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Update July 2002:
The Women's Health Initiative (WHI) Trial
This is an update on the paper I originally wrote in 1997 for the Second International Congress on Sex and Gender Issues. The original paper is left intact at the end of this page for historical purposes.
Much has changed since 1997. My original update in 1999 discussed the results of the HERS study (see below), which involved women with a history of heart disease who were taking estrogen (Premarin) and progesterone (Provera). The results of this study indicated an increased risk for those women of new cardiac problems, compared to women with a history of heart disease who were not taking the hormones.
I summarized the HERS results as follows:
In the August 1998 Journal of the American Medical Association, the results of the Heart and Estrogen/Progestin Replacement Study (HERS) were published. (10) This was a randomized, placebo-controlled, clinical trial involving 2, 763 postmenopausal women with established coronary disease, averaging age 67. Patients were randomized to either an estrogen-progestin combination or placebo.
Over the average follow-up of 4.1 years, there were 172 coronary heart disease (CHD) "events" (coronary death or nonfatal myocardial infarction) in the hormone treatment (HRT) group, and 176 "events" in the placebo group. Hormone treatment had no effect on the risk of coronary events, despite favorable effects on the lipid profile (11% reduction in LDL-cholesterol, 10% increase in HDL-cholesterol). HRT appeared to increase the risk of CHD events during the first year of therapy and then decrease the risk after two years. In other words, there was a clear trend for benefit if patients tolerated the therapy for at least two years without an event.
HERS investigator Roger S. Blumenthal wrote in an editorial for Cardiology Today his hypothesis that the early increase in CHD events is due to a thrombogenic effect in a small percentage of suscetible women. Over time, these negative effects were outweighed by the positive effects on vasomotor tone and improvements in lipid profiles.
One very large-scale trial, and three smaller trials, are continuing to look at the effects of HRT on heart disease. The Women's Health Initiative (WHI) involves 27, 500 women with no prior history of CHD. This study will test both estrogen alone (in women who have had hysterectomy) as well as combined with progestin. The trial is scheduled to run for an average of nine years. The WAVE (Women's Angiographic Vitamin and Estrogen), WELL-HART (Women's Estrogen/Progestin and Lipid Lowering Hormone Atherosclerosis Regression Trial), and ERA (Estrogen Replacement and Atherosclerosis) trials will enroll up to 450 women each, using angiography to determine the progression of atherosclerosis in women with known coronary disease.
The results of the HERS trial, while disappointing to cardiologists treating women with CHD, are not necessarily applicable to populations without CHD. Perhaps screening for thrombotic disorders (protein C resistance, factor V Leiden mutation) will identify a group at high risk for HRT and give more assurance in treatment of low risk persons.
We did not have to wait nine years for the WHI results. On July 17, 2002, the Journal of the American Medical Association (JAMA) published an article entitled "Risks and Benefits of Estrogen Plus Progestin in Healthy Postmenopausal Women: Principal Results From the Women's Health Initiative Randomized Controlled Trial".
The study population was large: 16,608 postmenopausal women aged 50-79 years with no history of heart disease, and without a history of hysterectomy.. (There is another segment of the study which is still ongoing, evaluating the use of estrogen without progesterone in women who have had a hysterectomy. No early trends have yet been reported from this study.)
Participants were randomized to placebo versus active treatment, which consisted of conjugated equine estrogen (CEE), 0.625 mg daily, plus medroxyprogesterone acetate (MPA), 2.5 mg daily. (We know these drugs by their brand names, Premarin and Provera, but I will refer to them by the abbreviations.) The primary outcomes were coronary heart disease (CHD), as measured by new heart attack or cardiac death; and breast cancer. Secondary outcomes were stroke, pulmonary embolism, endometrial cancer, colorectal cancer, hip fracture, and death due to other causes.
