What are the diagnostic criteria and treatment options for hypogonadism?

Diagnosis of Hypogonadism

Hypogonadism requires both biochemical confirmation with morning total testosterone levels below 300 ng/dL measured on at least two separate occasions between 8-10 AM, plus specific symptoms such as decreased libido, erectile dysfunction, or diminished sense of vitality. 1, 2

Diagnostic Algorithm

Step 1: Initial Biochemical Confirmation

• Measure morning total testosterone (8-10 AM) on two separate days to confirm levels are consistently below the normal range (typically <300 ng/dL or <10.5 nmol/L) 1, 3, 2
• Single measurements are insufficient due to assay variability and diurnal fluctuation 1
• In men with obesity or borderline total testosterone, also measure:
  • Free testosterone by equilibrium dialysis 4, 1, 3
  • Sex hormone-binding globulin (SHBG), as low SHBG in diabetes and obesity can artificially lower total testosterone 4, 1, 3

Step 2: Distinguish Primary from Secondary Hypogonadism

Once low testosterone is confirmed, measure serum LH and FSH levels to determine the type of hypogonadism 4, 1, 5, 6:

• Primary (hypergonadotropic) hypogonadism: Low testosterone with elevated LH/FSH above normal range, indicating testicular failure 3, 5, 7
• Secondary (hypogonadotropic) hypogonadism: Low testosterone with low or inappropriately normal LH/FSH levels, indicating hypothalamic-pituitary dysfunction 3, 5, 7

This distinction is critical because it determines treatment options, particularly regarding fertility preservation. 1, 3

Step 3: Additional Workup for Secondary Hypogonadism

If secondary hypogonadism is identified, investigate reversible causes 1, 6:

• Measure serum prolactin to screen for hyperprolactinemia 1, 6
• Assess iron saturation to evaluate for hemochromatosis 1
• Consider pituitary MRI if prolactin is elevated or other pituitary dysfunction is suspected 1, 6
• Evaluate for obesity-related hypogonadism: Increased aromatization of testosterone to estradiol in adipose tissue causes estradiol-mediated negative feedback, suppressing pituitary LH secretion 1, 3
• Review medications: Opiates, GnRH agonists/antagonists, glucocorticoids, estrogens, and progestogens can cause secondary hypogonadism 3

Step 4: Assess Clinical Symptoms

Diagnosis requires both biochemical confirmation AND specific symptoms 1, 3:

Sexual symptoms (most specific):

• Decreased libido (diminished sexual desire) 4, 1, 5
• Erectile dysfunction 4, 1, 5
• Reduced frequency of sexual intercourse or masturbation 3

Physical symptoms:

• Diminished sense of vitality or energy 4, 1, 5
• Hot flushes 3
• Reduced physical strength, function, or activity 3

Cognitive symptoms:

• Concentration difficulties 3
• Memory problems 3
• Sleep disturbances 3

Important caveat: Symptoms alone are non-specific and cannot diagnose hypogonadism without biochemical confirmation. 1, 3 The European Association of Urology explicitly warns against using screening questionnaires or symptoms alone due to lack of specificity. 1

Treatment Considerations Based on Diagnosis

For Men NOT Seeking Fertility

Testosterone replacement therapy (TRT) is first-line treatment for confirmed hypogonadism 1, 5, 6:

• Transdermal testosterone gel 1.62% at 40.5 mg daily is the preferred first-line formulation due to stable day-to-day testosterone levels 1, 2
• Intramuscular testosterone cypionate or enanthate 50-400 mg every 2-4 weeks is a more economical alternative but carries higher risk of erythrocytosis 1
• Target mid-normal testosterone levels (500-600 ng/dL) when monitoring therapy 1
• Check testosterone levels at 14 and 28 days after initiation or dose adjustment, then every 6-12 months 1, 2

For Men Seeking Fertility Preservation

Testosterone therapy is absolutely contraindicated because it suppresses spermatogenesis and causes prolonged azoospermia 1, 3, 8:

• For secondary hypogonadism: Use gonadotropin therapy with recombinant hCG plus FSH, which stimulates the testes directly and restores both testosterone production and spermatogenesis 1, 3, 8
• For primary hypogonadism: Gonadotropins will not work because the testes cannot respond; assisted reproductive technologies with testicular sperm extraction may be required 1, 3

Absolute Contraindications to Testosterone Therapy

• Active desire for fertility preservation 1, 3
• Active or treated male breast cancer 1
• Prostate cancer on active surveillance or androgen deprivation therapy 1
• Hematocrit >54% 1
• Untreated severe obstructive sleep apnea 1

Expected Treatment Outcomes

Realistic expectations must be set with patients 1:

Proven benefits:

• Small but significant improvements in sexual function and libido (standardized mean difference 0.35) 1
• Modest quality of life improvements, primarily in sexual function domains 1
• Potential improvement in bone mineral density 1, 5
• May correct mild anemia 1

Minimal or no benefits:

• Little to no effect on physical functioning, energy, vitality, or cognition 1
• Less-than-small improvements in depressive symptoms (SMD -0.19) 1

The American College of Physicians recommends reevaluating symptoms at 12 months and discontinuing testosterone if no improvement in sexual function is seen. 1

Common Pitfalls to Avoid

• Never diagnose hypogonadism based on symptoms alone without biochemical confirmation on two separate morning measurements 1, 3
• Never start testosterone therapy without confirming the patient does not desire fertility, as this causes irreversible suppression of spermatogenesis 1, 3
• Never attempt to diagnose the type of hypogonadism (primary vs. secondary) while the patient is already on testosterone therapy, as exogenous testosterone suppresses LH/FSH and results will be misleading 1
• Never use testosterone therapy in eugonadal men (normal testosterone levels), even for weight loss, cardiometabolic improvement, cognition, vitality, or physical strength 1
• Never assume age-related decline in young men without investigating for secondary causes of hypogonadism, as reversible conditions must be addressed first 1