Maturitas 43 Suppl. 1 (2002) S79– S84                                                                                     ...
S80                               M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84gens in the menopause, for hot flashes, sw...
M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84                            S81   Can this be achieved with or without horm...
S82                                M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84mous article [9] Trudy Bush wrote that ‘...
M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84                           S83ments, after a proper evaluation of contraind...
S84                                   M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84art of probability, and Medicine is a...
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  1. 1. Maturitas 43 Suppl. 1 (2002) S79– S84 Is there a menopausal medicine? The past, the present and the future Manuel Neves-e-Castro * Clinica de Feminologia Holistica, A6. Antonio Augusto de Aguiar No. 24, 2o. Dto. 1050 -016 Lisbon, Portugal ´Abstract The menopause is not a disease. However it is the onset of risks for the diseases that are more prevalent after thefifth decade of a woman’s life. These are due both to the natural process of ageing and to the lack of the protectiveeffect of estrogens that are then secreted in much lower amounts. Estrogen treatments after the menopause should notbe considered as replacements, since hypoestrogenism is physiologic after age 50. They are only treatments with sexhormones, with specific indications, as there are also recommended treatments without hormones. This clarificationof concepts is essential in order to emphasize that hormonal treatments after the menopause are not obligatory andmay have good alternatives too. Thus, the ongoing discussion should not be about the pros and cons of long-termhormonal treatments but, instead, about what is best for the preservation of health, the prevention of diseases andthe maintenance of a good quality of a woman’s life after age 50. © 2002 Published by Elsevier Science Ireland Ltd.Keywords: HRT; Menopausal medicine; Menopausal treatments1. Historical background suggested by Theophile de Bordeu in 1755 but only in 1855 further developed by Claude Treatments with organs and their extracts were Bernard, in France. Baylis, Starling and Williamalready reported in ancient times in Egypt, Greece Hardy coined the name ‘hormones’. Stockard andand Rome. It took several centuries until in 1986 Papanicolaou described in 1917 the estrogenicthree German groups claimed that treatments effects in the vagina, and in 1924 Allen and Doisywith ‘ovarian powders’ relieved symptoms related found estrogenic effects in the uterus of the menopause. These observations contributed to the purifica- What we all know today about estrogens is due tion of hormone extracts from the ovaries, withto some fundamental concepts and observations fat solvents, by Parkes and Bellerby in 1926,made during the 19th and early 20th centuries. known as ‘estrin’. Estrone was isolated in 1929 byThe notion of an ‘internal secretion’ was first Butenandt, in pure form, from the urine of preg- nant women. Marian, in the UK, isolated estriol Lecture given during the 1st Postgraduate Academic also from the urine of pregnant women. Only inCourse on Menopause. EMAS: November 2001, Toledo(Spain) 1940 17b-estradiol was isolated from the urine of * Fax: + 351-21-353-4551 pregnant women, too, and from the placenta. E-mail address: (M. Neves-e-Castro). The first report of a therapeutic use of estro-0378-5122/02/$ - see front matter © 2002 Published by Elsevier Science Ireland Ltd.PII: S 0 3 7 8 - 5 1 2 2 ( 0 2 ) 0 0 1 5 1 - 2
