hormone replacement therapy

n. (Abbr. HRT)
The administration of estrogen and progestin to women to relieve the symptoms of menopause, prevent osteoporosis, and reduce the risk of heart disease.

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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.

(HRT)

The use of female hormones to relieve the symptoms that occur when the ovaries cease to function, either naturally (the menopause) or following surgical removal of the ovaries ('surgical menopause'). hormone replacement therapy controls such symptoms as hot flushes and vaginal dryness, and there is often an improvement in psychological wellbeing. It also has beneficial effects on bone density, preventing osteoporosis, and on plasma lipids (fats), which may decrease the incidence of coronary heart disease. hormone replacement therapy may, however, increase the incidence of endometrial cancer and possibly of breast cancer.

Replacement is usually with natural oestrogens (see estradiol; estriol; estrone) or conjugated oestrogens (a mixture of natural oestrogens obtained from the urine of pregnant mares). In women who have had a hysterectomy oestrogens alone may be given, in the form of tablets, skin patches, a gel for topical application, or a vaginal cream, ring, or tablets. For women who still have a uterus a progestogen must also be taken to protect against overgrowth of the endometrium (lining of the uterus), which is stimulated by oestrogens and may give rise to cancer. In sequential combined therapy a progestogen is added for 10–14 days at the end of each monthly (or for some preparations three-monthly) cycle. The combination of an oestrogen and a progestogen on a cyclical basis may give episodes of monthly or three-monthly bleeding. In continuous combined therapy an oestrogen and a progestogen are given every day. With this therapy, which is suitable for women who have not had a natural period for at least a year, most women stop having episodes of bleeding after an initial 2–3 month period of adjustment. Sequential and continuous combined preparations are available as tablets and/or skin patches; in sequential therapy these must be taken (or applied) in the prescribed order as the dosage of oestrogens may vary or the progestogen may be added on specific days. Progestogens may alternatively be taken in the form of capsules as an adjunct to oestrogen-only therapy. Synthetic and semisynthetic oestrogens are also used in hormone replacement therapy (see estropipate; tibolone). All hormone replacement therapy preparations are prescription only medicines.

Side effects:
include nausea, vomiting, weight gain, breast tenderness and enlargement, breakthrough bleeding, headache, dizziness, migraine, and increased blood pressure. The occurrence of migraine-type headaches for the first time, frequent severe headaches, or acute visual disturbances should be reported to a doctor immediately.

Precautions:
hormone replacement therapy should not be used by women who have cancer of the breast, uterus, or genital tract, thrombosis, or severe heart, liver, or kidney disease or by those who are pregnant or breastfeeding. It should be used with caution by women who have had thrombosis or thromboembolism, migraine, diabetes, epilepsy, porphyria, fibroids, or tetanus. If pregnancy occurs hormone replacement therapy should be stopped immediately. hormone replacement therapy may need to be discontinued before surgery.

Interactions with other drugs:
as for oestrogen, but interactions are much less likely to occur as the doses of oestrogen are relatively low.

Proprietary preparations:
see table.

Proprietary preparation	Oestrogen	Progestogen (alone or combined with an oestrogen)
Sequential combined therapy
Climagest	estradiol tablets	norethisterone tablets
Cyclo-Progynova	estradiol tablets	levonorgestrel/estradiol tablets
Elleste Duet	estradiol tablets	norethisterone tablets
Evorel Sequi	estradiol patches	norethisterone/estradiol patches
Femapak	estradiol patches	dydrogesterone tablets
Femoston	estradiol tablets	dydrogesterone/estradiol tablets
FemSeven Sequi	estradiol patches	levonorgestrel/estradiol patches
Novofem	estradiol tablets	estradiol/norethisterone tablets
Nuvelle	estradiol tablets	levonorgestrel/estradiol tablets
Premique Cycle	conjugated oestrogen tablets	medroxyprogesterone tablets
Prempak-C	conjugated oestrogen tablets	norgestrel tablets
Tridestra	estradiol tablets	medroxyprogesterone/estradiol tablets
Trisequens	estradiol/estriol tablets	norethisterone/estradiol/estriol tablets

Proprietary preparation	Oestrogen	Progestogen	Formulation
Continuous combined therapy
Angeliq	estradiol	drospirenone	tablets
Climesse	estradiol	norethisterone	tablets
Clinorette	estradiol	norethisterone	tablets
Elleste Duet Conti	estradiol	norethisterone	tablets
Evorel Conti	estradiol	norethisterone	patches
FemSeven Conti	estradiol	levonorgestrel	patches
Femoston-conti	estradiol	dydrogesterone	tablets
Indivina	estradiol	medroxyprogesterone	tablets
Kliofem	estradiol	norethisterone	tablets
Kliovance	estradiol	norethisterone	tablets
Nuvelle Continuous	estradiol	norethisterone	tablets
Premique	conjugated oestrogens	medroxyprogesterone	tablets
Oestrogen-only therapy
Bedol	estradiol		tablets
Climaval	estradiol		tablets
Elleste Solo	estradiol		tablets
Elleste Solo MX	estradiol		patches
Estraderm = skin patch	estradiol		patches
Estraderm MX	estradiol		patches
Estradiol Implants	estradiol		implants
Estradot	estradiol		patches
Estring	estradiol		vaginal ring
Evorel	estradiol		patches
Fematrix	estradiol		patches
FemSeven	estradiol		patches
Harmogen	estropipate		tablets
Hormonin	estriol/estradiol/estrone		tablets
Oestrogel	estradiol		gel
Ortho-Gynest	estriol		pessary or vaginal cream
Ovestin	estriol		vaginal cream
Premarin	conjugated oestrogens		tablets or vaginal cream
Progynova	estradiol		tablets
Progynova TS	estradiol		patches
Sandrena	estradiol		gel
Vagifem	estradiol		vaginal tablets
Zumenon	estradiol		tablets
Adjunctive progestogen therapy
Utrogestan		progesterone	capsules

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abbr. for hybrid-released translation.

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