Sex Hormone-Binding Globulin (SHBG) is an important protein that decreases the effects of sex hormones (especially testosterone) by binding to them. Unusually high SHBG levels can be indicative of several hormone disorders. Read on to learn more about this protein, the conditions associated with high levels, and factors that may lower it.
What is SHBG?
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 Blood Test
When Is the SHBG Blood Test Used?
The SHBG blood test is not routinely ordered and is most often used when symptoms of sex hormone imbalance are not accompanied by changes in their blood concentration [6, 7].
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 [8, 9, 6].
Additionally, SHBG levels can be used as a marker of conditions such as:
- Thyroid disorders [10, 11]
- Pituitary gland disorders [12]
- Polycystic ovarian syndrome (PCOS) [13, 14]
- Insulin resistance [15]
- Metabolic syndrome [16]
- Androgen receptor disorders [17]
- Eating disorders [18]
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.
Normal Ranges
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.
In men, they include [19, 20]:
- Arrested sexual development (in teenagers)
- Infertility
- Decreased sperm concentration and motility
- Decreased sex drive
- Impotence
- Reduced testicle size
- Breast growth
- Decreased body hair
- Hot flashes
- Reduced bone and muscle mass
- Decreased energy and motivation
In women, high SHBG levels may cause [21, 22, 23]:
- Decreased sex drive
- Irregular or absent periods
- Vaginal dryness
- Reduced bone and muscle mass
- Memory losses
- Depression and anxiety
- Tiredness
- Reduced wellbeing
Causes of High SHBG Levels
Causes shown here are commonly associated with high SHBG. Work with your doctor or other health care professional for an accurate diagnosis.
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 [24].
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 [25, 26, 27].
In an observational study on 40 male-to-female transgender people, SHBG levels increased after 12 months. During their transition, trans women take male sex hormone production blockers and female sex hormones, which can increase SHBG levels [28].
In two studies on almost 500 women, hormone replacement therapy increased SHBG levels [29, 30].
Studies in cells found increased SHBG production at high concentrations of the following female sex hormones:
2) High Thyroid Hormone Levels
Increased blood SHBG levels were measured in 3 observational studies on 70 people with excessive thyroid hormone production (hyperthyroidism) [10, 34, 35].
An observational study on 59 people with different types of hyperthyroidism found higher SHBG levels [36].
Similarly, thyroid hormone (T3) increased blood SHBG levels in a small trial on 7 healthy men [37].
Both T4 and T3 increased SHBG production in healthy and liver cancer cells [38, 39, 40, 41, 42].
3) Low Growth Hormone Levels
In an observational study on 74 men and women, SHBG levels were higher in those with a hereditary growth hormone deficiency [43].
4) Pregnancy
During mid to late pregnancy, SHBG levels increase by five to ten times [1].
In two studies on women undergoing ovarian stimulation, SHBG levels increased when they became pregnant, probably as a result of the increase in sex hormones [44, 45].
5) Liver Issues/Disorders
Since SHBG is mainly produced in the liver, liver damage can result in abnormal SHBG levels [46].
In a study on 167 men, chronic alcoholic liver inflammation (cirrhosis) was associated with increased SHBG levels [47, 48].
Similarly, abnormally high SHBG levels were measured in men with non-alcoholic liver cirrhosis in a study on 50 men [49].
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 [50].
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 [51].
This same link between disease severity (as measured by fibrosis) and SHBG was seen in 46 men with hepatitis C infections [52].
Excess iron levels in the liver (iron overload) can also cause high SHBG [53].
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 [54].
7) Smoking
Smoking has been associated with increased SHBG levels in several studies on 4,000 people [55, 56, 57, 58].
In two studies on over 100 people who quit smoking, SHBG levels started to drop within a few weeks [59, 60].
8) Significant Physical Exertion or Strain
In three studies on over 100 people, physical strain increased SHBG levels [61, 62, 63].
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) [64]
In another study on 12 people, SHBG levels were decreased following a marathon [65].
9) Stress
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 [66].
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) [67].
10) Malnutrition/Anorexia
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 [68].
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 [69].
11) HIV/AIDS
In two observational studies on over 1,300 men, those infected with HIV had higher blood SHBG levels [70, 71].
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 [72].
Conditions Associated With High SHBG Levels
While these conditions have been associated with high 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) Bone Loss
High SHBG was linked to reduced bone density in eight studies on ~3,500 people [73, 74, 75, 76, 77, 78, 79].
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) [80].
Seven observational studies on over 4,500 men and women associated high blood SHBG levels with an increased incidence of bone fractures [81, 73, 82, 83, 84, 85].
However, two studies on almost 8,000 men and women failed to find a link between high blood SHBG levels and increased risk of bone fractures [85, 86].
2) Alzheimer’s Disease
In a meta-analysis, high SHBG levels were linked to an increased incidence of Alzheimer’s disease. Two other studies on 1,700 people came to the same conclusion [87, 88, 89].
3) Prostate Cancer
High SHBG levels were strongly associated with an increased risk of prostate cancer in a study on almost 300 men. Another study found a slightly increased risk, but only in younger men [90, 91].
However, a meta-analysis of 8 studies and another study (on almost 1000 men) failed to find a link between high SHBG and increased incidence and death rate of prostate cancer [92, 93].
Factors That May Lower SHBG
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 [94].
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 [95].
In a clinical trial on 36 women, one cup of red wine daily reduced blood SHBG levels, while white wine did not [96].
2) 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 [97, 98]
- Magnesium [99, 100]
- Calcium [101]
- Zinc [101, 102]
- Vitamin D [103]
- Fish oil (or any other polyunsaturated fatty acid supplements) [104]
- Tongkat Ali [105]
Drugs That Lower 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.
Treatments with the following glucocorticoids used against inflammation, autoimmune diseases, and allergies decreased SHBG in several human trials:
- Prednisone [106]
- Prednisolone [107]
- Dexamethasone [108]
Takeaway
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.
Many unhealthy lifestyle conditions, from alcohol abuse and smoking to malnutrition, are associated with an increase in SHBG (sometimes clinically significant and other times not) and a shift in bioavailable testosterone.