  2. 2. S80 M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84gens in the menopause, for hot flashes, sweating, 2. Today’s problemsirritability and libido is certainly the one of Geistand Spillman [1] in 1932. Before going any further, I think that it is An enormous contribution to the hormonal relevant to ask some other questions, not abouttreatments for menopausal women was done by the good or the bad effects of the treatments withtwo pharmaceutical companies: Schering, in Ger- the so called female hormones but, instead, aboutmany, and Organon, in the Netherlands. The first the objectives that must guide medical practicepure estrogenic medicines available in the market and the characteristics of the subjects to whom itwere ‘Progynon’ from Schering, ‘Ovestin’ from is addressed.Organon, ‘Premarin’ from Wyeth. Meanwhile, As physicians, our main goal is to do our best to preserve and improve health, to prevent dis-other than pure injectable progesterone, synthetic eases and to diagnose and treat them well. There-progestagens were developed and marketed by fore, there are at least three major concepts:Schering (‘Primolut’) and Parke Davies (‘Nor- health maintenance, disease prevention, diagnosislutin’). This was what was needed to open a new and treatment of diseases.era in therapy, specially after Fuller Albright de- The WHO defines Health as ‘a condition ofscribed in 1940 the menopausal osteoporosis due physical, mental and social wellbeing and not onlyto hypoestrogenism, and Robert Wilson launched the absence of disease’. Thus; the first step is toin 1966 a campaign claiming that women could be assess Health, a very complex task much more‘feminine for ever’ if they were medicated with difficult than the diagnosis of disease.estrogens. The subject of our attention is a menopausal However, the first relevant scientific contribu- mid-aged woman. As a menopausal woman, she istions to this field were made by three pioneers: hypoestrogenic, and may suffer, at various levels,Robert B. Greenblatt (USA), Wulf H. Utian from its consequences. But, as a mid-aged(South Africa, and later in the USA) and Pieter woman, she will suffer, too, from the process ofvan Keep (The Netherlands). The first one devel- natural ageing, both from a biological and psy-oped an enormous experience in the treatment chologic prespective. This is our task to conjugatewith estradiol and testosterone subcutaneous im- and equate the problems, to transform complexplants; the second, started the first menopause equations into simpler questions, and to find theclinics and the third founded the International answers that best fit them.Menopause Society and organized the first Con- What do we know today about postmenopausalgresses on the Menopause. women? This was the beginning of many studies in the What do we know about their health promo-field of the menopause. There was great enthusi- tion strategies, disease prevention and treatmentsasm but still little knowledge about doses, combi- with or without female steroid hormones? There is no doubt that the lifetime risk ofnation treatments, diagnosis of risk factors, etc. death, for a 50-year-old postmenopausal woman,Quality of life was no doubt improved and, thus, is 30% for heart disease, 3% for breast cancer andwomen did not want to stop hormonal medica- 3% for hip fracture complications [2].The mortal-tions. Therefore, treatments were continued non ity due to heart disease is also much higher thanstop, sometimes with even higher doses and not the mortality due to breast cancer. However, theassociated with progestagens. And, as time went mortality among women who use postmenopausalon; the first side effects started being reported, as hormones is lower than among nonusers [3].it was to be expected. Could estrogens cause Therefore, the primary and secondary preventionendometrial and breast cancer? Could they cause of heart diseases is extremely important. The pre-vascular diseases? These were some of the ques- vention of osteoporosis comes next. And it goestions that the past has sent for the present to without saying that anything that contributes to aanswer. This is where we are now, in the present. better quality of life is equally important.
