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Delimited power

With the confusion unraveled, hormonal therapy proves safe for treating only the alterations typical of menopause for short periods

Throughout the world millions of middle aged women felt themselves defenseless when faced with the news over the last two years concerning hormonal therapy, the use of sexual hormones to reestablish the balance created by menopause, when the ovaries quit functioning. From 2002 until now, newspapers, magazines and radio and TV programs have spread the unexpected results of two of the most important studies concerning women’s health, in which almost 30,000 healthy volunteers participated. Carried out by the National Institutes of Health (NIH), the largest medical research center in the United States, both the clinical trials were closed down before their forecast date.

The first to be interrupted treated the volunteers with daily doses of estrogens and progesterone and indicated: the prolonged use of these hormones to replace those that were no longer produced by the ovaries could do more harm than good to health. Now, the treatment only with estrogens, evaluated in the second trial, did not show preventative action against cardiovascular illnesses. The sensation of betrayal unveiled especially hit the likely users of this treatment, who sum half a billion women throughout the world – close to 14 million in Brazil.

The consequences of the initial exaggeration are not all bad. If on the one hand the information released increased insecurity in the face of the anguishing choice – to take or not to take the hormones? -, on the other, the role of hormonal therapy in this transition stage in the life of a woman, in which the organism suffers alterations comparable only to those at the start of fertility, marked by the first menstruation around twelve years of age, has become clearer. Today one knows: hormonal therapy is indicated to treat the disagreeable symptoms of menopause, but not to prevent cardiovascular and mental illnesses, as had been believed. “Used with caution, hormonal therapy continues to be safe”, says Edmund Chada Baracat, a gynecologist at the Federal University of Sao Paulo (Unifesp) and President of the Brazilian Federation of the Gynecology and Obstetrics Associations (Febrasgo).

The anticipated conclusion of these studies generated a vigorous debate among doctors and researchers, to the point of provoking a protest from the professional associations that deal with women health. Although the controversy seems to be only at the beginning, the forecast is that over the next three months documents that should guide the actions of gynecologists with respect to hormonal therapy should be released. To sum it up, the trend is to confirm: hormonal therapy is important and functions well. However, this is in specific cases such as the finality of mollifying the symptoms of menopause, and not to give protection against chronic illnesses.

Rigorous selection

In Brazil, the Febrasgo intends to launch within three months a manual with medical recommendations on the use of female sexual hormones in the period that anticipates and is understood as the menopause – the climacteric, when the levels of estrogens and progesterone in the blood begin to go down and oscillate considerably. In the United States, the North American Menopause Society (NAMS), one of the most respected associations in this area, is preparing a document with its official position on this issue, which will be announced at the society’s annual general meeting in October in the American Capital, Washington.

Clearly while this is going on one does not have to throw away the tablet bottles containing hormone pills. In the Baracat’s opinion, the Brazilian document does not discard hormonal therapy. Instead, it adopts more rigorous criteria for the indication of this treatment, a vision shared by other specialists. There is a general guideline: the gynecologists must analyze, case by case, the need for and the safety factor of this therapy before recommending it. The decision should be taken jointly with the patients, comparing the risks and advantages in the use of these hormones, which, according to scientific evidence, help to prevent osteoporosis – the weakening of the bones, accelerated after menopause ‘ and the mollifying of the alterations in the genital organs. The decrease in female hormones reduces the natural lubrication of the vagina and causes a tightening of the muscles of this organ, a reason for pain during sexual intercourse.

Accustomed to hearing wonderful things about this treatment, women at the start of the mature phase of life – around fifty years of age, when their children have already been raised and they are hoping that their worries have at last begun to dissipate – become even more apprehensive. What’s the best option? Run the risks and take up the hormonal therapy, with the chance of improving one’s physical disposition, maintaining the dream intact and the skin firmer? Or pass through menopause without the help of hormones, confronting, for three or four years, the symptoms that appear with the end of ovary activity and of the inconvenience of menstruations?

These are difficult choices confronted by many, since four out of every five women show at least one of the symptoms of menopause, especially physiological alterations such as hot flushes, rising heat waves that, various times per day, come about as pressure in the head and flow down through the face to the chest, burning just like fire. Brought about by the lack of estrogens, hot flushes set off psychological alterations. And those that occur in early morning cause insomnia and irritability, as well as contributing towards the occurrence of depression.

