Mednotes

L6 RDA Ovarian and menstrual endocrinology

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aliasesL6 RDA Ovarian and menstrual endocrinology

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Overview

This lecture traces the ovarian cycle from constant primordial follicle activation through folliculogenesis, dominant follicle selection, ovulation and the corpus luteum, then relates ovarian hormone output (estrogen, progesterone, inhibin) to feedback control of the hypothalamic-pituitary-gonadal axis in the follicular and luteal phases, including the switch to positive feedback that drives the LH surge and a proposed neuroendocrine mechanism for that switch. It closes with clinical applications: assessing ovarian reserve with AMH, ovarian stimulation for IVF and its complication OHSS, polyendocrine metabolic ovary syndrome (formerly PCOS), and the parallel cyclical changes in the endometrium and cervical mucus that make up the menstrual cycle.

The ovarian and menstrual cycles across 28 days

  • Ovarian cycle: follicle growth, ovulation, corpus luteum growth and regression - driven by pituitary hormones.
  • Menstrual cycle: endometrial growth, maturation and shedding (menstruation) - driven by ovarian hormones.
  • Over a 28-day cycle: FSH is highest at the start of the follicular phase (days 1 to 5), then falls as oestradiol and inhibin B from the growing follicles increase negative feedback; FSH shows a small peak at ovulation alongside the LH surge, stays low through the luteal phase, and rises again at the end of the cycle. LH stays low through the follicular phase, rises sharply just before day 14 (the LH surge), then remains low through the luteal phase.
  • Estrogens rise through the follicular phase, peak just before ovulation, dip at ovulation, then show a second, smaller peak in the luteal phase.
  • Progesterone stays low in the follicular phase, peaks in the mid-luteal phase, and falls by day 28.
  • Inhibin (two forms, inhibin A and inhibin B) tracks in parallel with the other ovarian hormones: it rises through the follicular phase alongside estrogen, peaks around ovulation, rises again in the luteal phase tracking progesterone, then declines toward cycle end.
  • Uterine phases align to these hormone changes: Menses (~days 0-7), Proliferative phase (~days 7-14), Secretory phase (~days 14-28).

Folliculogenesis: from primordial follicle to ovulation

  • Primordial follicle activation is constant.
  • Early development (primordial -> primary -> secondary follicle) is gonadotropin-independent, under paracrine control, and takes >120 days (“Recruitment I”).
  • Small antral follicles (2 mm) become FSH-sensitive.
  • Medium antral follicles (6 mm) become FSH-dependent; this stage (“Recruitment II”) takes about 85 days.
  • From ~10 mm, follicles become LH-dependent, undergoing “Selection” then “Dominance” over about 14 days, reaching the ovulatory (Graafian) follicle at 20 mm.
  • Total time from primordial to preovulatory follicle is 5-7 months. Because an egg is ovulated roughly every month, the ovaries must hold several cohorts of follicles at staggered developmental stages at once; recruitment of the follicle that will eventually ovulate begins cycles in advance (a “selection window” precedes its ovulation).
  • At every stage, most follicles undergo atresia rather than progressing.
  • Follicles larger than 4-6 mm cannot survive without FSH: granulosa cells express FSH receptors, and insufficient FSH stimulation triggers apoptosis (follicle death).
  • Antral follicle counts are measured by transvaginal ultrasound: soundwaves pass unimpeded through the follicular fluid in the antrum, so each antrum appears as a black spot.

Follicle selection: from cohort to a single dominant follicle

The dominant follicle emerges through a sequence of feedback-driven steps:

  1. Early cycle: the corpus luteum has just regressed, removing progesterone negative feedback, so FSH starts to rise.
  2. Rising FSH recruits a cohort of follicles through the gonadotropin-independent, FSH-sensitive and FSH-dependent stages. The cohort’s collective hormone output (estradiol and inhibin) increases negative feedback on the hypothalamus/pituitary, so FSH plateaus and follicles begin to undergo atresia.
  3. As FSH plateaus, fewer follicles remain but grow much larger and produce even more hormone, driving FSH down further; more follicles undergo atresia, leaving only the largest, most hormone-productive ones.
  4. One dominant follicle becomes LH-dependent and grows massively; its very high inhibin output suppresses almost all further FSH release.
  5. The dominant follicle’s rising estradiol output switches its own feedback on the hypothalamus/pituitary from negative to positive.
  6. This strong positive feedback drives an LH surge; the dominant follicle at this point needs LH, not FSH. This window is the “periovulatory phase”.

