How should an infertile male with low luteinizing hormone, low follicle‑stimulating hormone, and low testosterone be evaluated and managed?

Management of Infertile Males with Low LH, Low FSH, and Low Testosterone

For an infertile male with low LH, low FSH, and low testosterone, initiate human chorionic gonadotropin (hCG) injections at 1,000–2,500 IU subcutaneously 2–3 times weekly to restore endogenous testosterone production, then add recombinant FSH after 2–3 months if sperm counts remain low; never prescribe testosterone monotherapy as it will worsen or induce azoospermia through negative feedback suppression of gonadotropins. 1, 2

Diagnostic Confirmation and Etiology Assessment

This hormonal pattern confirms secondary (hypogonadotropic) hypogonadism, where the pituitary fails to produce adequate LH and FSH, resulting in deficient testicular stimulation. 1, 2

Essential Initial Testing

• Measure serum prolactin to screen for hyperprolactinemia, which can suppress LH/FSH secretion and mimic hypogonadotropic hypogonadism. 1, 2 If prolactin is persistently elevated on repeat testing, refer to endocrinology for pituitary imaging to exclude prolactinomas. 1, 2

• Obtain pituitary MRI when testosterone is <150 ng/dL with low or low-normal LH, as non-secreting pituitary adenomas may be present even without elevated prolactin. 1, 2

• Perform baseline semen analysis before initiating therapy to document sperm parameters and establish whether azoospermia or severe oligospermia is present. 1, 2

• Check iron saturation studies to rule out hemochromatosis as a cause of pituitary dysfunction. 2

• Measure FSH levels to determine whether both gonadotropins are deficient (combined LH/FSH deficiency) or if LH deficiency is isolated. 1, 2

Treatment Protocol for Fertility Restoration

First-Line Therapy: hCG Monotherapy

Begin with hCG injections (1,000–2,500 IU subcutaneously 2–3 times weekly) to stimulate testicular Leydig cells and restore endogenous testosterone production. 1, 2, 3 This approach mimics LH action and generates the high intratesticular testosterone concentrations (50-100 times higher than serum levels) that are essential for spermatogenesis. 4

• After 2–3 months of hCG therapy, reassess serum testosterone levels to confirm normalization. 1, 2, 3

• Obtain repeat semen analysis once testosterone normalizes. 1, 2

Second-Line: Adding FSH Analogues

If sperm counts remain low or absent after testosterone normalization on hCG, add a follicle-stimulating hormone analogue (recombinant FSH, highly purified urinary FSH, or human menopausal gonadotropin containing both FSH and LH activity). 1, 2, 3

• Treatment with hCG followed by FSH analogues successfully initiates spermatogenesis in men with hypogonadotropic hypogonadism, with 75% of men achieving sperm in the ejaculate. 4

• Response to hCG correlates with baseline testicular size; men with larger testes respond better. 4

• Continue combined therapy for at least 6–12 months, as spermatogenesis induction requires prolonged treatment. 3, 5

Expected Outcomes

Case reports demonstrate that hCG alone can normalize testosterone levels, sperm concentration, and semen volume, resulting in successful conception. 6 In adult-onset hypogonadotropic hypogonadism, treatment with GnRH or gonadotropins reverses hypogonadism and restores fertility in appropriately selected patients. 7

Critical Management Pitfalls

Never Prescribe Testosterone Monotherapy

Exogenous testosterone is absolutely contraindicated in men desiring fertility. 1, 2, 3 Testosterone provides negative feedback to the hypothalamus and pituitary, suppressing LH and FSH secretion, which eliminates intratesticular testosterone production and causes azoospermia that can take months to years to recover. 1, 4, 2

Research definitively shows that FSH combined with exogenous testosterone cannot induce or maintain spermatogenesis in men with complete gonadotropin deficiency. 8 When exogenous testosterone replaced hCG in men already on gonadotropin therapy, sperm counts dropped to zero within 6 months. 8 Exogenous testosterone is unable to replace LH and intratesticular testosterone for spermatogenesis. 8

Monitoring for Side Effects

Gynecomastia is the most frequent side effect of hCG therapy due to aromatase-mediated conversion of testosterone to estradiol. 2 Monitor for breast tenderness or enlargement, and measure estradiol levels if these symptoms develop. 1, 2

Alternative and Adjunctive Fertility Options

Assisted Reproductive Technology

Discuss IVF/ICSI early in the treatment course, as these techniques offer higher pregnancy rates compared to empiric hormonal therapy alone, especially when the female partner's age is a limiting factor. 1, 2

Surgical Sperm Retrieval

Consider testicular sperm extraction (TESE) or testicular sperm aspiration (TESA) for men who remain azoospermic despite optimal gonadotropin therapy, to enable use of assisted reproductive technology. 1, 2

Limited Role of Other Medical Therapies

Selective estrogen receptor modulators (SERMs) and aromatase inhibitors may be used for infertile men with low testosterone, but their benefits are limited relative to results of ART. 1 These agents are more appropriate for men with low testosterone and elevated FSH (indicating primary testicular dysfunction), not for hypogonadotropic hypogonadism. 1

Monitoring and Follow-Up

• Re-measure testosterone, LH, and FSH after initiating hCG to confirm adequate gonadal stimulation. 2

• Repeat semen analysis every 3 months during treatment to assess response. 1, 2

• Continue treatment for at least 6–12 months before concluding that therapy has failed, as spermatogenesis induction requires prolonged stimulation. 3, 5