Sex Hormone-Binding Globulin (SHBG) is an important protein that decreases the effects of sex hormones (especially testosterone) by binding to them. Unusually high or low blood SHBG levels can be indicative of several hormone disorders. Mildly high SHBG can lower testosterone bioavailability. 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?
What Does SHBG Do?
SHBG binds to the following sex hormones, listed in order of affinity :
- 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 can also be made in these organs:
SHBG production is blocked by:
- Male sex hormones 
- Insulin 
- Prolactin 
- TNF-alpha (a cytokine) 
- Sugars (glucose and fructose) 
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 [22, 23, 1].
In adult women, SHBG progressively decreases from 20 – 60 years and starts increasing after that .
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 [27, 4, 5].
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 [3, 28, 29].
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 [5, 30, 31].
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 [32, 33].
Genetics of SHBG
- The rs6257 variant reduces blood SHBG levels and is associated with breast cancer in women and type 2 diabetes in both men and women [35, 36].
- The presence of the rs6258 variant reduces the affinity of SHBG for testosterone, and is associated with higher levels of free testosterone .
- The rs6259 variant increases SHBG levels by reducing its elimination and has been associated with a lower frequency of breast and uterine cancer in women, low sperm movement in men, and lower incidence of type 2 diabetes in both men and women [38, 39, 40, 36].
- rs1799941 increases blood SHBG levels and has been associated with a higher bone density and lower sperm quality in men, and a lower incidence of type 2 diabetes in both men and women [41, 42, 43].
- 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 variant 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 [44, 45, 46, 47, 41].
SHBG Blood Test
When Is the SHBG Blood Test Used?
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 [50, 51, 48].
Additionally, SHBG levels can be used as a marker of conditions such as:
- Thyroid disorders [52, 53]
- Pituitary gland disorders 
- Polycystic ovarian syndrome (PCOS) [55, 56]
- Insulin resistance 
- Metabolic syndrome 
- Androgen receptor disorders 
- Eating disorders 
Lab results are commonly shown as a set of values known as a “reference range”, which is sometimes referred to as a “normal range”. A reference range includes the upper and lower limits of a lab test based on a group of otherwise healthy people.
Your healthcare provider will compare your lab test results with reference values to see if your SHBG results fall outside the range of expected values. By doing so, you and your healthcare provider can gain clues to help identify possible conditions or diseases.
Remember that some lab-to-lab variability occurs due to differences in equipment, techniques, and chemicals used. Don’t panic if your result is slightly out of range – as long as it’s in the normal range based on the laboratory that did the testing, your value is normal.
However, it’s important to remember that a normal test doesn’t mean a particular medical condition is absent. Your doctor will interpret your results in conjunction with your medical history and other test results.
And remember that a single test isn’t enough to make a diagnosis. Your doctor will interpret this test, taking into account your medical history and other tests. A result that is slightly low/high may not be of medical significance, as this test often varies from day to day and from person to person.
Men: 10 – 57 nmol/L
Women: 18 – 144 nmol/L
High Levels of SHBG
The conditions we discuss here are commonly associated with high SHBG levels, but this single symptom is not enough for a diagnosis. Work with your doctor to discover what underlying condition might be causing your high levels of this protein and to develop an appropriate plan to improve your health.
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 .
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 [67, 68, 69].
In an observational study on 40 male-to-female transsexuals, SHBG levels increased after 12 months. During their transition, male-to-female transsexuals take male sex hormone production blockers and female sex hormones, which can increase SHBG levels .
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 people with different types of hyperthyroidism found higher SHBG levels .
Similarly, thyroid hormone (T3) increased blood SHBG levels in a small trial on 7 healthy men .
3) Low Growth Hormone Levels
During mid to late pregnancy, SHBG levels increase up to 5 – 10x .
5) Liver Issues/Disorders
Since SHBG is mainly produced in the liver, liver damage can result in abnormal SHBG levels .
Similarly, abnormally high SHBG levels were measured in men with non-alcoholic liver cirrhosis in a study on 50 men .
However, in another study on over 100 women, SHBG levels were within normal ranges in those with both alcoholic and non-alcoholic liver cirrhosis. However, the levels did increase in those with alcoholic cirrhosis who abstained from alcohol for 3 months .
In a study on 32 women with hepatitis, the disease severity was associated with higher SHBG levels. Severe hepatitis B viral infection was associated 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 .
This same link between disease severity (as measured by fibrosis) and SHBG was seen in 46 men with hepatitis C infections .
6) Alcohol Consumption
Alcohol consumption was associated with higher SHBG levels (as well as higher luteal estrogen and lower testosterone) in a study on 2,000 premenopausal women. It was not associated with changes in other sex hormones levels studied .
