What could be the cause of secondary hypogonadism and potential infertility in a male in his 30s with low Luteinizing Hormone (LH), normal Prolactin, and low or absent sperm count (Azoospermia)?

Secondary Hypogonadism (Hypogonadotropic Hypogonadism)

A male in his 30s with low LH, normal prolactin, and azoospermia/severe oligospermia most likely has hypogonadotropic hypogonadism (HH), which requires immediate evaluation to determine the underlying etiology before initiating fertility-preserving treatment with exogenous gonadotropins. 1

Diagnostic Approach

Confirm the Diagnosis

• Low or inappropriately normal LH and FSH levels despite low testosterone indicate hypothalamic-pituitary dysfunction, distinguishing secondary from primary hypogonadism 2
• Measure serum testosterone (two morning samples on separate days) and FSH in addition to the LH already obtained 1
• Normal prolactin effectively rules out hyperprolactinemia as the cause, which would otherwise present with similar hormonal patterns (low LH, low testosterone, azoospermia) 1, 3

Physical Examination Findings

• Assess testicular size and consistency—normal-sized testes (>15 mL) suggest the potential for spermatogenesis recovery with treatment, while small atrophic testes indicate more severe impairment 1, 4
• Palpate for bilateral vas deferens to exclude congenital bilateral absence of vas deferens (CBAVD), which would present differently 4
• Evaluate secondary sexual characteristics and body habitus, as HH may present with decreased facial/body hair and eunuchoid proportions if longstanding 1

Determine the Underlying Etiology

• Order pituitary MRI to evaluate for pituitary adenoma, infiltrative disease, or structural abnormalities causing HH 1
• Assess for functional causes: obesity, metabolic syndrome, type 2 diabetes, chronic illness, or medications that suppress the hypothalamic-pituitary axis 5
• Consider genetic testing for Kallmann syndrome or other congenital causes if there is history of anosmia, cryptorchidism, or delayed puberty 1

Genetic Testing Before Treatment

• Karyotype testing is mandatory for azoospermia or sperm concentration <5 million/mL to identify Klinefelter syndrome (47,XXY) or other chromosomal abnormalities 1, 4
• Y-chromosome microdeletion analysis is required for azoospermia or severe oligospermia (<1 million/mL), as 5% of severely oligospermic men have these deletions 1, 4

Treatment Strategy

Fertility Restoration (Primary Goal for Men in Their 30s)

• Refer to endocrinology or male reproductive specialist for gonadotropin therapy, which can initiate spermatogenesis and achieve pregnancies in many men with HH 1
• Treatment protocol: Start with hCG injections (typically 1500-2000 IU subcutaneously 2-3 times weekly) to normalize testosterone levels, monitoring serum testosterone response 1
• After testosterone normalization (usually 3-6 months), add FSH or FSH analogues (75-150 IU subcutaneously 3 times weekly) to optimize sperm production 1
• Combined hCG and FSH therapy provides optimal outcomes for secondary hypogonadism seeking fertility 2

Critical Treatment Pitfall to Avoid

• NEVER prescribe testosterone monotherapy to men desiring current or future fertility, as exogenous testosterone suppresses gonadotropin secretion and can result in complete azoospermia 1
• Testosterone provides negative feedback to the hypothalamus and pituitary, inhibiting LH and FSH secretion, which halts spermatogenesis 1

Alternative Medications (If Gonadotropins Not Available/Tolerated)

• Clinicians may use selective estrogen receptor modulators (SERMs), aromatase inhibitors (AIs), or hCG alone for infertile men with low testosterone, though these have limited benefits compared to combined gonadotropin therapy 1
• Clomiphene citrate 25-50 mg daily or anastrozole 1 mg twice weekly can increase endogenous LH/FSH and testosterone in men with functioning pituitary glands 1

Assisted Reproductive Technology Options

If Medical Treatment Fails or Time-Sensitive

• Surgical sperm retrieval (testicular sperm extraction/TESE) with intracytoplasmic sperm injection (ICSI) is an alternative if gonadotropin therapy fails or the couple requires immediate fertility treatment 1
• Intrauterine insemination (IUI) success rates are reduced with total motile sperm count <5 million, and IVF/ICSI should be considered instead 1

Prognosis and Counseling

• Men with HH have excellent fertility potential with appropriate gonadotropin treatment, as the testes retain spermatogenic capacity when properly stimulated 1, 2
• Treatment duration varies: testosterone normalization occurs within 3-6 months, but sperm appearance in ejaculate may take 6-12 months or longer 1
• Low sperm count itself is associated with increased risk of metabolic syndrome, cardiovascular disease, and osteoporosis, warranting comprehensive health assessment 6