Physiology of Ovulation and Menstruation (MBBS Notes)

1. Overview

• The menstrual cycle is a regular, cyclic change in the ovary (ovarian cycle) and uterus (uterine cycle). It is controlled by the hypothalamic-pituitary-ovarian (HPO) axis.
• The average cycle is 28 days, with a normal range of about 21 to 35 days. Day 1 is the first day of menstrual bleeding (Ganong's Review of Medical Physiology, 26e, p. 403).
• There are three linked cycles:
  • Ovarian: follicular phase, ovulation, luteal phase.
  • Uterine/endometrial: menstrual, proliferative, secretory phases.
  • Hormonal: GnRH, FSH, LH, estrogen, progesterone, inhibin.

2. Hormones involved

• LH acts on theca interna cells. These make androgens (androstenedione, testosterone).
• Androgens diffuse into the granulosa cells. FSH induces aromatase there, which converts androgens to estradiol.
• The textbook states that granulosa cells are the primary source of circulating estrogen, but theca cell androgens are necessary for its production (Ganong, p. 403).

3. The ovarian cycle

3.1 Follicle reserve

• The fetal ovary has more than 7 million primordial follicles. About 2 million remain at birth, and fewer than 300,000 remain at puberty.
• Only about 500 oocytes ovulate in a reproductive lifetime. The rest undergo atresia by apoptosis.
• Oocytes are arrested in prophase of meiosis I from fetal life until just before ovulation (Ganong, p. 404).

3.2 Follicular phase (days 1 to 14)

1. Recruitment: A rise in FSH at the end of the previous luteal phase recruits a cohort of antral follicles. This happens because estradiol, progesterone and inhibin have fallen after corpus luteum regression.
2. Selection: Around day 6 to 7, one follicle becomes dominant. It is the one with the most FSH receptors and the best estradiol production. The others undergo atresia. The exact mechanism is uncertain, but it is related to the follicle's ability to secrete estrogen (Ganong, p. 403).
3. Dominance: Rising estradiol and inhibin B from the dominant follicle suppress FSH by negative feedback. Smaller follicles lack enough FSH and regress. FSH also induces LH receptors on granulosa cells.
4. Follicle stages: primordial, primary, secondary (preantral), tertiary (antral/graafian). The antrum fills with follicular fluid.

3.3 Ovulation (about day 14)

• Estradiol above about 200 pg/mL, sustained for about 48 hours, switches from negative to positive feedback.
• The primary trigger is a rise of estradiol to very high threshold levels just before the surge. It has two effects (Medical Physiology, Boron, Ch. 55):
  • It sensitizes pituitary gonadotrophs to GnRH.
  • It induces a GnRH surge through hypothalamic (preoptic/kisspeptin) neurons.
• Rising activins and low-level progesterone from the preovulatory follicle augment the effect. Progesterone is not the primary trigger.
• LH surge timing: It peaks about 12 hours after onset and lasts about 48 hours. The peak is about 3-fold the baseline. A smaller FSH surge accompanies it.
• Ovulation occurs about 24 to 36 hours after the LH surge begins, and about 10 to 12 hours after the LH peak. Urinary LH detection predicts ovulation (The Developing Human; Tietz).

1. Resumption of meiosis I. The oocyte completes it and forms a secondary oocyte plus the first polar body.
2. The secondary oocyte starts meiosis II and arrests in metaphase II. It completes meiosis II only after sperm penetration (Ganong, p. 404).
3. Cumulus expansion. Hyaluronic acid synthesis is increased.
4. Increased prostaglandins (PGE2, PGF2α) and proteolytic enzymes (plasmin, collagenase, MMPs). These weaken the follicular wall and the stigma.
5. Local inflammatory-type response with increased vascular permeability.
6. Follicular rupture and release of the oocyte with its cumulus and corona radiata cells.
7. Luteinization. Granulosa and theca cells change to luteal cells. The steroid output shifts from estradiol to progesterone (Boron).

• Mittelschmerz: Fleeting lower abdominal pain. Minor bleeding into the peritoneum from the ruptured follicle causes peritoneal irritation (Ganong).
• Clear, watery, stretchy cervical mucus with ferning and spinnbarkeit.
• Biphasic basal body temperature. It rises by about 0.3 to 0.5 °C after ovulation because of progesterone's thermogenic action.
• Mid-cycle LH peak. Mid-luteal progesterone is above about 3 ng/mL.
• Ultrasound shows follicle collapse and free pelvic fluid.

