Menstruation and Amenorrhoea

Days 1 to 8

At the start of the cycle, levels of FSH and LH rise in response to the fall of estradiol and progesterone at menstruation. This stimulates development of 10 to 20 follicles. The follicle that is most sensitive to FSH is the ‘dominant’ follicle and is the one destined to reach full maturation and ovulation. This dominant follicle appears during the mid-follicular phase, while the remainder undergo atresia. With growth of the dominant follicle, estradiol levels increase.

Days 9 to 14

As the follicle increases in size, localized accumulations of fluid appear among the granulosa cells that surround the oocyte and become confluent, giving rise to a fluid-filled central cavity called the ‘antrum’ ( Fig. 4.2 ). This transforms the dominant follicle into a Graafian follicle, in which the oocyte occupies an eccentric position, surrounded by two to three layers of granulosa cells termed the ‘cumulus oophorus’.

Associated with follicular maturation, there is a progressive increase in the production of estrogen (mainly estradiol) by the granulosa cells of the developing follicle. As the estradiol level rises, the release of both gonadotrophins is suppressed (negative feedback), which serves to prevent the maturation of multiple follicles simultaneously.

The granulosa cells also produce anti-Müllerian hormone (AMH) which regulates folliculogenesis by restricting of the number of follicles undergoing maturation in order to select the dominant follicle. AMH production is highest in small pre-antral and antral follicles. Thus, AMH levels are sometimes used as a marker of ovarian reserve (egg supply), since levels decline as the woman approaches menopause. Women with many small follicles, such as those with polycystic ovary syndrome (PCOS), have high AMH levels.

Day 14

Ovulation is associated with rapid enlargement of the follicle, followed by protrusion from the surface of the ovarian cortex and rupture of the follicle, with extrusion of the oocyte and adherent cumulus oophorus ( Fig. 4.3 ). Some women can identify the time of ovulation because they experience a short-lived pain in one or other iliac fossa. Ultrasound studies have shown that this mid-cycle pain—known as ‘mittelschmerz’ (German for ‘middle pain’)—actually occurs just before follicular rupture.

The final rise in estradiol concentration is thought to be responsible for the subsequent mid-cycle surge of LH and, to a lesser extent, of FSH—positive feedback. Immediately before ovulation, there is a precipitous fall in estradiol levels and an increase in progesterone production. Ovulation follows within 18 hours of the mid-cycle surge of LH.

Days 15 to 28

The remainder of the Graafian follicle, which is retained in the ovary, is penetrated by capillaries and fibroblasts from the theca, which are the cells that surround the follicles. The granulosa cells undergo luteinization; these structures collectively form the corpus luteum ( Fig. 4.4 ). This is the major source of the sex steroid hormones estradiol and progesterone, which are secreted by the ovary in the post-ovulatory phase.

Establishment of the corpus luteum results in a marked increase in progesterone secretion and a second rise in estradiol levels. Progesterone levels peak 1 week after ovulation (day 21 of the 28-day cycle). Tests of serum progesterone at this time may be used in fertility investigations to confirm the development of a corpus luteum, implying that ovulation has occurred.

During the luteal phase, gonadotrophin levels reach a nadir and remain low until the regression of the corpus luteum, which occurs at days 26 to 28. If conception and implantation occur, the corpus luteum does not regress because it is maintained by human chorionic gonadotrophin (hCG) secreted by the trophoblast. The detection of the presence of hCG in a sample of urine or blood forms the basis of pregnancy testing. If conception and implantation have not occurred, which is the case for the majority of menstrual cycles, the corpus luteum regresses. Then, progesterone levels fall and menstruation is triggered. The consequent fall in the levels of sex hormones allows the FSH and LH levels to rise and initiate the next cycle.