Where Are We Now with Hormone Replacement Therapy?

Abstract

Menopausal symptoms can be grim, and the desire to replace the hormonal “deficit” with exogenous hormones remains strong. Since the 1950s, hormone replacement therapy has been used increasingly, while evidence on the risks of unwanted side effects has accumulated. What have we learned over these decades? Firstly, current biological theory does not predict the effects of hormones on cancer and cardiovascular disease well. Secondly, mass prescription requires large randomised clinical trials with long follow-ups. Observational studies of the putative effect of drugs, for coronary disease especially, are unreliable. Thirdly, mass markets engender massive vested interests–personal, departmental, and corporate. Genuine care for women demands scientific independence, since uncertainty allows expert, but illegitimate, conviction too easily. The balance now seems clearer than it was before we knew these risks; hormone replacement therapy works for symptoms but not for future health, which is not what had been widely promised. It can take decades to detect important and unanticipated side effects of medications reliably. Do the current regulatory provisions adequately provide for the sensible avoidance of more, tragic episodes? Regulators and legislators will be contemplating the implications, as they did after thalidomide, and hopefully we will not get the marketing so wrong again.

Résumé

Les symptômes de la ménopause peuvent être sévères et le désir de substituer le ≪ déficit ≫ hormonal par des hormones exogènes demeure fort. Depuis les années 50, le traitement hormonal de substitution est de plus en plus été utilisé, alors que se sont accumulées les preuves des risques d'effets secondaires indésirables. Qu'avons-nous appris ? Premièrement, la théorie biologique actuelle ne prédit pas bien les effets des hormones sur le cancer et les maladies cardiovasculaires. Deuxièmement, une prescription massive exige des essais cliniques aléatoires avec de longs suivis. Les études observatoires de l'effet putatif des médicaments, particulièrement sur les maladies coronariennes, ne sont pas fiables. Troisièmement, les marchés massifs suscitent la convoitise des individus, des départements et des entreprises. Se préoccuper vraiment des femmes exige l'indépendance scientifique car l'incertitude aboutit trop facilement à des convictions expertes, mais infondées. Le bilan semble maintenant plus clair qu'avant que nous ne connaissions ces risques ; le traitement hormonal de substitution fonctionne pour les symptômes, mais pas pour la santé future, contrairement à ce qui avait été promis. Des décennies sont parfois nécessaires pour détecter sûrement les effets secondaires des médications. Les dispositions actuelles prévoient-elles de faire preuve de bon sens en évitant d'autres épisodes, plus tragiques ? Les législateurs envisageront les conséquences, ainsi qu'ils l'ont fait après la thalidomide, et il faut espérer que la commercialisation ne commettra pas les mêmes erreurs.

Resumen

Los sı́ntomas de la menopausia pueden ser difı́ciles; por tanto, el deseo de suplir el ‘‘déficit’’ hormonal con hormonas exógenas continúa firme. Desde los años cincuenta, la terapia de reemplazo hormonal se utiliza con mayor frecuencia, mientras que se acumulan pruebas sobre los efectos secundarios indeseables. ¿Qué se ha aprendido? En primer lugar, la teorı́a biológica actual no pronostica bien los efectos de las hormonas en el cáncer y en la enfermedad cardiovascular. En segundo lugar, una formulación masiva requiere ensayos clı́nicos aleatorios con largos perı́odos de seguimiento. Los estudios observacionales del efecto esperado de los medicamentos, en particular con relación a la enfermedad coronaria, no son confiables. En tercer lugar, los mercados masivos generan intereses creados a nivel personal, departamental y corporativo. Verdadero interés en el bienestar de la mujer exige autonomı́a cientı́fica, ya que la incertidumbre propicia una convicción experta pero ilegı́tima. El equilibrio ahora parece ser más claro de lo que era antes de conocerse estos riesgos; la terapia de reemplazo hormonal es eficaz para controlar los sı́ntomas, pero no asegura futuro bienestar, lo cual no es lo que se habı́a prometido. La detección de los efectos secundarios de los medicamentos de manera fidedigna puede demorar décadas. ¿Las disposiciones actuales procuran evitar más episodios trágicos de manera sensata? Los reguladores y legisladores estudiarán las consecuencias, tal como hicieron después de la talidomida, y, se espera que la mercadotecnia no vuelva a ser tan desacertada.

Menopausal symptoms can be grim, and the desire to replace the hormonal “deficit” with exogenous hormones remains strong. Since the 1950s, hormone replacement therapy has been used increasingly,¹ while evidence on the risks of unwanted side effects has accumulated. Twenty-five years ago, the increased risk of endometrial cancer emerged, resulting in the addition of progestogen. Cohort studies had examined oestrogen alone and indicated important benefits, but, since the 1980s, combined preparations have dominated. Interpretations of the evidence were therefore confused, since whatever effects oestrogen or progestogen have on disease will differ. Eventually, evidence of increased risk of combined therapy on breast cancer, coronary heart disease, stroke and venous thromboembolism from randomised trial was reported.² This trial was stopped early, after an average of five years' follow-up among 17,000 women, during which around 40% stopped their trial drugs. The results from the oestrogen alone arm of the woman's health initiative study will reassess the role of combined therapy in 2005.

