What are the treatment options for hypogonadotropic hypogonadism in males?

Treatment Options for Hypogonadotropic Hypogonadism in Males

For males with hypogonadotropic hypogonadism who desire current or future fertility, human chorionic gonadotropin (hCG) is the first-line treatment, NOT exogenous testosterone, which will suppress spermatogenesis and impair fertility. 1, 2

Critical Treatment Decision Algorithm

Step 1: Assess Fertility Goals

If fertility is desired (now or future):

• Do NOT prescribe exogenous testosterone - it provides negative feedback to the hypothalamus and pituitary, suppressing gonadotropin secretion and causing oligospermia or azoospermia 1
• Initiate hCG therapy as first-line treatment 1, 2

If fertility is NOT a concern:

• Testosterone replacement therapy (TRT) is appropriate 3, 4
• Multiple formulations available: intramuscular testosterone esters (enanthate or cypionate), transdermal gels, or scrotal patches 5

Step 2: hCG Protocol for Fertility Preservation

Initial hCG monotherapy: 1, 2, 6

• Dosing: 500-2500 IU administered 2-3 times weekly via subcutaneous or intramuscular injection
• Goal: Normalize testosterone levels first
• Monitor response: Testicular size prior to treatment correlates with degree of response 1

Addition of FSH when indicated: 1, 7

• Add FSH injections after testosterone levels normalize on hCG alone
• Combined hCG + FSH achieves spermatogenesis in 86% of patients (95% CI 82%-91%), compared to only 40% (95% CI 25%-56%) with hCG alone 7
• This is particularly important in men with prepubertal hypogonadotropic hypogonadism 5

Step 3: Alternative Gonadotropin Options

Pulsatile GnRH therapy: 1, 5

• Can stimulate both testosterone production and spermatogenesis in hypothalamic defects (idiopathic hypogonadotropic hypogonadism, Kallmann syndrome)
• Major limitation: Not currently approved in the U.S. or Europe 1
• Poor patient compliance and high cost limit practical use 8

Treatment Outcomes and Monitoring

Expected responses with gonadotropin therapy: 7

• Significant increases in testicular volume in >98% of patients
• Penile size increases in >98% of patients
• Testosterone normalization in >98% of patients
• Median treatment duration: 18 months (interquartile range 10.5-24 months)

If medical therapy fails: 1

• If some sperm are found in ejaculate despite failed medical therapy, refer for intrauterine insemination (IUI) or assisted reproductive technology (ART)
• IVF provides approximately 37% live delivery rate per initiated cycle 1

Critical Pitfalls to Avoid

Common prescribing error: 1

• Many pubertal males with idiopathic hypogonadotropic hypogonadism are started on exogenous testosterone for pubertal induction, then remain on this therapy into adulthood and reproductive years
• This suppresses spermatogenesis and impairs fertility
• Recovery after testosterone cessation: Most azoospermic males recover sperm to ejaculate after stopping testosterone, but this may take months or rarely years 1, 2

Testosterone replacement contraindications for fertility: 1, 2

• Exogenous testosterone administration inhibits intratesticular testosterone production
• Depending on degree of suppression, spermatogenesis may decrease or cease completely
• Men interested in current or future fertility should never receive exogenous testosterone 1, 2

Testosterone Replacement Therapy (When Fertility Not Desired)

Indications: 3, 6

• Primary hypogonadism (congenital or acquired)
• Hypogonadotropic hypogonadism (congenital or acquired) when fertility is not a concern
• Confirm diagnosis with morning serum testosterone measured on at least two separate days, both below normal range 3

Formulations and dosing: 3, 5

• Testosterone gel 1.62%: Starting dose 40.5 mg (2 pump actuations) applied topically once daily to shoulders and upper arms; can adjust between 20.25 mg (1 pump) to 81 mg (4 pumps) 3
• Parenteral testosterone esters: Testosterone enanthate or cypionate are the most effective, safe, practical, and inexpensive preparations available 5

Important safety considerations with TRT: 1, 3

• Monitor for cardiovascular events - the TOM trial showed increased CV events in the TRT arm (23 vs 5 events), though evidence remains mixed 1
• Avoid secondary exposure to women and children - virilization has been reported in children secondarily exposed to testosterone gel 3
• Patients must wash hands immediately with soap and water after application and cover application sites with clothing 3
• Monitor for worsening benign prostatic hyperplasia symptoms 3
• Contraindicated in men with breast carcinoma or known/suspected prostate cancer 3

Modest benefits on other outcomes: 1

• Lumbar spine bone mineral density increases approximately 3.2%, femoral neck by 1.4% 1
• Improvements in sexual function in hypogonadal men with type 2 diabetes and metabolic syndrome 1
• Inconsistent effects on quality of life, well-being, mood, and erectile dysfunction 1