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Sex Hormone-Binding Globulin (SHBG) is an important protein found in the blood. It decreases the effects of sex hormones (especially testosterone) by reducing their availability but also enhances their functions by transporting them to their target tissues. Unusually high or low blood SHBG levels are normally caused by hormone imbalances and can be indicative of several disorders. Read on to learn more about this protein, the diseases associated with changes in its concentration, and how to maintain optimal levels.
What is SHBG?
SHBG binds to the following sex hormones, listed in order of affinity [R]:
- Dihydrotestosterone/DHT (male)
- Testosterone (male)
- Androstenediol (male)
- Estradiol (female)
- Estrone (female)
SHBG has a greater affinity for male sex hormones (androgens) than female sex hormones (estrogens).
The main functions of SHBG include:
SHBG production is blocked by:
- Male sex hormones [R]
- Insulin [R]
- Prolactin [R]
- TNF-alpha (a cytokine) [R]
- Sugars (glucose and fructose) [R]
SHBG can also be made in the:
SHBG levels are very low in babies of both sexes (10x lower than in their mothers) and increase gradually during childhood until puberty when they decrease 2x in girls and 4x in boys. The lower SHBG levels in boys allow for higher concentrations of available male sex hormones, which are necessary for their growth in height and the development of their sex organs [R, R, R].
In adult women, SHBG progressively decreases from 20-60 years and starts increasing after that [R].
Roles of Sex Hormone-Binding Globulin
1) Reduces the Availability and Activity of Sex Hormones
Only unbound (free) hormones can cross cell membranes and reach their targets. By binding to sex hormones, SHBG can reduce their availability and thus, their activity. However, unbound hormones also disappear more quickly from blood [R, R, R].
Because SHBG has more affinity for male hormones, it mainly reduces the activity and elimination rate of male sex hormones. SHBG levels are lower in men than in women, implying that both the activity and elimination rate of male sex hormones are higher in men. Conditions that cause increased SHBG production (e.g., hyperthyroidism) reduce the activity and elimination rate of sex hormones. Conditions that result in decreased SHBG levels (e.g., polycystic ovarian syndrome) increase both activity and elimination rate [R, R, R].
2) Transports Sex Hormones Through Blood
Since sex hormones are fatty molecules and can’t dissolve in water, they are transported through the body by binding to a protein like SHBG or albumin. While female sex hormones can undergo modifications that allow them to dissolve in water, male sex hormones need to be bound to transport proteins [R, R, R].
SHBG can bind to receptors on cell membranes and stimulate the production of a messenger molecule (cAMP), implying that it may not only transport sex hormones to their target tissues but also trigger biological effects [R, R].
SHBG Blood Test
Free testosterone levels can be indirectly calculated using SHBG by assuming that 44-65% of testosterone is bound to SHBG and 33-50% to albumin in men, while 66-78% is bound to SHBG and 20-30% to albumin in women. Free testosterone levels reflect the availability of this hormone more accurately than the total testosterone concentration [R, R, R].
Additionally, SHBG levels can be used as a marker of conditions such as:
- Thyroid disorders [R, R]
- Pituitary gland disorders [R]
- Polycystic ovarian syndrome (PCOS) [R, R]
- Insulin resistance [R]
- Metabolic syndrome [R]
- Androgen receptor disorders [R]
- Eating disorders [R]
Men: 10 – 57 nmol/L
Women: 18 – 144 nmol/L
Symptoms of High SHBG Levels
Symptoms of high SHBG are similar to those of low male sex hormone levels.
- Arrested sexual development (in teenagers)
- Decreased sperm concentration and motility
- Decreased sex drive
- Reduced testicle size
- Breast growth
- Decreased body hair
- Hot flashes
- Reduced bone and muscle mass
- Decreased energy and motivation
- Decreased sex drive
- Irregular or absent periods
- Vaginal dryness
- Reduced bone and muscle mass
- Memory losses
- Depression and anxiety
- Reduced wellbeing
Causes of High SHBG Levels
1) High Estrogen Levels
During the menstrual cycle, estrogen levels increase when the egg is released from the ovaries. In an observational study on 12 women, this rise in estrogen levels was accompanied by an increase in the SHBG concentration in the blood [R].
Birth control pills are powerful combinations of synthetic female sex hormones and progesterone. In three studies of 270 people, SHBG levels were up to 4x higher in women taking oral contraceptives. SHBG levels dropped after discontinuation but were higher than before treatment [R, R, R].
