JOHN STUDD
Abstract: The Women’s Health Initiative study worked on the assumption that one dose would fit all asymptomatic postmenopausal women. The investigators therefore often used the wrong dose, of the wrong hormones, on the wrong patients and therefore came to many wrong conclusions. Different combinations of different hormones are necessary for different symptoms and different age groups. Hormone replacement therapy may be commenced in the perimenopausal phase, the early postmenopause, the late post menopause or after hysterectomy and bilateral salpingo-oophorectomy or a premature menopause. These all require different treatments. Similarly, various indications such as vasomotor symptoms, sexual problems, depression or the treatment/prevention of osteoporosis all need different combinations of estradiol and possibly progestogen and testosterone, according to the specific requirements of the patient.
Introduction
Two major well-publicized studies, the Women’s Health Initiative (WHI) [1] and the Million Women Study (MWS) [2], have shaken the faith in the safety of hormone replacement therapy (HRT) of doctors and postmenopausal women alike, in spite of the criticism of the design and conclusions of the WHI study [3–5] and the many anxieties about the MWS data collection [6–8]. It is now difficult to respond to the WHI study in an optimistic way and for this to be considered and published. Following the North American Menopause Society (NAMS)/National Institutes of Health statement of October 2002 [9]many proscriptive guidelines from advisory bodies in Europe and North America have appeared, which advise prescribing hormone therapy at the lowest dose principally for menopausal vasomotor symptoms, and for the shortest time [10]. It was also recommended that HRT is not to be used as a primary treatment for low bone density and that it has no place in the prevention of coronary heart disease. In view of later considerations of the data, both these items of advice are questionable. There is no protest about the uncontroversial recommendation that the lowest dose should be used and that the appropriateness of continuing HRT should be reviewed each year, with full discussion of benefits and risks. However the‘lowest dose’ varies from patient to patient and should be one that is effective for a particular indication.What is missing from statements from regulatory authorities is the understanding that treatment should be individualized for a particular patient, her expectations and her pathology. Such variation of therapy is sound clinical practice but it is notable that the great fault of the WHI study is that there was no individualization – just the assumption that one dose of Prempro fitted all patients regardless of age and general health even though they were, by their inclusion criteria, asymptomatic and did not require therapy.The epidemiologists and investigators who designed the WHI were not aware of, or chose to ignore,the basic tenant of good practice relating to HRT. This is the knowledge that different women require a different dose, by a different route, of different combinations of different hormones, for different symptoms. This would also vary depending upon the surgical status and the age of the patient, and there will also be a difference depending on the clinical needs of the woman. The present contribution is an attempt to correct that omission by stating the variations necessary for effective treatment with estrogens with the possible addition of progestogens and androgens.
Age
Perhaps the most fundamental variation is one of age.The average age of the women in the WHI study was 63 years, with a range of 50–79 years, and 22% of those recruited for therapy were over 70 years old.The study demonstrated an increase in breast cancer and venous thromboembolism, a decrease in colon cancer and fractures of the hip and spine, as well as an unexpected increase in heart attacks and stroke [1].However it should be recognized that 97% of patients in normal clinical practice commence treatment below the age of 60 and it is this age cohort of patients that is of particular interest to the prescribing physician [11]. The data from this age group are reassuring, as a later report the WHI study in 2003 showed that the excess of cardiovascular events [12]occurred only in women starting estrogen and progestogen therapy 20 years after the menopause,and that there was a non-significant (hazard ratio ¼ 0.89) decrease in these events in women starting the therapy within 10 years of the menopause.
Similarly the estrogen only-arm [13], which was stopped in 2004 reportedly because of an excess of stroke, showed in the 50–59 year age group a 42% decrease in coronary heart disease – being much the same as the protection found in the former case–control studies. There was also a 28% decrease in breast cancer, a 41% decrease in colorectal cancer, a27% decrease in deaths and a 20% decrease in global index pathology. The 8% increase in stroke was in fact 19 patients in the control group and 19 patients in the active group. None of the considerable beneficial changes were significant but it does raise the question of why this age cohort of the estrogen only study was stopped, as the results could have confirmed the cardiovascular and colorectal benefits of the many earlier observational studies. It was a lost opportunity to solve this continuing controversy.
