Current thoughts on the safety of Hormone Replacement Therapy
John Studd, DSc, MD, FRCOG
Consultant Gynaecologist, Chelsea & Westminster Hospital, London
The history of clinical medicine is strewn with fashionable treatments supported by experts, the unscrupulous or the downright eccentric that have subsequently been discredited to become an odd footnote of medical history. The many biochemical placental function tests and the surgical ventrosuspension for all cases of infertility are examples in my specialty. We must not forget that bleeding for anaemia was fashionable for centuries. Will this be the fate of HRT for problems related to the menopause?
Over the last 20 years it has been believed that HRT had a hugely beneficial effect on post-menopausal women without being complicated by many major side-effects. There was some anxiety that there could be a very small increase in breast cancer but, as the survival was very much greater in women receiving HRT, it was easy to believe that it was not a major problem and that possibly the apparent increase was the result of over-stimulation of breast cancer with oestrogens rather than a malignancy. It was believed that oestrogens not only treated the hot flushes, insomnia, vaginal dryness and depression that occurred around the time of the menopause, but that it also prevented many heart attacks, strokes, colon cancer, Alzheimer's disease and osteoporotic fractures of the spine and the hip. There was also good evidence that women on HRT lived longer probably about 2.5 years longer hopefully in a state of less dependency, with less dementia or Alzheimer's disease.
There was always a little doubt that these optimistic observational studies were biased because physicians would tend to give oestrogens to healthy, thin, non-diabetic, non-hypertensive, non-smoking women. But the enthusiasm was such that in some countries, particularly the United States, oestrogens were given out to as many as 50% of the aged population in order to prevent strokes and dementia. It is for this reason that a huge randomised trial - the Women's Health Initiative (WHI) was set up in order to test the hypothesis that oestrogen therapy prevented these cardiovascular complications.
Almost 20,000 women were recruited from the age of 50-79 with the average age of 63 and 23% over the age of 70. Note that in the UK 96% of our patients start HRT below the age of 60. They used conjugated equine oestrogens (Premarin) which is the major oestrogen used in the USA but much less frequently used in Europe where the natural human oestradiol by tablet, patch, gel, intra-nasal spray or implant is used. The patients in the WHI study were overweight, more hypertensive with 40% receiving either statins or anti-hypertensive drugs. 7.7% had suffered a previous heart attack. Thus, they were not a healthy population and not at all comparable with the patients usually treated with HRT in this country. They were unbelievably selected for the study only if they had no symptoms.
The WHI study showed an increase in heart attacks, strokes, and breast cancer although confirming the decrease in colon cancer, hip fractures and spinal fractures. These complications were enough for many regulatory bodies to suggest that HRT was less safe, should be used in the lowest dose for the shortest possible time and only for severe vasomotor symptoms. It was claimed that oestrogens were no longer indicated for prevention of heart attacks and strokes and should not be first-line treatment for the prevention of osteoporosis.
These directives were issued in spite of protest that the WHI used the wrong population of the wrong age treated with the wrong oestrogens and come to the wrong conclusions even from their own data.
There were not enough patients in the 50-55 age group to make any comment about the effect on heart attacks. In a subsequent WHI publication, it was clear that the increase cardiovascular complications occurred in women over the age of 70 and in women who started HRT even in this population had a non-significant 11% decrease in cardiovascular events if oestrogen/progestogen therapy was started within 10 years of the menopause. One of the fundamental errors in this study is that one dose is not appropriate for all patients. They used a combination of Premarin with continuous progestogen as a non-bleeding preparation. The epidemiologists were not clinicians and were not aware that different women require different doses by different routes of different combinations of different hormones for different symptoms with different surgical status and for different ages.
Although the Premarin/Provera combination was a totally inappropriate treatment for these older women, it was not possible to determine whether the increase in complications in older women were due to the oestrogen or the progestogen component or a combination of both. Thus the oestrogen-only study was awaited with great interest particularly as it had not been stopped. On 3rd March 2003 it was discontinued with a mid-week Press conference which led to the newspapers reporting that the oestrogen-only arm of the WHI study was stopped because of an increase in strokes. The data did not support that judgement.
