9.1 Reproductive Physiology

Why a topic with no official sub-bullets still occupies 10%

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Gland anatomy (testis, ovary, uterus, placenta) lives in General Anatomy. Hormone effects on carbohydrate and lipid pathways live in Chemistry. This chapter is mechanism: who secretes what, which receptor, which feedback sign, and what happens if the pulse generator stops.

Quick Answer: Pulsatile GnRH → FSH and LH. LH drives theca/Leydig androgen synthesis. FSH drives Sertoli support and granulosa aromatization. High sustained estradiol triggers the LH surge and ovulation. hCG rescues the corpus luteum. Prolactin makes milk; oxytocin ejects it. DHT sculpts male external genitalia and prostate.

The HPG axis: pulses, not a steady drip

Gonadotropin-releasing hormone (GnRH) is a hypothalamic decapeptide released into the hypophyseal portal system, not into the general circulation in useful amounts. The pulse generator includes KNDy neurons (kisspeptin, neurokinin B, dynorphin) in the arcuate region. Kisspeptin is the proximate stimulator of GnRH neurons; loss of kisspeptin signaling delays or prevents puberty.

Pulse frequency and amplitude are not cosmetic. Faster pulses favor LH; slower pulses favor FSH. That is why a single serum LH/FSH pair is a snapshot of a pulsatile system. Continuous GnRH (or a long-acting agonist such as leuprolide) down-regulates pituitary GnRH receptors and suppresses FSH and LH after a brief flare. That pharmacologic fact is the cleanest way to remember that fertility requires pulses.

Anterior-pituitary gonadotrophs secrete:

FSH and LH share an alpha subunit with TSH and hCG. Specificity is in the beta subunit. The LH receptor is also the hCG receptor — the reason pregnancy can keep a corpus luteum alive after pituitary LH has fallen.

Feedback signs you must not mix:

• Low-to-moderate estradiol or testosterone: negative feedback on hypothalamus and pituitary.
• Inhibin (glycoprotein from Sertoli cells and granulosa cells): selective negative feedback on FSH, not LH.
• Activin stimulates FSH; follistatin binds activin and opposes it.
• High, sustained estradiol (late follicular phase): positive feedback that produces the LH surge. The sign of estrogen feedback is concentration- and time-dependent, not a personality trait of the molecule.
• Progesterone (with estradiol) is strongly negative on GnRH pulse frequency in the luteal phase and in pregnancy.

Worked scenario — pulse failure. A 19-year-old endurance athlete with very low energy availability has amenorrhea. GnRH pulse frequency is low, LH is low, estradiol is low, and FSH is inappropriately normal-to-low. The ovary is not the primary broken part; the hypothalamus has turned the generator down. Restore energy availability and pulses usually return. That is hypothalamic (functional) hypogonadism, not premature ovarian failure (which would raise FSH).

Male system: two cells, two gonadotropins

The adult testis has a dual endocrine-exocrine design. Leydig (interstitial) cells sit outside the seminiferous tubules. Sertoli cells line the tubules and envelope the germ-cell series.

LH → Leydig cells. The LH receptor is Gs-coupled. Cyclic AMP activates protein kinase A, StAR moves cholesterol into mitochondria, and the steroidogenic cascade yields testosterone. Intratesticular testosterone is far higher than serum testosterone; spermatogenesis needs that local concentration, not merely a normal blood total-T.

FSH → Sertoli cells. FSH (also Gs-cAMP) makes Sertoli cells secrete androgen-binding protein (ABP), which traps testosterone in the seminiferous fluid, plus inhibin B, growth factors, and the tight-junction proteins of the blood-testis barrier. The barrier isolates haploid cells from the immune system. Break it (trauma, mumps orchitis) and you have a mechanism for anti-sperm antibodies.

Sertoli cells also aromatize some androgen to estradiol. Male estrogen is not a leftover: it is required for epiphyseal closure, a portion of libido, and bone density. Aromatase deficiency or estrogen-receptor defects produce tall stature with unfused epiphyses in genetic males — a favorite discriminator from isolated androgen deficiency.