When to Start?
There are clear differences concerning the correct time to start therapy. Most women start HRT in the postmenopausal state, but this can be soon after a normal menopause in the early fifties age group or later in an over sixties age group. Hormone therapy may also be required in younger women after a premature menopause [14] or following hysterectomy and oophorectomy [15]. These groups should all be treated in different ways. HRT may also be prescribed to perimenopausal women in the transition phase before menstrual periods have ceased, if they have appropriate symptoms. These will require different doses of different hormones depending on age and clinical needs, and are discussed in detail below. Essentially, older women need a smaller dose and non-hysterectomized women may also require testosterone for specific symptoms.
Indications for starting hormone replacement therapy
The indications for HRT in this review are wider than those initially recommended by NAMS, the Committee on Safety of Medicines and the European Menopause and Andropause Society, where the advice is a result of the ‘one dose fits all’ WHI study and the incomprehensible data collection of the MWS. An alternative view is that hormone therapy prescribed intelligently is safe and associated with considerable quality-of-life benefits.
In Europe, estrogen has been given principally for the treatment of climacteric symptoms and for the improvement of low bone density. The symptoms may be due to the vasomotor instability of hot flushes and sweats with insomnia and tiredness, or pelvic atrophy with vaginal dryness, dyspareunia, sexual dysfunction and the urethral syndrome [16]. Estrogen may also be given for the prevention or treatment of osteoporosis in women with decreased bone density, as estrogens in the appropriate dose have ananabolic as well as an anti-catabolic effect on the skeleton [17].
More controversial indications would be for perimenopausal depression [18,19] or premenstrual syndrome (PMS), particularly in the years of the perimenopausal state [20,21]. Loss of energy and loss of libido in association with climacteric symptoms are distressing for the couple and should be indications for estrogen sometimes with the addition of testosterone [22].
The value of estrogen therapy in the prevention of coronary artery disease, Alzheimer’s disease and stroke is now controversial and would not with current knowledge be recommended. Similarly, the belief that estrogens are of value in the secondary prevention of further coronary artery disease seems no longer valid. Thus, estrogen therapy for prevention of these chronic cardiovascular and neurological disorders is no longer accepted, although many workers cling to the hypothesis of a ‘window of opportunity’ for prevention if estrogen therapy is started in the first ten years after the menopause before irreversible arterial and neurological degeneration has occurred.
The different indications are now discussed in more detail.
Vasomotor symptoms
The classical and the most common symptoms of the climacteric are the vasomotor symptoms of hot 666 J. Studd flushes, palpitations, night sweats with insomnia and headaches, which all respond well to estrogen therapy. Patients with these symptoms require low dose estradiol preparations by an oral route, by gel or by patch, for 3 months or longer, for the duration of symptoms. The commencing dose should be low bu tcan be increased to a dose which alleviates the symptoms. Because of the anxiety about breast cancer many other treatments have been used,particularly herbal remedies, selective serotonin reuptake inhibitors or clonidine, but none are as effective as estrogen in women who have these troublesome symptoms. The increasingly popular natural herbal remedies are usually no better than placebo; but even if pharmacologically active, they are uncontrolled, poorly investigated, of unknown estrogenic potency and not without serious side effects.
These patients receiving estrogens will, of course,need cyclical or continuous progestogens if they have an intact uterus in order to protect the endometrium from hyperplasia or malignancy [23]. There is now much debate about the progestogen component because this hormone, more than estrogen, seems to be implicated in the possible excess of breast cancer in the combined HRT preparations. There is also a problem in that progestogen reproduces PMS type symptoms [24] particularly in women who have progestogen intolerance [25]. This is a major reason why women discontinue therapy. These women should try a different progestogen, at a lower dose,or should consider the long cycle of progestogen every 3 months. A Mirena intrauterine system (IUS)delivering local progestogen within the uterine cavity should be considered [26].
