What is the management approach for a male patient with hypogonadism (low sex hormone production) presenting with low Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels?

Management of Male Hypogonadism with Low FSH and LH

For male hypogonadism with low FSH and LH (secondary/hypogonadotropic hypogonadism), the critical first decision is whether the patient desires fertility—if yes, gonadotropin therapy (hCG plus FSH) is mandatory and testosterone is absolutely contraindicated; if no, testosterone replacement therapy is first-line treatment. 1, 2, 3

Diagnostic Confirmation

Before initiating any treatment, confirm the diagnosis with the following steps:

• Repeat morning total testosterone measurements (drawn between 8-10 AM) on at least two separate occasions to establish persistent hypogonadism, with levels <300 ng/dL indicating hypogonadism 1, 2, 3
• Measure free testosterone by equilibrium dialysis in addition to total testosterone, especially in men with obesity, as this distinguishes true hypogonadism from low SHBG-related decreases 1, 3
• Confirm low or inappropriately normal LH and FSH levels despite low testosterone—this pattern definitively establishes secondary (hypogonadotropic) hypogonadism rather than primary (testicular) hypogonadism 2, 3, 4
• Assess for specific symptoms of testosterone deficiency, particularly diminished libido and erectile dysfunction, as these are the primary symptoms that respond to treatment 1, 2, 3

The distinction between primary and secondary hypogonadism is critical because secondary hypogonadism patients can potentially achieve both normal testosterone levels AND fertility with gonadotropin therapy, whereas primary hypogonadism patients can only receive testosterone replacement, which permanently compromises fertility. 2, 3

Treatment Algorithm Based on Fertility Goals

If Patient Desires Fertility Preservation

Gonadotropin therapy is the only appropriate treatment option:

• Use recombinant human chorionic gonadotropin (hCG) plus FSH as first-line therapy, as this combination provides optimal outcomes by directly stimulating the testes to produce both testosterone and sperm 1, 3, 5
• Testosterone replacement therapy is absolutely contraindicated in men seeking fertility, as exogenous testosterone suppresses the hypothalamic-pituitary-gonadal axis, causing azoospermia that may be prolonged or irreversible 1, 3, 6
• Gonadotropin therapy typically requires 12-24 months to promote testicular growth in almost all patients, induce spermatogenesis in approximately 80%, and achieve pregnancy rates around 50% 5

If Patient Does NOT Desire Fertility

Testosterone replacement therapy is first-line treatment:

Initial Treatment Selection

• Transdermal testosterone gel (1.62%) at 40.5 mg daily is the preferred first-line formulation due to more stable day-to-day testosterone levels compared to injectable preparations 1, 6
• Intramuscular testosterone cypionate or enanthate (100-200 mg every 2 weeks) is a more economical alternative, with annual costs of approximately $156 compared to $2,135 for transdermal preparations 1
• Target mid-normal testosterone levels (500-600 ng/dL) when monitoring therapy 1, 6

Expected Treatment Outcomes

Set realistic expectations with patients:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) are the primary proven benefits 1, 3
• Little to no effect on physical functioning, energy, vitality, depressive symptoms, or cognition, even with confirmed hypogonadism 1, 3
• Modest quality of life improvements, primarily in sexual function domains rather than general well-being 1

Monitoring Requirements

• Testosterone levels at 2-3 months after initiation, then every 6-12 months once stable 1, 6
  • For injectable testosterone: measure midway between injections (days 5-7) targeting 500-600 ng/dL 1
  • For transdermal testosterone: measure at any time after 2-3 months of stable therapy 1
• Hematocrit monitoring at baseline and periodically during treatment—withhold therapy if hematocrit >54% and consider phlebotomy in high-risk cases 1, 6
• PSA levels in men over 40 years at baseline and periodically—refer for urologic evaluation if PSA increases >1.0 ng/mL in first 6 months or >0.4 ng/mL per year thereafter 1
• Reevaluate symptoms at 12 months—discontinue testosterone if no improvement in sexual function to prevent unnecessary long-term exposure without benefit 1

Addressing Underlying Causes

Before or concurrent with testosterone therapy, address reversible causes of secondary hypogonadism:

• For obesity-associated secondary hypogonadism: attempt weight loss through low-calorie diets and regular exercise, as this can improve testosterone levels without medication through reduced aromatization of testosterone to estradiol in adipose tissue 1, 3, 7
• Evaluate for hyperprolactinemia by measuring serum prolactin, as this is a common reversible cause of secondary hypogonadism 1, 4
• Screen for medications that suppress gonadotropins (opiates, GnRH agonists/antagonists, glucocorticoids, estrogens, progestogens) 3
• Consider pituitary imaging (MRI of sella turcica) to identify structural causes of hypothalamic-pituitary dysfunction 1, 4

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation—use gonadotropin therapy instead 1, 3, 6
• Active or treated male breast cancer 1, 6
• Hematocrit >54% at baseline 1
• Untreated severe obstructive sleep apnea 1
• Known or suspected prostate cancer 1, 6

Critical Pitfalls to Avoid

• Never start testosterone without confirming the patient does not desire fertility, as this causes prolonged azoospermia that may be irreversible 1, 3
• Never diagnose hypogonadism based on symptoms alone without confirmed biochemical hypogonadism on two separate morning testosterone measurements 1, 2
• Never assume age-related decline in young men—always investigate for secondary causes of hypogonadism, as reversible conditions must be addressed first 1
• Never use testosterone therapy in eugonadal men (normal testosterone levels), even if symptomatic, as this violates evidence-based guidelines and provides no benefit 1, 3
• Do not expect meaningful improvements in energy, physical function, or mood from testosterone therapy, as the evidence shows minimal to no benefit in these domains 1, 3