8) Significant Physical Exertion or Strain
Changes in SHBG levels from exercise may be affected by age and level of exertion. 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) 
In another study on 12 people, SHBG levels were decreased following a marathon .
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) in a study on 39 people .
However, in an observational study on over 1,200 men, self-reported stress levels did not impact reproductive hormone levels (SHBG, LH, FSH, testosterone, calculated free testosterone, and inhibin B) 
Malnutrition (protein and calorie deficiency) is associated 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 those who gained at least 5% weight, SHBG dropped to normal levels 
However, in a study on 86 malnourished children (severe protein deficiency, general malnourishment, or anorexia), only those with severe protein deficiency or anorexia had elevated SHBG levels .
12) Acute Intermittent Porphyria
Acute intermittent porphyria, a rare genetic disorder, is associated with elevated SHBG. High levels of this hormone were observed in all 12 patients with a clinical manifestation of the disease in a study, while all but one of the 14 patients with latent porphyria had normal levels .
Conditions Associated With High SHBG Levels
1) Bone Loss
In an observational study on almost 10,000 elderly women, those with high SHBG levels had an average bone loss (2.2% a year) almost twice as high as those with low SHBG (1.2% a year) .
2) Alzheimer’s Disease
3) Prostate Cancer
All About Low SHBG Levels
The conditions we discuss here are commonly associated with low SHBG levels, but this single symptom is not enough for a diagnosis. Work with your doctor to discover what underlying conditions might be causing your low levels of this protein and to develop an appropriate plan to improve your health.
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) 
- Acne 
- Baldness 
- Increased body hair 
- Aggression 
- Erectile dysfunction 
- Gynecomastia (breast growth) 
- Infertility 
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 .
Similarly, Mexican-Americans (a population with a high risk of type 2 diabetes) had higher insulin and lower SHBG levels than non-Hispanic whites in a study on 96 people .
Diazoxide (a medication for low blood sugar) increased SHBG levels in a small study on 6 women with polycystic ovarian syndrome .
A clinical trial on 20 men found that insulin (0.1 – 0.4 UI/kg dosages) increased SHBG production in those with type 2 diabetes .
However, a study in cells suggested that the effect of insulin on SHBG levels is non-specific and reflects a reduced production of proteins .
2) High Growth Hormone Levels
Acromegaly is a disorder in which the pituitary gland produces too much growth hormone in adults. Several observational studies on over 100 people have measured lower SHBG levels in patients with acromegaly [139, 152, 153].
In overweight healthy men, injection of low growth hormone doses (0.02 U/kg/day for 14 days) decreased blood SHBG levels in a small clinical trial on 8 men .
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 on 20 people. In another study on 28 women with excessive prolactin production, the drug bromocriptine restored prolactin and SHBG levels [54, 155].
In a cell study, prolactin reduced SHBG production .
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 people with low thyroid hormone levels [53, 160, 161, 162, 163, 164].
6) High Growth Factor Levels
However, a study on over 1,000 men did not find an association between IGF-1 and SHBG levels .
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 on type 2 diabetics and PCOS. However, it’s difficult to prove causality based on these studies [167, 168, 169, 170].
Inflammatory markers, which indicate a pro-inflammatory state, were associated with lower SHBG levels in a study on over 400 women .
9) Genetic Mutations
Genetic mutations can result in low SHBG levels. For instance, a mutation in the SHBG gene resulted in undetectable levels of SHBG in two siblings .
10) High Sugar Levels
In genetically modified mice that produce human SHBG, a high-sugar diet reduced SHBG production by 50% after 1 week .
Conditions Associated With Low SHBG Levels
1) Type 2 Diabetes
A meta-analysis of 43 observational studies and over 13,000 people found a protective role of high SHBG from developing type 2 diabetes, especially in women .
Another meta-analysis of 15 studies found a reduced incidence of type 2 diabetes among men and women with mutations causing increased SHBG production .
2) Gestational Diabetes
Low pre-pregnancy SHBG was identified as a risk factor for developing diabetes during pregnancy in an observational study on over 250 women .
3) Obesity and Obesity-Related Conditions
Metabolic syndrome is a condition characterized by the following symptoms :
- 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 .
4) Breast Cancer
A meta-analysis of 9 studies found a link between low SHBG levels and increased risk of developing breast cancer .
5) Heart Disease
6) High Blood Pressure
In an observational study on almost 3,000 people, low SHBG was a risk factor for high blood pressure, but only in men .
