From the Guidelines
Elevated sex hormone-binding globulin (SHBG) levels should be managed by addressing the underlying cause, such as liver disease, rather than treating SHBG levels directly, as evidenced by the 2021 study published in Hepatology 1. Elevated SHBG is a protein produced mainly by the liver that binds to sex hormones, particularly testosterone and estradiol, reducing their bioavailability in the bloodstream. When SHBG levels are high, less free hormone is available to act on target tissues, leading to symptoms of hormone deficiency despite normal total hormone levels.
Common Causes of Elevated SHBG
- Liver disease
- Hyperthyroidism
- Eating disorders
- Excessive exercise
- Aging
- Certain medications (like estrogens, anticonvulsants, and some HIV medications)
- Genetic factors In cases of liver disease, such as advanced liver disease or cirrhosis, SHBG levels can rise due to increased estrogen levels and stimulation of SHBG synthesis, as noted in the 2021 study 1.
Management of Elevated SHBG
- Treating the underlying cause, such as liver disease or hyperthyroidism
- Adjusting estrogen-containing medications
- Hormone replacement therapy based on free hormone levels rather than total levels
- Lifestyle modifications, such as maintaining a healthy weight, moderating alcohol consumption, and balanced exercise Regular monitoring of both SHBG and free hormone levels is crucial to assess treatment effectiveness and adjust therapy as needed, as suggested by the 2020 study published in Diabetes Care 1.
From the FDA Drug Label
Norgestimate, in combination with ethinyl estradiol, does not counteract the estrogen-induced increases in sex hormone binding globulin (SHBG), resulting in lower serum testosterone. The estrogen (PO) increases sex hormone binding globulin (SHBG) levels, as it does not counteract the estrogen-induced increases in SHBG 2.
From the Research
Elevated Sex Hormone Binding Globulin (SHBG) Levels
Elevated SHBG levels have been associated with various clinical disorders, including:
- Obesity, metabolic syndrome, polycystic ovary syndrome, osteoporosis, breast and prostate cancer 3
- Cardiovascular disease (CVD) risk factors, with higher SHBG levels being associated with incident CVD in men 4
- Ischemic stroke, with low SHBG levels being prospectively predictive of stroke risk in women 5
Regulation of SHBG Expression
SHBG expression is regulated by various factors, including:
- Hormones such as thyroid and estrogenic hormones, which increase SHBG production and gene promoter activity 6
- Nutritional factors, such as monosaccharides, which decrease SHBG expression by inducing lipogenesis 6
- Drugs, such as tamoxifen, genistein, and mitotane, which increase SHBG production and gene promoter activity 6
Association with Mortality
Elevated SHBG levels have been associated with increased all-cause mortality in men with type 2 diabetes, particularly when combined with low total testosterone levels 7
- Men with type 2 diabetes and a combination of total testosterone <12 nmol/L and SHBG >35nmol/L had an increased risk of mortality, independent of age 7
Clinical Significance
SHBG stands as one of the mediators between various endocrine tissues and contributes to its own pathophysiological role in diseases 3