Oestrogen and testosterone liberties? God the following is really worrying.!
**Oestrogens and testosterone induce masculine or feminine physical characteristics, and should only be taken in the context of medical supervision to monitor risks (e.g., polycythaemia in transgender males, venous thromboembolism in transgender females).
For transgender females, oestrogen therapy alone is often insufficient to produce the desired feminising effects. Other treatments are therefore used in an off label manner. For example spironolactone, an aldosterone antagonist with weak oestrogenic properties is commonly used to support oestrogen therapy – off label. Cyproterone acetate has progestational and antiandrogenic properties, but it can lead to hepatic toxicity including jaundice, hepatitis. Hepatic failure has also been reported (fatalities reported, usually after several months, at dosages of 100 mg and above).
Specific effects of gender affirming hormones
Psychological effects
Young transgender people may have mental health problems, including anxiety, and suicidal ideation. De Vries 2014 (n =55) assessed gender dysphoria, body satisfaction, at baseline, puberty suppression, and in adulthood. De Vries 2011 reported on the original cohort (n=70) that showed that emotional problems and depressive symptoms decreased, while general functioning improved significantly during puberty suppression. High levels of bias with study participation mean the results should be treated with caution. The study found a decrease in gender dysphoria after surgery. However, it was not possible to disentangle the psychological benefits of hormone treatments from surgical interventions.
Cognitive and brain-related effects
Neuroimaging studies suggest CSHs affect brain structure and circuitries, ventricular volume and thickness, hypothalamic neuroplasticity, and functional connectivity. One study, Burke (2016) (n=62) investigated GAHs and brain function in adolescents, and reported that testosterone therapy in transgender males (n=21 mean age 16.1) was associated with altered cognitive processes, as assessed by the mental rotation task (MRT), a measure of visuospatial working memory that elicits cognitive sex differences. The study concluded that transgender males have atypical sexual differentiation of brain areas involved in visuospatial cognitive functioning.
Bone development
Klink 2015 found that lumbar spine bone mineral density scores fell during puberty suppression with GnRHa for transgender adolescent females but did not increase following oestrogen treatment. Endocrine Society Guidelines state monitoring BMD parameters in transgender adolescents is recommended both prior to and during gender-affirming hormonal treatment.
Haematological variables
Testosterone therapies stimulate erythropoiesis, and increases in haemoglobin and haematocrit are an anticipated physiological response. Jarin 2017 (n =116) reported that testosterone therapy in transgender males was associated with significant elevations in mean haemoglobin and haematocrit. Tack 2016 reported haemoglobin and haematocrit concentration variables increased but stabilised at six months. In transgender adolescent females estradiol. Olson-Kennedy 2018 report a significant decline in Hb concentrations after a 2-year course of estradiol.
Cardiovascular Health
Tack 2016; Jarin 2017 report no changes in LDL or triglycerides in the short term for transgender adolescent males. Olson-Kennedy 2018 report significant increases in triglyceride concentrations and HDL after two years of oestrogen treatment. None of the studies showed significant changes in mean total cholesterol concentrations. Olson-Kennedy 2018 report elevations in systolic and diastolic blood pressure with testosterone treatment after two years. Jarin 2017 reports no change in BP at six months. Jarin 2017, Olson-Kennedy 2018 and Tack 2016 report no changes in HbA, glucose, or insulin.
Conclusions
There are significant problems with how the evidence for Gender-affirming cross-sex hormone has been collected and analysed that prevents definitive conclusions to be drawn. Similar to puberty blockers, the evidence is limited by small sample sizes; retrospective methods, and loss of considerable numbers of patients in the follow-up period. The majority of studies also lack a control group (only two studies used controls). Interventions have heterogeneous treatment regimes complicating comparisons between studies. Also, adherence to the interventions is either not reported or inconsistent. Subjective outcomes, which are highly prevalent in the studies, are also prone to bias due to lack of blinding.
An Archive of Diseases in Childhood letter referred to GnRHa treatment as a momentous step in the dark. It set out three main concerns: 1) young people are left in a state of ‘developmental limbo’ without secondary sexual characteristics that might consolidate gender identity; 2) use is likely to threaten the maturation of the adolescent mind, and 3) puberty blockers are being used in the context of profound scientific ignorance.
The development of these interventions should, therefore, occur in the context of research, and treatments for under 18 gender dysphoric children and adolescents remain largely experimental. There are a large number of unanswered questions that include the age at start, reversibility; adverse events, long term effects on mental health, quality of life, bone mineral density, osteoporosis in later life and cognition. We wonder whether off label use is appropriate and justified for drugs such as spironolactone which can cause substantial harms and even death. We are also ignorant of the long-term safety profiles of the different GAH regimens. The current evidence base does not support informed decision making and safe practice in children.**