By Amanda Grimes
It is important to point out that this article is an observational piece and not a clinical study. As the author I am not medically qualified, or a clinical researcher. I have though, been a patient who has consistently used Hormone Replacement Therapy (HRT) as part of a treatment regime for Gender Identity Disorder (GID) and Transsexualism for the last 32 years. During that time I have meticulously monitored my general health and done my upmost to keep abreast of the latest clinical studies involving the use of HRT and hormone suppressant treatment. For this reason I will only address the use of HRT in Male to Feminine (MtF) transsexuals, with which I am familiar.
The treatment of transsexuals with HRT is often criticised by those who oppose the medical treatment of transsexuals generally, without any real understanding of the effects and risk factors surrounding their use. All too often, gender critical commentators will claim increased risks of cancer and other life threatening conditions inherent in the use of HRT. While there is some validity in the nature of their statements, these are often misdirected as there have been no long term studies carried out in relation to the use of HRT by transsexuals.
(Note: see Addendum. Ed.). All available studies of the effects on health of HRT use have to date been carried out on groups of postmenopausal natal females aged between 50-79 years old. While there are elevated risks from certain morbidities in long term use of HRT they are for the most part overstated or of more import not relevant to the treatment of MtF Transsexuals.
While taking any medication carries the risk of side effects and complications, claims that “taking hormones” causes cancer, stroke and cardio vascular disease, are vastly overstated and misleading. In this article I will examine these claims and in comparison to the significant and more up to date medical research in this field and I shall to reference it to its application in MtF Transsexual patients.
There are several types of hormonal medication in use for the treatment of transsexualism the more common of which are:
Oestrogen – Being either synthetic oestrogens such as Estradiol® or naturally occurring equine oestrogens such as Premarin®. Oestrogen is the primary feminising hormone and is responsible for the redistribution of fatty tissue on the body and the reduction in body hair.
Progesterone – Being ordinarily used for short term periods during the initial stages of transition. Long term use of this type of hormone should be avoided. These drugs are derivatives of Medroxyprogesterone such as Progestin® and Provera®. Use of progesterone is usually discontinued following Genital Reassignment Surgery (GRS) such as Vaginoplasty or Orchiectomy as they are primarily used to consolidate the redistributed body fats and after that their use is limited if not null in respect to non-uterine conditions (i.e. they are only relevant if you have a uterus).
In addition to these drugs, though I personally have no first hand experience of effects of them, as they were not in use when I transitioned, are Hormone Blockers used to negate or “block” the effects of the natal hormones of the patient. These are split into two types of drugs: Gonadotropin Releasing Hormones (GnRH) antagonists such as Lupron® and hormonal suppression drugs like Spironalactone and similar based drugs like Aldactone®. GnRH derivatives are used in pre-pubertal subjects to “block” the onset or continuance of natal puberty and Spironalactone-type drugs are used to suppress natal hormone production in post-pubertal subjects. We shall address these and the risk/benefit of these types of drugs in another article, as they deserve closer examination.
HRT increases the risk of Cancer!
Early trial studies were carried out by the Women’s Health Initiative (WHI) between 1993 and 2006 and the results published at various points throughout the trial. 160,000 subjects were studied. They were in three groups, two receiving active HRT and one a placebo. One using HRT took a combined 0.625mg of conjugated oestrogens and 2.5mg Progestin daily, a second group took oestrogen only HRT and the third was a control group medicated with a placebo. All groups were monitored for instances of increased colorectal, breast, ovarian and uterine cancers. In addition subjects were monitored and recorded for instance of venous thromboembolism, stroke and coronary heart disease (CHD).
Increased risks were noted in all but a few morbidities for the groups using HRT, though the elevated risks were not significant. We shall deal with the elevated numbers and what they mean in a moment, but there are certain aspects here which are important to note.
1. MtF TS are at no risk from uterine or ovarian cancers as we possess neither a uterus nor ovaries.
2. The elevated risks in other areas were in a group who commenced HRT between 50 and 79 years old; that demographic is already at increased risk for all listed morbidities.
