Sex Hormone-Binding Globulin (SHBG) is an important protein that decreases the effects of sex hormones (especially testosterone) by binding to them. Unusually low blood SHBG levels can be indicative of several hormone disorders. Read on to learn more about this protein, the conditions associated with low levels, and what factors may raise them.
What is SHBG?
What Does SHBG Do?
Sex hormone-binding globulin (SHBG), also known as testosterone-binding globulin, is a protein that binds to sex hormones and carries them through the blood [1, 2].
SHBG binds to the following sex hormones, listed in order of affinity [3]:
- 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
Sex hormone binding globulin is mainly made in the liver, where its production is stimulated by female sex hormones and thyroid hormones [6, 7].
SHBG can also be made in these organs:
- Brain [8]
- Kidneys [9]
- Breasts [10]
- Uterus [11]
- Placenta [12]
- Ovaries [13]
- Prostate [14]
- Testicles [15]
SHBG is also produced by some types of tumors, such as breast, ovarian, and uterine [16, 17, 18].
SHBG production is blocked by:
- Male sex hormones [6]
- Insulin [19]
- Prolactin [19]
- TNF-alpha (a cytokine) [20]
- Sugars (glucose and fructose) [21]
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 men, SHBG levels are stable for many years but progressively rise as they age, which causes a reduction in free but not in total male sex hormone levels [24, 25].
In adult women, SHBG progressively decreases from 20 – 60 years and starts increasing after that [26].
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, sex hormone binding globulin 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].
Other
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
There are several variations in the SHBG gene, that are associated with increased or decreased blood levels of this protein and are linked to different conditions [34]:
- 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 [37].
- 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].
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 sex hormone binding globulin levels are similar to those of excessive male sex hormone levels.
In females, they include [48, 49, 50, 51, 52]:
- Excessive body hair/male-pattern hair growth (hirsutism)
- Acne
- Dandruff
- Baldness
- 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) [53]
- Acne [54]
- Baldness [54]
- Increased body hair [54]
- Aggression [55]
- Erectile dysfunction [56]
- Gynecomastia (breast growth) [57]
- Infertility [58]
Causes of Low SHBG Levels
Causes shown here are commonly associated with low SHBG. Work with your doctor or other health care professional for an accurate diagnosis.
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 [59].
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 [60].
Diazoxide (a medication for low blood sugar) increased SHBG levels in a small study on 6 women with polycystic ovarian syndrome [61].
Three studies found reduced SHBG production in human liver cells treated with insulin [62, 63].
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 [63].
However, a study in cells suggested that the effect of insulin on SHBG levels is non-specific and reflects a reduced production of proteins [64].
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 [52, 65, 66].
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 [67].
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 [68, 69].
In a cell study, prolactin reduced SHBG production [19].
4) High Testosterone Levels
High testosterone levels are normally considered to reduce SHBG production. The addition of testosterone blocked SHBG production in two cell studies [70, 71].
However, testosterone had no effect on SHBG production in two cell studies and stimulated SHBG production in two other ones [7, 72, 73, 74].
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 [75, 76, 77, 78, 79, 80].
6) High Growth Factor Levels
In a cell study, the growth factors IGF-1 (insulin-like growth factor), EGF (epidermal growth factor), and TGF-alpha (transforming growth factor alpha) reduced SHBG production [81].
However, a study on over 1,000 men did not find an association between IGF-1 and SHBG levels [82].
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 [83, 84, 85, 86].
8) Inflammation
Inflammatory markers, which indicate a pro-inflammatory state, were associated with lower SHBG levels in a study on over 400 women [87].
In another study on almost 700 people, a marker of inflammation (hs-CRP) was associated with lower SHBG levels [88].
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 [89].
10) High Sugar Levels
In genetically modified mice that produce human SHBG, a high-sugar diet reduced SHBG production by 50% after 1 week [90].
Conditions Associated With Low SHBG Levels
While these conditions have been associated with low SHBG in clinical research, this is not necessarily an exhaustive list. Your doctor is best positioned to diagnose any conditions you may have and to determine whether SHBG is a relevant marker.
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 [91].
