John Studd, DSc, MD, FRCOG
Consultant Gynaecologist, Chelsea & Westminster Hospital, London
In spite of the certain health benefits of oestrogen therapy, there remains a great reluctance amongst women to start and continue hormone replacement therapy. Long-term treatment with oestrogens prevents many osteoporotic fractures, heart attacks (1), strokes, probably prevents much dementia and Alzheimer's disease (2) and is usually associated with improved general wellbeing. There is even evidence that users live for about 1.5 years longer and have fewer deaths from malignancies than non-users. But only 10-15% of UK women take oestrogens. There is, however, an optimistic report on British female general practitioners indicating that 50% of this highly informed group of women are still taking HRT 20 years after starting (3).
The objections to HRT are (1) the fear of breast cancer, (2) the withdrawal bleed, (3) the PMS symptoms from cyclical progestogen, (4) the belief that it is "unnatural" and (5) it has to be said that many women have more troublesome symptoms than off HRT.
Even in women who have had a hysterectomy and bilateral oophorectomy only 30 % continue oestrogen therapy for more than a year (4). This is astonishing because such women are known to be at very high risk of osteoporosis and HRT should be very straightforward, as there will be no bleeding nor symptoms of progestogen intolerance. It is important that we educate patients, gynaecologists and physicians that long-term oestrogen replacement is required in this sub-set of women. In our experience 95% 5 year compliance can be achieved by using oestradiol and testosterone implants in these patients (5).
The understanding of the effect of oestrogens on the skeleton has been hampered by the total absence of any study of the change in bone density related to plasma oestradiol levels until 1990. It is as if there has been a quarter of a century of published work on diabetes without a mention of blood sugar levels. It is known that there is a clear relationship between the incremental increase in bone density and the plasma oestradiol levels achieved by therapy. The dose, absorption and route of entry are important variables. It would appear that plasma oestradiol levels of 300 pmol/1 are necessary to ensure that there is an increase of bone density in the large majority of women. A dose of 2 mg of oestradiol valerate produces a plasma oestradiol level of 310 p.mol, and an increase in spine bone density of 6% over two years (6). Similarly the dose response from percutaneous oestradiol implants reveals that a dose of 25 mg produces plasma oestradiol levels of 350 p.mol and an increase at the hip and lumbar spine of 4% and 5% respectively. The results for the 50 mg and 75 mg pellets are 4% and 5% for the hip and 6% and 10% for the spine respectively, with oestradiol levels of 350 p.mol for the 50 mg and 518 p.mol for the 75 mg dose (7).
The woman over the age of 60 has had a bad time. There has been a mistaken view that it was not possible to increase the bone density with oestrogens and that such therapy is inappropriate in older women. Even now the vast majority of older women will receive bisphosphonates rather than oestrogens with their added benefits.
Data from oral oestrogens and also percutaneous oestrogens in older osteoporotic women show that the incremental increase in these patients is greater than in the younger postmenopausal woman. It is therefore important to realise that older women should not be denied HRT because of their age, but some means of making this acceptable by using a non-bleeding preparation or a lower dose should be attempted. Bone histomorphometric data from biopsies over a six year interval from osteoporotic women over the age of 60 (to be presented) show a large anabolic effect of oestrogens, with an increase in total bone volume, trabecular thickness, trabecular number and a decreased distance of trabecular separation (8).
The benefits of oestrogens in this age are also decreased giddiness and falls, cardiovascular protection, protection from strokes and vascular Alzheimer's dementia, as well as increased self-confidence and energy. The increase in collagen is vital to obtain greater bone strength but is also producing healthy better healing skin (9). It is important that these women are given a fair and well supervised trial of HRT as first choice therapy.
Bleeding remains a problem for the older woman. The non-bleeding regimens include continuous combined oestrogen/progestogen preparations, Tibolone and the use of the intra-uterine progestogen-releasing Mirena coil, or the progesterone Progestasert, which produce endometrial atrophy by a local effect.
Data concerning breast cancer continues to be confusing although it would appear that there may be a 20% increase in the incidence, or the pick-up, of breast cancer. This may be due to surveillance bias, and certainly all papers except one (10) show a very much reduced mortality in breast cancer as well as, strangely, even colon cancer in oestrogen users. There may be an improvement in host response in oestrogen users but there is little scientific data available on that subject.
Oestradiol is the natural oestrogen in women and, unlike the the components of Premarin, is a hormone that can easily be measured in order to assess the absorption and efficacy or response. It is available in oral form but will be converted to oestrone in the entero-hepatic circulation: This first pass effect can be avoided by using transdermal patches, transdermal gels, implants, creams, intra-vaginal cream and even by nasal aerosol.
The current challenge is to find an oestrogen or oestrogen-like hormone which protects the skeleton, cardiovascular system, the brain as well as the breast, while producing enough positive symptomatic benefits that women are happy to remain on the therapy for many years.