HRT

John Studd
Professor of Gynaecology, Chelsea & Westminster Hospital, London

Until recently it was believed that HRT was an extremely safe treatment for vasomotor symptoms, osteoporosis, depression and a major preventative measure for heart disease, colon cancer, Alzheimer's disease and probably strokes. This has all been turned upside down by two greatly flawed studies, The Women's Health Initiative, (WHI) and the Million Women Study (MWS). These will be discussed.

There is no evidence that oestradiol given in the appropriate dose in women below the age of 60 is associated with serious side effects although the addition of continuous progestogen may be the harmful factor in the causation of cardiovascular disease.

The WHI study studied a single preparation, Prempro (not available in this country), in the belief that one dose fits all patients. This is untrue because different women require different dose via a different route with different combinations of different hormones for different symptoms for different symptoms with different surgical status and for different ages. There was an added fault in that patients were recruited who were without symptoms - hence none of them needed this inappropriate therapy anyway.

This paper describes the different therapies required in women after hysterectomy and bilateral salpingo-oophorectomy, for premature menopause, for the perimenopausal patients with depression or libido problems, for women in the early post menopausal state and for older women in the late menopausal state.

Women with vasomotor symptoms or pelvic atrophy are easily treated with low dose oestradiol either by the oral route or by transdermal gel or patch. The treatment can last for the duration of the symptoms and there is no reason to limit therapy to 5 or 10 years. In patients with a uterus they will require endometrial protection with a progestogen which can be for the orthodox 14 days or continuously or, with patients with progestogen intolerance for 7 days each month.

Young women with premature ovarian failure need oestrogen therapy to protect their bones and their cardiovascular system as well as prevent symptoms until at least the age of 50 - the time of the normal menopause. If there is a suggested limit for the duration of HRT then the counting starts from the age of 50, the age of the normal menopause. It is important to check the bone density of these patients before treatment and every 3 years.

After hysterectomy and bilateral salpingo-oophorectomy, women need oestrogens, sometimes in the higher dose than for more mild symptoms. If they have lost their ovarian androgens, they benefit from the addition of testosterone. These women often suffer symptoms of the female androgen deficiency syndrome, (FADS) which is loss of energy, loss of libido and loss of self confidence, depression and headache. The ideal way to treat these patients is by implantation of oestradiol 25 mgs and testosterone 75 mgs every 6 months.

Patients with perimenopausal depression which is often linked with cyclical premenstrual depression are better treated with transdermal oestrogens in the form of oestradiol patches 100 mcgs or even 200 mcgs. This not only wipes out the cycles producing the cyclical symptoms of PMS but has a mental tonic effect for the perimenopausal women. These women of course require cyclical progestogen tablets but as these women with hormone responsive depression, (perhaps better called reproductive depression) are progestogen intolerant, a Mirena IUS should be considered.

Osteoporosis can usually be prevented by oestradiol therapy and the bone density can be increased in established osteoporosis by the use of oestrogens which produce plasma oestradiol levels of at least 300 pmol/L. This is a most effective therapy, more effective than bisphosphonates or SERMS but of course will not correct any deformity that may have occurred in established osteoporosis.

Many patients have loss of energy and loss of libido and these respond well to a higher dose of oestradiol with or without testosterone. Patients should have a clear explanation of the advantages and the putative dangers of HRT and their need for HRT assessed every year. The lowest effective dose should be used for the appropriate symptom or indication remembering that a higher dose is required for depression or correction of osteoporosis than for vasomotor symptoms.

Older post menopausal women who need oestrogens for pelvic atrophy or established osteopenia or osteoporosis should initially have a very low dose possibly with unopposed oestrogens because the major side effects of the WHI study occur in older women receiving combined oestrogen and progestogen therapy.

The strange syndrome of chronic fatigue syndrome/PMS is associated with low plasma oestradiol levels, low bone density and an excellent response to transdermal oestrogens with or without testosterone. This infrequently recognised condition needs further study.

There may be an increased risk of breast cancer after 5 or 10 years but these data are disputed and on a practical level it is very difficult to persuade women who feel well on HRT to discontinue. Until this issue is clarified, I believe patients should be advised to have a mammogram every 18 months.