Spermatogenesis versus spermiogenesis

Spermatogenesis is the entire diploid-to-haploid sequence. Spermiogenesis is the last remodeling of spermatids into spermatozoa (acrosome, flagellum, cytoplasmic shedding).

Human spermatogenesis takes about 64–74 days in the tubule. Epididymal transit and maturation add on the order of 10–14 days. Temperature must stay about 2–3 °C below core. The pampiniform plexus is a countercurrent heat exchanger; a varicocele can raise scrotal temperature and impair sperm quality. Cryptorchidism leaves the testis at core temperature and wrecks spermatogenesis while often leaving Leydig function relatively better preserved — which is why a stem can show low sperm count with near-normal testosterone.

Ejaculated sperm are not yet fertilization-competent. Capacitation in the female tract (cholesterol efflux, increased motility) precedes the acrosome reaction at the zona pellucida. Those are physiology, not andrology clinic trivia.

Androgen physiology: testosterone versus DHT

Circulating testosterone is largely bound to sex hormone-binding globulin (SHBG) and albumin. Free plus albumin-bound hormone is the bioavailable pool. The androgen receptor is a nuclear receptor; dihydrotestosterone (DHT) binds it with higher affinity than testosterone.

5α-reductase converts testosterone to DHT. Type 2 enzyme in genital skin and prostate is the exam isoform. Tissue actions split cleanly:

Worked scenario — 5α-reductase. A genetic male fetus makes testosterone and AMH but little DHT. Internal Wolffian structures form; external genitalia do not fully virilize. At puberty, rising testosterone may produce phallic enlargement and male muscle pattern, but the prostate and facial hair remain DHT-dependent. That split is the reason Part I asks you which enzyme, not which chromosome.

Fetal testis timing, for the same table: SRY directs testis determination. Sertoli AMH regresses Müllerian ducts. Leydig testosterone stabilizes Wolffian ducts. DHT virilizes the genital tubercle, folds, and swellings. Without a testis, the default internal ducts are Müllerian and the default external phenotype is female. That is reproductive physiology, not a gynecology rotation.

Oogenesis and the two-cell, two-gonadotropin follicle

Oogonia finish mitosis in fetal life. The newborn ovary already holds primary oocytes arrested in diplotene of prophase I (dictyotene). Meiosis I completes only at ovulation: the LH surge produces a secondary oocyte plus the first polar body, and the oocyte then arrests in metaphase II until fertilization. Meiosis II completion (second polar body) is a fertilization event. If an item asks when the oocyte becomes haploid in the practical sense of finishing meiosis I, the answer is ovulation, not fetal life and not menses.

Follicles mature as primordial → primary (cuboidal granulosa, zona pellucida) → secondary/preantral (theca appears) → antral → Graafian (dominant).

The two-cell, two-gonadotropin rule:

1. Theca cells + LH convert cholesterol to androstenedione (and some testosterone).
2. Androgen diffuses into granulosa cells.
3. Granulosa cells + FSH induce aromatase (CYP19) and convert androgen to estradiol.

The dominant follicle is the one that acquires enough FSH receptors and local estradiol/inhibin to survive the mid-follicular FSH drop that starves the rest of the cohort (atresia). Granulosa cells also acquire LH receptors late in the follicular phase so they can luteinize when the surge hits.

Menstrual cycle hormones: timing beats slogans

A textbook cycle is 28 days. The luteal phase is relatively fixed at about 14 days; the follicular phase is what lengthens or shortens the cycle. Day 1 is the first day of menses.

Exam trap: progesterone does not cause ovulation. Progesterone follows ovulation because the corpus luteum makes it. A small preovulatory progesterone tick exists, but the trigger you are supposed to name is the LH surge driven by high estradiol. Prostaglandins and local proteases execute rupture.