Another possibility is to have a shorter duration of progestogen every month. One regimen is for a progestogen such as norethisterone 5 mg or medroxyprogesterone acetate 5 mg to be taken for the first seven days of each calendar month, which will bring about a withdrawal bleed on about day 10 of each calendar month This will bring about 12 periods a year instead of 13, with fewer progestogenic symptoms of irritability, depression, tiredness and bloating.This option is an important concept, because following the demonstration of possible disadvantages of continuous progestogen there is currently a risk of accepting the other extreme of unopposed oestrogens [27], without considering the compromise of a shorter 7-day monthly course of progestogen which has already been shown to be effective in preventing endometrial pathology in early work on this subject [28].
Pelvic atrophy
Vasomotor symptoms such as vaginal dryness should be easy to treat with estrogens. After the menopause,women lose collagen from the skin, ligaments, bone matrix, genital tract and bladder which can be corrected with hormone replacement [29]. These patients with symptoms of pelvic atrophy should have the same low-dose estradiol, with the appropriate progestogen if necessary, for as long as it takes to eradicate the symptoms. Local vaginal estradiol or estriol can be used. Progestogen is not normally added to this therapy although endometrial proliferation and hyperplasia may rarely occur. If bladder symptoms of urgency and recurrent ‘cystitis’are present a higher dose may be required for a longer duration regardless of whether the route of administration is local, oral or transdermal.
Premature menopause
Apart from the sadness of infertility, women with a premature menopause have a higher incidence of osteoporosis, coronary heart disease, stroke and also depression [30]. Indeed it was this association which led to the concept of estrogens preventing these chronic diseases in older women. Estrogen therapy has been shown to increase bone density and also to improve the histomorphometric parameters of strength of bone even in young women with Turner’s syndrome [31]. They need HRT in the appropriate dose for these symptoms until at least until the age of 50, the time of the normal menopause. If there is to be a 5–10 year recommended limit for the duration of HRT, these treatment years should be counted from the age of 50, the age of natural menopause.In reality these young women with their excess risk of chronic disease are having their estrogen therapy discontinued or not started due to the anxiety created by the common misinterpretation of the WHI data.
Post hysterectomy and oophorectomy
Women who have had a hysterectomy should have continuous estrogens without progestogens and thus treatment should be straightforward, without bleeding and without PMS-type symptoms produced by progestogens which often limit the acceptability of HRT. However, these women may need a higher dose than is usual for vasomotor symptoms, and as the surgery usually occurs in premenopausal women they may well, like those with a premature menopause,need estrogens for a longer duration for relief of symptoms.
If the ovaries have been removed these women will have lost their ovarian androgens and be at risk of developing the female androgen deficiency syndrome,characterized by loss of energy, loss of libido,depression, loss of self-confidence and headaches[32]. These are frequent complaints in women who have had a hysterectomy with loss of ovaries and have Editorial 667 been receiving a low dose of estrogens over the years.These symptoms can usually be eradicated by the addition of testosterone, either in the form of implants (licensed for women in many countries) or Testogel, which although effective will have to be used off-license in women using about one-quarter of the dose recommended for men. However, the fact that it is not licensed in a particular country is not a good reason to deny women this important item of treatment. It should not be forgotten that testosterone is not only a normal female hormone but also is present in higher concentrations in young women than estradiol.
Estradiol and testosterone implants are the most effective and convenient route of administration for these women, with the pellets inserted into the wound on closure and repeated approximately every 6 months as a simple office procedure [15]. The fact that it is an old drug lacking in patent or profit or the benefit of costly licensing studies does not reduce its value in hysterectomized women or those with problems of loss of energy and libido or depression
Perimenopausal depression
There are many patients in their forties with severe recurrent depression, sometimes cyclical, who will respond well to transdermal estrogens. These patients with reproductive depression often reveal the changes of mood with changes in hormone levels because of a past history of postnatal depression,premenopausal depression as well as the severe depression in the perimenopausal years of the transition. Often they state that they were last well during the last pregnancy many years ago. They then developed postnatal depression which became cyclical as premenstrual dysphoric disorder when the periods returned, having only about ten good days per month free of PMS, periods and menstrual headaches. The depression then becomes less cyclical and more constant [33].
