Medicine (Austin & Northern Health) - Theses
Permanent URI for this collection
Search Results
1 - 3 of 3
-
ItemSafety and efficacy of genderaffirming hormone therapy for transgender individuals( 2023-06)There has been a significant increase in demand for gender-affirming hormone therapy for transgender and gender diverse (trans) individuals over recent years. Current hormone regimens for trans individuals desiring masculinisation typically involve standard testosterone doses and formulations recommended for hypogonadal cisgender men, while trans individuals desiring feminisation are treated with estradiol with or without an antiandrogen. International consensus guidelines give recommendations for gender affirming hormone therapy regimens, though recommendations are largely based on expert opinion and there are currently limited data underlying the safety and efficacy in this population. The aim of this thesis is to evaluate the safety and efficacy of gender-affirming hormone therapy regimens. Our first aim was to investigate the influence of testosterone treatment, compared to no treatment, on gender dysphoria, depression, and suicidality in trans individuals desiring commencement of testosterone. This randomised controlled trial demonstrated that testosterone treatment significantly improved gender dysphoria, depression, and suicidality compared to the control group, supporting the use of testosterone in this population. We then evaluated serum testosterone concentrations and prescription patterns of transdermal testosterone in 2 retrospective cross-sectional analyses. Both 1% testosterone gel and 5% testosterone cream were commonly prescribed at doses lower than those recommended for cisgender hypogonadal men. There was a high proportion of individuals with a non-binary gender identity using both transdermal formulations. Transdermal testosterone was able to achieve serum testosterone concentrations recommended in consensus guidelines. The following study explored the risk of polycythaemia with different testosterone formulations. One in four individuals treated with intramuscular testosterone enanthate and one in six individuals treated with testosterone undecanoate had polycythaemia; however, no individual treated with transdermal testosterone had polycythaemia. This reinforces the need for regular haematocrit monitoring in trans individuals treated with intramuscular testosterone. We then evaluated the prescription of oral estradiol valerate in 259 trans individuals to assess if body mass index correlated with estradiol dose and serum estradiol correlation. There was a weak positive correlation between estradiol dose and serum estradiol concentration (r = 0.156, p = 0.01) but no correlation between body mass index and estradiol dose (r = 0.048, p = 0.53) or serum estradiol concentration (r = -0.063, p = 0.41). Therefore, prescription of oral estradiol dose should not be based upon an individual’s body mass index. The following study investigated feminising hormone therapy regimens and cardiovascular risk factors in 296 transgender individuals undergoing feminising hormone therapy. Although there was no difference in serum estradiol concentration between individuals aged less than 45 years and those aged 45 years or older, a higher proportion of individuals aged 45 years or older were treated with transdermal estradiol. Of those treated with oral estradiol, the median dose was lower. The most prevalent cardiometabolic risk factors were hypertension, followed by current smoking, obesity, dyslipidaemia, and diabetes. Finally, we evaluated the efficacy of 100mg oral micronised progesterone on sleep quality, psychological distress, and breast development in transgender women newly commencing progesterone compared to a control group continuing standard care. Compared with controls over 3 months, there was no difference in sleep quality, psychological distress, or Tanner stage for breast development. This thesis adds a substantial body of knowledge towards the evidence base for gender-affirming hormone therapy. In trans individuals undergoing masculinising hormone therapy, this work supports the use of testosterone treatment to improve gender dysphoria, depression, and suicidality, but reinforces the need for regular monitoring of haematocrit in this population. In individuals undergoing feminising hormone therapy, this thesis demonstrates a change in prescription patterns with increased transdermal estradiol in older trans individuals, but no role for oral estradiol prescription based on body mass index and does not support commencement of low-dose micronised progesterone for sleep, anxiety, or breast development.
