Reproductive Physiology

The Hypothalamic-Pituitary-Gonadal (HPG) Axis

The HPG axis is a hierarchical hormonal cascade regulating reproduction in both sexes. Gonadotropin-releasing hormone (GnRH) is a decapeptide synthesised and released from GnRH neurons in the arcuate nucleus and preoptic area of the hypothalamus. Critically, GnRH must be released in a pulsatile fashion to maintain gonadotroph sensitivity in the anterior pituitary — continuous GnRH administration paradoxically downregulates GnRH receptors on gonadotrophs (receptor internalisation) → reduced LH/FSH secretion. This principle is exploited therapeutically: GnRH agonists (leuprolide, goserelin) given continuously produce a "chemical castration" effect used in prostate cancer, endometriosis, and precocious puberty.

Pituitary gonadotrophs respond to GnRH pulses by secreting luteinising hormone (LH) and follicle-stimulating hormone (FSH), both glycoprotein heterodimers (shared α-subunit with TSH and hCG; unique β-subunit). LH and FSH act on gonadal target cells via Gs-coupled receptors → cAMP/PKA signalling.

Female Reproductive Physiology: The Menstrual Cycle

The normal menstrual cycle averages 28 days (range 21–35 days) and is divided into the follicular phase (days 1–14) and the luteal phase (days 14–28), with ovulation at approximately day 14.

Follicular phase: During menstruation (days 1–5), oestrogen and progesterone levels are low → anterior pituitary releases FSH (and a small amount of LH) in response to hypothalamic GnRH. FSH stimulates growth and maturation of a cohort of primordial follicles → granulosa cells proliferate → aromatase (CYP19A1) converts androstenedione (from theca cells, driven by LH) to oestradiol (E2). Rising oestradiol initially exerts negative feedback (suppressing FSH and LH) but as a dominant follicle is selected (the largest follicle expressing the most FSH receptors), oestradiol continues to rise. The dominant follicle also produces inhibin B (a glycoprotein) which selectively suppresses FSH → other follicles undergo atresia (follicle selection). The endometrium proliferates under oestrogen (proliferative phase): endometrial glands and stroma thicken, spiral arterioles grow.

LH surge and ovulation: When oestradiol reaches a critical threshold (~200 pg/mL sustained for ≥48 hours), the feedback switches from negative to positive — oestrogen now stimulates rather than inhibits GnRH/LH release. This mid-cycle LH surge (triggered at approximately day 13) causes: resumption of meiosis I in the primary oocyte, prostaglandin-mediated follicle wall breakdown, rupture of the dominant follicle with release of the secondary oocyte (arrested in metaphase II) and surrounding cumulus cells. The released oocyte is swept into the fallopian tube fimbriae.

Luteal phase: The ruptured follicle is vascularised and luteinised (under LH influence) → forms the corpus luteum, which secretes large amounts of progesterone and oestradiol for approximately 14 days. Progesterone: converts the endometrium to the secretory phase (glandular coiling, glycogen secretion, spiral artery development) — optimal for blastocyst implantation; also raises basal body temperature (~0.3–0.5°C), thickens cervical mucus (preventing sperm entry and ascending infection), and suppresses myometrial contractility. If fertilisation does not occur: corpus luteum involutes (~14 days) → progesterone and oestradiol fall → endometrium loses hormonal support → prostaglandin F2α (PGF2α) causes spiral artery vasoconstriction → ischaemia → endometrial shedding (menstruation). If fertilisation occurs: the trophoblast of the implanting blastocyst secretes human chorionic gonadotrophin (hCG), which binds LH receptors on the corpus luteum → rescues it from involution → maintains progesterone production until the placenta takes over (luteoplacental shift, ~8–10 weeks gestation).

Male Reproductive Physiology

In males, LH acts on Leydig cells in the testicular interstitium → testosterone synthesis (via StAR-mediated cholesterol transport and CYP17A1/CYP11A1 enzyme cascade). Testosterone exerts negative feedback on both the hypothalamus (reduces GnRH pulse frequency) and the anterior pituitary (reduces LH/FSH sensitivity). Testosterone is converted peripherally to dihydrotestosterone (DHT) by 5α-reductase (expressed in prostate, skin, external genitalia) — DHT is the active androgen for male external genitalia differentiation, prostate growth, and androgenic alopecia. Finasteride and dutasteride inhibit 5α-reductase and are used for benign prostatic hyperplasia and androgenic alopecia. Testosterone is also aromatised (by CYP19A1 in adipose, liver, brain) to oestradiol, which is important for bone mineral density and libido in males.

