BMJ. 2012 Oct 9;345:e6409. doi: 10.1136/bmj.e6409.
Effect of hormone replacement therapy on cardiovascular events in recently postmenopausal women: randomised trial.
Bio-identical estradiol was used in this study. With a progestin in women with a uterus.
"In this randomised trial including 1006 women we found a significantly decreased risk of the composite endpoint of death, heart failure, or myocardial infarction when hormone replacement therapy was started early in postmenopause. The beneficial effect occurred in the 10 years randomisation phase and was maintained for an additional six years of non-randomised follow-up. The trend for all components of the endpoint was in the same direction (figs 3 to 6) and this finding was not associated with an increased risk of cancer, stroke, deep vein thrombosis, or pulmonary embolism. Thus this study implies that hormone therapy started in recently menopausal women and continued for a prolonged duration does not increase or provoke adverse cardiovascular events such as mortality, stroke, heart failure, or myocardial infarction."
"For the subgroup of women who had undergone hysterectomy and who received unopposed 17-β-estradiol/control we found a significant reduction in the combined endpoint of mortality or breast cancer in the treatment group. This is in accordance with findings from the Women's Health Initiative, where 10 739 women who had undergone hysterectomy were randomised to conjugated equine oestrogen or placebo 0.625 mg/day; all women (irrespective of age) in the conjugated equine oestrogen arm experienced a reduced risk of breast cancer (hazard ratio 0.77, 95% confidence interval 0.62 to 0.95).35"
"This is the first randomised trial to study healthy women treated early in postmenopause with 17-β-estradiol and norethisterone acetate, and the only study with a 10 year randomised intervention. Additionally the women were followed for a further six years after discontinuation of randomised treatment. Our findings suggest that initiation of hormone replacement therapy in women early after menopause significantly reduces the risk of the combined endpoint of mortality, myocardial infarction, or heart failure. Importantly, early initiation and prolonged hormone replacement therapy did not result in an increased risk of breast cancer or stroke."
The following study from 1998 on 46 male-to-female transsexuals shows that treatment with bio-identical estradiol does not pose risks.
Arch Sex Behav. 1998 Oct;27(5):475-92.
A follow-up study for estimating the effectiveness of a cross-gender hormone substitution therapy on transsexual patients.
"This follow-up study was carried out to validate the effectiveness of cross-gender hormone therapy embedded in a multistep treatment concept for transsexual patients. This therapy described in detail by the authors elsewhere and presented briefly below provides cross-gender hormone substitution to obtain an assimilation of secondary sex characteristics to the desired sex as quickly as possible. Personal and social background data of 46 male-to-female (M-to-F) and 42 female-to-male (F-to-M) patients passing through different stages of the treatment concept were included. In the Endocrinological Outpatient Clinic of the Max-Planck-Institute/Munich the effectiveness of cross-gender hormone replacement therapy as well as frequency and distribution of side effects were examined by follow-up examination of endocrinological parameters. Cross-gender hormones were administered either parenterally or orally. Blood samples were collected routinely after 2 to 6 months depending on the duration of hormone substitution and complication rate. The incidence of hyperprolactinemia in estrogen-treated M-to-F transsexuals lies in the range of studies published before, whereas the number of patients developing galactorrhea is significantly lower in our patients. The incidence of thromboembolic events during the time of cross-gender hormone treatment in our patients is negligible. Changes in hematological parameters are observed under cross-gender hormone therapy. With the cross-gender hormone regimen performed by us it is possible to generate less side effects in the treatment of transsexual patients than described before."
From full study (I have access), the most common side-effect was high levels of prolactin (24, probably due to Androcur which is known to increase prolactin). There was NO incidence of deep-vein thrombosis or embolism. There was only 1 single case where blood clotting parameters were pathologically (abnormally) altered under high-dose estrogen (not specified how much or if oral vs injected). Hemoglobin (red blood cells) also decreased which is to be expected in 15 of them.
Interestingly, it is noted further in the study that "single case reports of breast cancers...have been reported", not in the study, but in the general literature, which is to say that breast cancer risk is very rare in transsexual women.
This other study also shows that treatment with bio-identical estradiol poses very little risk as compared to non-bioidentical.
Exp Clin Endocrinol Diabetes. 2005 Dec;113(10):586-92.
Endocrine treatment of male-to-female transsexuals using gonadotropin-releasing hormone agonist.
