Menstruation

The endometrium is under the influence of sex steroids that circulate in females of reproductive age. Sequential exposure to oestrogen and progesterone will result in cellular proliferation and differentiation, in preparation for the implantation of an embryo in the event of pregnancy, followed by regular bleeding in response to progesterone withdrawal if the corpus luteum regresses. During the ovarian follicular phase, the endometrium undergoes proliferation (the ‘proliferative phase’); during the ovarian luteal phase, it has its ‘secretory phase’. Decidualization, the formation of a specialized glandular endometrium, is an irreversible process and apoptosis occurs if there is no embryo implantation. Menstruation (day 1) is the shedding of the ‘dead’ endometrium and ceases as the endometrium regenerates (which normally happens by day 5–6 of the cycle).

The endometrium is composed of two layers, the uppermost of which is shed during menstruation. A fall in circulating levels of oestrogen and progesterone approximately 14 days after ovulation leads to loss of tissue fluid, vasoconstriction of spiral arterioles and distal ischaemia. This results in tissue breakdown, and loss of the upper layer along with bleeding from fragments of the remaining arterioles is seen as menstrual bleeding. Enhanced fibrinolysis reduces clotting.

The effects of oestrogen and progesterone on the endometrium can be reproduced artificially, for example in patients taking the combined oral contraceptive pill or hormone replacement therapy who experience a withdrawal bleed during their pill free week each month.

Vaginal bleeding will cease after 5–10 days as arterioles vasoconstrict and the endometrium begins to regenerate. Haemostasis in the uterine endometrium is different from haemostasis elsewhere in the body as it does not involve the processes of clot formation and fibrosis.

In rare cases, the tissue breakdown and vasoconstriction does not occur correctly and the endometrium may develop scarring which goes on to inhibit its function. This is known as ‘Asherman’s syndrome’. The endocrine influences in menstruation are clear. However, the paracrine mediators less so. Prostaglandin F2a, endothelin-1 and platelet activating factor (PAF) are vasoconstrictors which are produced within the endometrium and are thought likely to be involved in vessel constriction, both initiating and controlling menstruation. They may be balanced by the effect of vasodilator agents, such as prostaglandin E2, prostacyclin (PGI) and nitric oxide (NO), which are also produced by the endometrium. Recent research has shown that progesterone withdrawal increases endometrial prostaglandin (PG) synthesis and decreases PG metabolism. The COX-2 enzyme and chemokines are involved in PG synthesis and this is likely to be the target of non-steroidal anti-inflammatory agents used for the treatment of heavy and painful periods.

Endometrial repair involves both glandular and stromal regeneration and angiogenesis to reconstitute the endometrial vasculature. VEGF and fibroblast growth factor (FGF) are found within the endometrium and both are powerful angiogenic agents. Epidermal growth factor (EGF) appears to be responsible for mediation of oestrogen-induced glandular and stromal regeneration. Other growth factors, such as transforming growth factors (TGFs) and IGFs, and the interleukins may also be important.

Greater understanding of mediators of menstruation is important in the search for medications to control heavy and painful periods. Mefenamic acid is a PG synthetase inhibitor which is widely used as a treatment for heavy menstrual bleeding. It is believed to act by increasing the ratio of the vasoconstrictor PGF2a to the vasodilator PGE2. Mefenamic acid reduces menstrual loss by a mean value of 20–25 per cent in women with very heavy bleeding, and further more effective agents are still being sought.

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