hormone replacement therapy

hormone replacement therapy Ovarian function starts to decline from as early as the twentieth week of embryological life, with oestrogen production falling to a critical level during a period known as the ‘climateric’.

De Gardanne (1816) coined the term ‘La Menespausie’ from the Greek men (month) and pausis (cessation). The menopause is normally diagnosed when a woman has not had a period for 12 months. Aristotle (384–22 bc) recognized that menstruation normally stopped around the age of 40 years but that some women could continue with their periods until their fiftieth year. In the seventeenth century less than a third of women lived to experience the menopause. However, the increase in life expectancy in the twentieth century has meant that most women will spend a third of their adult lives in the postmenopausal years.

The menopause, now occurring on average at 51 years in developed countries, is associated not only with a cessation of menstrual periods but also a wide range of symptomatic and physiological effects. These include hot flushes, night sweats, loss of energy, urogenital atrophy, osteoporosis, and ischaemic heart disease. A number of non-hormonal remedies have been used to treat menopausal problems, with varying degrees of success. Galen (ad 129–216) advised phlebotomy so that any ‘retained poisons’ could be released; the use of purgatives and the application of leeches was popular in the sixteenth century. In 1777 John Leake recommended
‘where the patient is delicate and subject to female weakness, night sweats or an habitual purging, with flushing in the face and a hectic fever: for such; ass's milk, jellies and raw eggs, with cooling fruits. At meals she may be indulged with half a pint of old, clear London porter, or a glass of Rhenish wine.’

Brown–Sequard (1889) is credited with pioneering the concept of hormone replacement therapy (HRT). He reported the rejuvenating effects of injections of testicular extracts, and postulated that ovarian extract would have the same effect. Two years later Murray developed the first effective form of HRT when he administered oral thyroid gland to treat myxoedema. The first three clinical trials of dried or fresh ovarian tissue to treat climateric symptoms were published in 1896, and in 1912 Adler produced the changes of oestrus by injecting watery extracts of ovary into virgin animals. However, it was not until 1923 that Allen and Doisy isolated the ovarian hormone oestrogen. The first commercial preparations of HRT were based on the work of Zondek and Laquer and became available in 1926. Premarin, derived from pregnant mares' urine, was introduced in 1943 and is probably still the most widely used preparation. The publication of Feminine Forever in 1966 brought HRT to the attention of the public, with many demanding that it should be a NHS benefit. General practitioners were initially divided, with some prescribing it enthusiastically and others being completely dismissive.

The three natural oestrogens in women are oestrone (E1), 17-beta-oestradiol (E2), and estriol (E3). Free oestrogens are lipophilic and freely transverse cell membranes, exerting their metabolic effect by binding to nuclear receptors. This stimulates the production of mRNA and hence protein production. E2, the most active oestrogen, because it binds to the receptor complex for the longest time, is found mainly before the menopause, as its serum concentration falls when ovarian follicular development ceases. E1 is the main postmenopausal oestrogen and is produced by conversion of adrenal androgens in peripheral fat. Oestrogens are conjugated in the liver and excreted in the urine or bile.

HRT can be administered orally, transvaginally, as an implant, or through the skin as a percutaneous cream, gel, or patch. There is clear evidence that it is effective in reducing the vasomotor symptoms of the menopause and enhances the quality of life. Skin, hair, and mood are also improved. Atrophy of the lower urogenital tract can be treated effectively with HRT, with many women finding a vaginal cream or oestrogen-releasing ring helpful. HRT is used for prophylaxis against a number of conditions as well as for treatment. The years immediately following the menopause are associated with an increase in bone loss, and by the age of 70 a woman may have lost 10–30% of her bone mass. HRT delays this period of accelerated loss: five years of treatment can halve the risk of osteoporotic fractures. This may be particularly important in thin women who smoke, take little exercise, and have a family history of osteoporosis, as they are particularly at risk of this problem. The increased risk of cardiovascular disease after the menopause is also reduced, presumably because of the favourable effect of oestrogens on lipids and blood flow in the coronary arteries.

The main side-effect of HRT is vaginal bleeding in those women who still have a uterus. Unopposed oestrogen therapy leads to an increased risk of endometrial carcinoma (cancer of the lining of the uterus), so progestogen therapy needs to be given for at least 12 days each month, inducing a regular withdrawal bleed. However, recently the use of Tibolone, a synthetic compound which combines oestrogenic and progestogenic activity with weak androgenic properties, and other continuous preparations have helped to overcome this problem. There is also a slightly increased incidence of breast carcinoma for those women who take HRT for more than 10 years, but the beneficial effects in terms of a reduction in deaths from osteoporotic fractures and heart disease far outweigh the potential risks. HRT can therefore be given indefinitely.

Linda Cardozo

Bibliography

Wilson R. A. (1966). Feminine forever. Mayflower-Dell, London.

See also bone; menopause; osteoporosis; sex hormones.