Postmenopausal hormone replacement therapy HRT

HRT refers to the use of oestrogen treatment in order to reverse or prevent problems due to the loss of ovarian hormone secretion after the menopause,

5 The mares are bred on 480 farms in the prairie provinces of Canada. The 80 000 foals that are produced each year have a less medicinal future than their mothers' urine: they are weaned at 120 days and sold for meat.

whether physiological or induced. The tissues sensitive to oestrogen include brain, bone, skin, cardiovascular and genitourinary. Consequently the two aims of HRT are:

• To reduce the everyday symptoms of oestrogen loss: hot flushes, sleeplessness, lethargy and depression, vaginal dryness

• To prevent the long-term complications associated with oestrogen deficiency: osteoporotic fractures (see Chapter 38) and coronary heart disease

Only the first is a proven indication for HRT. In addition, HRT must avoid causing disorders due to oestrogen excess, especially endometrial and breast cancer.

All types of HRT (oestrogen with or without progestogen) are effective in reducing the hot flushes experienced by more than 50% of postmenopausal women. The benefit is most during the first year of treatment when 80% of women report a reduced likelihood of flushes, and becomes less as the frequency of flushing diminishes, even in the placebo treated groups in trials. The other major value from HRT is the relief of vaginal dryness. Vaginal administration is the most effective route for treatment of dyspareunia and related symptoms.

Because most women do not suffer the long-term complications of oestrogen loss during the 5-10 years that HRT might be taken, it has been much more difficult to evaluate the second objective of HRT, i.e. reduction in coronary heart disease. For many years, the value of HRT seemed to be supported by the epidemiological data, which compared the incidence of fractures or coronary events in women taking, or not taking, HRT. These data suffered from the major flaws that most of the women were receiving 'unopposed' oestrogens (no progestogen), and that it was difficult to rule out the confounding effect of self-selection for HRT. In other words, taking HRT in such studies was simply a marker for women who took more care over their health. Concerns about the undesirable effects of progestogens, and the thrombotic effects of oestrogen, necessitate prospective randomized controlled trials to resolve questions about long-term benefits. The first of these, and a preliminary report from a second, are not favourable.

In the Heart and Estrogen/progestin Replace ment Study (HERS)6 daily therapy with conjugated oestrogen and progestin did not reduce the incidence of coronary events during four years of follow-up. The trial was too small to be informative about hip fractures but there was no difference in overall fracture rate between the groups. More recently, the Women's Health initiative primary prevention study in 27 000 (following a preliminary report) women has issued a warning letter that women on HRT are at increased risk of cardiovascular events during the first two years. A trial of unopposed oestrogen in 664 postmenopausal women with previous strokes has also found no benefit, and indeed a 2-fold greater risk of fatal strokes during 3 years of follow-up.7 These trials do not yet exclude a long-term benefit of HRT as might be expected from the beneficial effects of oestrogen on LDL, HDL and vascular tone; the effects may be outweighed in trials of secondary prevention by the increased risk of clotting. Advice for the present is not to initiate HRT solely on grounds of preventing coronary disease, stroke or fractures. On the other hand, HRT should not be withdrawn from patients who need symptomatic treatment.

Other unproven benefits of long-term treatment are reduced risk of senile dementia and prevention of colon cancer.

Preparations used for HRT. There are three types of regimen:

6 Hulley et al 1998 JAMA 280: 605-613. 2763 women with coronary disease were randomised to placebo or conjugated equine oestrogens plus medroxyprogesterone acetate. After 4 years 172 women in the hormone group and 176 women in the placebo group had a myocardial infarction or CHD death. There were significantly more events in the hormone group in the first year, but fewer in years 4 and 5. There were significantly more thromboembolic events in the hormone group (34) than controls (12). There was no difference in fracture incidence (130 vs 138), but the study was not powered to examine hip fractures, the commonest site of osteoporosis. The number of hip fractures overall (23) means that a substantial benefit of treatment could have been missed.

7 Viscoli et al 2001 New England Journal of Medicine 345: 1243-1249. Women received estradiol 1 mg or placebo. There were 99 strokes or deaths in the estradiol group vs 93 in controls. Twelve of the strokes in the estradiol group were fatal compared to four in controls.

1. Women without a uterus take continuous oestrogen alone.

2. Other women require oestrogen combined with progestogen to prevent endometrial proliferation.

a. In the commonest, 'sequential' regimen, women take oestrogen without break, and add a progestogen from approximately the 14th to 28th day of each cycle (different preparations vary in the exact length of progestogen prescribing). The first course is started on the 1st day of mentruation (if present), and 28-day cycles of treatment follow thereafter without interval.

b. In the 'continuous' regimen, appropriate only for women who have been amenorrhoeic for more than one year, fixed dose combinations of oestrogen and progestogen are taken without a break. Continuous combination HRT regimens will eventually induce amenorrhoea in most women, thereby eliminating one of the major deterrents to HRT use, withdrawal bleeding.

