This article proposes revised scientific methodology related to the use of estradiol only and with AA's. It details the scientific and statistical methodology needed to reach further conclusions, including meta-analysis of existing studies and one using new cohorts, including sensitivity analysis and confidence intervals:
Description of the intervention
Current guidelines suggest a combination of medical and surgical methods to treat gender dysphoria in transgender women. Hormone replacement therapy (HRT) aims to suppress the development of male attributes or reverse male attributes that have already developed. At the same time, the development of female attributes is supported. Where the HRT is not expected to be successful, which can be the case for facial bone structure, breast development and genitalia, surgical methods and techniques for permanent hair removal and hair transplantation may be used for further approximation of the body to a female body type (
WPATH 2011).
The guidelines of the working group led by Wyley C Hembree suggest treatment with both oestrogens and antiandrogens. Oestrogens can be administered as either oral oestrogen, transdermal estradiol patches, or by injection of estradiol valerate or estradiol cypionate. The application frequency differs depending on the patient’s reaction to the agent and the administration regimen; it could be multiple times per day or once every two weeks. Meanwhile, antiandrogens such as spironolactone or cyproterone acetate are commonly taken orally. Additionally, it is possible to block male puberty by treatment with gonadotropin‐releasing hormone (GnRH) agonist injections. (
Hembree 2017).
While not every transgender woman undergoes HRT in her transition, this intervention is still widely used (
Hembree 2017). We know of no studies identifying the ratio of patients who undergo HRT, nor do we know of studies investigating how much time passes between the start of transition (respectively the decision to transition) and the start of HRT. We also know of no studies on how often androgens are being prescribed in addition to or instead of 17‐beta‐estradiol, how often they are being taken, or which kinds of androgens are in use besides cyproterone acetate (CPA) and spironolactone.
How the intervention might work
Several hormonal substances and combinations are used clinically for HRT in transitioning women. Cyproterone acetate is a progestin, steroidal anti‐androgen and anti‐gonadotropin that blocks the receptors for testosterone (T) and dihydrotestosterone (DHT), and thereby prevents these steroidal hormones from exerting their androgenic effects. Hence, it stops processes like body hair growth, hair loss on the head, male body fat distribution and others (
Figg 2010;
WPATH 2011). According to the World Professional Association for Transgender Health (WPATH) guidelines, it is possible to suppress puberty with GnRH analogues or progestins such as medroxyprogesterone (
WPATH 2011).
Spironolactone acts as a weak androgen receptor antagonist (
Wenqing 2005). It also causes an increase in oestradiol levels (
Rose 1977), so that further virilisation is prevented and feminisation occurs (
WPATH 2011).
17‐beta‐estradiol is used to feminise the external appearance (
WPATH 2011). It binds to oestrogen receptors and thus ensures gene expression, which in turn feminises appearance (
Hye‐Rim 2012). In addition, estradiol suppresses gonadal testosterone production via the control systems of the hypothalamus (
Hayes 2000).
For feminisation therapy, whose goal is to adapt the physical appearance and the experience of the body to a female model (by inducing breast growth, softening facial features, and inducing other physical changes commonly regarded with a feminine appearance) (
WPATH 2011), the use of oral or transdermal oestrogen is recommended, and therapy with oestrogen in combination with antiandrogens is most common. Cotreatment with antiandrogens minimises the required dose of oestrogen, and thereby reduces the supposed risks of oestrogen identified in previous studies (
Schürmeyer 1986;
Prior 1989). Some antiandrogens are approved by WPATH — such as spironolactone, cyproterone acetate, GnRH analogists like goserelin, and 5alpha‐reductase inhibitors like finasteride — but there is no mention of recommended dosages (
WPATH 2011).
Why it is important to do this review
Antiandrogens like cyproterone acetate and spironolactone are prescribed to transgender women in transition by many gynaecologists and endocrinologists (
Schneider 2006;
Flütsch 2015), and they are commonly considered to be valuable drugs to support transition (
WPATH 2011;
Hembree 2017). However, clinical evidence suggests that this can result in adverse events; for example, CPA has significant potential for causing depression and for worsening depressive symptoms (
Seal 2012). We cannot rule out that CPA contributes to the genesis of other conditions and negatively influences the course of illnesses, including psychiatric, neurological and metabolic disorders (
Griard 1978;
Ramsay 1990;
Oberhammer 1996;
Giltay 2000;
Calderón 2009;
Bessone 2015).
The most common adverse events of spironolactone are hyperkalaemia, dehydration and hyponatraemia (
Greenblatt 1973). Furthermore, spironolactone might have an influence on anxiety behavior (
Fox 2016).
The adverse events of high estradiol doses described in studies from the 1980s and 1990s should be re‐evaluated because those studies used ethinyl estradiol and premarin (equine estradiol) (
Prior 1989), instead of bioidentical 17‐beta‐estradiol, and progestins instead of bioidentical progesterone. Unlike the bioidentical alternatives used today, substances administered in the past (e.g. equine oestrogens, ethinyl estradiol) were associated with diverse adverse effects like thrombophilia, cardiovascular problems, breast and prostate cancer, as well as liver, adrenal gland and neural dysfunction (
Griard 1978;
Calderón 2009;
Asscheman 2011).
The health risks attributed to estradiol doses high enough to suppress androgens have not been found in the parenteral or transdermal application of bioidentical estradiol. Thus it is unclear why those estradiol doses should be kept low in order to make the addition of androgen antagonists like CPA or spironolactone necessary.
In light of the latest discussions among experts (
Seal 2012;
Wierckx 2014), and current recommendations for hormonal gender affirmation treatment (
WPATH 2011) — which are strongly based on the values and preferences of health consumers — trials that show positive outcomes in the case of MTF, such as feminisation, satisfactory sexual function, reduced gender dysphoria, and high quality of life must be re‐evaluated (e.g.
Murad 2010).
In 2009, the overall quality of evidence relating to these outcomes was classified as low (
Hembree 2017). In 2011, WPATH summarised: "There is a need for further research on the effects of hormone therapy without surgery, and without the goal of maximum physical feminisation or masculinisation" (
WPATH 2011). It is necessary to determine whether subsequent trials have provided additional evidence for efficacy, or whether there is still a lack of evidence for these desired outcomes.
