What is the recommended surveillance and treatment for patients with hypogonadotropic (low sex hormone production due to underactive gonads) hypogonadism?

Surveillance and Treatment for Hypogonadotropic Hypogonadism

For patients with hypogonadotropic hypogonadism, the treatment approach depends critically on fertility goals: use human chorionic gonadotropin (hCG) 500-2500 IU subcutaneously 2-3 times weekly as first-line therapy if fertility is desired, or transdermal testosterone gel 1.62% at 40.5 mg daily if fertility is not a concern. 1, 2, 3

Diagnostic Confirmation and Etiology Assessment

Before initiating treatment, confirm the diagnosis with:

• Two separate morning total testosterone measurements demonstrating levels below 300 ng/dL 2, 4, 3
• Measure LH and FSH levels, which will be low or inappropriately normal in hypogonadotropic hypogonadism (distinguishing it from primary hypogonadism where they are elevated) 1, 4
• Evaluate the underlying etiology through pituitary imaging (MRI) to identify tumors, assess for history of cranial radiation (doses ≥40 Gy increase risk), chemotherapy exposure, or congenital conditions like Kallmann syndrome 1

Treatment Algorithm Based on Fertility Goals

For Patients Desiring Fertility (Current or Future)

Exogenous testosterone is absolutely contraindicated because it suppresses the hypothalamic-pituitary-gonadal axis, inhibiting spermatogenesis and causing oligospermia or azoospermia. 1, 5, 2, 4, 3

First-line therapy: hCG monotherapy

• Start hCG 500-2500 IU subcutaneously or intramuscularly 2-3 times weekly 1, 6
• This stimulates endogenous testosterone production while preserving testicular function 5, 6
• Monitor testosterone levels to ensure normalization before adding FSH 1

Add FSH if needed after 3-6 months:

• If spermatogenesis does not develop adequately on hCG alone, add recombinant FSH (rFSH), highly purified urinary FSH, or human menopausal gonadotropins 6, 7
• Combined hCG-FSH therapy for 12-24 months promotes testicular growth in nearly all patients, spermatogenesis in approximately 80%, and pregnancy rates around 50% 6
• Higher success rates occur in post-pubertal onset HH, larger baseline testicular volume (>4 mL), and higher baseline inhibin B levels 6, 8

Alternative: Pulsatile GnRH therapy (not currently FDA-approved in the U.S.)

• Physiologically mimics normal hypothalamic function 9, 10
• Requires portable pump for pulsatile administration 9

For Patients NOT Desiring Fertility

First-line therapy: Transdermal testosterone gel 1.62%

• Starting dose: 40.5 mg (2 pump actuations) applied once daily in the morning to shoulders and upper arms 2, 3
• Target testosterone range: 350-750 ng/dL 5, 2, 3
• Transdermal preparations are preferred over injectable formulations because they provide stable testosterone levels, avoid injection discomfort, and have lower risk of erythrocytosis 2, 4

Dose titration protocol:

• Check pre-dose morning testosterone at 14 and 28 days after starting or adjusting dose 3
• If testosterone >750 ng/dL: decrease by 20.25 mg (1 pump actuation) 3
• If testosterone 350-750 ng/dL: continue current dose 3
• If testosterone <350 ng/dL: increase by 20.25 mg (1 pump actuation) 3
• Maximum dose: 81 mg (4 pump actuations) 3

Injectable testosterone alternative:

• Testosterone cypionate or enanthate can be used but may cause fluctuating levels and injection site discomfort 2, 4
• Less preferred than transdermal formulations 2

Surveillance Protocol During Treatment

Initial Monitoring (First 3-6 Months)

• Testosterone levels at 14 and 28 days after initiation or dose adjustment 3
• Assess sexual symptoms and quality of life at 3 months 2
• Hematocrit at 3 months to detect early erythrocytosis 2, 4
• Baseline PSA in men >40 years before starting therapy 5

Long-Term Surveillance

• Testosterone levels every 6-12 months once stable 2
• Hematocrit monitoring periodically (testosterone can increase red blood cell production) 1, 2
• PSA monitoring annually in men >40 years 1
• Bone mineral density testing should be considered in hypogonadal patients, as prolonged hypoestrogenism/hypoandrogenism increases osteoporosis risk 1
• For patients on hCG-FSH therapy: semen analysis every 3-6 months to assess spermatogenesis response 6, 8

Absolute Contraindications to Testosterone Therapy

• Active or previously treated breast cancer (testosterone can stimulate tumor growth) 5, 2, 4
• Current desire for fertility (suppresses spermatogenesis) 1, 5, 2, 4
• Severe uncontrolled heart failure remains a contraindication 4

Special Populations

Adolescents with Delayed Puberty

• Start low-dose testosterone or low-dose gonadotropins at timing closer to normal pubertal onset (around age 12-13 years) to avoid excessive bone age advancement 8
• For congenital HH, consider preemptive FSH therapy prior to full gonadotropin replacement to optimize future fertility 8

Post-Cancer Survivors

• Girls/women with chemotherapy or radiation-induced premature ovarian insufficiency require hormonal therapy with estrogen and progesterone to prevent osteoporosis, cardiovascular disease, and urogenital atrophy 1
• Males with cranial radiation ≥30 Gy have highest risk of central hypogonadism and require long-term surveillance 1

Patients with Obesity

• Consider measuring free testosterone by equilibrium dialysis and SHBG if total testosterone is borderline low 4
• Weight loss through low-calorie diet and regular physical activity can modestly improve testosterone levels as adjunct to therapy 2

Common Pitfalls and How to Avoid Them

Pitfall #1: Starting testosterone in men who may want fertility later

• Always discuss fertility goals before initiating therapy 1, 2, 4
• Once on testosterone, recovery of spermatogenesis after cessation occurs in most but not all men 1

Pitfall #2: Inadequate dose titration

• Many patients remain undertreated; ensure testosterone levels reach target range of 350-750 ng/dL 2, 3
• Check levels at appropriate intervals (14 and 28 days) for dose adjustment 3

Pitfall #3: Failing to distinguish primary from secondary hypogonadism

• Always measure LH and FSH to guide treatment choice 1, 4
• Primary hypogonadism (high LH/FSH) will not respond to gonadotropin therapy 1

Pitfall #4: Discontinuing hCG too early in fertility treatment

• Normalize testosterone levels on hCG before adding FSH 1
• Continue combined therapy for 12-24 months for optimal spermatogenesis 6

Pitfall #5: Inadequate patient education about secondary exposure risk

• Children should avoid contact with unwashed or unclothed application sites 3
• Cover application site with clothing once dry 3
• Avoid swimming/showering for minimum 2 hours after application 3

Expected Benefits of Treatment

• Improved sexual function and libido with small to moderate effect sizes 1, 2, 4
• Enhanced sense of well-being and quality of life 2, 4
• Increased lean body mass and decreased body fat 2, 4
• Improved bone mineral density reducing fracture risk 2, 4
• For gonadotropin therapy: restoration of fertility in approximately 80% of patients with spermatogenesis and 50% pregnancy rates 6