effect of hormone produced by the fetus.[3]

Obese girls are more likely to have an early menarche due to lower levels of SHBG.[3] Anorexia or a lean physique in women leads to higher SHBG levels, which in turn can lead to amenorrhea.[3]

Now see another I read below, so basically low SHBG increase in weight --high decrease,:

Sex Hormone-Binding Globulin (SHBG), Serum

• Overview
• Specimen
• Clinical and Interpretive
• Performance
• Fees and Coding

LIS Resources

• Setup Information:
  Excel | PDF
• Sample Report
• Abnormal Report
• Setup Reference Guide

Useful For

Diagnosis and follow-up of women with symptoms or signs of androgen excess (eg, polycystic ovarian syndrome and idiopathic hirsutism)

An adjunct in monitoring sex-steroid and anti-androgen therapy

An adjunct in the diagnosis of disorders of puberty

An adjunct in the diagnosis and follow-up of anorexia nervosa

An adjunct in the diagnosis of thyrotoxicosis (tissue marker of thyroid hormone excess)

A possible adjunct in diagnosis and follow-up of insulin resistance and cardiovascular and type 2 diabetes risk assessment, particularly in women

In laboratories without access to bioavailable testosterone or equilibrium dialysis-based "true" free testosterone assays, sex hormone-binding globulin measurement is crucial in cases when assessment of the free testosterone fraction (aka free androgen index or calculated free testosterone) is required. At Mayo Medical Laboratories, both bioavailable testosterone (TTBS / Testosterone, Total and Bioavailable, Serum) and free testosterone (TGRP / Testosterone, Total and Free, Serum) measurements are available. Free testosterone (TGRP) is measured by equilibrium dialysis, obviating the need for sex hormone-binding globulin measurements to calculate free androgen fractions.

Clinical Information

Sex hormone-binding globulin (SHBG), a homodimeric 90,000 to 100,000 molecular weight glycoprotein, is synthesized in the liver. Metabolic clearance of SHBG is biphasic, with a fast initial distribution from vascular compartment into extracellular space (half-life of a few hours), followed by a slower degradation phase (half-life of several days).

SHBG binds sex steroids with high affinity (KD approximately 10[-10]M), dihydrotestosterone (DHT) ->testosterone (T) ->estrone/estradiol (E). Although each monomeric subunit contains 1 steroid binding site, the dimer tends to bind only a single sex-steroid molecule. The main function of SHBG is sex-steroid transport within the blood stream and to extravascular target tissues. SHBG also plays a key role in regulating bioavailable sex-steroid concentrations through competition of sex steroids for available binding sites and fluctuations in SHBG concentrations. Because of the higher affinity of SHBG for DHT and T, compared to E, SHBG also has profound effects on the balance between bioavailable androgens and estrogens. Increased SHBG levels may be associated with symptoms and signs of hypogonadism in men, while decreased levels can result in androgenization in women.

SHBG levels in prepubertal children are higher than in adults. With the increase in fat mass during early puberty they begin to fall, a process that accelerates as androgen levels rise. Men have lower levels compared with women and nutritional status is inversely correlated with SHBG levels throughout life, possibly mediated by insulin resistance. Insulin resistance, even without obesity, results in lower SHBG levels. This is associated with increased intra-abdominal fat deposition and an unfavorable cardiovascular risk profile. In postmenopausal women, it may also predict the future development of type 2 diabetes mellitus. Androgens and norethisterone-related synthetic progesterones also decrease SHBG in women.

Endogenous or exogenous thyroid hormones or estrogens increase SHBG levels. In men, there is also an age-related gradual rise, possibly secondary to the mild age-related fall in testosterone production. This process can result in bioavailable testosterone levels that are much lower than would be expected based on total testosterone measurements alone.

Reference Values

CHILDREN

Males

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

31-167

Stage II

11.5

49-179

Stage III

13.6

5.8-182

Stage IV

15.1

14-98

Stage V

18.0

10-57

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for boys at a median age of 11.5 (+/-2) years. For boys, there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.