These perimenopausal women respond well to moderately high doses of transdermal estrogens(either 100 mg or 200 mg) which not only suppress any residual cycle but also have a mood-elevating effect. As these women with hormone-responsive depression are often progestogen-intolerant, the continuous estradiol treatment should be supplemented with progestogen tablets for 7 days of each calendar month rather than the orthodox 14 days. A Mirena IUS is also useful in preventing the recurrent depression that often occurs with progestogen.
Estrogens do not convincingly help the depression of postmenopausal women apart from the domino effect of removing night sweats/insomnia or vaginal atrophy and sexual dysfunction. It seems to have little significant effect in the absence of these classical menopausal symptoms.
Low bone density
Although the new non-hormonal therapies for low bone density are currently more in favor, there is still a place for estrogen therapy – the only treatment that has been shown to decrease the risk of both vertebral and hip fractures. Estrogens are anabolic as well anticatabolicto the bone and are most effective in older women or in women with an osteoporotic skeleton.The increase of bone density with estrogens is dose dependent with a positive correlation between plasma estradiol levels and bone density. There is also a correlation between estradiol levels and histomorphometric changes of wall thickness, trabecular volume and new formation of matrix collagen[17]. No such data exist for bisphosphonates.
Plasma estradiol levels of 300 pmol/l are necessary for an increase in bone density in most patients.But as most North American patients are prescribed conjugated equine estrogens, estradiol measurements have not been a feature of American practice.
The advice from the regulatory authorities that estrogens should not be first-line therapy for the prevention or treatment of osteoporosis, particularly in otherwise healthy women under the age of 60, has been questioned [34]. Regrettably there has always been a conflict, almost a ‘turf war’, between bone physicians for whom the side-effects of bleeding, mastalgia and PMS symptoms with progestogen is uncharted territory and gynecologists who are more familiar with the problems of gonadal hormones. This has been reinforced by Banks and collaborators[35] of the MWS, who claim that on cessation of estrogen therapy bone density ‘rapidly’ reverts to pretreatment levels. This has been disputed [36,37], but it does further demonstrate the design problem of this study which relied upon a single questionnaire.In reality 10 years of moderately low-dose estrogen therapy will increase vertebral bone density by approximately 10%. It is both counter-intuitive and certainly against clinical observations that this benefit is rapidly lost. However, it is used as further justification to use non-hormonal therapy as first choice or to discontinue this therapy after a short course of estrogens in these younger women, in spite of the added quality-of-life benefits of hormone therapy.
Older menopausal women
Older women in the past have been shamefully neglected due to the belief that the osteoporotic skeleton did not respond to drugs which otherwise would increase bone density in younger women. In reality, the skeletal response to estrogen is greatest in women who have the lowest bone density and who are most years past the menopause [38]. It appears that this denial is occurring again following justifiable 668 J. Studd anxiety about the cardiovascular effects found in older women in the WHI study. These women require the lower starting dose of estrogens or bisphosphonates may be used as a first option. If older women are treated with estrogens it is advisable to start on low-dose unopposed therapy for the first three months, using estradiol patches or gels or oral estradiol 0.5 mg daily. At 3 months, after assessing the symptomatic response, a decision should betaken whether to continue to use low-dose unopposed oestrogens or to add a monthly low-dose, low duration progestogen component.
Bleed-free preparations
The desire to have estrogen therapy without a withdrawal bleeding opens up a large variety of therapeutic possibilities. The use of continuous estrogen and progestogen is effective, commonly used but is currently suspect because of the data from the WHI study. However it continues to be, with justification, the most frequently used preparation for this purpose. Recently there have been reports of low-dose or ultra-low-dose continuous estrogens producing relief of symptoms and bone protection without bleeding [27]. Tibolone is a complex gestogen with estrogenic and androgenic properties,which by depressing sex hormone-binding globulin levels [39] increases free testosterone, thus having a beneficial effect on energy, libido and depression[40]. The use of selective estrogen-receptor modulators with their certain protective effect on breast cancer is being evaluated, although this drug does produce vasomotor symptoms as well as the desirable endometrial atrophy and amenorrhea.
