Hormonal control of menstrual cycle

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Hormonal Control of the Menstrual Cycle

The menstrual cycle is a precisely orchestrated interplay between the hypothalamus, the anterior pituitary, and the ovaries - the hypothalamic-pituitary-ovarian (HPO) axis - with the uterine endometrium as the end-organ target. A typical cycle spans 21-35 days (average 28 days). Variability between women is almost entirely due to variability in the follicular phase; the luteal phase is nearly constant at 14 days.

The HPO Axis: Overview

The HPO axis showing KNDy neurons inhibiting GnRH, and ovarian hormones feeding back to hypothalamus and pituitary

The reproductive system is critically dependent on both negative and positive feedback loops. GnRH pulses drive pituitary gonadotropin release, while gonadal steroids and inhibins feed back to control cycle dynamics - Harrison's Principles of Internal Medicine 22E, p. 3172

The cycle is regulated through a series of negative and positive feedback loops that alter:

Pulsatile GnRH secretion from the hypothalamic arcuate nucleus
Pituitary response to GnRH (synthesis and release of LH and FSH)
Relative secretion of LH vs. FSH

Key principle: slow GnRH pulse frequencies favor FSH synthesis; high frequencies favor LH synthesis. FSH synthesis is further modulated by the activin-inhibin-follistatin system within pituitary folliculostellate cells.

Hormone Dynamics Across the Cycle

Comprehensive diagram showing FSH, LH, Inhibin B, Inhibin A, estradiol, and progesterone curves alongside follicle development stages and endometrial changes across follicular and luteal phases

Relationship between gonadotropins, follicle development, gonadal secretion, and endometrial changes during the normal menstrual cycle. - Harrison's Principles 22E, Fig. 404-8

Phase 1: Follicular Phase (Days 1-14)

Initiation - the FSH Rise

The follicular phase begins on day 1 of menstruation, but follicle recruitment is actually triggered in the late luteal phase of the prior cycle as the corpus luteum regresses. Falling progesterone, estradiol, and inhibin A remove negative feedback, allowing an approximately 20% rise in FSH. This modest FSH elevation is sufficient to recruit a cohort of secondary follicles, reflecting the marked sensitivity of resting follicles to FSH.

The Two-Cell, Two-Gonadotropin Model

Follicular steroidogenesis depends on coordinated action of both gonadotropins:

LH acts on theca cells to stimulate androgen (androstenedione, testosterone) production
FSH acts on granulosa cells to induce aromatase, converting androgens to estradiol (E2)

This is the "two-cell, two-gonadotropin" theory of estrogen biosynthesis.

Dominant Follicle Selection

As the cohort of follicles grows, they secrete rising estradiol and inhibin B. These together exert negative feedback on pituitary FSH secretion, causing FSH to fall by mid-follicular phase. The follicle destined to ovulate - the dominant follicle - has more FSH receptors and produces more estrogen than its neighbors, allowing it to survive the FSH decline while other follicles undergo atresia.

Late Follicular Phase

The exponential rise in estradiol causes two simultaneous events:

Continued negative feedback suppression of FSH (and initially LH)
At a threshold of sustained high estradiol, a switch to positive feedback at the pituitary, upregulating GnRH receptors and gonadotrope responsiveness

FSH-induced LH receptors appear on granulosa cells, and low levels of progesterone and 17-hydroxyprogesterone begin to be secreted by the preovulatory follicle.

Endometrial effect: Rising estradiol drives proliferative changes in the endometrium - growth of glands and stroma, elongation of spiral arteries, and thin watery "ferning" cervical mucus that allows sperm penetration.

Phase 2: Ovulation (Day ~14)

The sustained estradiol surge triggers the LH surge (and a smaller FSH surge), the proximate cause of ovulation. Key timing:

The LH surge precedes follicle rupture by 24-36 hours
During this window: the oocyte uncouples from granulosa cells, genes for inflammation and tissue remodeling are induced, and final oocyte maturation (completion of meiosis I) occurs

Low progesterone secreted from the peri-ovulatory follicle contributes to the timing of the surge, though it is not required to generate it. Hypothalamic GnRH secretion plays a permissive role in generating the preovulatory surge in humans (unlike rodents, where a GnRH surge also occurs).

At ovulation, cervical mucus peaks in quantity and becomes maximally watery and sperm-penetrable.