Females

Tanner Stages*

Mean Age

Reference Range (nmol/L)

Stage I

7.1

43-197

Stage II

10.5

7.7-119

Stage III

11.6

31-191

Stage IV

12.3

31-166

Stage V

14.5

18-144

*Puberty onset (transition from Tanner stage I to Tanner stage II) occurs for girls at a median age of 10.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African American girls. Progression through Tanner stages is variable. Tanner stage V (young adult) should be reached by age 18.

ADULTS
Males: 10-57 nmol/L
Females (non-pregnant): 18-144 nmol/L

Interpretation

Many conditions of mild-to-moderate androgen excess in women, particularly polycystic ovarian syndrome, are associated with low sex hormone-binding globulin (SHBG) levels. Most of these women are also insulin resistant and many are obese. A defect in SHBG production could lead to bioavailable androgen excess, in turn causing insulin resistance that depresses SHBG levels further. There are rare cases of SHBG mutations that clearly follow this pattern. SHBG levels are typically very low in these individuals. However, in most patients, SHBG levels are mildly depressed or even within the lower part of the normal range. In these patients, the primary problem may be androgen overproduction, insulin resistance, or both. A definitive cause cannot be usually established. Any therapy that either increases SHBG levels (eg, estrogens or weight loss), reduces bioactivity of androgens (eg, androgen receptor antagonists, alpha-reductase inhibitors), or reduces insulin resistance (eg, weight loss, metformin, peroxisome proliferator-activated receptor [PPAR] gamma agonists), can be effective. Improvement is usually associated with a rise in SHBG levels, but bioavailable or free testosterone levels should also be monitored.

The primary method of monitoring sex-steroid or antiandrogen therapy is direct measurement of the relevant sex-steroids and gonadotropins. However, for many synthetic androgens and estrogens (eg, ethinyl-estradiol) clinical assays are not available. In those instances, rises in SHBG levels indicate successful anti-androgen or estrogen therapy, while falls indicate successful androgen treatment.

Adult SHBG levels in boys with signs of precocious puberty support that the condition is testosterone driven, rather than representing premature adrenarche.

Patients with anorexia nervosa have high SHBG levels. With successful treatment, levels start to fall as nutritional status improves. Normalization of SHBG precedes, and may be predictive of, future normalization of reproductive function.

Thyrotoxicosis increases SHBG levels. In situations when assessment of true functional thyroid status may be difficult (eg, patients receiving amiodarone treatment, individuals with thyroid hormone transport-protein abnormalities, patients with suspected thyroid hormone resistance or suspected inappropriate thyroid-stimulating hormone [TSH] secretion such as a TSH-secreting pituitary adenoma), an elevated SHBG level suggests tissue thyrotoxicosis, while a normal level indicates euthyroidism or near-euthyroidism. In patients with gradual worsening of thyrotoxicosis (eg, toxic nodular goiter), serial SHBG measurement, in addition to clinical assessment, thyroid hormone, and TSH measurement, may assist in the timing of treatment decisions. Similarly, SHBG measurement may be of value in fine-tuning suppressive TSH therapy for patients with nodular thyroid disease or treated thyroid cancer. Results are not definitive in the short-term in patients receiving drugs that displace total thyroxine (T4) from albumin.

SHBG is also produced by placental tissue and therefore values will be elevated during pregnancy. Reference ranges for pregnant females have not been established in our institution.

In patients with known insulin resistance, "metabolic syndrome," or high risk of type 2 diabetes (eg, women with a history of gestational diabetes), low SHBG levels may predict progressive insulin resistance, cardiovascular complications, and progression to type 2 diabetes. An increase in SHBG levels may indicate successful therapeutic intervention.

