Treatment of Abnormal Sex Hormone-Binding Globulin (SHBG) Levels
The primary treatment for abnormal SHBG levels is to identify and address the underlying cause—whether elevated SHBG from hyperthyroidism, liver disease, or medications, or low SHBG from obesity, insulin resistance, or PCOS—rather than treating SHBG itself. 1
Diagnostic Workup for Abnormal SHBG
When SHBG levels are abnormal, measure both total and free testosterone (or calculate the free testosterone index using total testosterone/SHBG ratio) to accurately assess gonadal status, as free testosterone is a better indicator than total testosterone alone when SHBG is abnormal. 1, 2 A free testosterone index <0.3 indicates hypogonadism and warrants further evaluation. 1
Draw morning testosterone levels between 8 AM and 10 AM, and if low, repeat the measurement along with LH and FSH to distinguish primary (testicular) from secondary (pituitary-hypothalamic) hypogonadism. 3 If secondary hypogonadism is confirmed with low LH/FSH, evaluate for pituitary dysfunction with prolactin, iron saturation, pituitary function testing, and MRI of the sella turcica. 3
Management of Elevated SHBG
Identify and Treat Underlying Causes
Elevated SHBG results from hyperthyroidism, hepatic disease/cirrhosis, aging, certain medications (anticonvulsants, estrogens, thyroid hormone), smoking, and HIV/AIDS. 1, 2, 4
- Correct hyperthyroidism if present through appropriate thyroid management 2
- Evaluate liver function tests and manage hepatic disease appropriately 1, 2
- Review and discontinue causative medications when possible (anticonvulsants, estrogens, thyroid hormone) 1, 4
- Consider HIV testing in appropriate clinical contexts 1
- Address smoking cessation 2
Testosterone Replacement Therapy for Symptomatic Men
Consider testosterone replacement therapy when morning free testosterone by equilibrium dialysis is frankly low on at least 2 separate assessments, after completing the hypogonadism workup to rule out etiologies unrelated to the elevated SHBG. 3, 1, 2
Testosterone replacement can normalize free testosterone levels and may reduce elevated SHBG levels, with benefits including improved sexual function, well-being, muscle mass, and bone density. 2, 5 However, avoid TRT in men desiring fertility as it suppresses spermatogenesis; consider selective estrogen receptor modulators instead. 1
Transdermal testosterone preparations (gel or patch) are preferred over intramuscular injections due to stable day-to-day testosterone levels and avoidance of injection discomfort. 3 Testosterone injections offer the advantage of avoiding daily administration and are beneficial for patients with reduced disease-management skills or resources. 3 Gels dry quickly but can transfer to others via skin contact and have variable absorption; patches minimize transfer but may cause skin irritation and adherence issues. 3
Monitoring During TRT
Perform baseline digital rectal exam and PSA before initiating TRT, then monitor PSA every 3-6 months in the first year. 2 Check hematocrit/hemoglobin regularly as TRT can increase these values. 1, 2 Reassess total and free testosterone and SHBG levels after 3-6 months of treatment, adjusting based on symptom response and laboratory values. 1 Consider prostate biopsy if PSA rises >1.0 ng/mL in any year. 2
Management of Low SHBG
Identify and Treat Underlying Causes
Low SHBG results from obesity (particularly central/abdominal obesity), insulin resistance, high-dose glucocorticoids, growth hormone, testosterone, PCOS, Cushing's syndrome, and acromegaly. 1, 2, 4
- Address obesity and insulin resistance through weight loss interventions, as these are the most common causes of low SHBG 1, 2
- Review medications including glucocorticoids (prednisone), androgens, and anabolic steroids that lower SHBG 1, 2
- Evaluate for PCOS in women with hyperandrogenic symptoms, as low SHBG is a significant risk marker that contributes to increased free testosterone and worsening symptoms 2, 6, 7
- Screen for Cushing's syndrome and acromegaly in appropriate clinical contexts 1
Special Considerations in PCOS
In women with PCOS, low SHBG levels are strongly associated with disease risk and metabolic disturbances. 6, 7 Therapeutic interventions that improve SHBG levels in PCOS women reduce associated complications, making SHBG a useful biomarker for diagnosis and treatment monitoring. 6, 7 Low hepatic SHBG production may be a key step in PCOS pathogenesis, with decreased SHBG increasing androgen bioavailability and driving ovarian pathology and anovulation. 7
Obesity-Related Low SHBG in Men
In men with obesity and low total testosterone due solely to low SHBG, free testosterone levels are typically normal and testosterone replacement is not indicated. 3 However, a subset of men with obesity will have frankly low free testosterone due to increased aromatization of testosterone to estradiol in adipose tissue, causing estradiol-mediated negative feedback that suppresses pituitary LH secretion. 3 In these cases, testosterone replacement should be considered when morning free testosterone is low on at least 2 separate assessments. 3
Testosterone replacement in men with obesity and confirmed hypogonadism has demonstrated weight loss and improvements in fasting plasma glucose, insulin resistance, triglycerides, HDL cholesterol, lean body mass, and waist circumference. 3
Common Pitfalls to Avoid
Relying solely on total testosterone measurements can miss cases of functional hypogonadism caused by elevated SHBG, where total testosterone appears normal but free testosterone is low. 2 Always measure or calculate free testosterone when SHBG is abnormal. 1, 2
Not considering the impact of medications and medical conditions on SHBG levels leads to incorrect interpretation of testosterone results. 2 Systematically review all potential causes before initiating hormone replacement. 1