  3. 3. M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84 S81 Can this be achieved with or without hormonal population that comes to a physician’s office.treatments, or with a combination of both? For Observational studies are more in line with whathow long? And how does one know if such inter- is done in clinical practice, since the structure ofventions are indeed being efficacious? What is the the hormones taken is not identical and the dosesresult of a benefit/risk analysis, taking into con- administered have been adapted to each individ-sideration breast cancer and cardiovascular ual; however, they may suffer from possible biasevents? These are the problems of the present time that may interfere with the validity of their con-that must be solved for the future. clusions. A major misinterpretation of these stud- I shall not refer to HRT or ERT (replacement ies is the confusion of what is meant by antherapies) because, after the menopause one is not increased risk. An increased risk e.g. of 50% overreplacing any hormones. One can replace estro- a control group of women does not mean that ingens in a surgical or premature menopause, or in the treated group half of the women will suffercases of gonadal agenesis, but not in the natural that side effect! This is a relative risk; not anpostmenopause when hypoestrogenism is physio- absolute risk! It only means that there will be 50%logic. One replaces e.g. insulin in a type 1 dia- more cases in the treated group than what wasbetic, or cortisone in Addison’s disease. In the already expected in the control group. In thenatural postmenopause one may use hormonal largest observational study [4] on HRT and breasttreatments, just as nonhormonal medicines, but cancer a 35– 50% increased risk after 10–15 yearsnot hormonal replacements! This is not a question of HRT signifies that it caused only 6– 12 addi-of semantics. It is, specially nowadays, a funda- tional cases in 1000 women! Furthermore, a studymental concept to emphasize that hormonal treat- done with a particular progestagen or estrogen,ments are not necessarily obligatory in the and only with a fixed dose, cannot be extrapo-postmenopause. They are excellent, if not con- lated to other molecules and regimens. As to thetraindicated, either in the short or long term. And progestagens they can be either pregnane or es-it is important that women understand and be trane derivatives, without or with androgenicreassured that there are many different and properties, etc. The pharmacokinetics and efficacyequally good ways to promote health and prevent of different estrogens are not equivalent. Differentdiseases. The importance of a good nutrition, estrogens may have different activities in differentproper exercise and mental occupation are never tissues; the potency and efficacy of a specificsufficiently stressed by physicians and yet their estrogen can vary from tissue to tissue; and thereconsequences may far outweigh the role played by are differences among women with respect toany remedy. The negative impact of smoking, of estrogens in various tissues [5]. Estrogen receptorobesity or leanness, in terms of heart and bone b inhibits estrogen receptor a in cells with bothhealth, are seldom discussed with those women receptors; the cellular sensitivity to estradiol iswho seek hormonal treatments. reduced in cells with both receptors [6]. So, how is Many clinical trials (prospective) and observa- it possible to extrapolate data from one estrogentional studies (retrospective) related to the im- into another one, from one progestagen toproperly so called HRT’s have been recently another?published, sometimes first in the lay than in the As to the breast cancer increased incidencemedical press. Their interpretation by less critical under hormonal treatments, a major concernphysicians and by the women themselves is open among women and physicians, it is estimated thatto serious mistakes. Most of the fixed protocols only 1 in 397 women taking estrogens over 10which are required in clinical trials do not neces- years would develop a breast cancer that wouldsarily reflect good clinical practice, an art of ad- not ordinarily occurred if estrogen treatmentsjusting the right dose for a particular woman in were not used [7].order to avoid side-effects and yet achieve the And 1 excess breast cancer case is likely totreatment objectives. The selection of women for occur per 5–6 of first myocardial infarction or hipa clinical trial does not often reflect the general fracture that are prevented [8]. In a recent posthu-