7) Polycystic Ovarian Syndrome
Although two studies on over 800 women found a link between a variation causing reduced SHBG production and polycystic ovarian syndrome, two other studies on almost 600 women failed to find the same association [193, 194, 195, 196].
8) High Cortisol
Cushing’s syndrome is a condition with abnormally high cortisol levels .
9) Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is a genetic disorder in which the body produces insufficient cortisol and excessive male sex hormone levels .
In a study on 240 people, congenital adrenal hyperplasia was associated with higher SHBG levels in women but not in men .
Factors That Can Affect SHBG Levels?
Increasing SHBG Levels
Individuals wishing to increase their SHBG levels will be most likely women with symptoms of male sex hormone excess. If your SHBG levels are too low, discuss with your doctor what strategies may help you raise them. Never implement them in place of what your doctor recommends or prescribes.
Some lifestyle changes that may help increase SHBG levels include:
1) Physical Exercise
Similarly, moderate to intense exercise for a year increased SHBG and reduced estradiol and free estradiol levels in a trial on over 300 women .
A study on over 13,000 women found that exercise was associated with higher SHBG levels. Higher BMI was associated with lower SHBG levels .
2) Weight Loss
Weight loss from either a higher-protein/low-fat diet or a higher-carbohydrate/low-fat diet increased SHBG levels in a clincal trial on over 100 overweight and obese men .
3) Caffeine Intake
However, a clinical trial on 42 people had mixed results and did not find significant effects of coffee consumption (regular or decaf) on SHBG levels .
4) Dietary Changes: Mediterranean Diet
A study on 27 obese men found that a low-fat, high-fiber diet, with exercise, effectively increased SHBG levels .
Additionally, the following foods and beverages increased SHBG production. However, additional clinical studies need to be done before these findings are considered conclusive:
- Olive oil 
- Almonds and walnuts 
- Coffee and tea 
- Alcoholic beverages 
- Soy (rich in isoflavones) 
- Cabbage, broccoli, and cauliflower 
Factors That May Lower SHBG Levels?
SHBG reduces testosterone availability. Because testosterone can increase athletic performance and does lower naturally with age, some people may want to lower their SHBG levels .
Again, it is important to speak with your doctor before attempting any lifestyle or supplement regimen changes aimed at lowering SHBG levels.
1) Dietary Changes
High-protein diets were associated with reduced blood SHBG levels in a study on over 1,500 men .
In a clinical trial on 36 women, one cup of red wine daily reduced blood SHBG levels, while white wine did not .
2) Taking Supplements
The following supplements were found to decrease SHBG production and/or reduce its interaction with sex hormones, though further clinical studies are needed before these findings can be considered conclusive:
- Boron [228, 229]
- Magnesium [230, 231]
- Calcium 
- Zinc [232, 233]
- Vitamin D 
- Fish oil (or any other polyunsaturated fatty acid supplements) 
- Tongkat Ali 
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. Many drugs have side effects and should not be taken unless prescribed by a physician. 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.
Different combinations of birth control pills caused an increase in SHBG levels to different degrees in a clinical trial on 91 people, with 30 mg ethinylestradiol plus 2 mg dienogest having the strongest effect .
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 in a clinical trial on 46 women. Even on pill-free days, SHBG levels were elevated compared to pre-treatment .
SHBG levels in women currently taking birth control pills were 4x higher compared to those who have never taken it in a study on over 100 women. Discontinuing the pill decreased SHBG levels slightly, but they were still higher than those who had never taken it .
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) 
- Raloxifene (osteoporosis and breast cancer medication) 
- Bazedoxifene (osteoporosis medication) 
- Clomiphene (women infertility medication) 
- Ospemifene (medication for painful sexual intercourse in women) 
- Toremifene (breast cancer medication) 
SHBG levels raised after treatment with conventional antipsychotic medications (haloperidol, haloperidol with chlorpromazine, or chlorpromazine) in a clinical trial on 68 people but not with olanzapine, a second-generation antipsychotic, even when olanzapine was taken with conventional antipsychotics .
2) Drugs that Reduce SHBG levels
Treatments with the following glucocorticoids used against inflammation, autoimmune diseases, and allergies decreased SHBG in several human trials:
SHBG can be affected by many hormone pathways in the body. In turn, SHBG levels affect the bioavailability of sex hormones such as testosterone and estrogen.
Checking your lab values may help your doctor rule out some serious illnesses, but it can also give them a bigger picture of your hormone health.
Most unhealthy lifestyle conditions are associated with an increase in SHBG (sometimes clinically significant and other times not) and a shift in bioavailable testosterone.
Irregular SHBG Levels?
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