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Research Sex Hormone-Binding Globulin (SHBG)
Metabolic Health

Sex Hormone-Binding Globulin (SHBG)

Optimal Result: 24.6 - 122 nmol/L.

The sex hormone binding globulin (SHBG) test measures the concentration of SHBG in the blood. 

SHBG is a protein that is produced by the liver and binds tightly to testosterone, dihydrotestosterone (DHT), and estradiol (an estrogen). In this bound state, it transports them in the blood as a biologically inactive form.

The amount of SHBG in circulation is affected by age and sex, by decreased or increased testosterone or estrogen production, and can be affected by certain diseases and conditions such as liver disease, hyperthyroidism or hypothyroidism, and obesity.

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Sex hormone-binding globulin (SHBG) is a protein that binds tightly to the primary sex hormones testosterone, dihydrotestosterone, and estradiol (an estrogen). In this bound state, SHBG transports these hormones in the blood as biologically inactive forms. Therefore, changes in SHBG levels can affect the amount of hormone that is available to be used by the body’s tissues. The sex hormone-binding globulin test may be used to help evaluate men for low testosterone and women for excess testosterone production. A healthcare professional may order this test in conjunction with other tests to evaluate the status of a person’s sex hormones. In men, SHBG and total testosterone levels may be ordered to help determine the cause of infertility, a decreased sex drive, or erectile dysfunction. In women, SHBG and testosterone testing may be useful in helping to detect and evaluate excess testosterone production and/or decreased SHBG concentrations and in evaluating women suspected of having polycystic ovary syndrome (PCOS). Although small amounts of testosterone are produced by the ovaries and adrenal glands, even slight increases can disrupt the balance of hormones. Currently, the SHBG test is not performed frequently or routinely. Primarily, this test is ordered when the total testosterone results do not seem to be consistent with clinical signs and symptoms, such as: sexual problems in men, and irregular menstruation and/or excess hair growth in women.

What are normal SHBG levels?
The normal ranges for SHBG concentrations in adults are:

Males: 10 to 57 nanomoles per liter (nmol/L)
Females (nonpregnant): 18 to 144 nmol/L

Men typically have lower SHBG levels than women. However, a man’s SHBG level will usually increase with age as his testosterone levels drop.

Pregnancy usually raises SHBG levels. They typically return to normal after childbirth.

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The function and purpose of a SHBG test:

- The sex hormone binding globulin (SHBG) test may be used to help evaluate men for low testosterone and women for excess testosterone production. 

- It may be ordered in conjunction with other tests to evaluate the status of a person's sex hormones. 

- SHBG and total testosterone levels may be ordered for an adult male to help determine the cause of infertility, a decreased sex drive, or erectile dysfunction. 

- Measurement of SHBG in addition to testosterone is especially helpful when total testosterone results are inconsistent with clinical signs. 

Why measuring total testosterone may not be sufficient: 

Measurement of total testosterone in the blood does not distinguish between bound and unbound (bioavailable) testosterone but, as the name implies, determines the overall quantity of testosterone in the blood. In many cases, this is sufficient to evaluate excessive or deficient testosterone production. 

However, if a person's SHBG level is not normal, then the total testosterone may not be an accurate representation of the amount of testosterone that is available to the body's tissues. 

Measurement of SHBG helps health practitioners assess bioavailable testosterone with a simple total testosterone measurement. 

References:

- Pugeat M, Crave JC, Tourniare J, Forest MG: Clinical utility of sex hormone-binding globulin measurement. Horm Res 1996 [L]

- Tehernof A, Despres JP: Sex steroid hormone, sex hormone-binding globulin, and obesity in men and women. Horm Metab Res 2000 [L]

- Kahn SM, Hryb DJ, Nakhle AM, Romas NA: Sex hormone-binding globulin is synthesized in target cells. J Endocrinol 2002 [L]

- Hammond GL: Access of reproductive steroids to target issues. Obstet Gynecol Clin North Am 2002 [L]

- 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 [L]

What does it mean if your Sex Hormone-Binding Globulin (SHBG) result is too high?

