What are the evaluation and treatment options for a patient with high sex hormone-binding globulin (SHBG) and low-normal free testosterone levels?

Management of High SHBG with Low-Normal Free Testosterone

For patients with high SHBG and low-normal free testosterone, first confirm the diagnosis with morning total testosterone, free testosterone by equilibrium dialysis, and measure LH to determine if secondary hypogonadism is present—then initiate testosterone replacement therapy if hypogonadal symptoms are present and confirmed low free testosterone persists, as this will normalize free testosterone levels and reduce elevated SHBG. 1, 2

Diagnostic Workup

Initial Laboratory Assessment

• Obtain morning total testosterone on two separate occasions to confirm levels are truly in the normal range (≥300 ng/dL), as the diagnosis requires consistently low values 3
• Measure free testosterone by equilibrium dialysis (the gold standard method) along with SHBG to understand binding dynamics 1
• Calculate the free testosterone index (total testosterone/SHBG ratio), where a ratio <0.3 indicates hypogonadism even when total testosterone appears normal 2
• Measure serum LH levels to establish whether this represents secondary (low/normal LH) versus primary (elevated LH) hypogonadism 3, 1

Additional Testing Based on LH Results

• If LH is low or low-normal, measure serum prolactin to screen for hyperprolactinemia and potential pituitary pathology 3
• If total testosterone is <150 ng/dL with low/normal LH, obtain pituitary MRI regardless of prolactin levels to evaluate for non-secreting adenomas 3

Identify Underlying Causes of Elevated SHBG

High SHBG can be caused by multiple conditions that should be evaluated and addressed 2, 4:

• Hepatic disease or cirrhosis (SHBG is synthesized in the liver)
• Hyperthyroidism (thyroid hormones stimulate SHBG production) 5
• Medications: anticonvulsants, estrogens, thyroid hormone replacement 2
• Aging (SHBG naturally increases with age)
• HIV/AIDS
• Smoking

Symptom Assessment

Document specific hypogonadal symptoms that warrant treatment consideration 3:

• Reduced energy, endurance, and physical performance
• Fatigue and reduced motivation
• Depression, poor concentration, impaired memory, irritability
• Reduced libido and erectile dysfunction
• Infertility concerns

Perform targeted physical examination for signs of hypogonadism 3:

• Body habitus and virilization status (body hair patterns in androgen-dependent areas)
• Body mass index or waist circumference
• Gynecomastia
• Testicular size, consistency, and presence of masses
• Varicocele presence

Treatment Algorithm

Step 1: Address Reversible Causes

Before initiating testosterone therapy, optimize modifiable factors 2:

• Treat thyroid disorders if hyperthyroidism is present 5
• Review and discontinue medications that elevate SHBG when possible
• Address liver disease if present
• Implement metabolic interventions (weight loss in obese patients can improve functional hypogonadism) 1

Step 2: Initiate Testosterone Replacement Therapy

Testosterone replacement is indicated when 1, 2:

• Confirmed low free testosterone persists despite addressing underlying causes
• Patient has documented hypogonadal symptoms
• Free testosterone index <0.3

Testosterone therapy will normalize free testosterone levels and typically reduces elevated SHBG 6. Research demonstrates that testosterone enanthate (200 mg IM every 2 weeks) significantly decreased SHBG from 16.4 ± 2 to 4.3 ± 0.5 ng DHT bound/ml in hypogonadal patients while increasing free testosterone from 94 ± 20 to 271 ± 50 pg/ml 6.

Available testosterone formulations 7:

• Testosterone gel (50-100 mg daily): 74% of appropriately titrated patients achieved average serum testosterone within normal range (300-1,000 ng/dL)
• Testosterone enanthate injections (typically 200 mg IM every 2 weeks)
• Transdermal patches

Step 3: Fertility Preservation Consideration

For men desiring fertility, avoid testosterone replacement as it suppresses spermatogenesis 1, 2. Instead:

• Consider selective estrogen receptor modulators (SERMs) like clomiphene citrate for patients with low/normal LH levels 3, 1
• SERMs stimulate endogenous testosterone production while preserving fertility

Monitoring Protocol

Initial Follow-up (1-2 months) 1

• Assess symptomatic response to treatment
• Measure serum total and free testosterone levels
• Consider dose adjustments based on response

Ongoing Monitoring (3-6 month intervals for first year) 1

At each visit, evaluate:

• Symptom response to treatment
• Voiding symptoms (prostate-related)
• Sleep apnea symptoms
• Digital rectal examination
• Serum testosterone levels (total and free)
• PSA levels (before and during therapy) 2
• Hematocrit or hemoglobin (testosterone can increase red blood cell production) 2

Long-term Reassessment

Reassess testosterone (total and free) and SHBG levels after 3-6 months of treatment to confirm normalization and adjust therapy based on symptom response and laboratory values 2

Critical Pitfalls to Avoid

• Do not rely on total testosterone alone when SHBG is abnormal—free testosterone or free testosterone index is essential for accurate assessment 2, 4, 8
• Do not use screening questionnaires as a substitute for full patient evaluation and laboratory testosterone measurement 3
• Avoid testosterone therapy in men actively pursuing fertility without first discussing SERM alternatives 1, 2
• Do not overlook underlying causes of elevated SHBG (particularly hyperthyroidism and liver disease) that may be treatable 2, 5
• Be aware that certain oral androgens like oxandrolone can paradoxically lower SHBG through first-pass hepatic metabolism, potentially worsening the clinical picture 9