4.4 Reproductive Physiology: Sexual Differentiation, Spermatogenesis, the Menstrual Cycle, Parturition & Lactation

Why this area matters

The TOS lists "sexual differentiation, main and accessory sexual organs and their functions, physiology of menstrual cycle, parturition and lactation, male hormones, and spermatogenesis". This physiology explains OB-GYN topics such as abnormal uterine bleeding, infertility, contraception and labor, and Pediatrics topics such as ambiguous genitalia and breastfeeding.

Sexual differentiation

Sex develops at three levels:

1. Chromosomal sex. XX or XY is set at fertilization.
2. Gonadal sex. The SRY gene on the Y chromosome (acting through SOX9) turns the bipotential gonad into a testis at about the seventh week. Without SRY, an ovary develops.
3. Phenotypic sex. The fetal testis makes two hormones:
   • Anti-Müllerian hormone (AMH) from Sertoli cells makes the Müllerian (paramesonephric) ducts regress, so no uterus or fallopian tubes form.
   • Testosterone from Leydig cells keeps the Wolffian (mesonephric) ducts, which become the epididymis, vas deferens and seminal vesicles.
   • 5-alpha-reductase converts testosterone to dihydrotestosterone (DHT), which forms the penis, scrotum and prostate.

Without testicular hormones, the female pattern develops by default; the ovary is not needed for female internal or external development. Classic disorders:

The male: spermatogenesis and testosterone

• Leydig cells in the interstitium respond to LH by making testosterone.
• Sertoli cells in the seminiferous tubules respond to FSH (and to local testosterone). They form the blood-testis barrier, nourish germ cells, secrete androgen-binding protein and make inhibin B, which feeds back on FSH.
• Spermatogenesis takes about 64 to 74 days, from spermatogonia to spermatocytes, spermatids and spermatozoa. Sperm gain motility in the epididymis.
• It needs a scrotal temperature about 2 to 3°C below core temperature (which is why cryptorchidism and varicocele impair fertility) and a very high intratesticular testosterone. Exogenous testosterone or anabolic steroids suppress LH and therefore intratesticular testosterone, causing azoospermia and testicular atrophy.
• Accessory glands: the seminal vesicles supply most of the ejaculate volume, rich in fructose and prostaglandins. The prostate adds citrate, zinc, enzymes and PSA. The bulbourethral glands add lubricating mucus.
• Sexual response: erection is parasympathetic, through nitric oxide and cGMP in the corpora (PDE5 inhibitors prolong it). Emission is sympathetic. Ejaculation involves sympathetic and somatic (pudendal) reflexes.
• Testosterone actions include male internal ducts, pubertal growth of the penis and larynx, muscle mass, libido, erythropoiesis and epiphyseal closure. Closure is mediated partly by estradiol formed by aromatase.

The female: ovarian and endometrial cycles

Oocytes are arrested in prophase of meiosis I from fetal life until shortly before ovulation. Meiosis I completes just before ovulation, and the oocyte then arrests in metaphase II until fertilization. A typical 28-day cycle runs as follows:

Because the luteal phase is fairly fixed, cycle-length variation comes from the follicular phase. Ovulation occurs about 14 days before the next period, not necessarily on day 14. Progesterone raises basal body temperature by about 0.3 to 0.5°C and thickens cervical mucus.

Fertilization, implantation and the hormones of pregnancy

• Fertilization usually occurs in the ampulla of the fallopian tube within about a day of ovulation.
• The blastocyst implants about 6 to 7 days later, and the syncytiotrophoblast begins secreting hCG.
• hCG has an LH-like action that rescues the corpus luteum, so progesterone continues. It is detectable in serum around the time of the missed period and peaks at about 8 to 10 weeks.
• The placenta takes over progesterone production at about 7 to 9 weeks (the luteal-placental shift). Removing the corpus luteum before then causes miscarriage unless progesterone is given.
• Human placental lactogen (hPL) is anti-insulin and ensures glucose for the fetus; it contributes to gestational diabetes.
• Estriol production needs the fetal adrenal gland, fetal liver and the placenta working together.
• Progesterone keeps the myometrium quiet.

Parturition

As term approaches:

• the fetal hypothalamic-pituitary-adrenal axis matures, and fetal cortisol and placental CRH rise;
• estrogen increases myometrial oxytocin receptors and gap junctions (connexin 43);
• prostaglandins soften and ripen the cervix and stimulate contractions.

Stretch of the cervix triggers a neuroendocrine positive-feedback loop (the Ferguson reflex): stretch releases oxytocin, oxytocin strengthens contractions, and stronger contractions stretch the cervix further until delivery.

Lactation

• During pregnancy, estrogen develops the ducts and progesterone the lobules and alveoli, with prolactin and hPL. The very high estrogen and progesterone levels block milk secretion.
• After the placenta is delivered, those levels fall, and prolactin starts copious milk production within about 2 to 3 days. Colostrum, rich in secretory IgA, comes first.
• Suckling stimulates two reflexes:
  • anterior pituitary prolactin, which makes the next feed's milk;
  • posterior pituitary oxytocin, which contracts myoepithelial cells for milk ejection (let-down). Oxytocin can also be triggered by the infant's cry and inhibited by stress or pain.
• Prolactin suppresses GnRH pulsatility. Exclusive, frequent breastfeeding therefore delays ovulation, which is the basis of the lactational amenorrhea method.

Menopause

As the follicles run out, estradiol and inhibin fall and FSH rises; a high FSH is the hormonal marker. The results include vasomotor symptoms, urogenital atrophy and accelerated bone loss (osteoporosis), along with a less favorable lipid profile.