What is the recommended first‑line sperm induction protocol for a male patient with hypogonadotropic hypogonadism who wants to obtain sperm?

Sperm Induction Protocol for Hypogonadotropic Hypogonadism

First-Line Treatment: hCG Monotherapy

The recommended first-line sperm induction protocol for hypogonadotropic hypogonadism is human chorionic gonadotropin (hCG) monotherapy at 500-2500 IU administered 2-3 times weekly via subcutaneous or intramuscular injection, with the goal of normalizing testosterone levels first before adding FSH if needed. 1, 2

The degree of response to hCG correlates directly with baseline testicular size prior to treatment. 1 Men with testicular volumes >4 mL have significantly better outcomes than those with smaller testes. 3, 4

Initial Phase: hCG Monotherapy (First 3-6 Months)

• Start with hCG injections at 500-2500 IU administered 2-3 times weekly (most commonly 1500-2000 IU three times weekly). 1, 2
• The primary goal during this phase is to normalize serum testosterone levels, not immediate sperm production. 1, 2
• Monitor testosterone levels after 4 weeks of hCG pretreatment—target mid-normal range (500-600 ng/dL). 2, 4
• Measure testicular volume every 3 months, as increasing volume indicates positive response. 4
• Some men (approximately 23-30%) will achieve sperm in the ejaculate with hCG monotherapy alone, particularly those with adult-onset hypogonadotropic hypogonadism and prior spontaneous testicular development. 3, 5

Second Phase: Addition of FSH (After Testosterone Normalization)

FSH injections should be added only after testosterone levels normalize on hCG alone, typically after 3-6 months. 1, 2

• Add recombinant FSH at 75-150 IU subcutaneously 2-3 times weekly (most commonly 150 IU three times weekly). 2, 4, 6
• Combined hCG + FSH therapy achieves spermatogenesis in a higher percentage of patients compared to hCG alone—approximately 82-92% success rate. 5, 4
• The median time to sperm induction with combined therapy is 7.5 months, though some patients require 12-24 months. 4
• Perform semen analysis every 3 months after FSH addition to monitor response. 4

Critical Treatment Principles

Exogenous Testosterone is Absolutely Contraindicated

Men interested in current or future fertility should never receive exogenous testosterone therapy. 1, 2

Exogenous testosterone provides negative feedback to the hypothalamus and pituitary gland, inhibiting gonadotropin secretion and suppressing spermatogenesis, potentially causing azoospermia that can take months to years to recover. 1 This is a common pitfall among pubertal males with idiopathic hypogonadotropic hypogonadism who are started on testosterone for pubertal induction but remain on this therapy into their reproductive years. 1

Why Exogenous Testosterone Cannot Replace hCG

Exogenous testosterone cannot replace intratesticular testosterone production stimulated by hCG/LH. 7 Even when combined with FSH, exogenous testosterone fails to induce or maintain spermatogenesis in men with complete gonadotropin deficiency. 7 Intratesticular testosterone concentrations must be 50-100 times higher than serum levels for normal spermatogenesis, and this can only be achieved through LH (or hCG) stimulation of testicular Leydig cells. 2

Predictors of Successful Spermatogenesis

Positive Prognostic Factors

• Baseline testicular volume >4 mL is the strongest predictor of successful outcomes and earlier spermatogenesis induction. 3, 4
• Serum inhibin B concentration >60 pg/mL at baseline. 3
• No history of cryptorchidism (undescended testes). 3, 5
• Adult-onset hypogonadotropic hypogonadism with prior spontaneous testicular development responds better to hCG monotherapy than congenital forms. 3

Negative Prognostic Factors

• Multiple pituitary deficits. 5
• History of cryptorchidism. 3, 5
• Testicular volume <4 mL at baseline. 3, 4

Expected Treatment Outcomes

Spermatogenesis Success Rates

• Combined hCG + FSH therapy successfully induces spermatogenesis in 82-92% of men with hypogonadotropic hypogonadism. 5, 4
• Median time to sperm appearance is 7.5 months, with range of 3-24 months. 4
• Expected median sperm concentration after successful induction is 5.2 million/mL, with 35% total motility and 4% normal morphology. 4

Testicular Volume Response

• All patients should demonstrate marked and continuous increase in testicular volume during therapy. 5
• Median testicular volume increases from 4.0 mL at baseline to 9.0 mL after treatment. 4
• Lack of testicular volume increase suggests treatment failure or non-compliance. 5

Treatment Duration and Monitoring

Timeline Expectations

• Initial hCG monotherapy phase: 3-6 months to normalize testosterone. 2, 4
• Combined hCG + FSH phase: median 7.5 months to sperm appearance, though some require 12-24 months. 4
• Total treatment duration before achieving pregnancy: median 18 months. 2

Monitoring Protocol

• Testosterone levels: measure after 4 weeks of hCG, then every 3 months. 2, 4
• Testicular volume: measure every 3 months. 4
• Semen analysis: perform every 3 months after FSH addition. 4
• If no sperm appear after 12-24 months of combined therapy, consider referral for assisted reproductive technology. 1

When Medical Therapy Fails

If medical therapy for hypogonadotropic hypogonadism fails to result in pregnancy but some sperm are found in the ejaculate, referral for intrauterine insemination (IUI) or assisted reproductive technology (ART) is recommended. 1

IVF with intracytoplasmic sperm injection (ICSI) allows pregnancy to occur with very low numbers of sperm and provides approximately 37% live delivery rate per initiated cycle. 1, 6

Common Pitfalls to Avoid

• Never start FSH before testosterone normalizes on hCG—FSH cannot work effectively without adequate intratesticular testosterone. 1, 2
• Never use exogenous testosterone in men desiring fertility—this will completely suppress spermatogenesis. 1, 2
• Never discontinue treatment prematurely—some men require 18-24 months to achieve spermatogenesis. 2, 4
• Never assume treatment failure based on FSH levels alone—success depends on baseline testicular volume and etiology, not FSH levels. 3, 4
• Never skip baseline testicular volume measurement—this is the strongest predictor of treatment success. 3, 4

Special Considerations

Congenital vs. Adult-Onset Hypogonadotropic Hypogonadism

Men with congenital hypogonadotropic hypogonadism (e.g., Kallmann syndrome) require combined hCG + FSH therapy as an absolute requirement to maximize fertility potential, as hCG monotherapy is rarely successful in this population. 3 In contrast, previously virilized men with adult-onset hypogonadotropic hypogonadism and normal testicular volume respond well to hCG monotherapy. 3

Maintenance Therapy After Sperm Induction

Four of five men who achieved sperm densities >1 million/mL during combined hCG + hMG therapy maintained or increased sperm production while receiving continued hCG therapy after hMG was withdrawn. 5 This suggests that once spermatogenesis is established, some men can maintain sperm production on hCG monotherapy, though this should be monitored with regular semen analyses. 5