Detailed out in two articles in the Journal of the American Medical Association , one in July of 2002 and the other in April of this year, the results of this research knocked down – perhaps to a greater degree than one can explain – women confidence in hormonal therapy, until then considered the safest and most efficient alternative to combat the signs of menopause. It couldn’t be less.

The first clinical trial was able to count upon 16,608 volunteers aged between 50 and 79 years and pointed to, for example, the risk of developing breast cancer is 26% higher among women treated with estrogens and progesterone – the two types of sexual hormone that stop being produced during menopause – in comparison with those who received an innocuous compound (a placebo). Known as combined therapy since it brings together the two types of hormone, this treatment is indicated for women who maintain their uterus, since progesterone protects the organ against the effects of the estrogens, which raise the risk of cancer of the uterus.

As well as increasing the vulnerability towards breast cancer, the use of the two hormones elevated by 40% the risk of a vascular cerebral accident and by a third that of heart attacks, although they had reduced by 37% the probability of intestine cancer and by 33% that of hip fracture. The second trial, like the first one is part of the Women’s Health Initiative (WHI), a program launched in 1991 to investigate the illnesses common after menopause, pointed towards: the isolated use of estrogens increased by 33% the risk of the formation of clots in deep blood veins and the consequent probability of heart problems (heart attacks), in the lungs (lung embolism) and in the brain (vascular cerebral accident). On the other hand, the treatment with estrogens lowered the possibility of fractures as a result of osteoporosis and did not alter the development of breast cancer. It is worth recalling: neither of these two forms of treatment increased the mortality rate, according to the WHI coordinators whose project accompanied the health of 160,000 women.

The way they were presented, the figures are frightening. However, a detailed examination suggests that the reaction seems to be disproportional to the gravity of the results. In reality, the team that coordinated the trials presented a cautious opinion, which did not discard hormonal therapy in specific cases when selected with care. “Women with a uterus who currently take estrogens and progesterone should converse with their doctors in order to evaluate whether or not they should continue the treatment”, says at that time Jacques Rossouw, a WHI director. “If they had been consuming this combination of hormones for a short period in order to alleviate the symptoms (of menopause), it could be sensible for them to continue, assuming the benefits are greater than the risks.” Rossouw also counseled the revaluation of the prolonged use of these hormones to prevent illnesses and the same prudent tone appears in the presentation of the work with estrogens.

Changed habits

This is a position clearly distinct from that adopted throughout the world over the last fifteen years, a period in which prescribing female hormones grew fast. Since the 1950-s, studies suggested that the sexual hormones – in particular the estrogens – exercised protective action on the heart. In reinforcing this hypothesis, the epidemiological data had shown that up until about fifty years of age, when menopause generally occurs, the number of women with cardiac and vascular problems is much lower than men. From this age onwards the levels of estrogens and progesterone get lower and the cardiovascular problems become more frequent. Thus, the increase in the risk of cardiovascular illnesses began to be associated with the reduction of these hormones in the blood.

In 1966, American researchers made up a test in which they applied different treatments – among them, estrogens – to men with cardiac problems. The objective was to verify the influence of these measures on the reappearance of heart complications. Six years later, the organizers interrupted the part of the trial with the estrogens as a consequence of the high rate of recurring cardiac problems. However, in this case the volunteers were more likely to have had problems with this organ.

In the middle of the 90’s, another clinical experiment – this time with women who had suffered from cardiac problems, such as a heart attack – tried to evaluate if the association of estrogens and progesterone would diminish the risk of the disease coming back. Known by the acronym Hers (The Heart and Estrogen/ Progestin Replacement Study), this study presented yet again a result unfavorable to hormonal therapy. But it was not sufficient to discredit it, since this study had also counted on people with a high risk of suffering from cardiovascular disturbances.

Other studies have continued to indicate that the use of estrogens diminishes by up to 50% the risk of healthy people developing cardiac illnesses. All of them, nevertheless, had presented the same fragile point: they only included women who had already been taking this hormone, without confronting results with those who had not been in treatment. A comparison of the benefits and the damage done by hormonal therapy in people with their health in order was needed, and they would be selected in a chance manner to receive the hormones or a placebo, as is now happening with the WHI, whose results do not reach the importance proportioned by the alarm that they caused.