Once again if we look at the patients aged 50-59, we can see there was a decrease in heart attacks of 42%, a decrease in breast cancer of 28%, a decrease in colon cancer of 41%, a decrease in deaths of 27%. There was a slight non-significant increase in strokes of 8% which was 19 patients in the control group and 19 patients in the active group. This was hardly a reason to stop the study which, with a few more patients, could have shown a significant decrease in the incidence of breast cancer.
There were so many faults in the design of the WHI study that I believe it will be mostly discredited within another 2-3 years, particularly as most of the patients and most of the data from this study are inappropriate for our practice. They used a treatment we don't use on a group of patients we don't treat who had no symptoms. Their conclusions are similar to the statement that we should not perform an appendicectomy for gallbladder disease. We know that.
The evidence that oestrogens are safe and beneficial for women below the age of 60 who have appropriate symptoms remains convincing.
However, another major study which cast doubt on the safety of HRT was the Million Women's Study (MWS) from Oxford which claimed that there was a 30% increase in breast cancer in women taking unopposed oestrogens and a greater increase in women taking oestrogen plus progestogen. Once again this paper claimed that the risk starts at one year and disappears when HRT is stopped, has been severely criticised because its design and the many careless errors in the statistics and text. Of the 9364 patients in the Million Women Study with breast cancer, 2224 were excluded for unexplained reasons. The peak of breast cancer at one year after the mammography and questionnaire is certainly due to interval cancers missed at mammography with a well-recognised worst prognosis. This would have nothing to do with HRT. These cases were not excluded. There are many, many other objections to the design of this study.
The usual numerical estimate of excess breast cancer that we give patients is 12 per 1000 after 15 years of HRT. Even if this is true (and there is some evidence of a decrease in breast cancer) this risk is no greater than alcohol, being overweight, having no children, having a late first pregnancy or having a late menopause.
The following is my current advice on HRT prescribing.
- Oestrogen treatment should be used for the treatment of specific symptoms and low bone density.
- Although oestrogens appear to have no place for the secondary prevention of cardiovascular disease, they may still be indicated in early symptomatic menopausal women for protection against coronary heart disease and Alzheimer's disease.
- There is a window of opportunity in 45-60 year old symptomatic women who may show long-term cardiovascular and neurological benefits from early oestrogen therapy.
- Oestrogens commenced in older 60-79 year old women may do "early harm" before any benefit is achieved.
- The dose and route of oestrogens will depend upon the symptoms and the age of patient. Peri-menopausal and post-menopausal women with vasomotor symptoms should be given either oral or transdermal oestradiol with cyclical progestogen for endometrial protection.
- The usual duration of progestogen is 14 days but if the extra risk to the breast of progestogen is confirmed it is sensible to reduce the duration to seven days. This shortened course is also useful in women with progestogen intolerance.
- Women may wish to avoid bleeding by using low dose oestrogen and progestogen or by the use of Tibolone or they may wish to have a Mirena IUS inserted.
- Women with hormone responsive mood disorders should have a higher dose of transdermal oestrogens by patch, gel or implant. As these women are often progestogen intolerant, 7 day cycles of progestogen are permissible rather than the orthodox 14 day cycles.
- If loss of libido and loss of energy remain a problem, the addition of testosterone should be considered.
- Five year duration of HRT has been recommended but in reality women remain on HRT if they are feeling well with the relief of symptoms. It is often difficult to persuade such women to discontinue treatment even after 10 or more years.
- Women who have had an early menopause and women who have had a hysterectomy with loss of ovaries will need HRT for more than 5 years, until at least the normal age of menopause.
- After loss of ovarian androgens, following hysterectomy and bilateral oophorectomy women normally need the addition of testosterone as well as oestrogen.
- A mammogram should be performed each year and a breast examination every 6 months.