What is the diagnosis and treatment for a male patient with elevated Follicle-Stimulating Hormone (FSH) and Luteinizing Hormone (LH) levels?

Elevated FSH and LH in Males: Primary Testicular Failure

A male with elevated FSH and LH has primary testicular failure (primary hypogonadism), characterized by testicular dysfunction with compensatory pituitary hyperactivity attempting to stimulate failing testes. 1, 2, 3

Diagnostic Confirmation

Essential Laboratory Testing

• Measure total testosterone – expect low or low-normal values in primary testicular failure, as the failing testes cannot produce adequate testosterone despite elevated gonadotropin stimulation 1, 2
• Obtain at least two semen analyses separated by 2-3 months after 2-7 days of abstinence to assess actual sperm production, as elevated FSH >7.6 IU/L strongly suggests non-obstructive azoospermia or severe oligospermia 2, 4
• Check prolactin levels to exclude hyperprolactinemia, which can disrupt the hypothalamic-pituitary-gonadal axis and elevate gonadotropins 1, 2
• Assess thyroid function (TSH, free T4) because thyroid disorders commonly affect reproductive hormones – primary hypothyroidism causes hypogonadotropic hypogonadism with elevated FSH in children, while hyperthyroidism elevates SHBG and alters gonadotropin responses 2, 5

Mandatory Genetic Testing

If semen analysis confirms severe oligospermia (<5 million/mL) or azoospermia with elevated FSH and LH:

• Karyotype analysis is mandatory to screen for Klinefelter syndrome (47,XXY) and other chromosomal abnormalities, which are established genetic causes of primary testicular failure 1, 2, 4
• Y-chromosome microdeletion testing (AZFa, AZFb, AZFc regions) is essential, as complete AZFa and AZFb deletions predict near-zero sperm retrieval success and contraindicate testicular sperm extraction 2, 4

Physical Examination Priorities

• Measure testicular volume using Prader orchidometer – volumes <12 mL indicate testicular atrophy consistent with primary testicular failure 2, 4
• Assess for varicocele on standing examination, as palpable varicoceles with abnormal semen parameters warrant surgical repair to potentially halt progressive testicular damage 2, 4
• Evaluate testicular consistency and check for vas deferens/epididymal abnormalities to distinguish primary testicular failure from obstructive causes 2, 4

Common Etiologies of Primary Testicular Failure

Congenital Causes

• Klinefelter syndrome (47,XXY) – the most common genetic cause, presenting with small firm testes, elevated FSH/LH, low testosterone, and azoospermia or severe oligospermia 1, 2, 3
• Y-chromosome microdeletions (AZFa, AZFb, AZFc regions) cause variable spermatogenic failure ranging from oligospermia to azoospermia 1, 2
• Cryptorchidism (undescended testes) leads to progressive testicular damage if uncorrected, resulting in primary testicular failure 1, 3

Acquired Causes

• Chemotherapy or radiation exposure causes dose-dependent testicular damage, with radioactive iodine therapy producing FSH elevation and impaired spermatogenesis lasting up to 2 years 1, 5
• Orchitis (testicular inflammation), bilateral torsion, or trauma can destroy testicular tissue and cause primary failure 1, 3
• Toxic exposures including alcohol, heavy metals (lead, cadmium), and occupational exposures (oil/gas extraction) contribute to testicular dysfunction 1, 2
• Exogenous testosterone or anabolic steroid use suppresses spermatogenesis through negative feedback, but this represents secondary (not primary) hypogonadism with LOW FSH/LH 1, 2, 3

Treatment Approach Based on Fertility Goals

If Fertility is Desired

Critical: Never prescribe exogenous testosterone therapy if fertility is a current or future goal – testosterone completely suppresses FSH and LH through negative feedback on the hypothalamus and pituitary, causing azoospermia that can take months to years to recover 2, 4, 3

Fertility Preservation

• Immediate sperm cryopreservation is essential if any sperm are present on semen analysis – bank 2-3 separate ejaculates before any intervention, as once azoospermia develops, even microsurgical testicular sperm extraction (micro-TESE) only achieves 40-50% sperm retrieval rates 2, 4
• Varicocele repair should be strongly considered if a palpable varicocele is present with abnormal semen parameters, as correction can improve testosterone levels, reduce FSH, stabilize testicular volume, and improve fertility rates 2, 4