  4. 4. S82 M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84mous article [9] Trudy Bush wrote that ‘the evi- routes of delivery, doses, or different progestinsdence did not support the hypothesis that estro- have a more favourable or adverse effect on clini-gen use increases the risk of breast cancer and cal CVD end points’… In a recent publication [15]that combined hormone therapy increases the risk I wrote that ‘recommendations such as these ofmore than estrogen only. Additional observa- the AHA, written as they are, may be less helpfultional studies are unlikely to alter this conclusion’. than intended, both for clinicians and women’.A recent reanalysis of individual data from 52 Several well done studies, recently published [16],epidemiological studies [10] concluded that 1/9 concluded that in postmenopausal women withwomen who develop breast cancer may have an stable angina, under treatment with estradiol/affected mother, sister or daughter, a risk factor norethisterone acetate the number of ischemicto be kept in mind before the initiation of a events/24 h decreased by 0.82 events after treat-long-term hormonal treatment in the post- ment compared with an increase in the placebomenopause. And last, but not least, women who group, of 0.94, a highly significant difference (P=had breast cancer (clinically cured) and initiated 0.006)! And in the Nurse’s Health Study [17] therean estrogen treatment had less recurrences and a is evidence that estrogens prevent cardiovascularlonger survival than untreated controls [11]. diseases! The potential cardiovascular risks increased by These are examples of the difficulties in theestrogen/progestagen therapies have also been interpretation of many studies that show howvery much emphasized after the conclusions of the limited are the possibilities to extrapolate themHERS trial. I do not think that these risks are into clinical practice.realistic in our practice, as I have previously dis- An important recommendation is not to readcussed [12]. The HERS trial authors are the first only the titles of those publications, or only theto recognize [13] that ‘the discrepancy between the abstracts. The full paper should be critically readfindings of HERS and the observational studies before one makes up his own mind. Confusionsmay also reflect important differences between the are often made between ‘morbidity’ and ‘mortal-study populations and treatments’ and also that ity’, which are obviously very different. Many‘for women who stopped taking HERS medica- times those studies refer to ‘woman/year’, a con-tion, the risk of primary CHD events was elevated cept subject to criticism. When one refers e.g. toin the 1st month after stopping use of the medica- 100 woman/years this could mean either 100tion’. And again, they continue with these warn- women treated during 12 months or 400 womenings: ‘Perhaps postmenopausal hormone therapy treated during 3 months. Would the strength of ais beneficial in women who have not yet devel- conclusion be the same in either case?oped coronary disease but not in women who The benefits of estrogen treatments are quitealready have it’ and that ‘the findings of HERS evident for anyone who has a long experience inshould not discourage the use of hormone re- supporting postmenopausal women. We may orplacement therapy in the primary prevention of may not have a good tool for the primary preven-cardiovascular diseases’. Later on, the American tion of cardiovascular diseases with a very smallHeart Association issued a statement for Health- risk for breast cancer. We may increase bonecare Professionals about HRT and Cardiovascu- mineral density, wether or not fractures are ‘ipsolar disease [14] where it is written that ‘there are facto’ preventable. We may prevent colon cancerinsufficient data to suggest that HRT should be [18]. We may or may not prevent senile demen-initiated for the sole purpose of primary preven- tias. But what is quickly visible and felt, by thetion on CVD’. Most surprisingly, in a foot note of women themselves and by their attending physi-the same statement, the authors seem to contra- cians, is a remarkable improvement in mood anddict themselves: ‘the majority of data available to quality of life, by whatever mechanism, with ormake clinical recommendations are based on stan- without the support of measurements of mentaldard doses of oral CEE/MPA. Evidence is insuffi- performance, with appropriate scales. This iscient to determine whether different preparations, more than enough to contemplate estrogen treat-
