Male Reproductive Physiology

The Hypothalamic-Pituitary-Gonadal (HPG) Axis

• GnRH (Gonadotropin-Releasing Hormone) secreted by the hypothalamus in pulsatile fashion (every 60-90 minutes) stimulates the anterior pituitary to release FSH and LH
• LH (Luteinizing Hormone) acts on Leydig cells in the testis to stimulate testosterone synthesis from cholesterol via the steroid synthesis pathway (P450 enzymes)
• FSH (Follicle-Stimulating Hormone) acts on Sertoli cells to promote spermatogenesis and inhibin B production; Sertoli cells provide nutritional and developmental support to developing germ cells
• Testosterone and inhibin B provide negative feedback to the pituitary and hypothalamus to maintain homeostasis; DHT (dihydrotestosterone) provides additional feedback via androgen receptors

Spermatogenesis (74-day cycle)

• Occurs in the seminiferous tubules of the testes in specialized microenvironment (blood-testis barrier)
• Mitotic phase: Spermatogonial stem cells (diploid, 2n) undergo mitosis to maintain stem cell pool and produce primary spermatocytes
• Meiotic phase: Primary spermatocytes (4n DNA content) undergo Meiosis I → secondary spermatocytes (2n); then Meiosis II → haploid spermatids (1n)
• Spermiogenesis: Haploid spermatids transform into mature spermatozoa with acrosome, flagellum, and mitochondrial sheath; supported by Sertoli cell phagocytosis of excess cytoplasm
• Approximately 200-300 million sperm produced daily in healthy adult males; approximately 1,500 sperm produced per second
• Requires normal testicular temperature (2-3°C below body temperature); cryptorchidism or fever can impair spermatogenesis

Testosterone Production and Metabolism

• Leydig cells in the interstitium synthesize testosterone via the P450 side-chain cleavage enzyme (P450scc) and 17β-HSD
• Testosterone binds to androgen receptor (AR) in target tissues; some testosterone converted to DHT by 5α-reductase (more potent, especially in prostate and external genitalia)
• Testosterone also aromatized to estradiol in adipose tissue and testis, which is critical for bone health and male sexual function
• Approximately 95% of circulating testosterone bound to SHBG (sex hormone-binding globulin) and 5% free/bioavailable; SHBG increases with aging, illness, and estrogen excess
• Hepatic metabolism via conjugation produces water-soluble metabolites excreted in urine

Erectile Function and Sexual Response

• Penile erection requires autonomic and somatic neural integration: parasympathetic activation releases nitric oxide (NO) from endothelial cells → guanylate cyclase activation → increased cGMP → smooth muscle relaxation → vasodilation and increased cavernosal blood flow
• Phosphodiesterase-5 (PDE-5) normally degrades cGMP; inhibited by sildenafil and other PDE-5 inhibitors to enhance erectile response
• Sympathetic activation (via norepinephrine and α-adrenergic receptors) normally maintains penile flaccidity by promoting smooth muscle contraction and reducing cavernosal inflow
• Seminal fluid (prostatic secretion, seminal vesicle fluid, urethral glands) provides energy, buffering, and motility support; fructose from seminal vesicles fuels sperm metabolism
• Emission (sympathetic via hypogastric nerve) propels seminal fluid into urethra; ejaculation (somatic via pudendal nerve) contracts bulbospongiosus muscle to expel semen

Hypogonadism (Low Testosterone)

• Sexual symptoms: Erectile dysfunction, decreased libido, diminished morning erections, reduced sexual satisfaction, infertility (azoospermia if severe)
• Constitutional symptoms: Fatigue, decreased energy, mood disturbance/depression, cognitive difficulties ("brain fog"), hot flushes or night sweats (less common than in women)
• Physical examination findings: Decreased testicular volume (normal ≥15 mL by orchidometer), reduced facial/body hair density, gynecomastia (especially if estrogen:testosterone ratio elevated), decreased muscle mass/tone, increased abdominal adiposity
• Metabolic manifestations: Weight gain, decreased muscle strength, osteoporosis/bone loss with increased fracture risk, insulin resistance
• Clinical presentation varies with age of onset (congenital vs. acquired) and severity (primary vs. secondary)

Infertility (Male Factor)

• Oligozoospermia (low sperm count <15 million/mL): Often asymptomatic; detected on semen analysis during fertility workup
• Asthenozoospermia (poor motility): Sperm count normal but <40% forward motility; associated with flagellar defects or mitochondrial dysfunction
• Teratozoospermia (abnormal morphology): >50% abnormal forms; indicates defective spermiogenesis or epididymal pathology
• Azoospermia (no sperm): Complete absence of sperm in ejaculate; critical distinction between obstructive (normal testosterone, normal FSH, small testes) and non-obstructive (low/normal testosterone, high FSH, small testes) etiologies
• Couples may present with secondary infertility or known male factor; many men have no symptoms and condition discovered only during fertility evaluation

