What is the first-line therapy to lower Sex Hormone-Binding Globulin (SHBG) levels?

First-Line Therapy to Lower SHBG

The first-line approach to lowering elevated SHBG is addressing the underlying cause—specifically treating hyperthyroidism, managing liver disease, achieving weight loss in obesity, and discontinuing medications that elevate SHBG (such as estrogens, anticonvulsants, or thyroid hormone). 1, 2

Identify and Treat Underlying Causes

The most effective strategy is identifying and treating the condition causing elevated SHBG rather than attempting to lower SHBG directly 2:

• Hyperthyroidism: Treat with antithyroid medications, radioactive iodine, or surgery as thyroid hormone directly increases SHBG production 1, 2
• Liver disease/cirrhosis: Optimize hepatic function as the liver is the primary site of SHBG synthesis 1, 3
• Medication review: Discontinue or substitute medications that elevate SHBG including estrogens, anticonvulsants, and excessive thyroid hormone replacement 1, 2
• HIV/AIDS: Optimize antiretroviral therapy as HIV infection is associated with elevated SHBG 1, 2

Weight Loss and Metabolic Optimization

For patients with obesity or insulin resistance, weight loss is the most physiologically appropriate intervention to lower SHBG 1, 4:

• Obesity, particularly central adiposity, is strongly associated with lower SHBG levels through insulin-mediated mechanisms 1, 4
• Calorie restriction and improved energy balance reduce SHBG independent of androgen effects 4
• This approach addresses the root metabolic dysfunction rather than masking it 4, 3

Pharmacological Approaches (Secondary Options)

If addressing underlying causes is insufficient and clinical hypogonadism persists despite elevated SHBG, consider:

• Testosterone replacement therapy: Directly lowers SHBG while normalizing free testosterone levels in men with confirmed hypogonadism 1, 5

  • Testosterone enanthate (200 mg IM every 2 weeks) significantly reduces SHBG from elevated levels (16.4 ± 2 ng/mL) to normal range (4.3 ± 0.5 ng/mL) within 3 months 5
  • Monitor hemoglobin/hematocrit and PSA before and during therapy 1
  • Avoid in men desiring fertility as it suppresses spermatogenesis 1

• Growth hormone: Decreases SHBG in GH-deficient patients, but should only be used when clinically indicated for GH deficiency, not solely to lower SHBG 2, 6, 7

  • Low-dose continuous GH infusion (0.02 U/kg/day) reduces SHBG within 2-7 days 6
  • In GH-deficient boys, recombinant hGH (0.5 U/kg/week) decreased SHBG from 154 ± 14 nmol/L to 106 ± 5 nmol/L over 12 months 7

• Glucocorticoids: Lower SHBG but carry significant side effects and should not be used solely for SHBG reduction 1, 2

Clinical Pitfalls to Avoid

• Do not treat SHBG levels in isolation: The goal is addressing symptomatic hypogonadism (low free testosterone) or the underlying disease, not simply normalizing SHBG numbers 1, 2
• Measure free testosterone or calculate free testosterone index (total testosterone/SHBG ratio <0.3 indicates hypogonadism) to assess true androgen status 1, 2
• Avoid using medications to lower SHBG when they are not otherwise clinically indicated: Growth hormone, glucocorticoids, and androgens have significant side effects 2

Monitoring After Intervention

• Reassess total testosterone, free testosterone, and SHBG levels after 3-6 months of treating the underlying condition 1
• Monitor for symptom improvement rather than focusing solely on laboratory normalization 1
• If testosterone replacement is initiated, monitor for side effects including polycythemia and prostate changes 1