Sex Hormone-Binding Globulin (SHBG)

Understanding Elevated SHBG and Its Impact on Hormonal Balance

What Is SHBG?

Sex Hormone-Binding Globulin (SHBG) is a protein produced primarily by the liver that binds tightly to sex hormones, especially testosterone and estrogen, making them biologically inactive. Only free or bioavailable testosterone—which is not tightly bound to SHBG—can enter cells and exert hormonal effects.

Why Does SHBG Matter?

A high SHBG level means less free testosterone is available to the body's tissues than might be suggested by total testosterone levels. This can lead to symptoms of low testosterone (hypogonadism), even when total or bioavailable testosterone levels appear normal or elevated.

Causes of Elevated SHBG

Elevated SHBG may occur in various physiological and clinical contexts, including:

• Liver disease (SHBG is synthesized by the liver)

• Hyperthyroidism (thyroid hormones increase SHBG production)

• Eating disorders, such as anorexia nervosa

• Certain medications, including:

  • Oral contraceptives

  • Estrogen therapy

  • Corticosteroids

  • Anticonvulsants

• Pregnancy

• Aging

• Malnutrition or low protein intake

Clinical Implications

In Men:

• Increased SHBG may reduce free testosterone levels and lead to symptoms of hypogonadism, such as:

  • Fatigue

  • Decreased libido

  • Mood changes

  • Reduced muscle mass

Diagnostic Approach (per Endocrine Society Guidelines):

• Start with total testosterone

• If levels are abnormal, repeat the test

• If results are low-normal or if SHBG is abnormal:

  • Measure bioavailable testosterone

  • Calculate free testosterone using SHBG and total testosterone

  • Or directly measure free testosterone (via equilibrium dialysis)

In Women:

• Small amounts of testosterone are produced by the ovaries and adrenal glands.

• Even slight increases in testosterone—particularly if SHBG is low—can lead to androgen excess symptoms, such as:

  • Irregular or missed periods

  • Acne

  • Infertility

  • Excess facial/body hair (hirsutism)

• These symptoms are commonly seen in polycystic ovary syndrome (PCOS).

• SHBG and testosterone testing help assess androgen imbalance and guide PCOS diagnosis.

SHBG and Thyroid Disease

• Thyrotoxicosis (excess thyroid hormone) raises SHBG levels.

• Elevated SHBG may indicate tissue-level hyperthyroidism, even when thyroid hormone levels are difficult to interpret (e.g., with amiodarone use or abnormal thyroid transport proteins).

• Serial SHBG testing can aid treatment timing for conditions like toxic nodular goiter or TSH-suppressive therapy in thyroid cancer.

SHBG in Anorexia Nervosa

• Individuals with anorexia nervosa often have elevated SHBG, reflecting poor nutritional status.

• With treatment and improved nutrition, SHBG levels typically decline.

SHBG Reference Ranges

Typical SHBG reference values:

• Males: 10–57 nmol/L

• Females (nonpregnant): 18–144 nmol/L

(Note: Ranges may vary slightly by lab.)

Elevated SHBG with Normal/High Testosterone: A Closer Look

When SHBG is elevated but total, free, or bioavailable testosterone remains within or above the normal range, this reflects compensated endocrine function. The body may increase testosterone production to offset SHBG’s binding effect.

However, even in this state:

• Free testosterone may still be functionally low, leading to symptoms

• Individuals vary in sensitivity to these hormonal shifts

Key Consideration:

• Bioavailable testosterone includes both free and loosely albumin-bound testosterone (still usable by tissues), but SHBG-bound testosterone is inactive.

Clinical Evaluation Checklist

When elevated SHBG is detected, a full evaluation should include:

• Estradiol levels

• Thyroid function tests (TSH, Free T3, Free T4)

• Liver function tests

• Symptom assessment

• Medication and nutrition review

Management and Monitoring

Management depends on the cause:

• Treat underlying thyroid or liver disease

• Adjust hormone therapy if needed

• Improve nutritional status

• Review and modify medications impacting SHBG

Ongoing monitoring of SHBG, testosterone fractions, and symptoms helps fine-tune treatment for optimal hormonal balance.

Summary

Elevated SHBG—whether alone or alongside normal/elevated testosterone—requires contextual interpretation. It can both mask androgen deficiency symptoms and contribute to them by lowering free hormone availability. A comprehensive, symptom-driven approach that includes lab interpretation, clinical context, and targeted intervention is essential for effective management.

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.

Sex hormone-binding globulin is a protein that binds primarily to testosterone, making it biologically unusable by our bodies. For this reason, an abnormal level of SHBG indicates that too much or too little testosterone is present in the tissues. In men, this can cause sexual issues like erectile dysfunction or infertility. In women, it can cause irregular menstruation or excess facial hair growth. A healthcare professional may order a SHBG test when total testosterone levels do not fit with one or more of the above-mentioned symptoms.

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.