Another meta-analysis of 15 studies found a reduced incidence of type 2 diabetes among men and women with mutations causing increased SHBG production [92].
Similarly, two studies on 2,500 people found a link between low SHBG levels and increased type 2 diabetes risks [93, 36].
In two studies on 690 people, this correlation was only seen in women [94, 95].
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 [96].
3) Obesity and Obesity-Related Conditions
Metabolic syndrome is a condition characterized by the following symptoms [97]:
- Obesity
- 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 men and women [98].
Having low SHBG levels is a significant risk factor (several fold increased likelihood) for developing metabolic syndrome based on a study on almost 2,500 people [99, 100, 101].
Insulin sensitivity, the opposite of insulin resistance seen with diabetes, was associated with high SHBG levels in three studies on over 300 people [102, 103, 104].
4) Breast Cancer
A meta-analysis of 9 studies found a link between low SHBG levels and increased risk of developing breast cancer [105].
Two observational studies on almost 3,000 people found the same association [106, 107].
5) Heart Disease
In two studies on almost 4,000 women, low SHBG levels were associated with an increased risk of developing heart disease [108, 109].
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 [110].
7) Polycystic Ovarian Syndrome
SHBG levels were lower in 23 women with PCOS [61, 111].
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 [112, 113, 114, 115].
Another study examining all four SHBG SNPs (rs1779941, rs6297, rs6259, and rs727428) did not find any associations with PCOS [116].
8) High Cortisol
Cushing’s syndrome is a condition with abnormally high cortisol levels [117].
Cushing’s syndrome was linked to reduced SHBG levels in multiple studies on 135 people [118, 119, 120, 121].
9) Congenital Adrenal Hyperplasia
Congenital adrenal hyperplasia is a genetic disorder in which the body produces insufficient cortisol and excessive male sex hormone levels [122].
In a study on 240 people, congenital adrenal hyperplasia was associated with higher SHBG levels in women but not in men [123].
Factors That May Raise SHBG
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
Moderately intense aerobic exercise for a year increased SHBG levels in a clinical trial on over 100 people [124].
Similarly, moderate to intense exercise for a year increased SHBG and reduced estradiol and free estradiol levels in a trial on over 300 women [125].
A study on over 13,000 women found that exercise was associated with higher SHBG levels. Higher BMI was associated with lower SHBG levels [126].
2) Weight Loss
In multiple trials on over 300 people, SHBG levels increased after weight loss [127, 128, 129, 130].
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 [131].
3) Caffeine Intake
Regular coffee intake was linked to increased blood SHBG in multiple studies on 19,000 people [126, 132, 133, 134, 135].
Different types of caffeinated drinks (coffee, green tea, black tea, oolong tea, and cola) were linked to increased SHBG levels in 50 women [136].
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 [137].
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 [138].
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 [139]
- Almonds and walnuts [140]
- Coffee and tea [136]
- Alcoholic beverages [141]
- Soy (rich in isoflavones) [142]
- Cabbage, broccoli, and cauliflower [143]
Drugs That Increase 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.
Oral Contraceptives
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 [144].
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 [145].
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 [146].
Aromatase Blockers
Treatment with the aromatase blockers risedronate (35 mg/week) or letrozole (2.5 mg/day) increased SHBG levels in two clinical trials on over 100 men and women [147, 148].
Anti-Seizure Medication
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) [153]
- Raloxifene (osteoporosis and breast cancer medication) [154]
- Bazedoxifene (osteoporosis medication) [155]
- Clomiphene (women infertility medication) [156]
- Ospemifene (medication for painful sexual intercourse in women) [157]
- Toremifene (breast cancer medication) [158]
Metformin
Several clinical trials have found that metformin (type 2 diabetes medication) increased SHBG levels [159, 160, 161].
Certain Antipsychotics
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 [162].
Takeaway
Sex hormone binding globulin 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.
Various hormonal disorders, genetic mutations, and liver conditions are believed to cause SHBG to decrease. Low SHBG has been linked to metabolic diseases (like diabetes), breast cancer, heart disease, and PCOS. Physical exercise, caffeine, weight loss, certain dietary changes, and some pharmaceutical drugs may increase SHBG.