In an observational study on 40 male-to-female transsexuals, During their transition, male-to-female transsexuals take male sex hormone production blockers and female sex hormones, which can increase SHBG levels [R].
Studies in cells found increased SHBG production at high concentrations of the following female sex hormones:
2) High Thyroid Hormone Levels
An observational study on 59 patients with different types of hyperthyroidism found higher SHBG levels [R].
Similarly, intake of thyroid hormone (T3) increased blood SHBG levels in 7 healthy men (RCT) [R].
3) Low Growth Hormone Levels
In an observational study on 74 men and women, SHBG levels were higher in individuals with a hereditary growth hormone deficiency [R].
During mid to late pregnancy, SHBG levels increase up to 5-10x [R].
5) Liver Issues/Disorders
Since SHBG is mainly produced in the liver, liver damage can result in abnormal SHBG levels [R].
Similarly, abnormally high SHBG levels were measured in men with non-alcoholic liver cirrhosis (study on 50 men) [R].
However, in another study, SHBG levels were within normal ranges in women with both alcoholic and non-alcoholic liver cirrhosis. But levels did increase in women with alcoholic cirrhosis who abstained from alcohol for 3 months (a study of 111 women) [R].
In a study on 32 women with hepatitis, disease severity was associated with higher SHBG. Severe hepatitis B viral infection was correlated with higher SHBG levels but not uncomplicated or chronic hepatitis B viral infection. Women with severe hepatitis unrelated to hepatitis B also had elevated levels [R].
This same correlation between disease severity (as measured by fibrosis) and SHBG was seen in 46 men with hepatitis C infections [R].
Excess iron levels in the liver (iron overload) can also cause high SHBG [R].
6) Alcohol Consumption
Alcohol consumption was correlated with higher SHBG levels (as well as higher luteal estrogen and lower testosterone) in premenopausal women. It was not correlated with changes in other sex hormones levels studied (observational study on 2,000 women) [R].
8) Physical Exertion
Changes in SHBG levels from exercise may be affected by age. In 35 people, after a triathlon, SHBG levels were higher in the older participants (50-74 years old) but not the younger (~20 years old) [R]
In another study with 12 people, SHBG levels were decreased following a marathon [R].
Men and women undergoing a stress test had elevated levels of SHBG (and testosterone, estradiol, androstenedione, adrenocorticotropic hormone (ACTH), and cortisol levels, as well as increased heart rate, systolic blood pressure, and diastolic blood pressure) (study with 39 participants) [R].
However, in an observational study of 1,215 Danish men, self-reported stress levels did not impact reproductive hormone levels (SHBG, LH, FSH, testosterone, calculated free testosterone, and inhibin B) [R]
Malnutrition (protein and calorie deficiency) is correlated with higher SHBG levels.
In one study, SHBG levels were elevated in 29 female anorexic patients. When they were given a caloric IV infusion, their SHBG levels dropped. In patients that gained at least 5% weight, SHBG dropped to normal levels [R]
However, in a study with 86 malnourished children (severe protein deficiency, general malnourishment, or anorexia), only the children with severe protein deficiency or anorexia had elevated SHBG levels [R].
12) Acute Intermittent Porphyria
Acute intermittent porphyria, a rare genetic disorder, is associated with elevated SHBG. Of the 12 patients with a clinical manifestation of the disease, all of them had elevated SHBG. The remaining 14 patients had latent porphyria and all but one of them had normal levels [R].
Conditions Associated With High SHBG Levels
1) Bone Loss
In an observational study, women with high SHBG levels were had an average bone loss (2.2% a year) almost twice as high as women with low SHBG (1.2% a year) (study on 9,704 elderly women) [R].
2) Alzheimer’s Disease
3) Prostate Cancer
How to Lower SHBG Levels
SHBG reduces testosterone availability. Because testosterone can increase athletic performance, some people may want to lower their SHBG levels [R].
1) Dietary Changes
High-protein diets were associated with reduced blood SHBG levels (study with 1552 men) [R].
In a study on 36 women (RCT), one cup of red wine daily reduced blood SHBG levels, while white wine did not [R].
2) Taking Supplements
The intake of the following supplements decreases SHBG production and/or reduces its interaction with sex hormones:
- Boron [R, R]
- Magnesium [R, R]
- Calcium [R]
- Zinc [R, R]
- Vitamin D [R]
- Fish oil (or any other polyunsaturated fatty acid supplements) [R]
- Tongkat Ali [R]
Symptoms of Low SHBG Levels
Symptoms of low SHBG levels are similar to those of excessive male sex hormone levels.