3. The study looked only at subjects taking the combined Oestrogen and Progesterone HRT.
Results in both the HRT groups showed that cases of endometrial cancers were decreased in relation to those in the general population. However the results were affected by the larger number of women who had undergone hysterectomy before or during the trial period.
The combined oestrogen/progesterone (EP) group showed a marked increase in the instances of breast cancer, being an increase of +8 cases on the Attributable Risk to the Global Index, of 19 cases per 10,000 person-years seen in the general population.
In the findings of the 2002 stage report and a review of all papers brought together by James Clarke carried out in 2006, significant risk reductions were noted in the Oestrogen (E) only group across a wide number of risk factors. Below are excerpts from the report in respect of each of the significant risk to TS patients. The links to the reports via the Lancet review are contained at the end of this article.
Invasive breast cancer (IBC) 2002 paper
The value of 26% increase in the relative risk of invasive breast cancer in the E+P group has been cited over and over by many people in the scientific and non-scientific media, even though the authors of the WHI paper acknowledge that it “almost reached nominal statistical significance”. Since “almost” is not statistical significance, the statement should have been: there was no significant difference in IBC risk between the placebo group and the E+P group. As in the analysis of CHD, if the authors had used adjusted confidence intervals there would be no doubt that risks were not increased.
The authors then indicate that “the weighted test statistic used for monitoring was highly significant”. This statistic would not have been elevated if the authors had examined the data more carefully. The apparent increase in risk ratios from years 2-5 is accompanied by a decline in the placebo groups (Figure 3A and Figure 3B). As discussed below, in the final analysis of these data this upward trend is not statistically significant (Figure 4A and Figure 4B). The final hazard ratio of 1.26 has an adjusted 95% confidence interval of 0.83-1.92, and the absolute risk increase is 0.08% or 8/10,000 person years. Such a broad confidence interval which includes 1.0 indicates there is no significant increase in risks due to hormone use. In addition, mere inspection of the data in Figure 3A clearly shows that four of the six values are not different from the no effect level, thus making it very unlikely that any real differences in risk existed.
Invasive breast cancer in the estrogen only studies
In the estrogen only arm of the WHI study invasive breast cancer was decreased by estrogen treatment [Anderson et al., 2004]. The hazard ratio was not statistically significant: 0.77 (CI, 0.59-1.01). A protective effect may be likely since the number of risk ratios which were near or below the no effect level were greater than those above this level (data not shown). In the final report on this aspect of the study similar data and conclusions were reached [Stefanick et al., 2006]
Venous thromboembolism in the estrogen only study
No data on a yearly basis were published for VTE in the estrogen only study; therefore, it was not possible to graph risk ratios or percent incidence as a function of time [Anderson et al., 2004]. The authors indicate the final hazard ratio was 1.33 (95% CI, 0.86-2.08) and that this was not significant. However, they say that the risk for the subgroup, deep vein thrombosis (DVT), is significant (HR 1.47; CI, 0.87-2.47). Since no yearly data were provided for DVT it was not possible to draw a graph; however, the authors did provide yearly data for pulmonary thrombosis (PE) which show the same erratic risk ratio and incidence values as in most of their other data (data not shown). Therefore, it is likely that the data for deep vein thrombosis shows similar, if not greater variation. This likelihood, plus the small absolute increase (0.06%) and the broad confidence intervals which cross 1.0, make it difficult to accept these values as significant.
This expectation of a high degree of variability and uncertainty was borne out by the data in the final paper from the WHI studies on venous thrombosis [Curb et al., 2006]. In this paper the authors provide hazard ratios and non-adjusted 95% confidence intervals for DVT, PE and venous thrombosis, VT (Figure 7). If adjusted 95% CIs had been used, all values would have included 1.0 and would have been judged insignificant. It is clear why the authors of this paper make no statement concerning statistical significance.