  5. 5. M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84 S83ments, after a proper evaluation of contraindica- estrogens. Nitroglycerin seems to be as efficacioustions, for the length of time that is needed and as standard estrogen therapy in prevention ofacceptable on the basis of frequent reassessments. oophorectomy-induced bone loss, in women [23],Let it be remembered that at the central nervous in addition to its vascular effects. Phytoestrogenssystem estrogens act like neurotransmitters and may eventually be useful. Testosterone is againare, so far, the only existing molecules with nerve being considered for some women. Dehidroepi-growth activity. androsterone is still inconclusive. Of course there are cases when the so called But the important issue, after all, is not theHRT is not possible [19] either because it is hormonal treatment after the menopause. What iscontraindicated, or is not wanted by women, or important is the best possible approach to preven-even because it may not be needed. Under these tive medicine in a mid-aged woman. This requirescircumstances one must carefully evaluate risk from the attending physician (gynaecologist, en-factors or existing diseases (cardiovascular, can- docrinologist) the development of many talents ascer, bone, CNS). an empathic human being, capable of establishing There are nowadays many good nonhormonal a good raport, as an internist, who is able tomedicines that can be used alone or in combina- interprete symptoms that are not necessarily re-tion(or even in addition to hormonal treatments) lated to his speciality and, no doubt, as a goodlike statins, bisphosphonates, thiazide diuretics, well informed scientifically minded specialist.b-blockers, calcium-chanel blockers, ACE in- This is why I do not think there is ahibitors, tranquilizers, psychotropics, Vitamin D menopausal medicine; there is only the Medicinederivatives, calcium, calcitonin, aspirin, etc. And I of mid-aged women who reach the menopause. Inrecall what I said before about the unquestionable his lectures Leon Speroff concludes that ‘There ismerits of regular exercise, well balanced nutrition, only one Medicine’. I go one step beyond and saystop smoking, mental occupation, etc. All the that there are only two Medicines: the Goodabove have well proven beneficial effects both for Medicine and the Bad Medicine. Was it not thesymptom relief and for the primary and secondary case, then a gynaecologist would be only confinedprevention of the disease that are more prevalent to the prescription of hormones or would have toafter the menopause [20,21]. be constantly referring the postmenopausal And worth considering, too, are some other woman to many other different specialists. Thismodified estrogen receptor ligands, like SERM’s, referral will only be needed when he becomestibolone, or new estradiol conjugates (sulfamates), aware that he has reached the natural limit of hisand newer and better progestagens that are also competence in another area.being developed (drosperinone). The therapeutic support during the climac- terium is not confined only to drugs. It is not the menopause that is going to be treated. It is a3. The coming days woman, in a very special period of her life, with affective and hormonal imbalances, who needs to The future looks promising. The combination be supported and treated as a whole, that she is.of hormonal and nonhormonal remedies is cer- It is essential to adopt a holistic vision of thetainly a good strategy to augment the positive middle aged woman and be concerned with all theeffects and to decrease side effects. Lower doses of aspects that define Health (WHO).hormones are being shown to be as effective as For a woman, the menopause is like an Alarm-the present standard doses of estrogens. New Clock! An alarm given by Nature, as a reminderdelivery systems are expected to improve treat- that she must stop and reflect about the next 30ment continuation (compliance). Progestagen years she may still live. An opportunity for aloaded intrauterine devices [22] can be inserted to check-up. The time to set new goals and defineprotect the endometrium and avoid systemic ad- strategies to fulfil them.ministration of progestagens in association with Sir William Osler once said that ‘Science is an