Hypothalamic “interpretation” of circulating hormones (the hypothalamus only senses blood hormone levels, not follicle status directly):

Hormone patternInferred ovarian statusHypothalamic response
Low estrogen, low inhibin, no progesteroneOnly small antral folliclesStimulate follicle growth: release FSH and LH
Medium estrogen, medium-high inhibin, no progesteroneMedium antral follicles growingSelect a preovulatory follicle: limit FSH, continue LH
Very high estrogen, no progesteroneOne preovulatory follicle readyStimulate ovulation: induce the LH surge
High progesterone, medium-high estrogenCorpus luteum presentLuteal phase: do nothing
No progesterone, no estrogenNo pregnancy this cycleStimulate follicle growth again: release FSH and LH

Ovarian steroidogenesis: the two-cell, two-gonadotropin model

  • LH binds receptors on theca interna cells, driving (via cAMP/ATP) conversion of cholesterol to androgens (testosterone/androstenedione).
  • These androgens diffuse into granulosa cells, where FSH binds its receptor and drives cAMP/ATP-dependent aromatase activity, converting the androgens to estrogens (oestrone/oestradiol), released into the capillary.
  • The theca layer is vascularised; the FSH-dependent granulosa layer is avascular.
  • Inhibin (inhibin A and inhibin B) is produced by granulosa cells of antral follicles, stimulated by FSH.

HPG axis feedback: follicular phase, luteal phase, and the LH surge

  • Follicular phase: estradiol exerts negative feedback on both hypothalamus and pituitary, inhibiting GnRH, LH and FSH - switching to positive feedback just before ovulation. Inhibin acts only on the pituitary, inhibiting FSH alone (a late-follicular-phase effect).
  • Luteal phase: progesterone acts at the level of the hypothalamus, inhibiting GnRH, FSH and LH. Inhibin again acts at the pituitary, inhibiting FSH only.
  • GnRH/LH pulse pattern changes across the cycle: luteal phase shows infrequent, low-amplitude pulses (negative feedback dominant); mid-follicular phase shows frequent, regular, small-amplitude pulses (negative feedback from estrogen alone); the preovulatory surge shows a large increase in GnRH pulse frequency and amplitude, producing a sustained GnRH elevation matched by a broad LH surge (positive feedback).
  • Proposed neuroendocrine mechanism for the negative-to-positive switch: GnRH neurons are regulated by Kisspeptin neurons, which respond to estrogen and release kisspeptin as a neurotransmitter. Two proposed populations are hypothesised: an inhibitory population producing negative feedback (active early-mid follicular phase) and a stimulatory population producing positive feedback (activated late in the follicular phase when estrogen is very high). Increased pituitary sensitivity to GnRH caused by elevated estrogen is also proposed to contribute.

Ovulation and the corpus luteum

  • Ovulation is follicle rupture at the ovarian surface (the “stigma”), releasing the oocyte-cumulus complex; this has been directly observed by histology, laparoscopy and live imaging (human and mouse).
  • After ovulation, the mural granulosa and theca cells remaining in the ovary luteinise to form the Corpus luteum (CL).
  • The CL produces progesterone, estrogen and inhibin. Progesterone and estrogen negative feedback prevent LH and FSH secretion; inhibin also suppresses FSH secretion.
  • If no pregnancy occurs, the CL degenerates to the corpus albicans, steroid synthesis stops, and LH/FSH secretion resumes.
  • Luteal phase length (12-13 days) is less variable than the follicular phase.
  • If pregnancy occurs and the embryo implants (6-7 days after ovulation), the embryo produces hCG, which rescues the corpus luteum by binding the same receptor as LH on the CL (this is why pregnancy tests detect hCG).

Clinical assessment: ovarian reserve, AMH, and ovarian stimulation

  • Ovarian stimulation for fertility treatment: a GnRH agonist or antagonist first suppresses endogenous LH and FSH; daily FSH injections (150-450 IU) are given until at least one follicle reaches ≥20 mm; an hCG injection (10,000 IU) triggers final maturation, and eggs are retrieved about 48 hours later.
  • Ovarian reserve has two definitions:
    • The number of primordial follicles remaining - relates to time to menopause, but has no reliable measurement.
    • The number of follicles that can be stimulated for retrieval (“functional ovarian reserve”) - usually taken as the number of follicles >2 mm.
  • Antral follicle count (AFC, by ultrasound) declines with age.
  • Anti-Müllerian hormone (AMH) is produced by granulosa cells of developing follicles and correlates with AFC; AMH blood tests are cheaper than transvaginal ultrasound.
  • AMH reference ranges guide IVF counselling: above the 25th centile for age gives “very likely normal ovarian reserve” (~80% chance of 6+ eggs in IVF); between the 25th and 10th centiles gives ~50% chance of 6+ eggs; below the 10th centile is “very likely reduced ovarian reserve” (~20% chance of 6+ eggs). Thresholds of 5 pmol/L mark “diminished” and 1 pmol/L “very diminished” reserve.
  • AMH does not predict natural fertility in young women: time-to-pregnancy shows essentially no correlation with AMH level (r = -0.10). Infertility is defined as no clinical pregnancy after 12 months of unprotected intercourse.
  • Ovarian hyperstimulation syndrome (OHSS): occurs in 5-10% of women receiving hCG for ovarian stimulation. High functional ovarian reserve is a risk factor. Caused by blood vessels around ovarian follicles leaking fluid, swelling the ovaries. Symptoms: swelling, pain, nausea, vomiting, thirst. Severe cases (~1% of hCG treatments) cause breathing difficulty, blood clots and kidney failure. High AMH identifies at-risk patients, who are given lower FSH doses during stimulation, since lower FSH produces fewer large mature follicles and thus lower risk.