On May 31, 2002, after a mean of only 5.2 years follow up, the WHI data and safety monitoring board recommended stopping the trial of estrogen/progesterone versus placebo because of a significantly increased incidence of breast cancer and CHD in the treatment group. Of all the outcomes measured, the only ones with a favorable "risk ratio" were colorectal cancer and hip fractures. Absolute risks were reported in units of "person-years." A unit of 10,000 person-years corresponds to 10,000 persons taking the drugs for one year, or 5,000 persons taking the drugs for two years, and so on. (The point being that the positive or negative risk ratio is magnified by the number of years a person has been taking the drugs.)
The absolute risks were as follows, in number of cases of disease greater or less than expected per 10,000 person-years:
Breast cancer +8
Pulmonary embolus +8
Hip fracture -5
Colorectal cancer -6
The absolute excess risk of all events included in the global index was 19 per 10,000 person-years.
The study group drew this conclusion: "The risk-benefit profile found in this trial is not consistent with the requirements for a viable intervention for primary prevention of chronic diseases, and the results indicate that this regimen should not be initiated or continued for primary prevention of CHD." (Emphases are mine)
|In interpreting the results of this study for an audience of male to female transsexual patients on hormone therapy, I must take into account many factors.
First: The specific reason for treatment in the study population, as mentioned above, is for the primary prevention of chronic diseases including coronary heart disease. In that context, the benefits of treatment do not equal the risks of treatment.
A much more extensive bio-statistical analysis of the Women's Health Initiative results, by Sarah Fox, Ph.D., is presented here.
So much of medicine is about this "risk-benefit" ratio. Any intervention involving a person's body involves some risks. The question is whether the benefits to be expected from the intervention are greater than the risks involved. For example, in my specialty of cardiology, it is generally recognized that angioplasty and stenting of a left main coronary artery is very high risk. For these patients, coronary bypass surgery will produce the same benefits and is actually lower risk - safer - than the less invasive stent procedure. I sometimes find myself in the position of trying to explain the risk-benefit ratio on a rather urgent basis.
So we see that CEE/MPA hormone treatment has been found to have a risk for coronary heart disease and breast cancer that overshadows the expected benefits. This study does not address the other uses of hormone therapy. Specifically omitted from the list are menopausal symptoms, which can be disabling for some women, and which are quite preventable with hormones.
In the case of transsexual medicine, the risk-benefit ratio will likely be quite different from that of postmenopausal women. The benefits of estrogen therapy are obvious in the physical feminization and the emotional stress reduction that nearly every MTF transsexual experiences. Many of us will look at the data and conclude, with our physicians, that the benefits outweigh the potential risks, even taking into account the results of the WHI study. Given this different risk-benefit expectation, I cannot make any blanket recommendation unfavorable to hormone treatment for transsexual persons.
Still, there are serious issues which we must address regarding the safety of hormone therapy.
First of all, I must stress that the risk-benefit ratio changes drastically in persons with a history of cardiovascular disease. A transsexual person who has had coronary disease or stroke is in a higher risk group than one who has no such history. I strongly recommend all such persons undertake HRT only under the supervision of a cardiovascular specialist, who can help with other medical treatments (blood pressure and cholesterol lowering, blood thinner medicines) to further reduce risks. HRT is not absolutely contraindicated in these persons, but it is more problematic.
Next, let's look at the actual hormones which were used in the WHI: conjugated equine estrogens and medroxyprogesterone. It is my strong opinion, which is shared by other TS physicians I know, that these two drugs are inferior and outdated. CEE has long been known to increase risk of blood clotting problems, and is sometimes poorly metabolized by the liver. There are also, of course, humanitarian reasons to avoid CEE due to the likelihood that the horses who furnish the urine from which CEE is made are subject to cruel treatment.
A much better drug is estradiol, a naturally occuring estrogen. It is available as tablets of 1 or 2 milligrams (generic or brand name Estrace). The usual dose for preop treatment is 4 milligrams daily, and for postop 2 milligrams. These tablets are also dissolvable, and many doctors (including gynecologists I have spoken with) recommend letting estradiol dissolve under the tongue rather than swallowing it. This not only gives better absorption, but avoids the metabolism by the liver which might stimulate more blood clotting problems. Estradiol can also be given by injection or by transdermal patches, but the sublingual route seems to me to be the best. I believe the use of estradiol rather than CEE will reduce a person's health risks, and urge physicians to change their patients to estradiol.