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John Studd
Professor of Gynaecology, Chelsea & Westminster Hospital, London

Over the years clinical medicine has a record of fashionable treatments supported by the experts, the unscrupulous or the eccentric that are subsequently discredited to become an odd footnote of medical history. The many biochemical placental functional tests and ventrosuspension for all causes of infertility are examples in our specialty. Bleeding for anaemia was with us for centuries. Will this be the fate of HRT for problems related to the menopause?

Oestrogens are no longer regarded by regulatory authorities as safe treatment for anything but severe vasomotor symptoms in the lowest dose for a short duration and many primary care practices have stopped such prescribing altogether for understandable medico-legal reasons. This has occurred as a response to the reports from two well publicised and badly flawed studies, The Women's Health Initiative (WHI) ⁽¹⁾ and the Million Women Study (MWS) ⁽²⁾ where a mid week press conference was used to achieve maximum front page coverage of data before the scientific community had an opportunity to examine the studies.

After 30 years of sound epidemiological and laboratory research the value of estrogens for the treatment of climacteric symptoms, peri menopausal depression, urogenital atrophy, loss of libido and osteoporosis was accepted. Perhaps there was also prevention and treatment of coronary heart disease (CHD) vascular dementia, strokes and Alzheimer's disease (AD) These were mostly case control studies with their inherent selection bias towards good outcome. A primary prevention trial was needed.

It was acknowledged that there was probably a small increase in breast cancer but as the mortality rate was less than in untreated women it was possible that the apparent risk was an artefact of precise pathological diagnosis between ductal in situ and invasive cancer as the tissues had not been examined by a second independent reviewer although there had been many requests for this. A review of the cases of endometrial carcinoma in HRT users from Sweden resulted in a down-grading of 40% of the cancers to atypical hyperplasia ⁽³⁾. Perhaps the 1.2% increase in breast cancer over 15 years ⁽⁴⁾ could be explained in this way.

This optimism was first challenged by the HERS placebo controlled study which failed to detect any improvement in CHD in this secondary prevention study of women with established CHD with a mean age of 66.3. In spite of an increase in HDL and a decrease in LDL cholesterol there was a non-significant increase in coronary events at one year and a non significant reduction at four years ⁽⁵⁾. The concept of early harm and late benefit of HRT in this age group was suggested.

The several WHI reports published in tandem with hostile editorials ^(6)(7)(8) - was a study of a treatment that we rarely use on a population of women that we do not treat. The investigators used the wrong treatment on the wrong women and came to the wrong conclusions even for their own study group. They selectively recruited 8,506 asymptomatic women for the study of Premarin 0.625 plus 2.5mg MPA and reported that there was no improvement in quality of life scores in these women without climacteric complaints ⁽⁹⁾. If there were no symptoms it is not surprising that treatment fails to show any improvement. The investigators did not appreciate the need of a different dose of a different estrogen, by a different route with a different combination of type, dose, duration and route of gestogen administration depending on the indication symptoms and side effects of therapy ⁽¹⁰⁾. Regrettably one dose does not fit all. It was a study of staggering clinical incompetence.

The women in the study were inappropriate because they were aged 50-79 with an average age of 63 with 23% being over 70 years of age. They were not women suitable for a primary prevention study as 40% were either on statins or anti hypertensives, they were overweight and 7.7% had suffered a previous coronary thrombosis. The reported results were devastating and although further analysis of the data was more than reassuring the front pages reports ensured that it remained in the public memory.

The trial was stopped after 5.2 years because of unacceptable side-effects. These were a 29% increase in CHD, a 41% increase in strokes and a 26% increase in breast cancer and a 100% increase in VTE. The study did confirm a decrease of hip fracture, vertebral fracture and colonic cancer of 34% no doubt because the age was appropriate for study of these conditions. The age of the patient, overlooked by all leader writers is the critical factor. A subsequent WHI report revealed that the cardiovascular events were significantly increased only in women who started HRT more than 20 years after their menopause and that there was a non-significant reduction RR 0.89 in these complications in women who start therapy within 10 years of their menopause ⁽¹¹⁾.

As it was not possible to deduce whether the complications were due to Premarin, MPA or a combination of both, the results of the oestrogen-only arm were eagerly awaited particularly as the study had not yet been discontinued. It was stopped after 7 years ⁽¹²⁾ and with the now familiar editorial and media manipulation we learn that there was an increase in strokes with no increase in heart attacks or breast cancer. This summary is false.