Polyendocrine metabolic ovary syndrome (formerly PCOS)

  • Polyendocrine metabolic ovary syndrome (PMOS) is diagnosed by 2 of 3 criteria (ESHRE/ASRM consensus):
    1. Oligo- and/or anovulation - the leading cause of infertility in reproductive-age women.
    2. Hyperandrogenism (clinical and/or biochemical).
    3. Polycystic ovaries (≥12 follicles of 2-9 mm, ovary volume >10 cm3, or elevated serum AMH).
  • Pathophysiology: inappropriately high-frequency, high-amplitude LH secretion. Strongly correlated with insulin resistance, diabetes and obesity.
  • Clinical features include hirsutism and acne (from hyperandrogenism), and a “string of pearls” appearance of multiple small peripheral follicles on ultrasound.
  • Treatment: suppression of androgen production (oral contraceptives, chronic GnRH agonist), blockade of androgen receptors (flutamide), treatment of insulin resistance (metformin), lifestyle changes (weight loss), and less commonly acupuncture or surgical wedge sectioning/drilling of the ovary.

The menstrual cycle: endometrium, cervix, and endometriosis

  • Endometrium: absence of progesterone causes breakdown (menses). Oestradiol drives proliferation, making the endometrium thicker and richly vascularised (proliferative phase). Progesterone promotes secretion of thick, glycogen-rich material from endometrial glands, which become increasingly coiled and complex (secretory phase).
  • Cervical mucus changes across the cycle:
    • End of menses: “G-type” mucus - a tight mesh that blocks sperm motility, and acidic (reducing sperm survival).
    • Ovulation: “E-type” mucus - induced by estrogens, sparse and open, supporting sperm survival and motility.
    • Luteal phase: “G-type” mucus again - induced by progestogens, including progestogenic contraceptives.
  • Endometriosis: tissue similar to endometrium grows outside the uterus (e.g. between the uterus and rectum). Lesions are often highly painful, with heterogeneous symptoms; some endometriotic lesions remain sensitive to estrogen and progesterone.

Self-test

  1. Distinguish the ovarian cycle from the menstrual cycle in terms of what drives each.
  2. Describe how a follicle’s gonadotropin dependence changes as it grows from primordial to preovulatory, including the approximate sizes at which each transition occurs.
  3. Why must the ovaries contain follicle cohorts at staggered developmental stages at any one time?
  4. Explain why a follicle larger than 4-6 mm dies if FSH support is insufficient.
  5. Describe, in order, the steps by which a single dominant follicle is selected from a growing cohort.
  6. Distinguish the actions of estradiol and inhibin on the HPG axis during the follicular phase.
  7. Distinguish the follicular-phase and luteal-phase negative feedback loops.
  8. Describe the two-cell, two-gonadotropin mechanism of ovarian estrogen synthesis.
  9. Explain the proposed neuroendocrine mechanism underlying the switch from negative to positive estrogen feedback.
  10. Describe what happens to the corpus luteum if pregnancy does, and does not, occur.
  11. A patient undergoing ovarian stimulation is identified as high risk for OHSS. What is the underlying pathophysiology of OHSS, and what change to her stimulation protocol reduces the risk?
  12. Distinguish the two definitions of “ovarian reserve” and how each is assessed.
  13. Does AMH predict natural fertility in young women? What does the evidence show it predicts instead?
  14. List the diagnostic criteria for PMOS (formerly PCOS), and describe the underlying LH abnormality.
  15. Describe how cervical mucus changes across the menstrual cycle and the functional significance of each type.
  16. Integrative: explain how the dominant follicle’s rising estradiol output triggers the LH surge, and how this differs from estradiol’s effect earlier in the follicular phase.

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