The use of progesterone is still open to question. I have often wondered just how much benefit we get from adding progesterone to estrogen treatment. Personally, I haven't taken progesterone for years. Still, I recognize there are TS persons who swear by its benefits, and we must consider how to best prescribe it. I feel very strongly that natural progesterone (brand name Prometrium) should be used in preference to MPA. Natural progesterone, as far as our present knowledge goes, does not have the adverse effects of MPA on blood cholesterol or blood pressure levels. There are no studies demonstrating health risks of natural progesterone. I recommend that physicians change their patients from MPA to Prometrium.
Cardiologists often speak of "risk factors" for heart disease. We refer to cigarette smoking, cholesterol, diabetes and blood pressure as treatable risk factors, as opposed to age and family history of heart disease, which are not treatable. When we cannot eliminate a risk factor, we simply become more diligent in screening for possible existing problems and in reducing those factors which are treatable.
Even if we do consider HRT as a "risk factor" for cardiovascular disease (and I'm not saying we must), we can choose to continue it under medical observation, and we can do everything possible to reduce the other risk factors. Keep your weight, blood pressure, blood sugar and cholesterol under control.
And for the sake of your overall health, by all means DO NOT SMOKE CIGARETTES. This is the single most important intervention for many persons. The risk of CHD and stroke is magnified many times in persons who smoke cigarettes while taking estrogen in any form. I know that quitting is not easy, but it must become a life priority for you, or sooner or later you will pay the price.
I am writing from the viewpoint of a cardiologist who also happens to be a male-to-female transsexual person. These recommendations are my opinion only, and are not to be taken as specific instructions or orders. Readers should discuss them with their personal physician prior to making changes in their medical treatment. To the best of my knowledge, this paper reflects the state of the science in 2002. If other studies are reported which will change the recommendations, I will give them prompt attention.
Rebecca Allison, M.D., FACP, FACC
Original 1997 Presentation
In my cardiology practice, I have observed the same patterns of disease incidence as my colleagues: prior to menopause, females have a much lower incidence of coronary heart disease than males. We may infer that female sex hormones convey a protective effect against cardiovascular disease. This inference is confirmed by large studies such as the Nurses' Health Study (1), designed to follow women with no known coronary disease prospectively. 48, 470 postmenopausal nurses were enrolled in this study. The risk for significant coronary artery disease was found to be twice as great in those women who did not take hormone replacement therapy.
How do these findings relate to hormonal treatment of male to female transsexuals?
Three Cardiovascular Effects
I will discuss the effects of estrogen and progestins on three aspects of cardiovascular physiology. The effect most recognized as beneficial is the effect on blood lipids - primarily cholesterol and its components. Elevated levels of LDL-cholesterol (low density lipoprotein cholesterol) lead to incorporation of cholesterol into the endothelium (internal lining) of the blood vessels, which begins an atherosclerotic plaque. HDL-cholesterol (high density lipoprotein cholesterol) has an opposite effect, promoting clearance of the harmful LDL cholesterol from the blood and aiding regression of plaque.
The effects of estrogen on blood clotting are more controversial. A study published more than twenty years ago, the Coronary Drug Project (2), evaluated the effects of five different drug regimens which were considered to have beneficial effects on cholesterol levels. Two of those drug regimens involved estrogen, and the study showed an increased tendency to thromboembolic (blood clotting) disorders. I will discuss the reasons this study should not be extrapolated to today's treament of male to female transsexuals. Some effects of estrogen may even promote thrombolysis (dissolving of blood clots).
Finally I will mention estrogen effects on vasoreactivity: the ability of the blood vessels to dilate and constrict appropriately in response to stimuli. The loss of normal vasoreactivity or vasomotor tone is associated with both an increased incidence of hypertension, and an increased tendency to endothelial dysfunction and atherosclerosis.
Do the Data Apply to Transsexuals?
