Male & Female Reproductive Physiology
The HPG axis, the menstrual cycle, and the hormones of pregnancy
The hypothalamic-pituitary-gonadal axis
Pulsatile GnRH runs the axis. The hypothalamus releases GnRH in pulses into the portal circulation, driving anterior pituitary FSH and LH, which act on the gonads. Pulsatile GnRH stimulates the axis, whereas continuous GnRH downregulates its receptors and suppresses it; this is the basis of continuous leuprolide therapy. Faster pulses favor LH and slower pulses favor FSH. Sex steroids (estrogen, progesterone, testosterone) and inhibin provide negative feedback.
- Hypothalamus: GnRHPulsatile release
- Pituitary: FSH, LHGonadotropins
- GonadsSex steroids and inhibin
- Negative feedbackEstrogen, progesterone, testosterone, inhibin
Clinical correlates. Anything that disrupts GnRH pulses lowers FSH and LH: hyperprolactinemia inhibits GnRH, and in Kallmann syndrome GnRH neurons fail to migrate, causing hypogonadotropic hypogonadism with anosmia.
The ovary and the menstrual cycle
Two cells, two gonadotropins. Ovarian estrogen synthesis needs both follicular cell layers. LH stimulates theca cells to convert cholesterol into androstenedione, which diffuses to the granulosa cells, where FSH-induced aromatase converts it to estradiol. Granulosa cells also secrete inhibin B, which selectively inhibits FSH. In the testis, Leydig cells (LH) play the theca role and Sertoli cells (FSH, inhibin B, aromatase) the granulosa role.
Timing. The cycle has a variable follicular phase and a fixed luteal phase of about 14 days, with ovulation on day 14 of a 28-day cycle. Differences in cycle length come from the follicular phase; the corpus luteum reliably lasts about two weeks.
- Menses (days 1–5)Endometrial shedding
- Follicular / proliferative phaseFSH, rising estrogen
- Ovulation (day 14)LH surge
- Luteal / secretory phaseProgesterone, fixed 14 days
Follicular phase: FSH builds estrogen. FSH recruits a cohort of follicles, and a dominant follicle emerges. Its rising estradiol drives endometrial proliferation, with straight tubular glands. At low-to-moderate levels, estrogen exerts negative feedback on FSH and LH, starving the smaller follicles so the cohort is pruned to a single dominant one.
The estrogen surge flips to positive feedback. When estradiol stays high and sustained just before mid-cycle, feedback on the pituitary switches from negative to positive, producing the LH surge. Ovulation follows about 24–36 hours later, and the oocyte completes meiosis I. Mid-cycle pain from the ruptured follicle is mittelschmerz.
The pre-ovulatory surge is the one time estrogen exerts positive feedback to spike LH.
Luteal phase: progesterone rules. After ovulation the corpus luteum secretes progesterone (dominant) and some estrogen. Progesterone converts the endometrium to a secretory pattern with coiled glands and spiral arteries, raises basal body temperature and thickens cervical mucus. Without fertilization and hCG, the corpus luteum begins to regress about 10 days after ovulation; progesterone falls, the spiral arteries constrict, and the functional layer is shed as menses.
Estrogen and progesterone
Three estrogens. Estradiol, from the ovary, is the most potent. Estrone comes from peripheral aromatization in adipose tissue and dominates after menopause. Estriol, from the placenta, dominates pregnancy. Potency: estradiol > estrone > estriol.
| Feature | Estrogen | Progesterone |
|---|---|---|
| Main source | Granulosa cells (estradiol); adipose (estrone); placenta (estriol) | Corpus luteum; placenta after weeks 8–10 |
| Endometrium | Proliferative | Secretory |
| Cervical mucus | Thin, watery | Thick, scant |
| Feedback | Negative on FSH/LH, positive before ovulation | Inhibits LH and FSH |
| Other actions | Upregulates progesterone and LH receptors; raises transport proteins and HDL; closes epiphyseal plates | Raises basal body temperature; relaxes uterine smooth muscle to maintain pregnancy |
Progesterone as a marker. A rise in mid-luteal progesterone confirms that ovulation occurred, and its fall triggers menstruation. By opposing estrogen's proliferative drive, progesterone also protects the endometrium from hyperplasia.
Male reproductive physiology
Leydig makes testosterone, Sertoli makes sperm. LH drives Leydig cells, which lie in the interstitium outside the blood-testis barrier, to make testosterone. FSH drives Sertoli cells, which line the seminiferous tubules and support spermatogenesis. "Sertoli Support Sperm."
| Feature | Leydig cell | Sertoli cell |
|---|---|---|
| Stimulus | LH | FSH |
| Location | Interstitium, outside the blood-testis barrier | Seminiferous tubules; tight junctions form the barrier |
| Products | Testosterone | Inhibin B, androgen-binding protein, MIF; aromatizes testosterone to estrogen |
| Feedback | Testosterone inhibits LH | Inhibin B inhibits FSH |
| Failure pattern | Low testosterone, high LH | Low sperm count and inhibin B, high FSH, normal testosterone |
Sertoli cells are temperature-sensitive, so heat from a varicocele or cryptorchidism impairs sperm production and inhibin output.
Testosterone branches. 5α-Reductase converts testosterone to the more potent DHT, which acts on the prostate, external genitalia and hair follicles; aromatase converts it to estradiol. Testosterone itself drives libido, muscle mass and spermatogenesis, and it closes the epiphyseal plates by way of estrogen. Androgen-binding protein keeps intratesticular testosterone high; exogenous testosterone suppresses LH and FSH, so the testes shrink and sperm production falls.
Pregnancy and menopause
hCG rescues the corpus luteum. The syncytiotrophoblast secretes hCG, which acts like LH to keep the corpus luteum producing progesterone for the first 8–10 weeks, until the placenta becomes self-sufficient. It is the basis of pregnancy tests. hCG shares its α subunit with LH, FSH and TSH, and its β subunit resembles that of TSH, so very high levels, as in molar pregnancy or hyperemesis, can stimulate the thyroid and cause transient hyperthyroidism with a suppressed TSH.
hPL diverts fuel to the fetus. Human placental lactogen, also from the syncytiotrophoblast, increases maternal insulin resistance and lipolysis, shunting glucose and free fatty acids to the fetus; this can unmask gestational diabetes. After the luteal-placental shift at about weeks 8–10, the placenta supplies progesterone and estriol.
Menopause. Depletion of ovarian follicles, at an average age of about 51, drops estrogen and inhibin. With negative feedback lost, FSH rises markedly, more than LH, making it the best hormonal marker. Peripheral aromatization of adrenal androstenedione to estrone becomes the main estrogen source.
Menopause symptoms, HAVOC: Hot flashes, Atrophy of the vagina, Osteoporosis, Coronary artery disease.