Basal body temperature rises after ovulation because progesterone is thermogenic. It is a retrospective marker, not a predictor you can use the morning of ovulation.

Uterine lining: estradiol grows glands and stroma (proliferative). Progesterone then induces glycogen-rich secretory glands and spiral-artery maturation. Withdrawal of both steroids is what starts menses in a nonpregnant cycle. Anovulatory cycles can still bleed (estrogen withdrawal or estrogen breakthrough) but they lack a true secretory transformation — the physiology behind irregular, often heavier bleeds when a corpus luteum never formed.

Pregnancy: hCG rescue, then the placental shift

Fertilization is typically in the ampulla. The blastocyst implants about day 6–7. Syncytiotrophoblast secretes human chorionic gonadotropin (hCG) into maternal blood. hCG binds the LH/hCG receptor on the corpus luteum and keeps progesterone (and estradiol) flowing until the placenta can do the job.

The luteal-placental shift around weeks 8–10 is why surgical removal of the corpus luteum before that window can abort a pregnancy, and why it is usually tolerated after the placenta is steroidogenic. Do not invent a Part I-required calendar of obstetric visits; do memorize the shift and the hCG receptor.

Estriol is a three-compartment synthesis: fetal adrenal DHEA-S → fetal liver 16-hydroxylation → placental aromatase. Low estriol can flag a fetal or placental synthesis problem. Maternal cholesterol, not fetal cholesterol, is the main substrate for placental progesterone.

hPL (chorionic somatomammotropin) is GH-like. It reduces maternal insulin sensitivity so maternal tissues burn more fat and leave glucose for the fetus. That is the physiologic background of gestational diabetes, not a chemistry-chapter glycolysis map.

Maternal cardiovascular set points change: blood volume rises on the order of 40–50%, cardiac output rises, systemic vascular resistance falls (placenta is a low-resistance circuit), and a physiologic anemia appears because plasma volume outruns red-cell mass. Minute ventilation rises (progesterone stimulates breathing); PaCO2 falls slightly. Those are reproductive-physiology set-point changes, not pathology until they overshoot.

Parturition is a feed-forward loop, not a single hormone. Near term, myometrial oxytocin receptors increase. Stretch of the cervix and uterus reflexively increases oxytocin release (Ferguson reflex). Oxytocin is Gq-coupled on myometrium (IP3, calcium). Prostaglandins ripen the cervix and add contractions. Fetal cortisol and placental CRH help mature lungs and time the cascade. Oxytocin also contracts myoepithelial cells of the breast — same peptide, different organ.

Lactation: synthesis versus ejection

Pregnancy estrogen, progesterone, prolactin, and hPL grow ducts and alveoli. High estrogen and progesterone block copious milk secretion until they collapse at delivery. Then prolactin is unopposed and lactogenesis II begins.

Exam trap: prolactin does not squirt milk out of the nipple. Oxytocin does. Oxytocin does not write the milk recipe. Prolactin does. Dopamine agonists suppress prolactin; dopamine antagonists (many antipsychotics) raise prolactin and can cause galactorrhea and hypogonadism because prolactin suppresses GnRH.

Suckling-induced GnRH suppression is the physiology of lactational amenorrhea. It is incomplete contraception, but it is real negative feedback.

Closing the male loop: systemic androgen effects

Beyond spermatogenesis, testosterone (after conversion where needed) increases skeletal muscle protein synthesis, laryngeal growth, RBC mass (which is why a hematocrit can rise with exogenous androgens), and libido. SHBG is increased by estrogen and thyroid hormone and decreased by androgens and insulin — so a total testosterone number can mislead if SHBG has moved. For Part I, know that free hormone is the active idea and that DHT versus testosterone versus estradiol split the tissue list.

If a stem gives high prolactin, low GnRH, low LH, and low testosterone in a man, the testis may be innocent. Hyperprolactinemia is a hypothalamic brake. That item is reproductive physiology even though the tumor, if present, is a lactotroph adenoma.

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