Summary and conclusions
The principles of hormone therapy for the menopausal or perimenopausal woman can be summarized thus. These items are not entirely consistent with the current advice of regulatory bodies, but they do reflect a studied analysis of the available data as well as a long clinical and academic interest in the subject. Medical practitioners of all levels require guidance for the hormonal treatment of middle-aged women. These views should be considered, discussed and criticized as a fresh clinical approach is urgently needed. Currently many women suffering severe hormonal disorders are being needlessly denied appropriate, safe hormone therapy.
(1) Estrogens are safe when started below the age of 60 years, particularly if progestogen is not required, and are positively indicated in women with a premature menopause. It should be used for treatment of specific climacteric symptoms and low bone density, and the advice that estrogens should not be the first option for prevention or treatment of osteoporosis in this age group is questioned. The dose and route will depend on the symptoms and age of the patient.
(2) Women with a uterus need endometrial protection with progestogen. The usual duration is 14 days, but if the extra risk to the breast from progestogen is confirmed it would be sensible to reduce the duration to 7 days each calendar month. This shortened course is also useful in women with progestogen intolerance and is adequate for endometrial protection. Alternatively,a Mirena IUS can be inserted. The long term value and safety of low-dose unopposed estrogen is unproven.
(3) Estrogen-only therapy commenced before age 60 is associated with a considerable but nonsignificant decrease in coronary heart disease,osteoporotic fractures, colon cancer and deaths.These results are consistent with the previous case–control studies. There may also be a decrease in breast cancer in women receiving estrogens without progestogen.
(4) Estrogens appear to have no place for the secondary prevention of cardiovascular diseas ebut there may be a ‘window of opportunity’ in 45–60-year-old symptomatic women who may show long-term cardiovascular and neurological benefits from early estrogen therapy. Estrogens commenced in women older than 69–79 years may do ‘early harm’ before any benefit can be achieved and should be avoided if possible;or women may be started on a very low dose of estrogens.
(5) A moderately high dose of transdermal estrogens is useful for perimenopausal depression as well as premenstrual depression. Progestogen is necessary for endometrial protection and cycle control even though these patients may be intolerant to small doses and short duration of any progestogen.
(6) Patients may wish to avoid bleeding by using low-dose estrogen and progestogen, tibolone or have a Mirena IUS inserted.
(7) If loss of libido and loss of energy remain problems, the addition of testosterone to estrogen should be considered. Androgen as well as estrogen is often necessary after hysterectomy and bilateral oophorectomy. Hysterectomized women do not need progestogen.
(8) A duration of 5 years has been recommended but in reality women remain on HRT if they are feeling well with relief of symptoms. It is difficult to persuade these women to stop even after 10 or more years [41]. The need for estrogens should be reviewed each year for long-term users, with clear discussion of current views on safety.
(9) In spite of the reassuring data from estrogen only studies, the possible increase in breast cancer remains a problem. Until the controversy concerning breast cancer risk is clarified it is probably advisable that regular mammograms should be performed each year and breast examination every 6 months, although it is correct to recognize that many oncologists would doubt the value of these frequent examinations.
The optimistic recommendations in this paper are now supported by the latest publication from the WHI,which reports that starting Prempro before age 60 results in 24% fewer cases of coronary heart disease and a 30% decrease in total mortality [42]. Age is the most critical factor whether estrogen only or estrogen plus progestogens was used. Both the NAMS [43] and the International Menopause Society [44] have now changed their guidelines, recognizing the efficacy for many indications for HRT outlined in this review and the long-term safety of such therapy. This belated conversion to the clinical realities of HRT has been warmly welcomed [45].
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