The Menstrual Cycle - MBBS Physiology

Overview

I. The HPO Axis - The Control System

• Kisspeptin - stimulates GnRH neurons
• Neurokinin B - stimulates kisspeptin release
• Dynorphin - inhibits kisspeptin release (terminates each pulse)

II. The Two-Cell, Two-Gonadotropin Theory (High-Yield!)

• Theca cells lack aromatase; granulosa cells lack 17α-hydroxylase early on - hence the obligatory two-cell cooperation.
• Rising estrogen from granulosa cells negatively feeds back to reduce FSH, creating a selection pressure that only the dominant follicle (with the most FSH receptors) can survive. All others undergo atresia. - Berek & Novak's Gynecology, p. 289

III. Ovarian Phases

Phase 1: Follicular Phase (Day 1-14)

• At birth, the ovaries contain ~2 million primordial follicles. By puberty, <300,000 remain. Only ~500 reach maturity in a lifetime.
• At the start of each cycle, FSH (rising because the previous corpus luteum has degenerated) stimulates a cohort of primordial follicles to develop.
• By day 6, one dominant (Graafian) follicle is selected based on its superior FSH receptor count and estrogenic microenvironment. Others undergo atresia via apoptosis.
• The Graafian follicle fills with follicular fluid (antrum formation). The primary oocyte is arrested in prophase I of meiosis and completes the 1st meiotic division just before ovulation, ejecting the first polar body.
• Granulosa cells secrete increasing amounts of estradiol (17β-estradiol), which:
  • Proliferates the endometrium (stimulates gland and stromal growth, elongates spiral arteries)
  • Makes cervical mucus thin, watery, elastic, alkaline ("spinnbarkeit" - can be stretched into a thread), and shows "ferning" pattern on a glass slide (channels form to allow sperm transit)
  • Exerts negative feedback on FSH/LH (keeps levels modest through most of the follicular phase)

Ovulation (Day ~14)

• Progesterone secretion by granulosa cells just before ovulation also contributes to the FSH midcycle surge.
• The LH surge triggers:
  1. Completion of meiosis I in the oocyte → secondary oocyte (arrested in metaphase II)
  2. Rupture of the Graafian follicle → ovum released into peritoneal cavity, picked up by fimbriae
  3. Luteinization of the follicle remnant
• Brief lower abdominal pain from peritoneal irritation by follicular fluid = Mittelschmerz - Ganong's Review of Medical Physiology, p. 404-405

Phase 2: Luteal Phase (Day 14-28)

• The ruptured follicle fills with blood (corpus hemorrhagicum), then granulosa and theca cells proliferate under LH stimulation to form the corpus luteum (yellowish, lipid-rich luteal cells).
• VEGF is essential for corpus luteum vascularization.
• The corpus luteum secretes large amounts of progesterone + estrogen + inhibin.
• Duration is a remarkably constant 14 days.
• If no fertilization: Corpus luteum degenerates at ~day 24 → corpus albicans (scar tissue). Progesterone/estrogen fall → menstruation.
• If fertilization occurs: hCG (from trophoblast) rescues the corpus luteum, which persists through the first trimester.

IV. Uterine Phases

Phase 1: Menstrual Phase (Day 1-4/5)

• Corpus luteum regression → progesterone and estrogen withdrawal → endometrial ischemia (spasm of spiral arteries, mediated by PGF2α) → necrosis and shedding of the stratum functionale.
• The stratum basale (supplied by straight basilar arteries) is NOT shed and regenerates the endometrium.
• Normal menstrual flow: duration 3-5 days (range 1-8 days), volume 30 mL average (normal up to 80 mL).
• Menstrual blood is predominantly arterial (75% arterial, 25% venous).
• Contains fibrinolysin from endometrial tissue → prevents clotting (clots in menstrual blood indicate excessive flow).
• Contains prostaglandins → responsible for dysmenorrhea (uterine cramps). - Ganong's Review of Medical Physiology, p. 405-406

Phase 2: Proliferative (Follicular) Phase (Day 5-14)

• Driven by estrogen from the growing follicle.
• Endometrium increases rapidly in thickness (days 5-14).
• Glands elongate but do not secrete; stroma grows.
• Spiral arteries elongate.

Phase 3: Secretory (Luteal) Phase (Day 14-28)

• Driven by progesterone (+ estrogen) from the corpus luteum.
• Glands become tortuous and coiled, accumulate glycogen in vacuoles, and secrete mucus.
• Stroma becomes edematous.
• Spiral arteries become more coiled and elongated.
• Progesterone causes cervical mucus to become thick, viscous, cellular - no ferning, no spinnbarkeit (blocks sperm - fertilization window has passed).
• Progesterone has a mild thermogenic effect → basal body temperature rises ~0.5°C in the luteal phase. This is the basis of the "rhythm method" of contraception.
• The secretory phase is always 14 days regardless of cycle length. Variability in cycle length is due to variability in the proliferative phase. - Costanzo Physiology 7th Edition, p. 479

V. Hormonal Summary Table

VI. Feedback Mechanisms (High-Yield)

VII. Clinically Important Derivatives

VIII. Normal Menstruation - Key Numbers