What factors affect spermatogenesis in men, particularly those over 40 with potential hormonal imbalances, medical conditions, or lifestyle concerns?

Factors Affecting Spermatogenesis

Spermatogenesis is influenced by hormonal regulation (FSH, LH, and intratesticular testosterone), genetic factors, lifestyle exposures, medications, medical conditions, and age—with men over 40 facing increased risks of genetic abnormalities in offspring and progressive testicular dysfunction. 1

Hormonal Factors

Essential Hormones for Sperm Production

• FSH (Follicle-Stimulating Hormone) directly stimulates Sertoli cells and is negatively correlated with spermatogonia numbers—higher FSH typically indicates impaired spermatogenesis. 2, 3
• LH (Luteinizing Hormone) stimulates Leydig cells to produce intratesticular testosterone, which is 50-100 times higher than serum levels and absolutely essential for normal spermatogenesis. 2, 4
• Intratesticular testosterone is the critical androgen—men with complete congenital hypogonadotropic hypogonadism remain azoospermic on exogenous testosterone alone but respond to combined hCG (which stimulates intratesticular testosterone) plus FSH treatment. 4

Hormonal Patterns in Testicular Dysfunction

• Severely impaired spermatogenesis presents with elevated FSH (>7.6 IU/L), elevated or normal LH, and low or normal testosterone. 1, 2
• Obstructive azoospermia shows normal FSH, normal LH, and normal testosterone despite absent sperm in ejaculate. 1, 5
• Hypogonadotropic hypogonadism demonstrates low FSH, low LH, and low testosterone—this is potentially reversible with hCG and FSH treatment. 1, 3

Genetic Factors

Chromosomal Abnormalities

• Klinefelter syndrome (47,XXY) and other karyotype abnormalities are established causes of non-obstructive azoospermia and should be tested when sperm concentration is <5 million/mL. 2, 5
• Y-chromosome microdeletions in AZFa, AZFb, and AZFc regions cause spermatogenic failure—complete AZFa and AZFb deletions predict near-zero sperm retrieval success. 2, 5

Genetic Testing Indications

• Perform karyotype analysis for all men with azoospermia or severe oligospermia (<5 million/mL). 2, 5
• Y-chromosome microdeletion testing is mandatory when sperm concentration is <1 million/mL. 2, 5

Age-Related Effects

Paternal Age Over 40

• Advanced paternal age (≥40 years) increases the risk of de novo gene mutations, chromosomal aberrations, sperm DNA fragmentation, and offspring conditions including schizophrenia, autism, and chondrodysplasia. 1
• Clinicians should advise couples with advanced paternal age about these increased risks, though the absolute risk remains low despite elevated relative risk. 1

Lifestyle and Environmental Factors

Diet and Nutrition

• Low-quality evidence suggests that diets lower in fats and meats with more fruits and vegetables are preferable to high-fat diets for male fertility. 1
• The data on dietary factors remain limited with high risk of bias in most studies. 1

Tobacco and Substance Use

• Smoking has low-quality evidence linking it to small impacts on sperm concentration, motility, and morphology. 1
• Anabolic steroids completely suppress spermatogenesis through negative feedback on the hypothalamus and pituitary—recovery takes approximately 14 months for sperm output and 38 months for sperm motility after cessation. 1, 4
• Alcohol and drug use can affect spermatogenesis through multiple mechanisms. 1

Occupational and Environmental Exposures

• Toxic exposures including lead, cadmium, and occupational exposures in oil and natural gas extraction may contribute to non-obstructive azoospermia. 2
• Heat exposure to the testes should be minimized as it impairs spermatogenesis. 2

Obesity and Metabolic Factors

• Obesity (BMI >25) and metabolic syndrome impair male fertility through disruption of the hypothalamic-pituitary-gonadal axis. 2
• Weight normalization and metabolic optimization may improve hormonal parameters and spermatogenesis. 2