As virtually all women, (97% in my practice) start HRT before the age of 60, the younger cohort supplied in table form in the paper but not referred to in the abstract is of particular interest. These women show a significant decrease in heart attacks, a decrease in breast cancer, a decrease in colorectal cancer and mortality and no increase in strokes. This is quite a different outcome but the editorial still stressed the dangers of HRT ⁽¹²⁾.

WHI ESTROGEN-ONLY ARM (2004)

In spite of the proscription from many regulatory bodies there is virtually no evidence of increased cardio vascular risk in women who start HRT before the age of 60 .The evidence still suggests protection and although this has never been a common indication it does mean that many have changed their practise or their treatment based on a false message

Carelessness is the basis of the criticism of the MWS. How can a case-controlled study with its well recognised biases be taken so seriously when it also contains so many errors in presentation of the facts, including a table of the risks of ethinyloestradiol - a hormone never used in HRT - even using one tenth of the incorrect dose referred to in the paper? This would have picked by any clinician, but escaped the attention of the numerous co-authors, reviewers and editors, and brings into question the validity of all of the results as well as the basic clinical knowledge of the investigators ^{(13) (14)}.

Other specific objections include the use of a single questionnaire without any means of knowing any future change or discontinuation of HRT. Thus we cannot determine the duration of therapy. Having found 9364 breast cancers why are 2224 excluded from further study? If the cases, however, are to be excluded why not those which occurred in the first year as these were interval cancers missed at mammography with a worse prognosis and probably unrelated to treatment? How else do we explain the biologically unlikely 1.2 years average duration to diagnosis or the 1.7 years from duration to death when the mean survival or metastatic disease from diagnosis is 3 years? ⁽¹⁵⁾ It is suggested that the risk occurs soon after starting therapy and disappears on cessation. The excess of breast cancer in the WHI study began at 4 years but the MWS did not have the duration data to make such a deduction.

Similarly in a MWS follow up paper we learn that the risk of osteoporotic fracture decreases rapidly after starting therapy and the risk returns "rapidly" after stopping ⁽¹⁶⁾. This is also hard to understand as several years of appropriate ERT will produce a substantial increase in bone density which will not rapidly decline to pre treatment levels of density and fracture risk.

These apparent clinical enigmas have been accepted uncritically in the MSW papers because the numbers are so large. Rather than small errors being cancelled out by the large numbers as claimed by Beral ⁽¹⁷⁾ it is more logical that the errors have been multiplied to produce a study littered with confusion.

Caution in therapy is wise but the guidelines of the North American Menopause Society (NAMS) and various regulatory bodies are not justified by these data. The advice has not been modified by any review of age and the NAMS NIH WHI and the RCP(Edinburgh) web-sites all fail to address this age group.

The MWS study was, as was the many WHI reports, the subject of a mid-week press conference and front-page publicity for the conclusions and the authors ⁽¹⁴⁾. It may be pertinent that the same device was used for the report of the dangers of the MMR vaccine. It would seem that the more suspect the data the more these irregular and unscientific presentations of data will occur. This is press manipulation and a shameful betrayal of the responsibility that we owe to patients. The responsibility may be the journal or the authors but it must be discouraged.

