Hormone replacement therapy—estrogens + progestogens

Benefit to harm balance

Despite decades of accumulated observational evidence, the balance of benefits and harms for hormone use in healthy postmenopausal women is uncertain [ ]. For example, while estrogens prevent peripheral bone loss they do not prevent vertebral fractures [ ] and in a 2-year placebo-controlled, crossover study in 34 healthy postmenopausal women, treatment with transdermal estrogen alone (Menorest 50 micrograms/day) did not improve lipid profiles or any indices of arterial function [ ].

The view was often defended by earlier workers that, at least for certain classes of users, some form of combined estrogen + progestogen treatment is likely to be more appropriate and perhaps more physiological than estrogen replacement alone. Many variants have been used and none is likely to be ideal for all subjects. Some have argued that in the climacteric there are sound reasons for using estrogen with intermittent progestogen and that it is much underused, despite the fact that uterine bleeding and other adverse progestogenic effects are, with some combined formulations (but not all), major reasons for patient non-compliance and early withdrawal [ ].

Quite apart from the constantly changing spectrum of the available data, one explanation for the confusion is the relatively high proportion of poor-quality clinical work, particularly studies that are designed to promote particular commercialized forms of treatment from among the many alternatives available. A study that cannot be faulted on that score is the Women’s Health Initiative, a randomized, controlled, primary prevention trial (planned to last for 8.5 years), in which 16 608 postmenopausal women aged 50–79 years with an intact uterus at baseline were recruited at 40 US clinical centers over the period 1993–98 [ ]. In one part of this study, 8506 participants received conjugated equine estrogens 0.625 mg/day plus medroxyprogesterone acetate 2.5 mg/day; 8102 were given placebo. The primary desired outcome was reduction of coronary heart disease (non-fatal myocardial infarction and death), with invasive breast cancer as the primary anticipated adverse outcome. After a mean of 5.2 years, the data and safety monitoring board recommended stopping the trial of estrogen plus progestogen versus placebo because the test statistic for invasive breast cancer exceeded the stopping boundary for this adverse reaction and the global index statistic supported harms exceeding benefits. The estimated hazard ratios (and 95% confidence intervals) were:

• coronary disease 1.29 (1.02, 1.63; n = 286);

• breast cancer 1.26 (1.00, 1.59; n = 290);

• stroke 1.41 (1.07, 1.85; n = 212);

• pulmonary embolism 2.13 (1.39, 3.25; n = 101);

• colorectal cancer 0.63 (0.43, 0.92; n = 112);

• endometrial cancer 0.83 (0.47, 1.47; n = 47);

• hip fracture 0.66 (0.45, 0.98; n = 106);

• death due to other causes 0.92 (0.74, 1.14; n = 331).

What the above amounts to is that the absolute excess risks per 10 000 woman-years attributable to the use of an estrogen plus a progestogen were seven more coronary heart disease events, eight more strokes, eight more pulmonary embolisms, and eight more invasive breast cancers, while the risk reductions per 10 000 woman-years were six fewer colorectal cancers and five fewer hip fractures. The absolute excess risk of events included in the global index was 19 per 10 000 woman-years. The overall harms in this study thus clearly exceeded the benefits. All-cause mortality was not affected.

Other published studies, many of which are of limited scope, have not run closely parallel to the above findings from the Women’s Health Initiative, and the data on cardiovascular effects remain particularly confusing. Although Beral and colleagues pointed out optimistically that “substantial new data should soon be available from randomized trials of estrogen-alone hormonal replacement therapy versus placebo”, they added that “few additional trial data on combined hormone replacement therapy are expected for about a decade” [ ]. They also pointed out that existing randomized trials are too small to provide reliable evidence on some basic matters, including the relative risks of the various compounds in use.

Observational studies

In 104 women with established postmenopausal osteoporosis, continuous estrogen + progestogen therapy resulted in increases in bone mineral density of the femoral neck and a fall in systolic blood pressure; the most common adverse reactions were mastalgia (44%) and vaginal bleeding (29%) [ ].

The combined use of estradiol and dydrogesterone reduce both diastolic and systolic blood pressures in postmenopausal women in whom the diastolic pressure had been raised [ ]. Evidence is also advanced from various quarters that adding a progestogen to adequate dosages of an estrogen promotes new bone formation, restores bone that has been lost and reduces the risk of carcinoma of the breast.

When 16 diabetic and hypertensive postmenopausal women aged 47–57 years were treated cyclically with estradiol plus norgestrel, existing proteinuria and even creatinine clearance often improved [ ]. The effects were unrelated to conventional risk factors for vascular complications, such as raised blood pressure, plasma glucose, or serum cholesterol.

General adverse effects and adverse reactions

Of 206 postmenopausal women who took the oral combination of estradiol valerate plus norethisterone, eight withdrew because of bleeding during year 1 [ ]. During years 2 and 3 there were no withdrawals because of bleeding and 133 patients had completed the study by the end of year 3. There were serious adverse reactions in 24, but there was no definite relation to therapy. The numbers of adverse events reported each year by the patients who completed the study are shown in Table 1 . The authors concluded that this combination was effective in the majority of patients and was well tolerated.

Distinguishing adverse reactions due to estrogens or progestogens

When patients have adverse reactions during combined hormone replacement therapy it is necessary to determine whether the progestogen or the estrogen is causing the problem. If heavy bleeding or breast tenderness is the primary complaint, the estrogen component is probably the problem and therefore the dose should be reduced. If the patient complains of irritability, depression, water retention, or headaches, the problems are probably due to the progestogen component and the latter should in that case be changed or the dose adjusted; since several different progestogens are in use (particularly norethindrone, norethindrone acetate, medroxyprogesterone acetate, and micronized progesterone) there is a degree of choice.