Medical Conditions

Endocrine Disorders

• Diabetes and erectile dysfunction may affect fertility through multiple mechanisms including vascular and hormonal dysfunction. 1
• Thyroid dysfunction (both hyperthyroidism and hypothyroidism) disrupts the hypothalamic-pituitary-gonadal axis—hyperthyroidism specifically causes asthenozoospermia, oligozoospermia, and teratozoospermia that are reversible with treatment. 2
• Hyperprolactinemia can disrupt gonadotropin secretion and should be excluded in men with elevated FSH. 2

Testicular Conditions

• Varicocele (dilated testicular veins) causes progressive testicular damage—repair can improve testosterone levels, reduce FSH, stabilize testicular volume, and improve semen parameters. 2
• Cryptorchidism (undescended testicles) increases risk of impaired spermatogenesis and testicular cancer. 2
• Testicular atrophy (volume <12 mL) indicates compromised testicular reserve and increased risk of progressive spermatogenic failure. 2, 5

Infections and Inflammation

• Genitourinary infections can cause abnormal sperm DNA fragmentation and pyospermia (elevated white blood cells in semen). 1
• Sexually transmitted infections may contribute to inflammatory processes affecting spermatogenesis. 2

Medications

Medications That Suppress Spermatogenesis

• Exogenous testosterone provides negative feedback to the hypothalamus and pituitary, suppressing FSH and LH secretion and causing azoospermia—this should never be prescribed to men desiring fertility. 2, 3, 5
• Anti-depressants can cause abnormal sperm DNA fragmentation, which is potentially reversible upon discontinuation. 1
• Certain medications alter the hypothalamic-pituitary-gonadal axis, reduce libido and erectile function, and have toxic effects on sperm—clinicians should consult specialized databases for reproductive effects of specific medications. 1

Medications That May Improve Spermatogenesis

• hCG (human chorionic gonadotropin) stimulates intratesticular testosterone production and can improve spermatogenesis in men with hypogonadotropic hypogonadism or oligospermia. 2, 3
• FSH analogues may improve sperm concentration in men with idiopathic oligozoospermia, though benefits are modest and not FDA-approved for this indication. 2, 3
• Aromatase inhibitors may decrease estrogen production and improve spermatogenesis in select cases. 2
• Selective estrogen receptor modulators (SERMs) have limited benefits that are outweighed by assisted reproductive technology advantages. 2, 3

Sperm DNA Fragmentation

• Elevated sperm DNA fragmentation adversely affects natural fertility and assisted reproductive technology outcomes, including increased miscarriage rates. 1
• Causes include anti-depressant use, genitourinary infections, oxidative stress, and advanced paternal age—some causes are reversible. 1
• Routine DNA fragmentation testing is not recommended in initial evaluation, as no prospective studies demonstrate improved fertility outcomes from testing. 1

Critical Pitfalls to Avoid

• Never prescribe exogenous testosterone to men desiring fertility—it causes complete suppression of spermatogenesis that can take months to years to recover. 2, 3, 5
• FSH levels alone cannot predict fertility status—up to 50% of men with non-obstructive azoospermia and elevated FSH have retrievable sperm via microsurgical testicular sperm extraction. 2, 3
• Single semen analyses are insufficient—perform at least two analyses separated by 2-3 months due to natural variability. 2, 5
• Correct reversible causes before making definitive conclusions—thyroid dysfunction, infections, medications, and metabolic factors should be optimized first. 2

Paracrine and Local Factors

• Growth factors including transforming growth factors, epidermal growth factor, fibroblast-like growth factors, insulin-like growth factors, interleukins, inhibin, and activin regulate spermatogenesis through autocrine and paracrine mechanisms. 6
• Local control factors within the testis regulate cell proliferation, meiosis, and differentiated function beyond systemic hormonal control. 6
• Sertoli cells secrete multiple growth factors that support spermatogenesis and require functional androgen receptors for normal sperm production. 4, 7