A high SHBG level means that it is likely that less free testosterone is available to the tissues than is indicated by the total testosterone test. This may be seen in:

-Liver disease

-Hyperthyroidism

-Eating disorders like anorexia nervosa

-Corticosteroids or estrogen use (hormone replacement therapy or oral contraceptives

-Pregnancy

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Increased SHBG in men may be associated with symptoms of low testosterone levels (=hypogonadism) because less testosterone is available to the body's tissues. The Endocrine Society professional guidelines recommend measuring total testosterone in the initial screen for testosterone deficiency. If abnormal, the test is repeated on another day. If repeat results are low-normal and/or if SHBG is abnormal, they recommend one of the following:

- Measure bioavailable testosterone (using ammonium sulfate precipitation or SHBG). 

- Calculate free testosterone from total testosterone and SHBG 

- Measure free testosterone (using a method called equilibrium dialysis) 

In women, small amounts of testosterone are produced by the ovaries and adrenal glands. 

Even slight increases in testosterone production can disrupt the balance of hormones and cause symptoms such as irregular or missed menstrual periods, infertility, acne, and excess facial and body hair (hirsutism). These signs and symptoms and others are often seen with polycystic ovary syndrome (PCOS), a condition characterized by an excess production of male sex hormones (androgens). SHBG and testosterone testing may be useful in helping to detect and evaluate excess testosterone production and/or decreased SHBG concentrations and in evaluating women suspected of having PCOS.

Thyrotoxicosis (an excess of thyroid hormone in the body) increases SHBG levels. In situations when assessment of true functional thyroid status may be difficult (e.g., 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 (e.g., 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.

Patients with anorexia nervosa have high SHBG levels. With successful treatment, levels start to fall as nutritional status improves.    

What are normal SHBG levels?
The normal ranges for SHBG concentrations in adults are:

Males: 10 to 57 nanomoles per liter (nmol/L)
Females (nonpregnant): 18 to 144 nmol/L

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Elevated SHBG levels and normal/elevated Testosterone markers:

Elevated levels of Sex Hormone-Binding Globulin (SHBG) with normal or elevated testosterone levels (total, free, and bioavailable) suggest a complex hormonal balance where the body compensates for high SHBG by maintaining sufficient testosterone levels. This indicates effective endocrine regulation but may also point to underlying health conditions such as liver disease, hyperthyroidism, or age-related changes, as the liver produces SHBG and its levels can be influenced by thyroid hormones. Clinically, this scenario can present differently depending on individual symptoms; while normal or high free testosterone levels can mitigate symptoms of androgen excess, elevated SHBG may reduce free testosterone availability enough to cause symptoms of low testosterone, such as fatigue or decreased libido. It's crucial to consider a detailed hormonal profile, including estradiol and thyroid hormones, and evaluate for liver and thyroid function. Addressing underlying causes, adjusting hormone therapy if necessary, and regular monitoring are essential for effective management. This comprehensive approach ensures any contributing factors are treated, maintaining an optimal hormonal balance and mitigating adverse symptoms.

What does it mean if your Sex Hormone-Binding Globulin (SHBG) result is too low?

A low SHBG level means that more of the total testosterone is bioavailable and not bound to SHBG.

Decreases in SHBG are seen with:

- Obesity

- Polycystic ovary syndrome

- Hypothyroidism

- Steroid use

- Cushing disease

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IN WOMEN:

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 (e.g., estrogens or weight loss), reduces bioactivity of androgens (e.g., androgen receptor antagonists, alpha-reductase inhibitors), or reduces insulin resistance (e.g. 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 (e.g., 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.

SHBG is also produced by placental tissue and therefore values will be elevated during pregnancy. In patients with known insulin resistance, "metabolic syndrome," or high risk of type 2 diabetes (e.g., 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.

What are normal SHBG levels?
The normal ranges for SHBG concentrations in adults are:

Males: 10 to 57 nanomoles per liter (nmol/L)
Females (nonpregnant): 18 to 144 nmol/L

Men typically have lower SHBG levels than women. However, a man’s SHBG level will usually increase with age as his testosterone levels drop.

Pregnancy usually raises SHBG levels. They typically return to normal after childbirth.

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