Of course, most published data on the effects of female sex hormones on the cardiovascular system have been from studies performed on genetic females, rather than male to female transsexuals. One could question whether these studies are applicable to the transsexual population. Evidence suggests that they are, certainly in respect to vasoreactivity, and probably in respect to cholesterol.
Lipids (Cholesterol, Triglycerides)
The PEPI (Postmenopausal Estrogen/Progestin Intervention) Trial (3) comprised three treatment arms: estrogen alone; estrogen with medroxyprogesterone acetate (Provera); and estrogen with micronized progesterone. The LDL cholesterol was lowered in all treatment groups. The HDL cholesterol was higher in all groups, but the highest levels were obtained in women taking estrogen alone or with micronized progesterone.
Numerous other studies have confirmed the PEPI findings. In the August 28, 1997, New England Journal of Medicine, a study compared estrogen and progesterone with simvastatin, a standard drug treatment to lower cholesterol. It was found that estrogen increased HDL cholesterol comparably to simvastatin, and reduced both LDL-cholesterol and Lp(a), another lipoprotein which increases cardiac risk. (4)
When we consider the unquestionable benefits of lowering LDL-cholesterol, proven in many large scale trials, it becomes clear that estrogen therapy may play a beneficial role in preventing the cardiovascular complications of hypercholesterolemia.
Most studies indicate that estrogen increases plasma triglyceride levels. The significance of an elevated triglyceride in the absence of an elevated cholesterol is probably minimal, and the addition of progesterone seems to prevent much of the increase.
It has been thought that the risk of venous thrombosis and/or pulmonary embolism is increased in persons taking estrogen. In 1975 the Coronary Drug Project (2) evaluated five drug regimens reported to lower cholesterol. These drugs included conjugated estrogens in 2.5 mg and 5 mg dosages, as well as thyroxine, niacin, and clofibrate. The estrogen components of the study were terminated early because of increased incidence of thromboembolism and nonfatal myocardial infarction. It should be noted that the test subjects were elderly males with a known history of coronary disease. No controls were established with regard to other cardiovascular treatment, especially aspirin use and cigarette smoking. These results should not be extrapolated to the younger, healthy transsexual population.
The Lancet in 1996 reported a slight increased incidence of venous thromboembolism in women on postmenopausal hormone replacement, but the absolute numbers were very low: one in 5000 had venous thrombosis and one in 20,000 had pulmonary embolism. (5)
The incidence of thrombotic complications is significantly increased in women taking the higher doses of estrogen found in oral contraceptives, especially if they also smoke cigarettes. This is a good reason to counsel transsexual patients against taking excessive doses of estrogen. Lower doses are much less dangerous.
In low doses, estrogen inhibits platelet aggregation and reduces PAI-1, plasminogen activator inhibitor. (6) This promotes thrombolysis and helps to dissolve smaller intravascular thrombi.
Certain persons may have an increased risk for spontaneous thromboembolic disorders. The Leiden Factor V mutation occurs in 2 per cent of the population and increases risk of thrombosis 30 fold in women on oral contraceptives. These may be the persons who experience complications on low dose estrogen. Other abnormalities predisposing to blood clotting include deficiencies of Protein C or Protein S.
To summarize, "The effects of estrogen on hemostasis and thrombosis are highly dose dependent... in general, the balance is shifted away from thrombosis with low dose estrogen, and towards thrombosis with high dose estrogen." (7)
The layer of smooth muscle which surrounds the arteries constricts and relaxes in response to certain stimuli. The major stimulus is the biochemical pathway called the renin-angiotensin system. Angiotensin, an inactive precursor compound, is enzymatically converted to a strong vasoconstrictor called angiotensin II, which produces elevation of blood pressure and a tendency to endothelial dysfunction. Opposing this effect are the vasodilating compounds thromboxane, bradykinin, and nitric oxide, which stabilize the blood vessel and increase its ability to dilate.
Estrogen has definite effects on vasoreactivity in women and in men. It produces increased plasma renin activity, but diversion of renin-angiotensin activity away from angiotensin II and towards other compounds which are not vasoconstrictors. Estrogen increases production and activity of nitric oxide, functioning as an antioxidant.