(1) Writing Group for the Women's Health Initiative Investigators. Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the Women's Health Initiative randomised controlled trial. J.Am.Med.Assoc 2002;288;321-33
(2) Million Women Study Collaborators, Beral V. Breast cancer and hormone-replacement therapy in the Million Women Study. Lancet 2002;362;419-27
(3) Persson I, Adami HO, Lindgren A, Norlinder H, Pettersson B, Silver S. (1986) Reliability of endometrial cancer diagnoses in a Swedish Cancer Registry - with special reference to classification bias related to exogenous estrogens. Acta Pathol Microbiol Immunol Scand, 94 (3) 187-94
(4) Collaborative Group on Hormonal Factors in Breast Cancer. Breast cancer and hormone replacement therapy; collaborative reanalysis of data from 51 epidemiological studies of 52,705 women with breast cancer. Lancet 1997, 350, 1047-59
(5) Hulley, S., Grady, D., Bush, T. et al for the Heart and Estrogen/progestin Replacement Study Research Group. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in postmenopausal women. JAMA 1998, 280, 605-13.
(6) Lagro-Janssen T., Rosser, WW., van Weel, C. Breast cancer and hormone-replacement therapy; up to general practice to pick up the pieces. Lancet 2003, 362, 414-5
(7) Stampfer MJ, Colditz GA Willett WC et al. Post menopausal estrogen therapy and cardio-vascular disease; ten year follow-up from the Nurses' Health Study. N Engl J Med 1991, 325,756-62.
(x) De Lignieres B, de Vathaire F, Fournier S, Urbinelli R, Allaert F, Le MG, Kuttenn F.. (2002) Combined hormone replacement therapy and risk of breast cancer in a French cohort study of 3175 women. Climacteric, 5(4), 332-40
(8) Sourander L, Rajala T, Raiha I, Makinen J, Erkkola R, Helenius H (1998) Cardiovascular and cancer morbidity and mortality and sudden cardiac deaths in postmenopausal women on oestrogen replacement therapy (ERT). The Lancet, 352, 1965-69.
(9) Women's Health Initiative Investigators, Hays, J., Ockene, JK., Brunner, RL., Kotchen, JM., Manson, JE., Patterson, RE., Granek, IA., Shumaker, SA., Brzyski, RG., LaCroix, AZ., Granek, IA., Valanis, BG. Effects of estrogen plus progestin on health-related quality of life. New Engl J Med 2003, 348;1839-54
(10) Chlebowski RT, Hendrix SL, Langer RD, Stefanick ML, Fass M, Lane D, Rodabough RJ, Gilligan MA, Cyr MG, Tomson CA, Khandekar J, Petrovitch H, McTiernan A; WHI Investigators. Influence of estrogen plus progestin on breast cancer and mammography in healthy postmenopausal women: the Women's Health Initiative Randomised Trial. JAMA 2003, 289 (24), 3243-53
(11) Speroff, L (2003) The Million Women Study and breast cancer. Maturitas, 46 (2003) 1-6
(12) Hulley, SB., Grady, D. The WHI Estrogen-alone trial - do things look any better? (2004) JAMA 291, 14, 1769-1771
(13) Genazzani, AR., Gambacciani, M. (2003) The sound of an International anti-HRT herald. Maturitas, 46 (2) 105-6
(14) Studd, J. "Up to general practice to pick up the pieces" - what pieces?- a response to WHI and WHI. Maturitas 2003, 46, 95-96
(15) Emily Banks
(16) Banks, E., Beral, V., Reeces, G., Balkwill, A., Barnes, I. for the Milloion Women Study Collaborators. Fracture incidence in relation to the pattern of use of hormone therapy in postmenopausal women. JAMA 2004, 291, 18, 2212-2220
(17) Beral

References
(1) Hulley, Grady, Bush T et al. Randomized trial of estrogen plus progestin for secondary prevention of coronary heart disease in post-menopausal women.
(2) Writing Group for Women's Health Initiative Investigators.(2002) Risks and benefits of estrogen plus progestin in healthy postmenopausal women; principal results from the Women's Health Initiative randomized controlled trial. JAMA, 288, 321-33
(3) Beral V. Million Women Study Collaborators (2003) Breast cancer and hormone-replacement therapy in the Million Women Study. The Lancet, 362, 419-427
(4) Lagro-Jannsen T., Rosser WW., van Weel C., (2003) Breast cancer and hormone-replacement therapy; up to general practice to pick up the pieces. The Lancet, 362, 414-415
(5) Studd J. "Up to general practice to pick up the pieces" - what pieces? - a response to WHI and MWS. Maturitas, 46 (2003) 95-97
(6) Hays J, Ockene JK, Brunner RL, Kotchen JM, Manson JE, Patterson RE, Aragaki AK, Shumaker SA, Brzyski RG, LaCroix AZ, Granek IA, Valanis BG,: Women's Health Initiative Investigators. (2003) Effects of estrogen plus progestin on health-related quality of life. N Eng J Med, 348, 1839-56
(12) Sturdee DW., MacLennan AH. (2003) Is combined estrogen/progestogen hormone therapy worth the risk? Climacteric, 6 (3), 177-9

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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.

1. Oestrogen treatment should be used for the treatment of specific symptoms and low bone density.
2. 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.
3. 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.
4. Oestrogens commenced in older 60-79 year old women may do "early harm" before any benefit is achieved.
5. 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.
6. 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.
7. 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.
8. 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.
9. If loss of libido and loss of energy remain a problem, the addition of testosterone should be considered.
10. 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.
11. 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.
12. After loss of ovarian androgens, following hysterectomy and bilateral oophorectomy women normally need the addition of testosterone as well as oestrogen.
13. A mammogram should be performed each year and a breast examination every 6 months.