Dittrich R, Binder H, Cupisti S, Hoffmann I, Beckmann MW, Mueller A.
SourceDepartment of Obstetrics and Gynaecology, Erlangen University Hospital, Universitätsstrasse 21-23, 91054 Erlangen, Germany
"Sixty male-to-female transsexuals were treated with monthly injections of gonadotropin-releasing hormone agonist (GnRHa) and oral oestradiol-17beta valerate for 2 years to achieve feminisation until SRS. There was a significant decline in gonadotropins, total testosterone and calculated free testosterone. In general, the treatment regimen was well accepted. An equal increase in breast size was achieved compared to common hormone therapy. Two side effects were documented. One, venous thrombosis, occurred in a patient with a homozygous MTHFR mutation. One patient was found to be suffering from symptomatic preexisting gallstones. No other complications were documented. Liver enzymes, lipids, and prolactin levels were unchanged. Significantly increased oestradiol and SHBG serum levels were detectable. In addition, an increase in bone mass density, in the femoral neck and lumbar spine, was recorded. We conclude that cross-sex hormone treatment of male-to-female transsexuals using GnRHa and oestradiol-17beta valerate is effective, and side effects and complication rates can be reduced using the treatment regimen presented here."
The only complications were seen in individuals with preexisting conditions or mutations.
A long-term follow-up study of mortality in transsexuals receiving treatment with cross-sex hormones
Eur J Endocrinol April 1, 2011 164 635-642
"The increased risk of cardiovascular mortality was observed only in those who were still using ethinyl estradiol. No increased risk was found in former users who had changed to other formulations and lower doses of estradiol."
"An increased risk of cardiovascular disease was also reported in women using oral contraceptives (OC), in particular if they used OC pills with a higher ethinyl estradiol content, even more so when they were smokers (21, 22, 23). The increased risk, however, disappeared after discontinuing OC use (24). In those MtF who had continued using ethinyl estradiol, subjects had used equally relatively high doses (...) up to advanced age, which could explain our finding of an increased rate of cardiovascular death."
"The total cancer mortality rate was not increased. The statistically significant increase in mortality rate of lung cancer may be related to heavier smoking in the transsexual population."
""The decreased mortality rate for colon cancer, also observed in the Women's Health Initiative (14), is similarly remarkable"
"We did not observe any cases of breast cancer in the population studied, neither in MtF nor in FtM, in agreement with the low prevalence of breast cancer in the literature."
From The TRANSSEXUAL PHENOMENON
Harry Benjamin, M.D. , 1966
"The fear of developing cancer through hormone treatments crops up from time to time, especially if there are irresponsible newspaper reports, for instance, of the results of someone's experiments with mice and rats to produce cancer artificially with estrogen. Such experiments admittedly have no bearing on the reactions of the human organism. Is the attempt to apply experiments with the cancer-susceptible mouse to the human area anything but ludicrous?" asked Dr. Robert A. Wilson, whose extensive work has thoroughly debunked the cancer fear of women receiving estrogen during their change of life.[5]
In my own clinical material of 152 male transsexuals, 141 of whom were treated with medium to fairly large doses of estrogen, some over several years, no incident of breast or any other cancer was observed. One may argue that these are mostly young men, less apt to develop a malignancy. The experiences of urologists, however, who treated elderly and old men with even much larger doses of estrogen for cancer of the prostate, must then be recalled. With the exception of one disputed case of breast cancer (it may have been a metastasis of the prostatic cancer) reported in the medical literature, no such incident was observed in hundreds if not thousands of cases. In a personal communication from Dr. Elmer Belt, one of the outstanding and most experienced urologists in the country, he said:
In regard to the taking of Stilbestrol as a cause for cancer of the breast, we have placed several hundred men on this material (I imagine if we were to search our records we would find the number to be in excess of two thousand) and in all of these cases we have not seen a single occurrence of cancer of the breast, although the dosages we used were of a very high level. "
"Finally, and to conclude the discussion of the nonsurgical therapy for transsexuals, it may be most interesting in future years to watch these patients who have received estrogen over a long period of time. Will they be less prone to develop coronary heart disease and other circulatory ailments that go with the process of aging? A wellknown cardiologist, noted for his research in cholesterol metabolism, who had occasion to see a number of transsexuals under estrogen therapy, remarked jokingly, "These people will probably live forever.""