Instead, they state that VT risk is associated with the use of estrogen during the first two years of exposure. It is clear that the very wide non-adjusted confidence intervals associated with the 0-2 year span for all three groups make it impossible to conclude anything concerning this period. The later time periods show no increased risk due to hormone treatment. It is puzzling why the authors in the 2004 paper conclude that the HR for DVT is significant and yet in the 2006 paper they conclude the HR is not significant, yet the data are virtually identical.
Coronary heart disease in the estrogen only study
In this study the authors conclude that estrogen alone does not affect the risk of CHD in post-menopausal women (HR, 0.91; 95% CI, 0.75-1.12; [Anderson et al., 2004]). The final results of the estrogen alone study were divided into age groups of 50-59, 60-69 and 70-79 years [Hsia et al., 2006]. The conclusion was that estrogens provide no protection against CHD with the possible exception of those in the 50-59 age group (HR, 0.61; 95% nominal CI, 0.25-1.50). However, the incidence and risk ratio data for CHD in each of these groups is more erratic and variable than any of the data shown thus far. These results will be the subject of another paper and will not be discussed further here.
Stroke in the estrogen only study
Risk ratios and incidence
The risk ratios for stroke in this study are low but generally above the no effect level (Figure 9A). These minimal ratio values are the result of very variable incidence levels, which indicate that these groups were not different from one another for the first five years of the study (Figure 9B). This period is followed by a small increase in the estrogen group at year 5, which is followed by a steady decline to low levels equal to those of the placebo group. Such declines in the risk ratio and incidence in the estrogen group suggest a beneficial effect of estrogen treatment. The authors indicate that the final hazard ratio of 1.39 was significant; however, this was based on non-adjusted 95% CI. When the adjusted 95% CI is used (0.97-1.99), the HR becomes statistically insignificant.
What This Means
These and further studies, carried out by Stamford University and the WHI in 2012, 2015 and 2016, support the initial findings that increased risks of breast cancer are associated only with combined Oestrogen and Progesterone HRT and that no significant increase arises from Oestrogen only HRT. So if you are taking Oestrogen-Only HRT you are at no more risk of developing breast cancer than the general population.
Since the publication of those later reports Wyeth has withdrawn its production and sale of combined HRT such as PremPak C® in most Western countries.
In respect of colorectal cancers, there was a small but marked reduction in the instances of these in both the Oestrogen Only and Combined HRT groups. This means you would be less likely to contract bowel cancer than a woman who is not prescribed HRT.
Coronary Heart Disease (CHD)
The studies in Oestrogen Only HRT showed no significant change in instances of CHD except in the 50-59 age group where a reduction of CHD was noted. No conclusions are drawn from this and the issue is subject to further studies.
Venous Thromboembolism (DVT)
A slight increase of 0.06% risk was noted in the instances of DVT in the Oestrogen Only group and that was only noted within the first 2 years of treatment. This is a strong indicator that these instances were elevated in subjects with a predisposition for DVT and other venal condition. After year 2 there was no noted increased risk.
There is an elevated risk of stroke in both Combined and Oestrogen Only HRT though that equates to a hazard ration of 1.99 compared to 0.97 Global Index. This means for every 10,000 women per year taking Oestrogen Only HRT and additional 1 will be subject to stroke. The authors of the report concluded that this was insignificant.
As can be seen from the results of the studies cited above the risk from HRT in FtM Transsexuals is minimal and often overstated by the general media and those who are critical of their use in TS. Many of the elevated cancer risks associated with HRT affects body parts which are not relevant to TS patients. There is it seems no elevated risk beyond that of the general female population for those body parts which are common to both natal female and MtF TS.
It is though important to note that all the risks listed herein are subject to environmental and lifestyle factors.
It is essential therefore that TS do their best to avoid things like excessive alcohol consumption, smoking and higher levels of obesity just as it is for the general population. Where possible TS should also keep regular checks on their general health including blood pressure, liver function and breast health as a precaution. Personally as a woman in my 50’s now I have a doctor applied blood pressure check every six months, liver function every twelve months and mammogram every eighteen months in addition to my own personal checks.
