Hormone Biomarkers: Sex Hormone Binding Globulin (SHBG)

Optimal Takeaways

Sex hormone-Binding Globulin (SHBG) binds and transports sex hormones in the blood. It is produced in the liver, and liver dysfunction will affect circulating levels. Low levels may be associated with an increased risk of cardiometabolic dysfunction, inflammation, PCOS, and cancer. Elevated levels may be associated with hyperthyroidism, cardiovascular disease, malnutrition, and symptomatic hypogonadism.

Standard Range:           

• Male 10 - 50 nmol/L
• Female 17 - 124 nmol/L

The ODX Range:

• Male 40 - 46 nmol/L
• Female 50 - 80 nmol/L

Low levels of SHBG may be associated with hypothyroidism, hyperprolactinemia, menstrual irregularities, progestins, hirsutism (Thaler 2015), cardiovascular disease, coronary heart disease, stroke, arthritis, inflammation, cancer, insulin resistance, liver disease, PCOS, oophorectomy, COPD, and smoking (Wang 2021), hyperinsulinemia, and type 2 diabetes (O’Reilly 2019).

Low SHBG is also associated with fatty liver, excess fructose intake obesity, glucose dysregulation, metabolic syndrome, PCOS, and increased risk of developing diabetes and cardiovascular disease (Goldstajn 2016)

High levels of SHBG may be associated with hyperthyroidism, psychological stress, activation of the HPA axis (Thaler 2015), potential prostate cancer risk (Garcia-Cruz 2013, Thaler 2015), increased incidence of CVD (Gyawali 2019), and increased mortality in diabetic men over age 66 with low testosterone below 346 ng/mL (12 nmol/L) (Ramachandran 2018). Elevated SHBG is also associated with active anorexia nervosa, kwashiorkor, decreased bone mineralization, and increased fracture risk (Goldstajn 2016).

Overview

Sex hormone binding globulin (SHBG) transports sex steroids in the blood with an affinity for androgens (e.g., testosterone and DHT) five times that of estrogens. Researchers note that the SHBG appears to have additional roles at the level of the cell receptor and may influence how hormones affect target cells, suggesting that not only free or bioavailable hormones exert physiological effects. SHBG is produced to some extent in the hypothalamus and pituitary but is primarily synthesized in the liver. Therefore, endocrine and liver disorders are associated with alterations in SHBG levels (Goldstajn 2016). Genetic factors also influence SHBG production and levels (Simons 2021), and three genetic polymorphisms have linked low SHBG to an increased risk of diabetes (Wallace 2013).

Energy balance, physical activity, and dietary factors also influence SHBG metabolism. For example, a diet low in protein and fat can increase SHBG. Moderate alcohol intake can reduce SHBG levels, but excessive alcohol intake can increase SHBG levels by 3-fold. Medications can also influence SHBG synthesis and serum levels (Thaler 2015).

Low SHBG may be caused by inflammation, elevated androgens, and fatty liver and associated with obesity, glucose dysregulation, insulin resistance, polycystic ovary syndrome, low HDL, increased cardiovascular risk, and increased risk of diabetes, including gestational diabetes (Goldstajn 2016).

Low SHBG may increase the risk of metabolic syndrome and its related components. A review of data from the Framingham Offspring Study concluded that lower levels of SHBG in men were associated with a progressively increased risk of metabolic syndrome, especially with increased adiposity and hypertriglyceridemia. Research suggests the odds of having metabolic syndrome increased by 78% for each standard deviation decline in SHBG (Basin 2011).

A review of NHANES data found risk factors for low SHBG in a sub-cohort of 1477 individuals included high BMI, diabetes, COPD, heart disease, smoking, and being non-Hispanic. The review defined low SHBG in men as below 12.3 nmol/L for those under 50 and below 23.5 nmol/L for those 50-80. In women, levels were considered deficient if they were below 14.5 nmol/L in those less than 30 years old and below 21.9 nmol/L in those 30-80 years old (Wang 2021).

A large retrospective cohort study of 15,907 men and 42,034 women found that the risk of type 2 diabetes increased when SHBG dropped below 40 nmol/L in men and below 50 nmol/L in women. Hyperinsulinemia reduces the hepatic output of SHBG and compromises its role as a moderator of the association between sex steroid activity and metabolic dysfunction. The increase in insulin and decrease in SHBG promotes the rise in free androgens observed in hyperinsulinemic states such as PCOS (O’Reilly 2019).