3.4 Luteal phase (days 15 to 28)

• The ruptured follicle fills with blood, forming the corpus hemorrhagicum. Luteal cells then proliferate and become yellow and lipid-rich, forming the corpus luteum. VEGF-driven angiogenesis is essential for this (Ganong).
• The corpus luteum secretes progesterone (peak about day 21 to 22, mid-luteal), estradiol (second smaller peak) and inhibin A.
• Its lifespan is a fixed 14 days, under LH support.
• If pregnancy does not occur: The corpus luteum degenerates at about day 24, roughly 4 days before menses. It is replaced by scar tissue, the corpus albicans (Ganong). Falling estradiol, progesterone and inhibin release the pituitary from negative feedback, so FSH rises again and a new cohort is recruited.
• If pregnancy occurs: hCG from the trophoblast rescues the corpus luteum (the same receptors as LH). It persists until the placenta takes over steroid production at about 8 to 10 weeks.

4. The uterine (endometrial) cycle

• Stratum functionalis (superficial two-thirds): shed in menstruation. It is supplied by long, coiled spiral arteries.
• Stratum basalis (deep layer): retained, and the source of regeneration. It is supplied by short, straight basal arteries (Ganong, p. 405).

• Cervical mucus: Under estrogen it is copious, watery and elastic, with a ferning pattern. Sperm can penetrate it. Under progesterone it is scant, thick and non-elastic, with no ferning (Costanzo Physiology, 7e, p. 478).
• Uterine tube: Estrogen increases ciliary activity and contractility. Progesterone increases secretion and decreases contractility.
• Vagina: Estrogen causes epithelial proliferation. Progesterone causes differentiation, with desquamation.
• Myometrium: Estrogen increases contractility. Progesterone decreases it.
• Breast: Estrogen drives duct growth. Progesterone drives alveolar and secretory development.

5. Physiology of menstruation

• Duration is 3 to 7 days (average 4 to 5).
• Blood loss is about 30 to 80 mL, and over 80 mL is menorrhagia.
• The discharge consists of blood, endometrial tissue, mucus and vaginal epithelial cells. It is generally non-clotting because of fibrinolysins in the endometrium.

1. The corpus luteum regresses (luteolysis) about 4 days before menses. Estrogen and progesterone fall abruptly.
2. Loss of progesterone destabilizes lysosomal membranes in endometrial cells. Hydrolytic enzymes are released.
3. Local prostaglandin synthesis rises sharply (PGF2α and PGE2, via COX-2 and phospholipase A2).
4. PGF2α causes intense vasoconstriction of the spiral arteries. This leads to endometrial ischemia, hypoxia and necrosis of the functionalis. PGF2α also causes myometrial contractions, which explain the pain of dysmenorrhea.
5. Matrix metalloproteinases (MMPs) break down the extracellular matrix. Tissue breaks down and the vessels rupture.
6. Cyclic vasodilatation follows the ischemia, and blood escapes into the uterine cavity. Bleeding stops through the following mechanisms:
   • Myometrial contraction.
   • Constriction of the spiral arteries.
   • Platelet and fibrin plugs.
   • Rising estrogen from the new follicular cohort, which restores the epithelium.
7. Repair starts from the stratum basalis within about 48 hours, even while menstruation continues. Estrogen from the new follicles drives the re-epithelialization.

6. Feedback control (HPO axis) summary

7. Factors that modify the cycle (brief)

• Low body fat, intense exercise or stress reduces GnRH pulses and can cause hypothalamic amenorrhea.
• Hyperprolactinemia suppresses GnRH.
• Perimenopause: Follicle depletion leads to falling inhibin B and rising FSH. Cycles become irregular.
• Hormonal contraceptives suppress the LH surge, so ovulation does not occur.

8. Clinical correlations (viva and short-note points)

• Anovulatory cycles: Seen at menarche, perimenopause and in PCOS. Estrogen acts unopposed with no progesterone, which gives a thick proliferative endometrium. This can lead to heavy irregular bleeding or endometrial hyperplasia.
• Primary amenorrhea: No menses by age 15 (or 3 years after thelarche).
• Dysmenorrhea: Caused by excess PGF2α. NSAIDs (prostaglandin synthase inhibitors) are effective.
• Menorrhagia: More than 80 mL blood loss per cycle.
• Luteal phase defect: Inadequate progesterone leads to poor endometrial receptivity.
• Ovulation induction: hCG mimics the LH surge (Medical Physiology, Boron).

9. Quick revision table

Recent evidence check