In addition to these it is also reasonable to assume a decreased risk in typical male cancers such as testicular and prostate cancer. The first is obvious in post-operative TS and the second results from the fact that the majority of treatments available for men with prostate cancers involve blocking testosterone or the administration of female hormones.
The risks therefore are at best positive or neutral and at worst minimal and I would encourage all those concerned with transsexuals and their care to carefully research all the available data for themselves before believing statistics bandied around on the main or social media platforms.
Much of the criticism of the use of HRT in TS patients is poised in such a way as to appear revelatory to the unsuspecting user of such drugs. It is however important to recognise that the propensity for elevated risk of cardio conditions and cancers has been highlighted for decades by those prescribing HRT to their TS patients.
Every time one opens a new pack of oestrogen pills the manufacturer’s warning list is enclosed advising of all possible side effects from the mundane to the potentially life threatening ones. This does little or nothing to deter these patients from taking these drugs or undertaking much more risky surgical procedures. For myself (and I have heard similar things to this from others) if the doctor had said unequivocally, “Take this it will allow you to can live as a woman but in 30 years it will kill you!” I would still have elected to take the HRT, so unacceptable would be the alternative.
While this article was in editorial review, a paper was published, entitled
‘Cross-sex Hormones and Acute Cardiovascular Events in Transgender Persons: A Cohort Study’. This paper, detailed a broad research study into the incidences of ‘venous thromboembolism (VTE), ischemic stroke (IS) and myocardial infarction in transgender persons’ to see if there was correlation with hormone use.
The study, which is available HERE (link) concluded that ‘The patterns of increases in VTE and ischemic stroke rates among transfeminine persons are not consistent with those observed in cisgender women. These results may indicate the need for long-term vigilance in identifying vascular side effects of cross-sex estrogen.’
However, though some elevation of risk was observed, this was very low, less than for other risk factors like smoking or alcohol consumption and the authors did not recommend changes to the prescribed hormone regimes for transitioning subjects, only that their doctors and other health advisors should maintain vigilance. This is in line with observations in the article above.
We found a number of questionable areas in the 2018 paper:
• There is no mention of the age of the patients at the date of ACVE
• There is no direct subject contact; all data is taken from electronic client records only
• These are variable drug dosages rather than dose-specific studies with only estrodiol (synthetic oestrogen) and Spironalactone (No equine derived HRT was considered, nor alternative testosterone-blockers.)
• There was no distinction between the effects of estrodiol and those of Spironolactone.
• No separation of studies with post-operative TS, who would not have used Spiro; comparable studies in natal females never use testosterone suppressants such as Spiro
• The study could not determine whether patients were obtaining alternative or further HRT outside of the Kaiser Permanente treatment centres or not
• VTE peaked at 2 Years, thereafter levelling just over the control, as in previous studies; showing an inclination towards pre-disposition to such events (in other words, the subjects were already high-risk)
• IS peaked at 6 years after which results levelled to those in the control (similar to above)
• ACVE was only elevated in the higher dosage patients (2-10mg estrodiol 5.6mg mean average daily); there was no elevated level of ACVE detected in the lower dosage group (0.3mg-10mg 4.1mg mean average daily) It is likely that the lower dosages are Post-Operative and so not using Spironalactone.
• It considered only patients using Spironalactone (Spiro) as a testosterone blocker. This is important because while Spiro is widely used in the USA it is much less so elsewhere, with Cyproterone acetate (CPA) being more popular. This may have different side-effects.
As regards ‘transmasculine’ (FtM) respondents, the study was inconclusive and made no comment.
This is an interesting study, but the level of increased risks that were identified would only amount to an increase in hazard of a percentage point or so above that for natal women. That tiny increase in risk, less than for smoking or alcohol use, has to be set against the documented successfulness of transition in cases of Gender Dysphoria, especially Homosexual GD or HSTS, as well as potential reduction of risk in other clinical areas.