FSH acts on Sertoli cells (somatic cells of the seminiferous tubule) → activates spermatogenesis and secretes androgen-binding protein (ABP, maintains high intratubular testosterone), inhibin B (negative feedback on FSH secretion), and anti-Müllerian hormone (AMH, produced in fetal life to cause Müllerian duct regression; also produced in adult males and females — used clinically to assess ovarian reserve). Sertoli cells form the blood-testis barrier (tight junctions between adjacent cells) — segregates post-meiotic germ cells from immune surveillance (preventing autoimmune orchitis).

Spermatogenesis: Complete process takes ~72 days and occurs in the seminiferous tubule. Spermatogonia (2N) → primary spermatocytes (4N, enter meiosis I) → secondary spermatocytes (2N) → spermatids (1N) → spermatozoa (1N) via spermiogenesis (acrosome formation, flagellum development, cytoplasm condensation). Spermatozoa are released into the tubule lumen and transported to the epididymis (where they acquire motility and fertilisation capacity over ~12 days) → vas deferens → urethra.

Pregnancy Physiology

After fertilisation (occurs in the fallopian tube ampulla), the zygote undergoes cleavage (mitotic divisions without cell growth) → morula → blastocyst (inner cell mass + trophoblast + blastocoel). By day 6–7, the blastocyst implants into the secretory endometrium. The syncytiotrophoblast (invasive outer layer) secretes hCG from approximately day 8 → detectable in urine (basis of pregnancy tests) by day 10–12. hCG peaks at ~10 weeks, declines, then stabilises. Placental hormone production: (1) Progesterone: initially from corpus luteum (hCG-maintained) then placenta takes over (~8–10 weeks). Maintains uterine quiescence, suppresses immune rejection. (2) Oestrogen (predominantly oestriol, E3): requires cooperative synthesis — DHEA-S from fetal adrenal glands is aromatised by the placenta (syncytiotrophoblast) → oestriol. Low oestriol is a biomarker of feto-placental compromise. (3) hPL (human placental lactogen / chorionic somatomammotrophin): promotes maternal lipolysis and insulin resistance → redirects glucose to the fetus; also stimulates breast development. Causes gestational diabetes in susceptible women. (4) Relaxin: relaxes pelvic ligaments; promotes cervical ripening.

Parturition: Progesterone levels fall near term (functional progesterone withdrawal via receptor changes in myometrium). Oestrogen rises → upregulates oxytocin receptors and prostaglandin production in the uterus. Oxytocin (posterior pituitary) binds Gq-coupled receptors on myometrial cells → IP₃/Ca²⁺ → myometrial contraction. Positive feedback (Ferguson reflex): fetal head stretches the cervix → neurally stimulates posterior pituitary → more oxytocin → more contractions → more cervical stretch. Prostaglandins E2 and F2α (from cervix/decidua) cause cervical ripening (collagenase activation) and augment contractions.

Clinical Correlations

PCOS (Polycystic Ovary Syndrome): the most common endocrine disorder in reproductive-age women (prevalence ~8–13%). Features: hyperandrogenism (acne, hirsutism, androgenic alopecia), oligo/anovulation (irregular periods), and polycystic ovarian morphology on ultrasound (≥20 follicles per ovary, or ovarian volume >10 mL). Biochemistry: elevated LH:FSH ratio (often >2:1 — LH excess drives theca cell androgen production); elevated testosterone and DHEA-S; insulin resistance (exacerbates androgen excess as insulin stimulates ovarian theca cells to produce androgens, and suppresses SHBG → more free testosterone). Management: lifestyle modification (first line); COCP (suppresses LH/FSH, increases SHBG); metformin (insulin sensitiser); clomiphene or letrozole (ovulation induction); spironolactone (anti-androgen).

Menopause: natural cessation of menses (median age 51 in NZ) due to depletion of ovarian follicles → no oestrogen/progesterone production → FSH and LH rise markedly (loss of negative feedback). Symptoms: vasomotor (hot flushes — decreased oestrogen impairs thermoregulatory set-point in hypothalamus), genitourinary syndrome (vaginal atrophy, dyspareunia, urinary symptoms), sleep disturbance, mood changes. Long-term consequences: osteoporosis (oestrogen normally inhibits osteoclast activity via RANK/RANKL pathway); cardiovascular disease risk ↑; cognitive changes. Treatment: menopausal hormone therapy (MHT, formerly HRT) — oestrogen ± progestogen; risks vs benefits individualised (↑ breast cancer risk with combined therapy, ↑ VTE with oral route — transdermal preferred).

Male hypogonadism: primary (testicular failure: ↑LH/FSH, ↓testosterone, e.g., Klinefelter syndrome XXY) vs secondary (hypothalamic/pituitary failure: ↓LH/FSH, ↓testosterone, e.g., pituitary tumour, haemochromatosis). Testosterone replacement is indicated in symptomatic men with confirmed hypogonadism.