Immediate effect

Randall Stafford, from Stanford University in the United States, estimates the prescription and consumption of female hormones for North Americans between 1995 and 2003. In an article in the Journal of the American Medical Association on January 7th , he demonstrated that the effects of the divulging of WHI and Hers were not small. The calculations showed: the number of prescriptions for hormonal therapy in the United States rose from 58 million in 1995 to 90 million in 2002. But then dropped following the publication of the trials, reaching a level lower than the initial one, around 57 million prescriptions.

As was expected, the most representative drops occurred with the prescriptions indicated with the greatest frequency in the United States, and for this reason, adopted by the WHI: Premarin (conjugate estrogens of equine origin) and Prempro (equine estrogens and progestagen, a compound with action similar to that of progesterone), both produced by the Wyeth laboratory.The fear aroused seem to overblown. In the communications in which they announced the suspension of research, the WHI coordinators made clear: it is not possible to generalize the data.

“This study didn’t have as its objective an analysis of the risks and benefits in the use of these hormones for short periods in the treatment of menopause symptoms”, the text informs, which is available on the Internet page of the National Heart, Lung and Blood Institute, one of the twenty seven centers of the National Health Institutes of the United States. Both experiments were planned with the goal of measuring, in the case where they exist, the benefits of this treatment against cardiovascular diseases, an application very distinct from the main indication of this therapy – to placate the symptoms of menopause. As a secondary objective, there was also an attempt to verify if the consumption of female hormones for periods greater than five years (long term) influenced in a positive manner the health of the bones and the nervous system.

In the article on the use of estrogens published in April in the Journal of the American Medical Association , the authors of the study state: “The data corroborates the current recommendations of the Food and Drug Administration (FDA: the American agency that controls medicines) for women who have already passed through menopause: they should make use of a mixture of estrogens only to mitigate the symptoms of menopause, at the lowest dosage and for the shortest time possible”. In reality, the FDA also indicates the use of the therapy in order to prevent osteoporosis.

Furthermore, there were reciprocal exaggerations. The articles and the news stories highlighted the relative risks. “In the clinical area, the most important thing is to know the absolute risk”, comments the gynecologist Aarão Mendes Pinto Neto, from the Medical Sciences College of the State University of Campinas (Unicamp). An example helps to understand the difference.

In the trial with estrogens and progesterone, the women who received the hormonal therapy ran a 26% greater risk of developing breast cancer than those who took the placebo – this is relative data, which indicates an elevated proportion. In absolute terms this number represents eight more cases of breast cancer in a group of 10,000 women per year of treatment. Or that is to say, while every year 31 cases of cancer per group of 10,000 women who use the placebo were detected, during the same period this level was at 41 cases per 10,000 among those treated with the hormones. “The absolute risk is thus not so very high”, comments Baracat, from Unifesp.

The epidemiologist Deborah Grady, from the University of California in San Francisco, considered to be a specialist in the risk analysis and benefits of hormonal therapy, published in the New England Journal of Medicine on May 8th an attacking commentary on the WHI set of results. In Deborah’s opinion, there is a balance between losses and gains. The risks brought about by this treatment with the objective of preventing chronic illnesses such as osteoporosis are small. But as well so are the benefits, which do not justify its indication for healthy women who do not show any hot flushing, for example. In essence, Deborah reinforces the FDA position – the use of hormonal therapy only to combat the symptoms of menopause.

By luck, the physical and psychological annoyances of menopause are the main reasons that lead women in climacteric to the gynecologist – exactly as in Brazil. Researchers from Unicamp interviewed 456 women at home in Campinas, a city in the interior of the State of Sao Paulo, aged between 45 and 60 years. The objective was to discover why they had gone to the doctor. Published in 2002 in theRevista de Saúde Publico (Public Health Magazine), the study revealed that the symptoms of menopause had lea 63% of them to the gynecologist. Of this total, 82% said that they felt nervous, 70% had hot flushes, 68% headaches and 59% intense sweating, according to another article published in December of 2003 in the same magazine. One in every five women in menopause stated that they had felt a reduction in sexual desire.