Special calendar packs of the various regimens are available. The oral preparations, Prempak C and Femoston, use, respectively, conjugated oestrogen and oestradiol as their oestrogen. Progestogens are used mainly by mouth and include dihydrogesterone, medroxyprogesterone, norgestrel and norethisterone. Individual progestogens can be given orally in combination with an oestrogen given by subcutaneous depot injection or by transdermal patch. One patch (Estracombi) provides both hormones but obviously the doses cannot be separately titrated to provide the minimum necessary to prevent both flushing and (if undesired) withdrawal bleeding.

A popular alternative to oestrogen therapy is the drug tibolone (Livial), which is a synthetic steroid with weak oestrogenic, progestogenic and androgenic properties. It is administered as a daily oral dose of 2.5 mg to suppress vasomotor symptoms and to prevent postmenopausal osteoporosis. The main adverse effect is vaginal bleeding, which needs investigation if persistent. Vasomotor menopausal symptoms may occasionally be helped by low doses of clonidine (Dixarit).

Contraception. HRT in routine use does not provide contraception and any potentially fertile woman who needs to use HRT should take appropriate precautions. A woman is considered potentially fertile for 2 years after her last menstrual period if she is under 50 years, and for 1 year if she is over 50 years. A woman who is under 50 years and free of all risk factors for venous and arterial disease can use a low-oestrogen combined oral contraceptive pill to provide both relief of menopausal symptoms and contraception; it is recommended that the oral contraceptive be stopped at 50 years of age since there are more suitable alternatives.

Adverse effects of HRT

The commonest reasons for withdrawal are irregular or withdrawal bleeding and breast pain. Concerns about musculoseletal symptoms and weight gain were not substantiated in the long-term trials.

The more serious complications are venous thromboembolism and cancer of the endometrium or breast. These risks are small in absolute terms, particularly so for the risks of cancer during the first 5 years of treatment.

For venous thromboembolism, the excess risk is 4/1000 woman years, which may be considered clinically insignificant except in women with predisposing factors, e.g. previous personal or family history of thromboembolism, or recent surgery.

Carcinoma of the endometrium is associated only with unopposed oestrogens, which increase risk by 2-fold during 5 years rising to 7-fold with longer treatment. Because endometrial cancer is uncommon, the absolute risk is about one-tenth that of thromboembolic disease; the risk reduces over 5-10 years after stopping treatment.

Carcinoma of the breast can occur with any type of HRT. Some 45 in every 1000 women aged 50 years will have breast cancer over the next 20 years, rising by only 2,6 and 12 cases, respectively, for women who take HRT for 5, 10 or 15 years. A family history of breast cancer does not increase the risks from HRT.

The risk of gallstones may be increased up to 2fold. HRT does not increase risk of ovarian cancer.

Blood lipids: the effect of oestrogens is on balance favourable, but the addition of a progestogen (unless gestodene or desogestrel) reverses the balance.

Contraindications to oestrogen therapy include women who may have an oestrogen-dependent neoplasm, e.g. breast cancer, who may be pregnant, or have a disposition to thromboembolism. Hypertension, liver disease or gallstones, migraine, diabetes, uterine fibroids or endometriosis may all be made worse by oestrogen. These are not necessarily absolute contraindications, and HRT should not for instance be denied to a poly-symptomatic woman with mild hypertension. If necessary, it may be permissible to treat both the hypertension and the postmenopausal symptoms with separate drugs.


Contraception: see p. 721.

Menstrual disorders: see p. 729.

Vaginitis. Senile vaginitis usually responds to daily use of an oestrogen pessary or cream (which can also be used in small girls with vaginitis). Absorption can occur sufficiently to cause systemic effects in both the subject and her male sexual partner.

Inhibition of lactation. Oestrogens are no longer recommended because of associated risk of thromboembolism.

Androgen-dependent carcinoma. Diethylstilbestrol (stilboestrol) is rarely used to treat prostate cancer because of its adverse effects. It is occasionally used in postmenopausal women with breast cancer. Toxicity is common.

To reduce sexual urge in men whose activities are qualitatively or quantitatively unacceptable to the community and/or to themselves is an occasional indication for oestrogens: 1 mg of stilboestrol daily should be enough (see also Antiandrogen (cyproterone) and benperidol).

Epistaxis: as a last resort in recurrent cases, e.g. telangiectasia.

Atrophic rhinitis may benefit, as also may acne.



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