  6. 6. S84 M. Ne6es-e-Castro / Maturitas 43 (2002) S79–S84art of probability, and Medicine is an art of [10] Beral V. The collaborative Group on Hormonal Factorsuncertainty’. This is the challenge in our daily in Breast Cancer (Oxford). Familial Breast Cancer. Lancet 2001;358(9291):1389 – 99.practice. This is why physicians should only give [11] Wren BG. Hormonal therapy following breast cancer. In:advice, whereas women are the ones who must Neves-e-Castro M, Wren BG, editors. Menopause Hor-make the decisions. mones and Cancer. London, New York and Washington Let us not be totally dominated by the Evi- DC: Parthenon Publishing, 2002:55 – 66.dence Based Medicine and let us allow some room [12] Neves-e-Castro M. The Queen... is naked!. Maturitas 2001;38(3):235 – 7.for the Medicine Based Evidence. [13] Hulley S, Grady G, Bush T, et al. Randomized trial of Preventing a woman from the benefits of a estrogen plus progestin for secondary prevention of coro-sound postmenopausal hormone therapy, because nary heart disease in postmenopausal women. J Am Medof the fear of rare side effects, does not seem to be Assoc 1998;280:605 – 13.satisfactory Medicine… Good clinical judgement [14] Mosca L, Collins P, Herrington DM, et al. Hormone replacement therapy and cardiovascular disease. Circula-must prevail! tion 2001;104(4):499 –503. [15] Neves-e-Castro M. Imaginary Woman. Maturitas 2001;40:8 –9.References [16] Sanderson JE, Haines CJ, Yeung L, et al. Anti-ischemic action of estrogen-progestogen continuous combined hor-[1] Geist SH, Spillman F. The therapeutic use of amniotin in mone replacement therapy in postmenopausal women the menopause. Am J Obstet Gynecol 1932;23:697 –707. with established angina pectoris: a randomised, placebo-[2] Cummings SR, Black DM, Rubin SM. Lifetime risks of controlled, double-blind, parallel-group trial. J Cardio- hip, Colles, or vertebral fracture and coronary heart vasc Pharmacol 2001;38(3):372 – 83. disease among white postmenopausal women. Arch In- [17] Grodstein F, Manson JE, Colditz GA, et al. A prospec- tern Med 1989;149(11):2445 –8. tive, observational study of postmenopausal hormone[3] Grodstein F, Stampfer MJ, Colditz GA, et al. Post- therapy and primary prevention of cardiovascular disease. menopausal hormone therapy and mortality. N Engl J Ann Intern Med 2000;133(12):933 – 41. Med 1997;336(25):1769 –76. [18] Al-Azzawi F, Wahab M. The relationship of sex steroid[4] Beral V. The Collaborative Group on Hormonal Factors therapy and colon cancer. In: Neves-e-Castro M, Wren in Breast Cancer (Oxford). Breast cancer and hormone BG, editors. Menopause Hormones and Cancer. London, replacement therapy: collaborative reanalysis of data New York and Washington DC: Parthenon Publishing, from 51 epidemiological studies of 52705 women with 2002:107 – 16. breast cancer and 108411 women without breast cancer. [19] Neves-e-Castro M. When hormone replacement therapy Lancet 1997;350:1047 –59. is not possible. In: Studd J, editor. The Management of[5] Ansbacher R. The pharmacokinetics and efficacy of dif- the Menopause; The Millennium Review. New York Lon- ferent estrogens are not equivalent. Am J Obstet Gynecol don: Parthenon Publishing, 2000, 2000:91 – 102. 2001;184(3):255 – 63. [20] Genazzani AR, Gambacciani M. Cardiovascular disease[6] Hall JM, McDonnell DP. The estrogen receptor ß-Isofor and hormone replacement therapy. IMS Expert Work- (Erß) of the human estrogen receptor modulates ER shop. Climacteric 2000;3:233 – 40. (transcriptional activity and is a key regulator of the [21] Zhao X-Qyuan C., Hatsukami T.S. et al., Effects of cellular response to estrogens and antiestrogens. En- prolonged intensive lipid-lowering therapy on the charac- docrinology 1999;140:5566 –78. teristics of carotid atherosclerotic plaques in vivo by[7] Santen RJ, Pinkerton JA, McCartney C, et al. Clinical MRI:a case-control study. Arterioscler. Thromb. Vasc. Review 121: Risk of Breast Cancer with Progestins in Biol. 2001;21(10):1623-29,1563-1564. Combination with Estrogen as Hormone Replacement [22] Raudaskoski T, Tapanainen J, Tomas E, et al. Intrauter- Therapy. J Clin Endocrinol Metab 2001;86(1):16 –23. ine 10 microg and 20 microg levonorgestrel systems in[8] Moerman CJ, Van Hout BA, Bonneux L, et al. Post- postmenopausal women receiving oral estrogen replace- menopausal hormone therapy: less favourable risk benefit ment therapy: clinical, endometrial and metabolic re- ratios in healthy Dutch Women. J Intl Med sponse. Br J Obstet Gynaecol 2002;109(2):136 – 44. 2000;248(2):143 – 50. [23] Wimalawansa SJ. Nitroglycerin therapy is as efficacious[9] Bush TL, Whiteman M, Flaws JA. Hormone replacement as standard estrogen replacement therapy (Premarin) in therapy and breast cancer: a qualitative review. Obstet prevention of oophorectomy-induced bone loss: A human Gynecol 2001;98(3):498 –508. pilot clinical study. J Bone Miner Res 2000;15(1):2240 – 4.