A genetic variant of SHBG (Asp327->Asn) introduces an additional glycosylation site in 10% to 20% of the population, resulting in significantly slower degradation. These individuals tend to have higher SHBG levels for any given level of other factors influencing SHBG.

Cautions

Human antimouse antibodies may be present in specimens from patients who have received immunotherapy utilizing monoclonal antibodies. Other heterophile antibodies may also be present in patient specimens. This assay has been specifically formulated to minimize the effects of these antibodies on the assay. However, results from patients known to have such antibodies must be carefully evaluated.

Clinical Reference

1. Pugeat M, Crave JC, Tourniare J, Forest MG: Clinical utility of sex hormone-binding globulin measurement. Horm Res 1996;45:148-155

2. Tehernof A, Despres JP: Sex steroid hormone, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000;32:526-536

3. Kahn SM, Hryb DJ, Nakhle AM, Romas NA: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 2002;175:113-120

4. Hammond GL: Access of reproductive steroids to target issues. Obstet Gynecol Clin North Am 2002;29:411-423

5. Elmlinger MW, Kuhnel W, Ranke MB: Reference ranges for serum concentrations of lutropin (LH), follitropin (FSH), estradiol (E2), prolactin, progesterone, sex hormone binding globulin (SHBG), dehydroepiandrosterone sulfate (DHEA-S), cortisol and ferritin in neonates, children, and young adults. Clin Chem Lab Med 2002;40(11):1151-1160

SHBG - Clinical: Sex Hormone-Binding Globulin (SHBG), Serum

This is very interesting...hmmmm..more reading on how to incesae SHBG.

Ok I ws reading more on SHBG and woundering if you reduce IGF-1 it will reduce it. Nt even sure if I should increase SHBG..sill reading.

 

[Abc123]

So I've been on Armour since March. I started at 1.5gr. I've worked my way up to 2.75gr. I feel this dose is optimal for me since temps been about 98.4 around 3pm
But I'm having issues with my nipples getting puffy and swollen. Do you know the reason for this? Is it because there is too much T4 that my body can handle? Causing a rise in Estrogen? Do I need to lower NDT and try to add in T3?
Any help is much appreciated! I'm finally feeling well but having these issues with nipples flaring up.

I'm currently away from home and cannot take blood labs until a few weeks.

 

[Giraffe]

But I'm having issues with my nipples getting puffy and swollen. Do you know the reason for this?

Related thread: Puffy Nipples

 

[RKIII]

Yes +1 to high progesterone being a cause. I had a hunch that was what the link was going to go.

 

[ddjd]

Also low dose pure T3 gives estrogenic symptoms. I find this is really hard to get right. What seems logical and right in theory often fails in practice.

I'm the same T3 seems to cause Estrogenic symptoms for me also

 

[ddjd]

and took an OTC aromatase inhibitor

Did you use aromasin/Exemestane?

 

[ddjd]

Elevated T3 levels can increase E2. An increase in thyroid hormone increases Sexual Hormone-Binding Globule. SHBG attaches itself to sex hormones rendering them inactive. That could be throwing the balance of sex hormones out of balance resulting in estrogenic symptoms. You would need to confirm this with a blood test. I experienced this with high T3 and high out of range E2.

But ray says high SHBG is anti estrogenic?

 

[Mito]

A genetic variant of SHBG (Asp327->Asn) introduces an additional glycosylation site in 10% to 20% of the population, resulting in significantly slower degradation. These individuals tend to have higher SHBG levels for any given level of other factors influencing SHBG.

SHBG Gene Promoter Polymorphisms In Men Are Associated With Serum Sex Hormone-binding Globulin, Andr

 

[ddjd]

SHBG Gene Promoter Polymorphisms In Men Are Associated With Serum Sex Hormone-binding Globulin, Andr

 

[ddjd]

SHBG Gene Promoter Polymorphisms In Men Are Associated With Serum Sex Hormone-binding Globulin, Andr

i cant find that gene but I found this other one rs727428 which im homozygous in