Phase 3: Luteal Phase (Days 14-28)

Corpus Luteum Formation

The ruptured follicle transforms into the corpus luteum, which secretes:

Progesterone (dominant hormone)
17-hydroxyprogesterone
Inhibin A
Estradiol (via continued aromatization of theca-derived androgens by luteinized granulosa cells)
Relaxin

Endometrial Effects

The combined action of progesterone and estrogen produces secretory transformation of the endometrium:

Glands become tortuous and glycogen-filled
Stroma becomes edematous
Spiral arteries elongate and coil further
Cervical mucus becomes thick, non-elastic, and non-ferning (hostile to sperm)
Basal body temperature rises (~0.2-0.5°C) due to progesterone's thermogenic effect on the hypothalamic temperature set point

Negative Feedback and Corpus Luteum Regression

Progesterone, estradiol, and inhibin A suppress GnRH and gonadotropin secretion, maintaining low FSH and LH throughout the luteal phase. The corpus luteum is LH-dependent and has a finite lifespan (~12-16 days). Progesterone-induced decreases in LH pulse frequency and diminished post-receptor signaling both contribute to its demise. As the corpus luteum regresses, estradiol and progesterone fall abruptly, removing support for the endometrium.

Menstruation

The progressive loss of hormonal support causes inflammation, local hypoxia and ischemia, cytokine release, and vascular changes in the endometrium, leading to shedding (menstruation). Simultaneously, the drop in inhibin A and gonadal steroids allows FSH to begin rising again, initiating the next cycle.

If Pregnancy Occurs

If fertilization and implantation take place, the embryonic trophoblast secretes hCG (human chorionic gonadotropin), which mimics LH by binding to LH receptors on luteinized granulosa cells. This rescues the corpus luteum, sustaining progesterone and estradiol production and maintaining the secretory endometrium until the placenta takes over steroidogenesis (luteal-placental shift) at approximately 8-10 weeks.

Key Feedback Summary

Hormone	Source	Feedback at Hypothalamus	Feedback at Pituitary
Estradiol (low-moderate)	Granulosa cells	Negative (via KNDy neurons)	Negative (more for FSH than LH)
Estradiol (high, sustained)	Dominant follicle	Permissive/positive	Positive - triggers LH surge
Progesterone	Corpus luteum	Negative (via KNDy/dynorphin)	Negative
Inhibin B	Early-mid follicular granulosa	-	Suppresses FSH selectively
Inhibin A	Dominant follicle, corpus luteum	-	Suppresses FSH selectively
Activin	Pituitary (autocrine)	-	Stimulates FSH synthesis

Menstrual Cycle at a Glance

Feature	Follicular Phase	Ovulation	Luteal Phase
Duration	10-14 days (variable)	Day 14	14 days (constant)
Dominant hormone	Estradiol	LH/FSH surge	Progesterone
Endometrium	Proliferative	-	Secretory
Cervical mucus	Watery, ferning, sperm-friendly	Peak	Thick, non-ferning
BBT	Normal	-	Elevated
Key gonadal event	Follicle growth, dominant selection	Ovulation	Corpus luteum function

Sources:

Harrison's Principles of Internal Medicine 22E (2025), pp. 3172-3175 - primary source for HPO axis and feedback mechanisms
Berek & Novak's Gynecology - two-cell/two-gonadotropin model, phase summary
Costanzo Physiology 7th Edition, pp. 478-480 - phase-by-phase hormone events
Medical Physiology (Boron & Boulpaep) - HPO axis driving the cycle

In flowchart

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Hormonal Control of the Menstrual Cycle - Flowchart

Here's the full flowchart of hormonal control of the menstrual cycle. It covers:

HPO Axis at the top (Hypothalamus → GnRH → Pituitary → FSH/LH)
Follicular Phase (Days 1-14): follicle recruitment, the two-cell/two-gonadotropin model, dominant follicle selection, and the negative→positive feedback switch of estradiol
Ovulation (Day 14): the LH surge triggering follicle rupture 24-36 hours later
Luteal Phase (Days 14-28): corpus luteum forming and secreting progesterone + estradiol, with negative feedback suppressing FSH/LH
Two outcome branches: menstruation (if no pregnancy) vs. hCG rescue of corpus luteum (if pregnancy occurs)

Color coding: blue = follicular, orange = ovulation, green = luteal, red dashed = negative feedback, green dashed = positive feedback.

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