Medical Treatment Options (Limited Efficacy)

• FSH analogue treatment may improve sperm concentration, pregnancy rate, and live birth rate in men with idiopathic infertility and FSH <12 IU/L, though benefits are modest (Grade B evidence) 2, 4
• Aromatase inhibitors may decrease estrogen production and improve spermatogenesis in the infertility setting, though benefits are limited compared to assisted reproductive technology 2, 4
• Selective estrogen receptor modulators (SERMs) like clomiphene have been used off-label with limited benefits that are outweighed by ART advantages 2, 4

Assisted Reproductive Technology

• IVF/ICSI offers superior pregnancy rates compared to empiric hormonal therapy and should be discussed early, especially given female partner age considerations 2, 4
• Microsurgical testicular sperm extraction (micro-TESE) is the gold standard for sperm retrieval in non-obstructive azoospermia, achieving 40-60% sperm retrieval rates despite elevated FSH – micro-TESE is 1.5 times more successful than conventional TESE and causes less testosterone suppression 2, 4
• Up to 50% of men with non-obstructive azoospermia and elevated FSH still have retrievable sperm via micro-TESE, so elevated FSH alone does not preclude fertility attempts 2, 4

If Fertility is Not Desired

Testosterone replacement therapy is indicated for symptomatic hypogonadism once fertility goals are abandoned 1, 3

Testosterone Replacement Indications

• Low testosterone with symptoms including reduced libido, erectile dysfunction, decreased spontaneous erections, decreased energy, reduced physical strength, hot flushes, low mood, or decreased motivation 1, 3
• Primary hypogonadism is specifically listed as an FDA-approved indication for testosterone replacement – these men have low testosterone with elevated FSH and LH 3

Monitoring on Testosterone Therapy

• FSH and LH levels decrease with testosterone treatment due to negative feedback on the pituitary – this is expected and consistent with published literature on long-term testosterone therapy 3
• Testosterone levels should be monitored with pre-dose morning measurements at approximately 14 and 28 days after starting treatment, with dose adjustments targeting 350-750 ng/dL 3

Critical Pitfalls to Avoid

Reversible Causes Must Be Excluded First

• Thyroid dysfunction disrupts the hypothalamic-pituitary-gonadal axis – hyperthyroidism causes asthenozoospermia, oligozoospermia, and teratozoospermia that reverse with treatment, while hypothyroidism causes hypogonadotropic hypogonadism 2, 5
• Metabolic stress, obesity (BMI >25), and acute illness can artificially elevate FSH and suppress testosterone – repeat hormonal testing after 3-6 months of metabolic optimization and resolution of acute illness 2, 4
• Medications including glucocorticoids, opioids, and certain antiandrogens can disrupt gonadotropin secretion and should be reviewed 1, 2

Diagnostic Errors

• Do not diagnose primary testicular failure based on a single FSH/LH measurement – FSH levels fluctuate due to pulsatile secretion, and minor technical problems in hormone assays can cause variations 2, 4
• Do not assume complete azoospermia based on elevated FSH alone – FSH levels alone cannot definitively predict sperm retrieval success, and some men with maturation arrest have normal FSH despite severe spermatogenic dysfunction 2, 4
• Do not overlook obstructive causes – obstructive azoospermia presents with normal testicular size, low ejaculate volume, acidic semen, and normal FSH/LH, requiring different management 2

Treatment Errors

• Never prescribe testosterone if fertility is desired – this is the single most critical error, as exogenous testosterone will cause azoospermia through negative feedback suppression of FSH and LH 2, 4, 3
• Do not delay genetic testing if azoospermia or severe oligospermia is confirmed – complete AZFa/AZFb deletions contraindicate TESE and fundamentally alter counseling 2, 4
• Do not delay sperm banking if any sperm are present – progressive spermatogenic failure is common in men with elevated FSH and small testicular volumes, and once azoospermia develops, retrieval success drops to 40-50% 2, 4