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UPDATE ON WOMEN'S HEALTH INITIATIVE (WHI) STUDY AND MILLION WOMEN'S STUDY (MWS) ON UNDERSTANDING OF THE SAFETY OF HRT

John Studd, DSc, MD, FRCOG
Consultant Gynaecologist, Chelsea & Westminster Hospital, London

Until two years ago HRT was quite straightforward. It stopped menopausal symptoms of hot flushes and vaginal dryness, improved depression and sexuality, had a protective influence on osteoporosis, heart attacks, strokes, colon cancer and probably Alzheimer's disease. There was probably a very slight increase in breast cancer but it was easy to believe that this was surveillance bias or the difficult precise pathological diagnosis in an organ stimulated with oestrogens (no independent review of breast pathology in these studies has ever taken place) as the mortality rate from breast cancer in these patients was much less than national averages in all papers. Women on HRT also lived an average 2.5 years longer than non-users.

These conclusions were the results of 30 years of clinical epidemiological and scientific data which seems to have been eclipsed by the conclusions of two large but greatly flawed studies.

The American WHI study of "healthy" 19,000 women confirmed the slight increase in breast cancer, the decrease in the hip fracture, the decrease in vertebral fracture and the decrease colon cancer but surprisingly revealed more heart attacks and more strokes. The mortality was not increased. Although this was meant to be a primary prevention study of the sort of menopausal women that we treat, the patients were of an average age 50-79, average age 63 with 23% of patients recruited over the age of 70. They were all given a standard dose of Premarin 0.625 mgs and MPA 2.5 mgs. The patients were overweight, 40% were hypertensive, 40% were receiving statins and 8% had had a previous heart attack. Thus the wrong patients of the wrong age group were given the wrong treatment and therefore the conclusions are very, very suspect. There were not enough patients in the 50-55 year group to make any observation about risks. This is regrettable that is the usual age when patients in this country commence HRT.

In fact looking at the raw data there is no increase in heart attacks year by year but in year 4 there was an unexplained drop of heart attacks and strokes in the placebo group which sprung the statistical significance thus stopping the oestrogen/progestogen arm of the trial.

A subsequent paper from WHI indicated that there was no improvement in quality of life with this HRT preparation. This was no surprise as the patients were asymptomatic as part of their inclusion criteria for the study. If there was no improvement in quality of life, there would be no problem but as women often have their lives transformed by the improvement of insomnia, depression, anxiety, dyspareunia etc., the personal dilemma for them is whether they should abandon this treatment. Regrettably this paper is now being referenced to indicate that HRT is not only dangerous but it doesn't even remove symptoms.

This has led to a huge decrease in the prescribing of HRT to the extent that one of the WHI investigators, Professor Susan Johnson, has publicly stated that the reaction to the WHI result has been too extreme.

To confuse things even more, it has been reported recently (04.03.04) that the oestrogen arm of the trial has now been stopped because the increase in strokes in this population has been confirmed. However, there is no increase in breast cancer or heart attacks in these 11,000 women studied over seven years.

It is no wonder that both doctors and patients are confused.

The Million Women Study was (if possible) even worse with more than 12 obvious errors and discrepancies in the text even to the table referring to ethinyloestradiol instead of oestradiol which was not picked up by the authors, clinical reviewers, or the editors. If these errors are above the surface, it brings into doubt the conclusions from the data collection and statistics under the surface. For example, the large increase in breast cancer after one year of oestrogen therapy is clearly undiagnosed breast cancer from the index mammogram as studies of the biology of breast cancer indicate that it takes five years before it is diagnosed as a 1.0 cm lump. Similarly the average time of diagnosis to death being 2.4 years is hard to believe as the average survival for metastatic breast disease is 3 years.