- Excessive body hair/male-pattern hair growth (hirsutism)
- Voice deepening
- Increased muscle mass
- Reduced breast size
- Irregular or absent periods
- Enlargement of the clitoris
- Weight gain
Though rare, low SHBG in males may cause:
- Early puberty (in children) [R]
- Acne [R]
- Baldness [R]
- Increased body hair [R]
- Aggression [R]
- Erectile dysfunction [R]
- Gynecomastia (breast growth) [R]
- Infertility [R]
Causes of Low SHBG Levels
1) High Insulin Levels
In a study on 47 women with polycystic ovarian syndrome (PCOS), high blood insulin levels were linked to low SHBG concentration [R].
Similarly, Mexican-Americans (a population with a high risk of type 2 diabetes) have higher insulin and lower SHBG levels than non-Hispanic whites (study on 96 individuals) [R].
Intake of diazoxide (a medication for low blood sugar) increased SHBG levels in women with polycystic ovarian syndrome (study on 6 patients) [R].
Another study found that insulin (0.1-0.4 UI/kg dosages) increased SHBG production in men with type 2 diabetes (trial with 20 men) [R].
However, a study in cells suggested that the effect of insulin on SHBG levels is non-specific and reflects a reduced production of proteins [R].
2) High Growth Hormone Levels
Acromegaly is a disorder in which the pituitary gland produces too much growth hormone in adults. Several observational studies with over 100 people have measured lower SHBG levels in patients with acromegaly [R, R, R].
In overweight healthy men, injection of low growth hormone doses (0.02 U/kg/day for 14 days) decreased blood SHBG levels (clinical trial on 8 individuals) [R].
3) High Prolactin Levels
A prolactinoma is a tumor in the pituitary gland that causes the excessive production of the hormone, prolactin (PRL). Prolactinomas reduced blood SHBG levels in a study with 20 people. In another study on 28 women with excessive prolactin production, treatment with the drug bromocriptine restored prolactin and SHBG levels [R, R].
In a cell study, the addition of prolactin reduced SHBG production [R].
4) High Testosterone Levels
5) Thyroid Hormone Levels
The relationship between low thyroid hormone levels (hypothyroidism) and SHBG concentration is unclear. While three studies found decreased SHBG levels in hypothyroid patients, three other studies measured normal SHBG levels in patients with low thyroid hormone levels [R, R, R, R, R, R].
6) High Growth Factor Levels
However, a study with 1,135 men did not find a correlation between IGF-1 and SHBG levels [R].
7) Non-Alcoholic Fatty Liver Disease
Since SHBG is made in the liver, non-alcoholic fatty liver disease may affect its levels in the body.
Low SHBG levels have been associated with non-alcoholic fatty liver disease in studies done with type 2 diabetics and PCOS, however, it’s difficult to prove causality based on these studies [R, R, R, R].
Inflammatory markers, which indicate a pro-inflammatory state, were associated with lower SHBG levels in 433 women [R].
9) Genetic Mutations
Genetic mutations can result in low SHBG levels. A mutation in the SHBG gene resulted in undetectable levels of SHBG in two siblings [R].
10) High Sugar Levels
In genetically modified mice that produce human SHBG, a high sugar diet reduced SHBG production by 50% after 1 week [R].
Conditions Associated With Low SHBG Levels
1) Type 2 Diabetes
A meta-analysis of 43 observational studies of over 13,000 people found a protective role of high SHBG from developing type 2 diabetes, especially in women [R].
Another meta-analysis of 15 studies found a reduced incidence of type 2 diabetes among men and women with mutations causing increased SHBG production [R].
2) Gestational Diabetes
Low pre-pregnancy SHBG is a risk factor for developing diabetes during pregnancy in an observational study of 256 women [R].
3) Obesity and Obesity-Related Conditions
Metabolic syndrome is a condition characterized by the following symptoms [R]:
- High blood pressure
- High blood sugar levels
- High blood triglyceride levels
- Low blood levels of HDL cholesterol
In a meta-analysis of 52 studies, metabolic syndrome was associated with low SHBG levels in both sexes [R].
4) Breast Cancer
5) Heart Disease
6) High Blood Pressure
In an observational study of 2,816 people, low SHBG was a risk factor for high blood pressure, but only in men [R].
7) Polycystic Ovarian Syndrome
Although two studies with 857 women total found a link between a variation causing reduced SHBG production and polycystic ovarian syndrome, two studies of 596 women failed to find the same correlation [R, R, R, R].
8) High Cortisol
Cushing’s syndrome is when people have abnormally high cortisol [R].
9) Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is a genetic disorder in which the body produces insufficient cortisol and excessive male sex hormone levels [R].
In 240 people, congenital adrenal hyperplasia was associated with higher SHBG levels in women but not in men [R].
How to Increase SHBG Levels
Individuals wishing to increase their SHBG levels will be most likely women with symptoms of male sex hormone excess. Some lifestyle changes that can help them include:
1) Dietary Changes: Mediterranean Diet
A study of 27 obese men found that a low-fat, high-fiber diet, with exercise, effectively increased SHBG levels [R].
Additionally, the following foods and beverages increase SHBG production:
- Olive oil [R]
- Almonds and walnuts [R]
- Coffee and tea [R]
- Alcoholic beverages [R]
- Soy (rich in isoflavones) [R]
- Cabbage, broccoli, and cauliflower [R]
2) Physical Exercise
Similarly, moderate to intense exercise for a year increased SHBG and reduced estradiol and free estradiol levels in 320 women (RCT) [R].
A study of 13,547 women found that exercise was associated with higher SHBG levels. Higher BMI was associated with lower SHBG levels [R].
3) Caffeine Intake
However, a randomized control trial with 42 people had mixed results and did not find significant effects of coffee consumption (regular or decaf) on SHBG levels [R].
4) Weight Loss
Weight loss from either a higher-protein/low-fat diet or a higher-carbohydrate/low-fat diet increased SHBG levels (RCT with 118 overweight/obese men) [R].
Drugs That Control SHBG Levels
Note: By writing this section, we are not recommending these drugs. We are simply providing information that is available in the scientific literature. Please discuss your medications with your doctor.
1) Drugs That Increase SHBG Levels
Because they include synthetic female sex hormones, birth control pills can increase SHBG levels.
Treatment with different combinations of birth control pills all caused an increase in SHBG levels, to different degrees, with the highest from 30 mg ethinylestradiol with 2 mg dienogest (DB-RCT of 91 subjects) [R].
Both a triphasic birth control (containing ethinylestradiol and gestodene) and a monophasic version (containing 35 mg ethinylestradiol and 250 mg norgestimate) increased SHBG levels 200-240% on days 11 and 21. Even on pill-free days, SHBG levels were elevated compared to pre-treatment (RCT with 46 women) [R].
SHBG levels in women currently taking birth control pills were 4x higher compared to women who have never taken it. Discontinuing the pill decreased SHBG levels slightly, but they were still higher than those who had never taken it [R].
SHBG levels increased in epileptic patients treated with anti-seizure medication in several studies:
Selective Estrogen Receptor Modulators
The following selective estrogen receptor modulators increased SHBG levels in clinical trials:
- Tamoxifen (breast cancer medication) [R]
- Raloxifene (osteoporosis and breast cancer medication) [R]
- Bazedoxifene (osteoporosis medication) [R]
- Clomiphene (women infertility medication) [R]
- Ospemifene (medication for painful sexual intercourse in women) [R]
- Toremifene (breast cancer medication) [R]
SHBG levels raised after treatment with conventional antipsychotic medications (haloperidol, haloperidol with chlorpromazine, or chlorpromazine) but not with olanzapine, a second-generation antipsychotic, even when olanzapine was taken with conventional antipsychotics (RCT of 68 patients) [R].
2) Drugs that Reduce SHBG levels
Treatments with the following glucocorticoids used against inflammation, autoimmune diseases, and allergies decreased SHBG in several human trials:
Genetics of SHBG
- The rs6257 mutation reduces blood SHBG levels and is associated with a higher risk of breast cancer in women and type 2 diabetes in both men and women [R, R].
- The presence of the rs6258 mutation reduces the affinity of SHBG for testosterone, resulting in higher levels of free testosterone [R].
- The rs6259 variant increases SHBG levels by reducing its elimination and has been associated with a decreased risk of breast and uterine cancer in women, low sperm movement in men, and reduced risk of type 2 diabetes in both men and women [R, R, R, R].
- rs1799941 increases blood SHBG levels and has been associated with a higher bone density and lower sperm quality in men, and a reduced risk of type 2 diabetes in both men and women [R, R, R].
- The SHBG gene can be longer or shorter depending on the number of repeats of a certain sequence. More than 6 repeats (rs35785886 variant) decreases SHBG production. This mutation is associated with conditions such as polycystic ovarian syndrome (PCOS), excessive body hair, delayed onset of the first period, and coronary artery disease in women, and low sperm concentration and increased bone density in men [R, R, R, R, R].
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