Erectile Dysfunction (ED)

• Difficulty achieving erection with sexual stimulation; may be complete inability or partial insufficiency
• Inability to maintain erection during sexual activity ("loss of firmness")
• Reduced morning erections (indicator of vascular/neurological vs. psychological etiology)
• Often accompanied by decreased libido, relationship stress, depression, and anxiety (psychological comorbidity is common)
• Organic causes typically produce gradual onset over months to years; psychological causes typically produce acute onset with preserved morning erections
• Cardiovascular risk factor: ED often precedes clinically apparent coronary artery disease by 2-3 years

Premature Ejaculation (PE)

• Ejaculation occurring with minimal sexual stimulation, before desired; often within 1-3 minutes of penetration (for vaginal intercourse)
• Distress or interpersonal difficulty as a result
• Lifelong (primary) PE present since first sexual experience; acquired PE develops after period of normal function (suggests psychological or hormonal etiology)
• Less commonly associated with endocrine pathology than ED; more often psychological or related to neurotransmitter function (serotonin)

Prostatitis/Urogenital Inflammation

• Dysuria, frequency, urgency with or without fever (depending on acute vs. chronic, bacterial vs. non-bacterial)
• Perineal, lower abdominal, or low back pain
• Erectile dysfunction and decreased libido common in chronic prostatitis

Testicular Masses and Pain

• Palpable testicular mass on self-examination (often detected by patient)
• Acute testicular pain (testicular torsion—surgical emergency; orchitis from viral/bacterial infection)
• Chronic testicular ache (chronic orchitis, post-vasectomy pain syndrome

Cell assignments examiners test relentlessly

• Sertoli = Support, FSH, inhibin B; Leydig = LH, testosterone. Sertoli tight junctions form the blood-testis barrier, sequestering haploid germ cells from immune surveillance — the reason vasectomy or testicular trauma can generate antisperm antibodies.
• Isolated high FSH with low inhibin B points to seminiferous tubule/Sertoli damage (e.g., prior chemotherapy, non-obstructive azoospermia) even when testosterone and LH are normal.

Localizing the lesion

• Primary (hypergonadotropic) hypogonadism: low testosterone with high LH/FSH — think Klinefelter (47,XXY), tall stature, small firm testes, gynecomastia.
• Secondary (hypogonadotropic): low testosterone with low/inappropriately normal LH/FSH — Kallmann syndrome (anosmia from failed GnRH neuron migration), hyperprolactinemia, opioids, exogenous androgens. Always check prolactin and iron studies before calling it idiopathic.

Best next step questions

• Diagnosing hypogonadism: an early-morning fasting total testosterone, confirmed on a second morning sample, per the Endocrine Society testosterone therapy guideline. The classic distractor is treating off one random afternoon level. Obesity lowers SHBG, so total T reads low while free T is often normal — measure free T (equilibrium dialysis or calculated); note obesity can also cause true functional secondary hypogonadism, so interpret with LH/FSH.
• Male infertility workup: semen analysis is the first test — not hormones, not scrotal ultrasound. The AUA/ASRM male infertility guideline advises at least one semen analysis on initial evaluation alongside a reproductive history, with a repeat sample when the first is abnormal or discordant with the clinical picture; conventional practice is to obtain two samples given substantial intra-individual variability.

Traps

• Exogenous testosterone suppresses LH/FSH and intratesticular testosterone → azoospermia. Do not give testosterone to a man seeking fertility (Endocrine Society); hCG or a SERM such as clomiphene preserves spermatogenesis.
• PDE-5 inhibitors are contraindicated with any nitrate (life-threatening hypotension from unopposed cGMP accumulation) — an absolute contraindication in the AUA erectile dysfunction guideline.
• 5α-reductase deficiency: normal testosterone, low DHT, elevated T:DHT ratio — Wolffian structures present (testosterone-dependent) but ambiguous external genitalia (DHT-dependent), with virilization at puberty.
• Estradiol from aromatization closes epiphyses in men; aromatase or estrogen-receptor defects cause tall stature with unfused epiphyses and osteoporosis despite normal testosterone.
• Varicocele is left-sided (bag of worms, left gonadal vein into left renal vein); a new isolated right-sided varicocele demands imaging for retroperitoneal malignancy.