Because it may double the risk of breast cancer for long-term use³ and of heart disease in the first year of use, combined therapy is problematic. These risks are incommensurate with debilitating symptoms, but women need to be able to judge the risks for themselves. The balance now seems clearer than it was before we knew these risks; hormone replacement therapy works for symptoms but not for future health, which is not what had been widely promised.⁴

What have we learned over these decades? Firstly, current biological theory does not predict the effects of hormones on cancer and cardiovascular disease well. Secondly, mass prescription requires large randomised clinical trials with long follow-ups. Observational studies of the putative effect of drugs, for coronary disease especially,⁵ are unreliable. Thirdly, mass markets engender massive vested interests–personal, departmental and corporate. Genuine care for women demands scientific independence, since uncertainty allows expert, but illegitimate, conviction too easily.⁶ Beware of all such profitable bandwagons.

Understanding the pathogenesis of coronary heart disease, knowing that combined hormone replacement therapy has an unambiguously beneficial effect on lipid concentrations but increases the risk of coronary heart disease, is challenging if oestrogen alone is cardioprotective.⁷ Menopausal hormones, especially progestogen, probably act by accelerating existing tumours in the breast. Once we get the life course biology right, the pharmacological role on disease prevention will mean massive opportunities (and mass markets). Hormone replacement therapy shows that good intentions can be seriously misleading; hence adequate, as opposed to merely plausible, science is required. Prof John Bailar of the University of Chicago reminds us, “We never know as much as we think we do.”⁸

Meanwhile, women with menopausal symptoms have to make decisions. In today's BMJ [14 Feb 2004] a clinical net benefit analysis provides insight by balancing current benefit for symptoms against future benefit and risk.⁹ It is one way of combining the risks and benefits of future events while ameliorating current discomfort. The latest risk estimates are combined with quality of life weightings associated with symptoms for women aged 50. This kind of analysis is essential but inevitably aggregated and somewhat static. However, the effects assumed for breast cancer and coronary heart disease are probably too conservative (because so many women in the trial stopped treatment). A relative risk of breast cancer of around two for combined treatment would considerably decrease the reported chance of net benefit compared with the 1.27 assumed. Similarly, a near doubling of risk of coronary heart disease in the first year would make things still worse, from an assumed overall relative risk of 1.08. These higher risk values would make the probability of net harm considerably greater for any woman.

Combined hormone replacement therapy is not indicated for women who have no symptoms. Only with severe symptoms (the consequent reductions in quality of life are such that a woman would sacrifice three months in a year to eliminate them) do these analyses show the net benefit with hormone replacement therapy to be positive. Taking hormone replacement for moderate symptoms requires special justification if an average women wishes to benefit in the long run. Menopausal symptoms and risk of breast cancer will always dominate women's decisions, while successfully preventing osteoporosis requires long term use of hormone replacement therapy and cannot be justified by the greater interim hazards of doing so.

We will be increasingly invited to play up the risks of the diseases against which hormone replacement offers effective and downplay the increased risks. As is already the case, we are invited to believe that the women's health initiative study¹⁰ and the million women study are less relevant than is currently thought or flawed with biases. Subgroups will be cited for which the bad effects are not observed–the latest results on coronary heart disease from the women's health initiative study provide (unsafe) opportunities to cite subgroups for which the bad effects are not observed.¹¹ This is a predictable bandwagon effect, not to be ignored–but such claims are often not plausible, never mind adequate. Reputations (and money) are at stake. Where is the scientific evidence for alternative inferences, more reliable than we now have? That the simple message above, intuitive to public health a while ago, has had to wait to achieve credibility is pitiable.

At least two further developments are now indicated. One is providing hormone therapy with which it is easier to cut the dose gradually. Women can test their individual metabolic balances with progressively lower doses and presumably thereby lower their risk of breast cancer and cerebrovascular disease. As it is, patches and pills can often be cut–but what is required is a product for achieving the lowest doses that can be found to combat symptoms with fewest side effects.

Further, the increased availability of natural remedies that do not need licences requires care with efficacy and safety. If they work for some, fine, but evidence from trials would be essential for women to be assured that they pose no greater risks than hormone replacement therapy. Safety data are vital for products whose constituents are not necessarily entirely known and that may contain, for example, phytoestrogens in large doses. What are the long-term effects of these preparations, taken on the assumption that being natural they are safe? Will adequate research be done to ensure that we avoid another half century of uncontrolled experimentation on menopausal women? Women have greater expectations of menopausal remedies now–given the false promise of the hormone replacement therapy bandwagon.

It can take decades to detect important and unanticipated side effects of medications reliably. Do the current regulatory provisions adequately provide for the sensible avoidance of more, tragic episodes? Tucker conservatively estimates an extra 1400 cases of breast cancer, 1200 cases of heart disease, and 1400 cases of stroke–against 860 fewer hip fractures and 1000 fewer cases of colorectal cancer per year in the United States alone.¹² Regulators and legislators will be contemplating the implications, as they did after thalidomide, and hopefully we will not get the marketing so wrong again. Severe menopausal symptoms are rated as having worse effects on quality of life than having any of the diseases–pills for symptoms and prevention pose complicated public health problems. Hormone replacement therapy may be a mere example of what is to come–the opportunities remain enormous.

Figure 1 Pharmaceutical company, 2002

Acknowledgements

This editorial was originally published 14 February 2004 in the BMJ as follows: McPherson K. Where are we now with hormone replacement therapy? BMJ 2004;328:357–58. It is reprinted here with kind permission of the BMJ Publishing Group. An abstract has been added by RHM using text from the article.