Two studies in the June 1997 Journal of the American College of Cardiology reported on arterial reactivity in transsexual males taking estrogen (8), (9). They studied male to female transsexuals on long term estrogen, compared with matched male controls (8), (9) and female controls (9). They found significantly enhanced vascular reactivity in the transsexual groups, comparable to genetic females. The significance of this is that vascular reactivity allows for arterial relaxation and prevents spasm.
Conclusion and Recommendations
In conclusion, a regimen of relatively low dose estrogen, with or without micronized progesterone, can be expected to confer long term reduced risk of cardiovascular disease in postmenopausal females and in male to female transsexuals.
General evaluation of cardiovascular risk factors should include a measurement of blood pressure and a lipid profile (total cholesterol, LDL- and HDL-cholesterol, triglycerides) before and after initiation of therapy. Persons who smoke cigarettes should be emphatically urged to stop smoking, and should be made aware of the consequences and greatly increased risk of cardiovascular disease if they continue to smoke.
The routine use of low dose (81 mg) aspirin in male to female transsexuals, especially over age 40, should be considered, for persons who have no bleeding disorders or contraindication to taking aspirin. This low dose may help to counteract any possible increased incidence of thrombotic events. Transdermal or injectable estrogen may have a reduced risk for thrombotic problems, since they are less likely than oral estrogen to stimulate the liver to produce proteins involved in the clotting process.
Certain persons may be at increased risk of cardiovascular disease, and should have special evaluation prior to the initiation of estrogen therapy. Persons with a history of hypertension should be followed closely and treated appropriately, preferably with medication which inhibits angiotensin-converting enzyme. Persons with a past history or family history of blood clotting disorders should have laboratory evaluation for conditions such as Factor V Leiden mutation.
Persons with a family history of cardiovascular disease should have more extensive screening, with electrocardiograms and probably treadmill exercise testing. The finding of coronary heart disease should be managed in the usual manner. Such persons should not be automatically rejected for estrogen therapy. If appropriate attention is given to reducing other risks, an informed decision may be made between patient and physician to proceed. Several alternatives may be considered, including the use of a more powerful anticoagulant such as warfarin. Orchiectomy may permit lower doses of estrogen to be administered more safely.
Physicians treating transsexual patients should be encouraged to report results of long term followup with regards to the incidence of cardiovascular disease, so future data can be directly applicable to transsexual medicine rather than inferred from general population studies.
1. Stampfer MJ et al., "Postmenopausal estrogen therapy and cardiovascular disease: Ten-year follow-up from the Nurses' Health Study", The New England Journal of Medicine, Vol. 325, 1991:756-62
2. The Coronary Drug Project, Journal of the American Medical Association, Vol. 231, 1975: 360-81
3. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial: Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women, Journal of the American Medical Association, Vol. 273(3), 1995:199-208
4. Darling GM et al., "Estrogen and Progestin Compared with Simvastatin for Hypercholesterolemia in Postmenopausal Women", The New England Journal of Medicine, Vol. 337, No. 9, August 28, 1997: 595-601
5. Daly E et al., "Risk of Venous Thromboembolism in Users of Hormone Replacement Therapy", The Lancet, Vol. 348, October 12, 1996: 977-80
6. Julian D, Wenger NK, Heart Disease In Women, Mosby 1997, p. 253
7. Ibid., p. 252
8. McCrohon JA et al., "Arterial Reactivity Is Enhanced in Genetic Males Taking High Dose Estrogens", Journal of the American College of Cardiology, Vol. 29, No. 7, June 1997:1432-6
9. New G et al., "Long-Term Estrogen Therapy Improves Vascular Function in Male to Female Transsexuals", Journal of the American College of Cardiology, Vol. 29, No. 7, June 1997:1437-44
10. Hulley S et al, "Randomized Trial of Estrogen Plus Progestin For Secondary Prevention of Coronary Heart Disease in Post-Menopausal Women," Journal of the American Medical Association, Vol. 280, 1998: 605-613.