The normal menstrual cycle
The ovary
- The ovarian cycle can be divided into 3 phases;
- The follicular stage
- Ovulation
- The luteal stage
- The follicular stage
Follicular stage
- Development of the oocyte beyond the pre-antral stage is stimulated by LH and FSH
- At the start of the menstrual cycle FSH begins to rise at the pituitary us released from the negative feedback effects of progesterone, oestrogen and inhibin
- Rising FSH induces steroidogenesis in a cohort of follicles
- Thecal cells are stimulated by LH to produce androgens from cholesterol
- FSH stimulated granulosa cells to convert androgens to oestrogens (aromatisation)
- FSH also stimulates proliferation of the granulosa cells
- The ideal situation for the initial stages of follicular development is high levels of FSH and low levels of LH. If LH levels are too high thecal cells wil produce large amounts of androgens with inhibit aromatisation and cause follicular atresia
- Inhibin enhances LH induced androgen synthesis and has a negative feedback on FSH levels. It is produced by granulosa cells under the influence of FSH
- The most advanced follicle at mid-follicular phase becomes the dominant follicle
Ovulation
- Late in the follicular phase, FSH induces LH receptor on granulosa cells
- Eventually oestrogen levels reach a stage where they exert a positive feedback on LH.
- There is a surge of LH around day 12
- LH induces luteinisation of the dominant follicle resulting in its production of progesterone
- The periovulatory surge in FSH is probably induced by the positive feedback effects of progesterone
- Prior to the release of the oocyte at the time of ovulation, the LH surge also resumes meiosis of the oocyte
- Proteolytic enzymes within the follicle cause follicular wall breakdown and release of the oocyte
Luteal Phase
- Characterised by the production of progesterone by the corpus luteum
- Corpus luteum is derived from granulosa cells and some thecal cells
- The production of progesterone by the corpus luteum is dependant on continued pituitary LH production
- However progesterone has a negative feedback effect on the release of gonadotrophins
- Corpus luteum regresses at the end of the luteal phase, a process called luteolysis. Occurs 14 days after ovulation
- As the corpus luteum dies, levels of oestrogen, progesterone and inhibin decline
- The pituitary is therefore released from the negative feedback effect of these hormones and levels of gonadotrophins begin to rise
The pituitary gland
- LH and FSH are released by the pituitary via stimulation by pulses of GnRH
- The response of the pituitary is modulated by ovarian hormones, oestrogen and progesterone
- Low levels of oestrogen have an inhibitory effect on LH whilst high levels have a positive feedback effect
- The mechanism of action of the positive feedback effect of oestrogen is an increase in GnRH receptor expression in the pituitary and an increase in GnRH release
- In contrast to the effects of oestrogen, low levels of progesterone have a positive feedback effect on LH and FSH levels
- High levels, such as those seen in the luteal phase inhibit gonadotrophin production
The hypothalamus
- Alterations of the amplitude and frequency of GnRH pulsations is responsible for the fine tuning of gonadotrophin production
- GnRH is suppressed in anorexia nervosa and excessive exercise, leading to anovulation
- GnRH agonists are widely used to treat endometriosis and other gynae disorders, although agonists, they are long acting and the continuous exposureof the pituitary to moderately high levels of GnRH results in down-regulation and desensitisation of the pituitary and gonadotrophin levels are reduced
- Such desensitisation of the pituitary takes 3 weeks to be achieved
The endometrium
Menstruation
- Levels of oestrogen and progesterone fall as the corpus luteum fails at the end of the luteal phase
- The initiated menstruation
- Withdrawal of progesterone results in spiral artery vasoconstriction, production of pro-inflammatory cytokines such as MCP-1 and IL-8 which attracted macrophages and neutrophils into the endometrium
- Leuokocytes and endometrial stromal cells release MMP which breakdown the extracellular matrix
- This leads to ischaemia of the upper endometrium, shedding of the functional endometrium (stratum compactum and stratum spongiosum) and bleeding from fragments of arterioles remaining in the basal endometrium
- Menstruation ceases as the damaged spiral arterioles vasoconstrict and the endometrium regenerates
- Oestrogen mediates endometrium regeneration
- Prostaglandin synthase inhibitors such as mefenamic acid are a first line treatment for menorrhagia.
- The act to increase the ratio of vasoconstrictor prostaglandin F2alpha to vasodilator prostaglandin PGE2
The proliferative/follicular phase
- Menstruation ceases one endometrial repair is completed around day 5-6 of the cycle
- Glandular and stromal growth then occurs under the influence of oestrogen
- During this time the epithelial lining of the glands changes from a single layer of columnar cells to pseudostratified epithelium with frequent mitoses
- Stromal component re-expands
- Over this period endometrial thickness increases from 0.5mm to 3.5 to 5mm
The secretory/luteal phase
- Characterised by endometrial glandular secretory activity mediated by progesterone
- Under the action of progesterone, oestrogen-induced cellular proliferation I inhibited and the depth of the endometrium remains fixed
- Glands and spiral arteries become more tortuous
- Shortly after ovulation, vacuoles appear in the glandular cells, these progress to the apex of the cells and are release in to the gland lumen
- Peak secretary activity occur at the time of implantation, 7 days after the gonadotrophin surge
- Ovulation is confirmed by serum progesterone measurements in the luteal phase
- Within the stroma oedema is induced under the influence of oestrogen and progesterone
- In the late secretory phase progesterone induces irreversible decidualisation of the stroma. This leads to endometrial apoptosis and menstruation unless pregnancy occurs
Clinical features
- Normal menstrual cycle is considered to be between 21 and 35 days long with any irregularity being less than 7 days
- Menstrual flow is normal between 2 to 7 days
- Only 15% of women have a 28 day cycle
- Length of the menstrual cycle is determined by the follicular phase
- Luteal phase is fairly fixed at 14 days
- Normal menstrual loss is around 35ml
- Above 80ml is considered excessive