Menstrual Cycle Physiology — Hormonal Phases, LH Surge and Endometrial Changes

The menstrual cycle is the body's regular, cyclic preparation for ovulation and a possible pregnancy. It is really two cycles running in parallel: one in the ovary (follicular phase, ovulation, luteal phase) and one in the endometrium (menstrual, proliferative and secretory phases). The follicular phase of the ovary lines up with the menstrual and proliferative phases of the uterus; the luteal phase lines up with the secretory phase.

Day 1 is the first day of heavy menstrual flow. The FIGO parameters for a normal cycle are summarised below. Menarche has a median age of about 12.4 years and menstrual cycles cease at menopause, at an average age of about 51 years.

From puberty, the hypothalamus secretes GnRH in pulses. GnRH is carried to the anterior pituitary, binds its G-protein-coupled receptor and triggers release of FSH and LH. These act on the two cell types of the ovarian follicle — theca cells and granulosa cells — to make the sex steroids that act back on the uterus and pituitary.

• GnRH pulse frequency matters: slow pulses favour FSH secretion; fast pulses favour LH secretion.
• Negative feedback (most of the cycle): oestradiol, progesterone and inhibin B reduce FSH and LH secretion.
• Positive feedback (just before ovulation): once oestradiol reaches a critical level and stays there, it stimulates a surge of LH and a smaller rise in FSH.
• Inhibin B inhibits and activin stimulates FSH release from the anterior pituitary.

The follicular phase always begins on day 1 and ends with ovulation; in a 28-day cycle it covers days 1 to 14. Its length is the variable part of the cycle. FSH recruits a cohort of follicles; around cycle day 7 several 9–10 mm antral follicles can be seen in each ovary. Rising oestradiol and inhibin B then suppress FSH, so the non-dominant follicles degenerate (atresia).

The dominant follicle survives because FSH also induces more FSH receptors in it, so it becomes more sensitive to FSH even as FSH falls. It grows about 2 mm per day to reach 18–29 mm (average about 23.6 mm) and FSH induces LH receptors in it, preparing it for ovulation.

In the uterus the proliferative phase runs in parallel. Oestradiol from the growing follicles drives growth of the endometrial stroma and glands from the basal layer and lengthens the spiral arteries. By ovulation the endometrium reaches its maximum thickness, typically 8–12 mm. Oestradiol also changes the cervical mucus, creating channels that help sperm enter.

Ovulation usually occurs about 14 days before the next menses, so on day 14 only in a 28-day cycle. Through the follicular phase oestradiol rises. When it reaches a critical concentration and stays there (about 2 days), its action on the hypothalamic-pituitary unit flips from negative to positive feedback. The pituitary gonadotrophs make more GnRH receptors and become more sensitive to GnRH, and a nonsteroidal ovarian factor (GnSAF) that restrains this sensitising effect falls away.

The result is the LH surge: LH rises about 10-fold, with a smaller rise in FSH. LH raises intrafollicular proteolytic enzymes, weakening the follicle wall, and the follicle releases the oocyte. Ovulation occurs roughly 36 to 44 hours after the onset of the LH surge. The same surge luteinises granulosa and theca cells, so the follicle converts to the corpus luteum and progesterone replaces oestradiol as the main steroid.

• At ovulation the oocyte has begun meiosis II and is arrested in metaphase II; it completes meiosis only if fertilised.
• Primordial follicles hold primary oocytes arrested in prophase I from fetal life until they are recruited.
• If more than one follicle ovulates, non-identical (fraternal) multiple gestation can result.
• Cervical mucus becomes increased and watery around ovulation, favouring sperm entry.

After ovulation, LH and FSH convert what remains of the follicle into the corpus luteum, which secretes progesterone (and some oestrogen). Unlike the follicular phase, the luteal phase is relatively constant at about 14 days within a woman. Progesterone drives the secretory phase of the endometrium.

• Endometrial glands become complex and secretory; glycogen accumulates as an energy store.
• The surface area of the spiral arteries increases.
• Cervical mucus becomes thick and less elastic, making sperm passage harder.
• Basal body temperature rises slightly.
• Rising progesterone gives negative feedback on LH release.

If an ovum is fertilised and implants, the trophoblast releases hCG, which stimulates the corpus luteum to keep making progesterone (the 'rescue' of the corpus luteum). If not, the progesterone and oestradiol levels fall rapidly at the end of the luteal phase, and GnRH is released from feedback inhibition so FSH rises again for the next cycle.

Menses is a hormone-withdrawal bleed. The abrupt fall of progesterone and oestradiol at the end of the luteal phase removes the support that sustained the thick secretory endometrium, which then sheds. The first day of bleeding becomes day 1 of the next cycle, so menstruation sits in the early follicular phase.

• Normal menses lasts 8 days or less.
• Menstrual fluid contains blood, endometrial cells, vaginal secretions and biochemical molecules including proteolytic enzymes, cytokines and fibrinolysis products.
• Menstrual fluid typically does not contain clots unless flow is very heavy.

If the LH surge fails, ovulation does not occur, no corpus luteum forms and progesterone is not secreted in significant amounts. The endometrium never matures and there is no synchronised progesterone withdrawal. Oestrogen keeps stimulating growth, the proliferative endometrium thickens until it breaks down, and bleeding comes at irregular intervals with flow from scant to heavy.

Anovulatory cycles are common in the first 12 to 18 months after menarche and again before menopause, and are frequently linked to endocrine and metabolic disorders of the HPO axis such as polycystic ovary syndrome, thyroid disease and hyperprolactinaemia.

• Trigger of ovulation — the LH surge, produced by oestradiol positive feedback; timing 36–44 h after surge onset.
• Which phase is constant — the luteal phase (about 14 days); the follicular phase varies.
• Hormone-to-phase matching — proliferative = oestrogen; secretory = progesterone; menses = hormone withdrawal.
• Cell-to-hormone matching — theca cells and LH (androgens); granulosa cells and FSH (aromatase, oestradiol).
• Meiotic arrest — prophase I until recruitment; metaphase II at ovulation.
• Graph interpretation — identify the curve (LH spike, progesterone only after ovulation, oestradiol double peak) and the day.
• Anovulatory bleeding — unopposed oestrogen, no secretory change, PCOS, adolescents and perimenopause.