Reproductive Physiology: The Menstrual Cycle

Hypothalamic-Pituitary-Ovarian (HPO) Axis

• Hypothalamus: secretes GnRH in a pulsatile fashion from the arcuate nucleus
• Anterior pituitary: gonadotrophs secrete FSH and LH in response to GnRH
• Ovary: produces oestradiol, progesterone, inhibin, AMH in response to gonadotrophins
• Feedback loops: predominantly negative feedback; positive feedback from oestradiol triggers the LH surge

GnRH Pulsatility

• Pulsatile GnRH is ESSENTIAL — continuous GnRH causes receptor downregulation and gonadotrophin suppression (basis of GnRH agonist therapy after initial flare)
• Follicular phase: high-frequency, low-amplitude pulses → favour FSH secretion
• Luteal phase: low-frequency, high-amplitude pulses → favour LH secretion

Ovarian Cycle

Follicular Phase (Days 1-14, variable length)

• Primordial follicle recruitment: pool of resting follicles begins growth (takes ~85 days from primordial to pre-ovulatory)
• FSH-dependent growth: rising FSH recruits a cohort of antral follicles
• Dominant follicle selection: the follicle with highest FSH receptor density and local growth factors outcompetes the cohort
• Two-cell, two-gonadotrophin theory:
  • LH stimulates theca cells → produce androgens (androstenedione, testosterone)
  • FSH stimulates granulosa cells → aromatase converts androgens to oestrogens (oestradiol)
• Rising oestradiol from the dominant follicle exerts negative feedback → FSH declines → non-dominant follicles undergo atresia
• Inhibin B: secreted by granulosa cells; selectively suppresses FSH (not LH)

Ovulation (Day 14, approximately)

• Positive feedback: sustained high oestradiol (>200 pg/ml for >36 hours) switches feedback from negative to positive
• Triggers the LH surge (lasts ~36-48 hours)
• LH surge initiates: resumption of meiosis I in oocyte, luteinisation of granulosa cells, prostaglandin and collagenase production → follicle rupture
• Ovulation occurs ~36 hours after onset of LH surge, ~12 hours after LH peak
• Oocyte released with cumulus cells; captured by fimbriae into fallopian tube
• Oocyte is viable for ~12-24 hours after ovulation

Luteal Phase (Days 14-28, fixed ~14 days)

• Corpus luteum forms from remnants of ovulated follicle
• Granulosa lutein cells → progesterone (major product) + oestradiol
• Theca lutein cells → androgens → oestradiol
• Progesterone: peaks at day 21 (7 days post-ovulation); >30 nmol/L confirms adequate ovulation
• Corpus luteum requires LH for maintenance
• If no implantation: corpus luteum degenerates after ~14 days → progesterone and oestradiol decline → endometrial shedding (menstruation)
• If implantation occurs: hCG from trophoblast rescues corpus luteum; maintains progesterone production until placenta takes over (~8-12 weeks)

Endometrial Cycle

Menstrual Phase (Days 1-5)

• Withdrawal of progesterone and oestradiol → prostaglandin release → vasoconstriction of spiral arteries → ischaemic necrosis → shedding of functional layer

Proliferative Phase (Days 5-14)

• Oestradiol-driven: endometrial regeneration from basal layer
• Glandular proliferation, stromal growth, spiral artery development
• Endometrium thickens from ~1mm to ~8-12mm

Secretory Phase (Days 14-28)

• Progesterone-driven: glandular secretion, stromal decidualisation, coiling of spiral arteries
• Day 16-19: subnuclear glycogen vacuoles in glands (earliest histological sign of ovulation)
• Day 20-23: implantation window — endometrium most receptive; pinopodes on surface epithelium
• Day 24-28: pre-decidual changes in stroma; preparation for implantation or menstruation

Key Hormonal Markers

| Hormone | Key Role | Clinical Use | |---------|----------|-------------| | FSH (Day 2-5) | Ovarian reserve assessment | >10 IU/L suggests diminished reserve | | LH | Ovulation trigger | LH:FSH >2:1 suggests PCOS | | Oestradiol | Follicular maturation marker | Triggers LH surge at >200 pg/ml | | Progesterone (Day 21) | Confirms ovulation | >30 nmol/L = adequate ovulation | | AMH | Ovarian reserve (antral follicle number) | Does not change across cycle | | Inhibin B | Selectively suppresses FSH | Marker of follicular activity |

Important Facts for MRCOG

• GnRH must be pulsatile — continuous GnRH suppresses gonadotrophins
• Two-cell, two-gonadotrophin model: theca (LH → androgens), granulosa (FSH → oestrogens)
• LH surge: triggered by positive oestradiol feedback; ovulation ~36h after onset
• Luteal phase is fixed (~14 days); follicular phase is variable
• Day 21 progesterone >30 nmol/L confirms ovulation
• Implantation window: days 20-23 (6-10 days post-ovulation)
• AMH does not vary across the menstrual cycle — can be measured any day
• hCG rescues the corpus luteum; placenta takes over steroidogenesis by 8-12 weeks

Clinically reviewed by NHS obstetricians and gynaecologists

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