How to manage high Sex Hormone-Binding Globulin (SHBG) levels?

Management of High Sex Hormone-Binding Globulin (SHBG) Levels

The primary approach to managing high SHBG is identifying and treating the underlying cause—particularly hyperthyroidism, hepatic disease, aging, HIV/AIDS, or medications—while simultaneously addressing functional hypogonadism through testosterone replacement therapy when free androgen index is <0.3, after optimizing reversible factors. 1, 2

Diagnostic Evaluation

Calculate Free Androgen Index First

• Never rely on total testosterone alone—always measure SHBG simultaneously to calculate the free androgen index (total testosterone/SHBG ratio), as SHBG variations can mask true androgen status 1
• Free androgen index <0.3 indicates functional hypogonadism requiring intervention 1
• Repeat free testosterone measurement on a separate morning to confirm the pattern 2

Identify the Underlying Cause

High SHBG is driven by specific conditions that must be systematically evaluated:

Endocrine causes:

• Hyperthyroidism—check TSH, free T4, and free T3 1, 2
• Aging—a physiological increase that may still require treatment if symptomatic 1

Hepatic causes:

• Chronic liver disease—check liver function tests, as SHBG is produced by the liver 3
• Note that SHBG initially rises in compensated cirrhosis but ultimately declines with progression to decompensated disease 3

Systemic diseases:

• HIV/AIDS—obtain HIV testing if risk factors present 1
• Chronic inflammatory conditions 1

Medication-induced:

• Anticonvulsants, particularly phenytoin 1
• Smoking 1
• Review all current medications for SHBG-elevating effects 3

Measure Gonadotropins

• Check morning LH and FSH levels to distinguish primary testicular failure (normal/high FSH with low testosterone) from secondary/central hypogonadism (low FSH with low testosterone) 3, 2
• This distinction guides whether the elevated SHBG is causing functional hypogonadism or if there is concurrent primary gonadal dysfunction 1

Treatment Algorithm

Step 1: Optimize Reversible Factors

Thyroid optimization:

• If hypothyroidism is present, review and optimize thyroid hormone dosing with an endocrinologist, as thyroid disorders alter SHBG production and reduce bioavailable testosterone 2
• If hyperthyroidism is present, treat with antithyroid medications, radioactive iodine, or surgery as appropriate—SHBG will normalize with euthyroid state 4

Metabolic optimization:

• The European Association of Urology identifies metabolic diseases and chronic systemic conditions (type 2 diabetes, metabolic syndrome) as causes of secondary hypogonadism 3, 2
• Optimize diabetes control and address insulin resistance, as these conditions affect the hypothalamic-pituitary axis 2

Medication review:

• Discontinue or substitute SHBG-elevating medications when clinically feasible 3, 1
• Consider alternative anticonvulsants if phenytoin is being used 1

Step 2: Address Functional Hypogonadism

When to initiate testosterone replacement therapy (TRT):

• Free androgen index <0.3 with hypogonadal symptoms (decreased libido, erectile dysfunction, decreased spontaneous erections, low mood, decreased motivation, fatigue) 3, 1, 2
• Total testosterone <230 ng/dL (8 nmol/L) usually benefits from TRT 3
• Total testosterone 231-346 ng/dL (8-12 nmol/L) with symptoms may be considered for a 4-6 month trial after careful discussion of risks and benefits 3
• Total testosterone >350 ng/dL (12 nmol/L) does not usually require substitution 3

TRT considerations with high SHBG:

• TRT can normalize free testosterone levels and may reduce elevated SHBG 2
• Critical caveat: TRT suppresses spermatogenesis—do not use if fertility is desired 2
• In patients >70 years or with chronic illness, use easily titratable formulations (gel, spray, patch) rather than long-acting injectables 3
• Target repletion goals in the middle range (350-600 ng/dL) 3
• In patients with congestive heart failure history, use caution due to fluid retention risk 3

Baseline testing before TRT:

• Hematocrit and hemoglobin 3, 2
• Prostate-specific antigen (PSA) 3, 2

Step 3: Lifestyle Modifications

Weight management and exercise:

• A low-fat (<10% calories), high-fiber diet plus daily exercise decreases insulin and increases SHBG in obese individuals 5
• However, in the context of already-elevated SHBG, focus on moderate exercise and balanced nutrition rather than extreme caloric restriction 5, 6
• Smoking cessation, as smoking increases SHBG 1
• Moderate alcohol consumption (<14 units/week for women, <21 units/week for men) 3

Dietary considerations:

• Total calorie intake, fat content, fiber, and protein content can alter SHBG levels 6
• Calorie restriction reduces insulin followed by SHBG increase, but isocaloric low-fat diets have no significant effect 7
• In the setting of high SHBG, avoid extreme dietary interventions that further elevate SHBG 6

Monitoring and Follow-Up

Reassessment Timeline

• Reassess total testosterone, free testosterone, and SHBG after 3-6 months of any intervention (thyroid optimization, metabolic management, or TRT initiation) 2
• Continue TRT beyond 6 months only if clinical benefit is demonstrated 3

Safety monitoring on TRT

• Monitor hemoglobin/hematocrit and PSA at 6-month intervals 3, 2
• Discontinue TRT if hematocrit rises excessively or PSA increases significantly 3

Treatment adjustment

• If free androgen index remains <0.3 despite TRT, consider increasing dose 2
• If underlying cause (e.g., hyperthyroidism) is corrected and SHBG normalizes, reassess need for continued TRT 2

Special Populations

Women with PCOS

• In PCOS, accelerated GnRH pulsatility causes LH hypersecretion and FSH hypofunction, resulting in hyperandrogenism despite often normal or low SHBG 1
• Anti-obesity agents (liraglutide, semaglutide, exenatide, orlistat) combined with lifestyle interventions increase SHBG and improve metabolic parameters 3
• Combined oral contraceptive pills (COCP) increase SHBG and reduce free androgen index 3

Men with chronic liver disease

• SHBG rises in compensated cirrhosis due to altered estrogen metabolism and disruption of the hypothalamic-pituitary axis 3
• Free testosterone declines from both hypogonadotropic hypogonadism and increased SHBG 3
• Evaluate for sexual dysfunction (erectile dysfunction, decreased libido) and consider TRT if free androgen index <0.3 and no contraindications 3
• Differential diagnosis includes psychogenic causes, alcohol use, medication effects (spironolactone, beta-blockers), and autonomic dysfunction 3

Post-bariatric surgery patients

• Monitor micronutrients including zinc, copper, selenium, and vitamin D, as deficiencies can affect hormonal balance 3
• SHBG may normalize with weight loss and improved insulin sensitivity 3