Research updates
2. New methods of contraception   p 7
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5. Antigestagens - an alternative pill Link to the Medical Research Council web site
The menstrual (oestrus cycle)
The menstrual cycle is a cycle of events associated with the development and release of mature gametes. The onset of the first menstrual cycle represents the start of puberty and the cycle, which lasts about 28 days, continues until the menopause. The events of the cycle are controlled by hormones, to ensure the production of a mature gamete is synchronised with the readiness of the uterus to receive it, should it be fertilised.

Inside the ovaries are follicles, hollow balls of cells, containing a developing egg cell, or oocyte. The menstrual cycle involves the development of one of these follicles, there being three main stages:

Figure 12. The menstrual cycle.

The control of the menstrual cycle involves the interaction of four key hormones: follicle stimulating hormone (FSH) and luteinising hormone (LH), which are produced by the pituitary in response to a releasing hormone from the hypothalamus; also, oestrogen and progesterone, which are produced by the ovaries.
Main stages
  1. follicular stage, during which the follicular cells grow and divide and produce hormones, and a mature female gamete develops.
  2. ovulation, which is the release of the oocyte from the ovary
  3. luteal stage, during which the follicle cells in the ovary develop to form the corpus luteum. This structure secretes hormones which maintain the reproductive system in a condition to allow implantation and maintain pregnancy.

At the end of the luteal stage, menstruation takes place, during which the lining of the uterus is shed.

Antigestagens
As soon as antigestagens, compounds that antagonise the action of progesterone, were discovered it was clear that they would have great potential in helping to control reproduction. Chemists at Roussel-UCLAF in France synthesised the first antigestagen, mifepristone, in 1980. It was soon shown that it could be used to induce abortion. Combined with a prostaglandin, mifepristone is now licensed as a safe alternative to established surgical abortion procedures in ten European countries, including the UK, and China.
Using antigestagens as a contraceptive
Mifepristone has other potential uses, including contraception, but the ethical and political controversies surrounding its role in the ‘abortion pill’ have impeded research. It can act as a ‘true’ contraceptive by preventing ovulation. The CDN has recently been investigating whether antigestagens could be developed into an alternative to existing contraceptive pills.
'The pill'

As used by millions of women world-wide, the most popular method of contraception in the UK is the combined oral contraceptive pill. As its name implies, it is a mixture of synthetic oestrogens and progesterones which act by preventing ovulation. This type of contraception doesn’t suit everyone. A few people suffer side effects due to the additional oestrogen, such as headaches and weight gain. Although the pill has an excellent safety record, there is a very slightly increased risk of complications such as blood clots in some women.

Antifertility effects of antigestagens
Progesterone is essential for the establishment and maintenance of pregnancy. It is formed in the corpus luteum in the ovaries and later on in pregnancy in the placenta.
Progesterone acts on hormone receptors in the uterus, the corpus luteum, the pituitary gland and the hypothalamus. Antigestagens are synthetic hormones which block the progesterone receptors.

Figure 13

The mini pill

The other type of pill currently available, sometimes called the ‘mini pill’, is composed purely of synthetic progesterone. Although this does not trigger any oestrogen side effects, it does have to be taken at precisely the same time each day and often results in unpredictable and frequent bleeding.

Non oestrogen pills

Because antigestagens do not behave like oestrogen, they may be suitable for women for whom existing contraceptive pills cause problems. Antigestagens block the action of progesterone by binding to receptors throughout the body (Figure 13). Hence they can prevent conception by two routes: preventing ovulation or affecting the development of the endometrium.

Current trials

Recent trials in Edinburgh and Shanghai show that a daily dose of 2-5 mg mifepristone suppresses ovulation and menstrual bleeding. In contrast to the progesterone-only pill, there is a more acceptable pattern of bleeding thus improving patient acceptability and satisfaction. The dose is less than a hundredth of the amount required to induce abortion. Larger clinical studies are now required to confirm the safety and effectiveness of this promising new oestrogen-free method of contraception for women.

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Question 7

The results of research into the action of mifepristone in inhibiting ovulation show that there is no surge in LH, suggesting that the hypothalamus and pituitary gland are involved. Explain this observation.