Low SHBG in women has been significantly associated with polycystic ovary syndrome, insulin resistance, type 2 diabetes, hypertriglyceridemia, low HDL, visceral fat accumulation, elevated diastolic blood pressure, elevated CRP, and increased free androgen index (Davis 2015). Evaluation of data from the Women’s Health Study revealed that women with metabolic syndrome had a lower mean SHBG of 32.6 nmol/L compared to a mean of 55.8 nmol/L without metabolic syndrome (Weinberg 2006).

Higher levels of SHBG may have negative implications as well. Data from the Men’s Androgen Inflammation Lifestyle Environment and Stress cohort study observed that the 5-year incidence of cardiovascular disease increased as SHBG increased to 46.7 nmol/L or above (Gyawali 2019).

Elevated levels of SHBG may be caused by thyroid hormone, estrogen, and adiponectin and are associated with more significant bone resorption, lower bone mineral density, and increased risk of fracture. Levels of SHBG tend to increase with age in men by approximately 1% per year and may decrease with age in women. SHBG may protect against breast cancer as its binding to breast cancer cells can inhibit proliferation. However, in men, increased SHBG may promote prostate cancer (Goldstajn 2016).

A population-based cross-sectional study of 965 men 40-80 years old found that an SHBG level above 44.4 nmol/L predicted symptomatic late-onset hypogonadism in those over age 59 (Liang 2021). A prospective study of 279 men with suspected prostate cancer revealed that an SHBG level of 66.25 nmol/L or above was associated with a 3.2-fold increased incidence of detection. Subjects at increased risk also had a bioavailable testosterone of 104 ng/dL (3.6 nmol/L) or lower (Garcia-Cruz 2013).

References

Bhasin, Shalender et al. “Sex hormone-binding globulin, but not testosterone, is associated prospectively and independently with incident metabolic syndrome in men: the framingham heart study.” Diabetes care vol. 34,11 (2011): 2464-70. doi:10.2337/dc11-0888

Davis, Susan R., and Sarah Wahlin-Jacobsen. "Testosterone in women—the clinical significance." The Lancet Diabetes & Endocrinology 3.12 (2015): 980-992.

García-Cruz, Eduardo et al. “Higher sex hormone-binding globulin and lower bioavailable testosterone are related to prostate cancer detection on prostate biopsy.” Scandinavian journal of urology vol. 47,4 (2013): 282-9. doi:10.3109/00365599.2012.747562

Goldstajn, Marina Šprem et al. “Sex Hormone Binding Globulin (SHBG) as a Marker of Clinical Disorders.” Collegium antropologicum vol. 40,3 (2016): 211-8.

Gyawali, Prabin et al. “Higher Serum Sex Hormone-Binding Globulin Levels Are Associated With Incident Cardiovascular Disease in Men.” The Journal of clinical endocrinology and metabolism vol. 104,12 (2019): 6301-6315. doi:10.1210/jc.2019-01317

Liang, Guoqing et al. “Serum sex hormone-binding globulin is associated with symptomatic late-onset hypogonadism in aging rural males: a community-based study.” Sexual health vol. 18,2 (2021): 156-161. doi:10.1071/SH20201

O'Reilly, Michael W et al. “Serum testosterone, sex hormone-binding globulin and sex-specific risk of incident type 2 diabetes in a retrospective primary care cohort.” Clinical endocrinology vol. 90,1 (2019): 145-154. doi:10.1111/cen.13862

Ramachandran, S et al. “The association of sex hormone-binding globulin with mortality is mediated by age and testosterone in men with type 2 diabetes.” Andrology vol. 6,6 (2018): 846-853. doi:10.1111/andr.12520

Simons, Pomme I H G et al. “Sex hormone-binding globulin: biomarker and hepatokine?.” Trends in endocrinology and metabolism: TEM vol. 32,8 (2021): 544-553. doi:10.1016/j.tem.2021.05.002

Thaler, Markus A et al. “The biomarker sex hormone-binding globulin - from established applications to emerging trends in clinical medicine.” Best practice & research. Clinical endocrinology & metabolism vol. 29,5 (2015): 749-60. doi:10.1016/j.beem.2015.06.005

Wallace, Ian R et al. “Sex hormone binding globulin and insulin resistance.” Clinical endocrinology vol. 78,3 (2013): 321-9. doi:10.1111/cen.12086

Wang, Yutang. “Definition, Prevalence, and Risk Factors of Low Sex Hormone-Binding Globulin in US Adults.” The Journal of clinical endocrinology and metabolism vol. 106,10 (2021): e3946-e3956. doi:10.1210/clinem/dgab416

Weinberg, Melissa E et al. “Low sex hormone-binding globulin is associated with the metabolic syndrome in postmenopausal women.” Metabolism: clinical and experimental vol. 55,11 (2006): 1473-80. doi:10.1016/j.metabol.2006.06.017