“The sample studied represents the Southern and Southeastern regions of the country”, says Pinto Neto, one of the research study’s authors. But is does not apply to all, since the characteristics of women in the North and Northeast are distinct. An analysis of the profile of women who undergo hormonal therapy, carried out by Renata Aranha and Eduardo Faerstein, from the State University of Rio de Janeiro, showed: in general, they had studied longer, belonged to the highest social classes and looked after their reproductive life cycle better than those who did not undergo therapy.

On one point all appeared to agree. The WHI research has responded to important questions, but this is not the final word. Doubts remain, and the principal merit of these studies is perhaps also their weakest point. The WHI study is the largest evaluation upon the impact of the use of female hormones after the start of menopause carried out with a sample and of treatment so homogeneous – Premarin compared with a placebo, and Prempro versus a placebo.

However the questioning suggests that their should be an examination of the age of the participants. Two thirds of them were more than 60 years of age when they began taking hormones, an age considered to be advanced. In general, menopause occurs around 50 years of age, when the risks of cardiovascular problems are less and their symptoms last two or three years. Furthermore, 35% of the volunteers were obese, a factor that raises even more the probability of the likelihood of cardiac and vascular illnesses.

Studies with laboratory animals have suggested that the estrogens could exercise a protecting role upon the central nervous system if administered as soon as possible after menopause begins, as was observed by Edmund Baracat, Ivaldo Silva and Luiz Eugenio Mello, all from Unifesp, in an article published at the end of 2003 in the magazine Menopause . But the data does not allow for conclusions, since research with human beings shows controversial results. A smaller sample of the WHI data, analyzed in an article in the Journal of the American Medical Association on June 23rd for example, does not recommend hormonal therapy for the prevention of illnesses concerning the central nervous system, as it increases the risk of schizophrenia and Alzheimer’s disease.

In Science of May 28th American specialists published a revision article concerning hormonal therapy in which they called attention to another detail of the WHI. In this project, the researchers evaluated only one type of formulation. Women without a uterus received 0.625 milligrams of equine estrogen, while those with a preserved uterus took 0.625 milligrams of equine estrogen and 2.5 milligrams of medroxyprogesterone acetate – high levels for the age of the volunteers.

Another important point: the estrogens of Premarin and Prempro are of animal origin, extracted from horses, which, according to the specialists, could well function in the human body in a different mode from female estrogens. It is believed that the manner in which the hormones are administered interfere in their efficiency. In the WHI tests, the hormones were consumed orally and for this reason are processed by the liver before falling into the blood stream – different from what happens naturally in the organism.

In search of alternatives

The team of the endocrinologist Poli Mara Spritzer, from the Federal University of Rio Grande do Sul, tested twenty women with moderate levels of high blood pressure another manner of administering progesterone and of estrogens over the period of a year. Described in 2003 in two articles – one in Experimental and Clinical Endocrinology & Diabetes and the other in Gynecological Endocrinology -, the experiment showed that hormonal therapy could be safe for treating women with hypertension for this period, assuming that they used natural hormones, but more similar to those produced by women than those of horses, in lower doses and applied by other methods. Instead of pills, the team from Rio Grande do Sul used estrogens in the form of gel, spread on the skin, and progesterone applied inside the vagina.

Alternatives to combat the symptoms of menopause, such as the use of isoflavone, a compound extracted from soya, or of a medicine that acts upon the central nervous system, just like the anti-depressives, as yet have not shown themselves to be efficient against hot flushing. As well as this, no other treatment has been so deeply studied as that of hormonal therapy. Whilst this is going on the researchers affirm: it is necessary to plan more appropriate studies for the evaluation of hormonal therapy in younger women, with lesser risks of illnesses in general, as well as, of course, the search for new treatments.

The Project
The Perception and Attitude of Women Confronting Climacteric and Menopause (96/10341-2); Modality: Regular Line of Research Project Assistance; Coordinator: Aarão Mendes Pinto Neto – Unicamp; Investment: R$ 16,942.00 (FAPESP) and R$ 8,000.00 (FAE/Unicamp)