The many other faults, including the use of a single questionnaire only, and the exclusion of 4000 cancers from analysis can be found as a chapter on my website (www.studd.co.uk)

My view, and one shared by the British Menopause Society, would be that

1. Oestrogens still have a place for menopausal symptoms with the lowest dose for the treatment of that particular symptom being used. The dose should, however, be high enough to solve the problem. For example, The dose for treatment of hot flushes would be less than for the treatment of hormone responsive depression
2. Oestrogen therapy remains first line therapy for the prevention and treatment of osteoporosis.
3. With our current state of knowledge oestrogens should not be used for the prevention of heart attacks, strokes or Alzheimer's disease. But there is no evidence that HRT as used in young menopausal women in the UK carries any extra risk of coronary heart disease or strokes.
4. Consideration should be given to the use of non-oral routes as this avoids the entero-hepatic circulation and the production of excess coagulation factors from the liver.
5. The need to give HRT should be reviewed annually and possibly long-term therapy with the reported extra risk of breast cancer (12 per 1000 at 15 years) should be avoided if possible.
6. Until the breast cancer controversy is cleared up, it would be wise to recommend annual mammograms.

The problem is that it may take a month for bad news to be accepted but ten years to correct it particularly if a major Press conference occurs several days before publication. This occurred in the WHI study, the Million Women Study and, to put things in context, the MMR study. It does seem that the controversial the data the more likely that it is presented to the Press in this way so it is front page news before the scientific community has had time to analyse and interpret the publications. We have to find a more sensible way of communicating important scientific work to the public.

• www.studd.co.uk

Postscript

On the 2nd March, 2004 there was a Press Release from WHI to say that they had discontinued the oestrogen-only study because it confirmed the increase in strokes found in the earlier oestrogen/progestogen study. However, they found no increase in breast cancer and no increase in heart attacks! I agree that it is all very confusing.

The message from me is that we should avoid using Premarin with its adverse effect upon triglycerides, using oestradiol preferably by the transdermal route - patches, gels or implants - which does not stimulate coagulation factors from the liver.

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WOMEN'S HEALTH INITIATIVE s(JAMA 228, 3, 17th July 2002)

The Women's Health Initiative (WHI) study hit the Press in July causing great anxiety as part of the study, the continuous-combined oestrogen/progestogen group, showed an increase in strokes, in heart attacks, as well as an increase in breast cancer. It did show a decrease in osteoporotic fractures and a decrease in colon cancer but the view was that the dangers exceeded the benefits and this part of the study was discontinued. They have continued the oestrogen-alone part of the study.

The problem with the study is that they used the wrong oestrogen and the wrong age population for the study. Premarin, a mixture of equine oestrogens is alone in elevating triglycerides which is a risk factor for cardiovascular disease. No doubt the risk is not reduced by daily low dose progestogens which attenuate the beneficial effects of oestrogens on cholesterol. There is no evidence that the more logical oestrogen, oestradiol, the normal oestrogen found in male and female humans has this effect. If administered transdermally it reduces both cholesterol and triglycerides.

The MRC, in their current trial, are also using Premarin. No doubt they, like the WHI study, chose Premarin because the Company offered to supply free drugs and placebos but this can now be seen as a false economy as it has jeopardised the validity of the whole study.

The other despairing aspect of the study is that 68% of patients were over the age of 60 and 22% of patients over the age of 70 with many patients recruited aged 79. Thus this is not a primary prevention study of younger post-menopausal women starting oestrogen therapy at about the age of 50-55. These patients, because of their age, will have a higher incidence of cardiovascular disease, diabetes, hypertension which makes these results virtually irrelevant to the question of the safety of these hormones in the appropriate younger age group.

One can see how it happened. Originally the WHI wished to recruit 10,000 women to placebo and 10,000 women to the active preparation but no American woman who reads the newspapers would stick to either group for a long time - hence the 75% drop-out rate. Women on the active group dropped out when bad news occurred and women in the placebo group dropped out when they were clearly not receiving benefits. It is also likely that the placebo patients would have taken more statins in order to reduce the risk of heart attacks knowing that they were on placebo. Although the incidence of statin consumption was the same at the beginning of the study, there is no mention of the incidence at the time the study was discontinued. They were clearly desperate for recruits for this well-paid study. The centres which needed recruitment included these inappropriate older women who were certain to have more cardiovascular disease.

I think the Press, in fact, got it right. The error was the committee that set up these trials ignoring the advice of many American and British clinicians and experts in the field. I regret the study is just about worthless to answer the question of primary prevention but I very much doubt whether the MRC study would be of any more use because it is using the same oestrogen.

Our patients at the Chelsea & Westminster Hospital can be reassured that we very rarely use any Premarin products preferring oestradiol either by tablet, by patch, by gel, by implant, by vaginal ring or by intra-nasal administration.

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HRT TODAY

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.

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