How to manage hypogonadism with low free and bioavailable testosterone levels?

Management of Low Free and Bioavailable Testosterone

In men with low free testosterone (45.3 pg/mL) and low bioavailable testosterone (93.1 ng/dL), you should initiate testosterone replacement therapy if hypogonadal symptoms are present, after confirming the diagnosis with a repeat morning total testosterone measurement and evaluating for contraindications. 1, 2

Diagnostic Confirmation Required

Before initiating treatment, complete the following workup:

• Measure morning total testosterone on at least two separate days to confirm persistent testosterone deficiency, as single measurements can be misleading 1, 3
• Assess sex hormone-binding globulin (SHBG) to understand the binding dynamics, since conditions like obesity, diabetes, and metabolic syndrome lower SHBG and can cause discordance between total and free testosterone 1, 2
• Measure luteinizing hormone (LH) and follicle-stimulating hormone (FSH) to distinguish between primary hypogonadism (elevated LH/FSH) and secondary hypogonadism (low or normal LH/FSH), as this determines treatment options and fertility preservation strategies 1

Critical caveat: Avoid testosterone testing during acute illness, as temporary suppression of the hypothalamic-pituitary-gonadal axis can produce falsely low results 1

Symptom Assessment

Evaluate for specific hypogonadal symptoms that guide treatment decisions 1:

Sexual symptoms (most specific):

• Reduced frequency of sexual intercourse
• Reduced frequency of masturbation
• Delayed ejaculation
• Erectile dysfunction 1

Physical symptoms:

• Hot flushes
• Decreased energy and physical strength
• Loss of muscle mass 1

Cognitive symptoms:

• Concentration difficulties
• Sleep disturbances 1

Evaluate Underlying Causes and Comorbidities

Screen for reversible causes that may be contributing to low testosterone 1:

• Obesity and metabolic syndrome: Weight loss can improve functional hypogonadism, as adipose tissue increases aromatization of testosterone to estradiol, causing estradiol-mediated negative feedback that suppresses LH secretion 2
• Type 2 diabetes: Mean testosterone levels are lower in diabetic men, though obesity is a major confounder 1
• Medications: Review drugs that interfere with testosterone production (glucocorticoids, opioids) or increase SHBG (anticonvulsants, thyroid hormone) 1
• Thyroid dysfunction: Both hyperthyroidism (increases SHBG) and hypothyroidism (decreases SHBG) affect testosterone binding 1

Treatment Algorithm

If Fertility is NOT a Concern:

Testosterone replacement therapy is the treatment of choice 1, 3:

• Starting dose: Testosterone gel 1.62% at 40.5 mg (2 pump actuations) applied topically once daily in the morning to shoulders and upper arms 3
• Dose titration: Measure pre-dose morning serum testosterone at 14 days and 28 days after starting treatment 3
  • Target range: 350-750 ng/dL total testosterone 3
  • If <350 ng/dL: increase by 20.25 mg
  • If >750 ng/dL: decrease by 20.25 mg
  • Maximum dose: 81 mg (4 pump actuations) 3

Application instructions to prevent secondary exposure 3:

• Apply to clean, dry, intact skin of upper arms and shoulders only
• Wash hands immediately with soap and water after application
• Cover application sites with clothing once dry
• Avoid swimming or showering for minimum 2 hours after application
• Wash application site thoroughly before skin-to-skin contact with others

If Fertility IS a Concern:

Do NOT use testosterone replacement therapy, as exogenous androgens suppress the hypothalamic-pituitary-gonadal axis and lead to azoospermia 3, 4

For secondary hypogonadism with fertility preservation:

• Gonadotropin therapy (hCG combined with FSH) is the preferred option, achieving spermatogenesis in approximately 80% of patients and pregnancy rates around 50% after 12-24 months 5
• Selective estrogen receptor modulators (clomiphene citrate) can be considered off-label for functional hypogonadism, though evidence for symptom improvement is insufficient for routine use 2, 4

Contraindications to Screen For

Absolute contraindications to testosterone therapy 3:

• Carcinoma of the breast
• Known or suspected prostate cancer
• Pregnancy in female partners (risk of secondary exposure causing virilization)

Relative contraindications requiring careful monitoring 3:

• Benign prostatic hyperplasia (monitor for worsening symptoms)
• Polycythemia or elevated hematocrit
• Severe cardiovascular disease (though recent large randomized trials show no increased risk of MI or stroke) 6, 7
• Sleep apnea
• Thrombophilia or history of venous thromboembolism

Monitoring Protocol

Initial follow-up at 1-2 months to assess efficacy and adjust dose 2

At 3-6 month intervals for the first year, then annually 2, 6:

• Symptomatic response to treatment (sexual function, energy, well-being)
• Serum testosterone levels (maintain 350-750 ng/dL)
• Prostate-specific antigen (PSA) in men ≥40 years 3, 6
• Hematocrit/hemoglobin (discontinue if hematocrit >54%) 3, 6
• Digital rectal examination for prostate assessment 2
• Liver function tests 1
• Lipid profile 1
• Voiding symptoms and sleep apnea symptoms 2

Expected Benefits

Testosterone replacement therapy in symptomatic hypogonadal men improves 1, 6, 7:

• Sexual function and erectile dysfunction
• Muscle mass and strength
• Bone density
• Depressive symptoms and well-being
• Mortality rates (3.1% vs 3.6% at 3 years)
• Cardiovascular outcomes (lower rates of atrial fibrillation and stroke)

Important note: A large randomized trial demonstrated that testosterone replacement does not increase the risk of myocardial infarction or stroke, even in high-risk patients, contradicting earlier concerns 6, 7