-
ItemBiological Actions of Estradiol in Men( 2022)ABSTRACT Context: Accumulating evidence suggests that many of the biological actions of testosterone (T) in men are dependent on endogenous aromatisation of T to estradiol (E2). However, few studies have been designed to measure effects of E2 in men directly, in the absence of T. The most prevalent contemporary cause of severe hypogonadism in older men is the use of gonadotrophin-releasing hormone analogs (GnRHa) as androgen deprivation therapy (ADT) for prostate cancer. ADT represents a unique situation in which the usual clinical and ethical imperative to treat severe male hypogonadism with T is absent. Men receiving ADT experience accelerated osteoporosis leading to fractures, accumulation of fat mass, loss of muscle mass, sexual dysfunction, hot flushes, and, reportedly, adverse neuropsychological effects. This thesis reports on a project designed to test the hypothesis that low dose E2 treatment of men receiving GnRHa for prostate cancer would mitigate some of the adverse effects of the induced hypogonadism, by restoring E2 action (E2 ‘add-back’). There were two overarching aims: first, to directly examine the isolated effects of E2 in men in the absence of T in order to provide new information on the biological role of E2 in men; and second, to test the efficacy of transdermal E2, a readily available and cheap therapeutic, for the mitigation of ADT-induced side effects. Methods: Two randomised controlled trials (RCTs) were conducted in men undergoing ADT for prostate cancer. These trials tested the hypotheses that transdermal E2 would: 1. Reduce the ADT-associated unbalanced and accelerated bone remodelling, leading to better maintenance of volumetric bone mineral density (vBMD). 2. Reduce the ADT-associated increase in fat mass. 3. Reduce ADT-associated changes in cognition. 4. Reduce hot flushes and thereby improve quality of life. Trial 1 aimed to assess the effects of two low doses of transdermal E2 on serum E2 concentrations and to assess the effects of E2 add-back on bone remodelling markers and hot flushes. This trial was a 28-day RCT, randomising 37 participants to transdermal E2 0.9mg/d, 1.8mg/d, or matching placebos. Fasting morning pre-dose serum sex steroids were measured by liquid chromatography mass spectrometry. Hot flushes were measured by prospective 7-day diary. Carboxyl-terminal type 1 collagen telopeptide (CTX) and pro collagen type 1 amino-terminal propeptide (P1NP) were measured by electrochemiluminescence. Trial 2 aimed to assess the efficacy of transdermal E2 0.9mg/d on total vBMD at the tibia and total fat mass (co-primary endpoints), as well as on cognition, hot flushes, and quality of life. This trial was a 6-month RCT, randomising 78 participants to transdermal E2 0.9mg/d, or matching placebo. Total vBMD was measured by high resolution peripheral quantitative CT at baseline and study end. Body composition was measured by dual x-ray absorptiometry at baseline, month 3 and month 6. At each visit, sex steroids, bone remodelling markers, and hot flushes were measured as per trial 1. Quality of life was measured by the Functional Assessment of Cancer Therapy – Prostate and the Aging Males’ Symptom Scale instruments. Cognition was assessed by a validated, tablet computer-based cognitive battery. Results: In trial 1, transdermal E2 0.9-1.8 mg daily increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. Day 28 serum E2 concentrations ranged from 106 to 870 pmol/L in the 0.9mg dose group (median 208 pmol/L; interquartile range: 157-332) and 96-1814 pmol/L in the 1.8mg dose group (median 200 pmol/L; interquartile range 144-660). Over 28 days, transdermal E2 reduced serum CTX, increased serum P1NP, and reduced hot flushes. In trial 2, serum E2 increased in the E2 group over 6 months compared to the placebo group, mean adjusted difference (MAD) 207 pmol/L (95% CI 123-292), p<0.001. E2 add-back did not significantly change total vBMD at the distal tibia, MAD 2.0 mg hydroxyapatite per cm3 (95% CI -0.8 – 4.8), p=0.17. E2 increased cortical vBMD at the distal radius, and estimated failure load at the tibia and radius, and reduced CTX and P1NP. E2 add-back did not significantly change total fat mass, although the confidence interval suggested a likely increase in the E2 group, MAD 1007g (95% CI 124-1891), p=0.09. E2 increased android fat, MAD 164 g (95% CI 41-286), p=0.04. E2 did not change performance over time in any pre-defined cognitive domain. E2 reduced daily hot flush frequency, mean adjusted difference (MAD) -1.6 hot flushes per day (95% CI -2.7 to -0.5), p=0.04. but had no significant effect on quality of life. Conclusion: These two trials offer new insights into the biological actions of E2 in men by providing direct observations of E2 effects, in the absence of T. Over 6 months, E2 add-back reduced the bone remodelling rate, and had beneficial effects on bone to increase aBMD at lumbar spine and ultra-distal radius, cortical vBMD at radius, and estimated failure load, a measure of bone strength, at both radius and tibia. Contrary to the hypothesis, these data suggest that E2, in the absence of T, increases fat mass, suggesting that the effect of E2 on fat might be more complex than reported in studies inferring E2 effects to reduce fat from paradigms in which T is present. E2 had no observed effect on cognition, suggesting that any short-term effects of E2 on cognition in men, are likely to be subtle. Transdermal E2 add-back durably reduced hot flushes, thus providing high quality evidence for this intervention to be used clinically.
-
ItemThe effect of gender-affirming hormone therapy on the health and well-being of transgender Australians( 2021)There is increasing demand for gender-affirming hormone therapy, used by transgender individuals to align physical characteristics with their gender identity. Although hormone therapy improves quality of life and psychological functioning, significant barriers to accessing appropriate healthcare persist. Hormone therapy is often started at a young age and continued lifelong, yet little is known about the long-term effects on metabolic and bone health, both highly regulated by sex hormones. Our aim was to understand the sociodemographic characteristics of transgender Australians, the level of training and confidence of Endocrinologists in transgender health, and the prescribing practices of experienced medical practitioners. We report findings from a series of surveys. Transgender adults (n=928) reported alarmingly high rates of self-harm (63%), attempted suicide (43%) and discrimination within healthcare settings (26%). Barriers included difficulties navigating the healthcare system and finding doctors to prescribe. Better training for doctors was a priority with only 4% of Endocrinologists and trainees (n=147) reporting any training in transgender health during medical school, 91% desired more training. Experienced prescribers (n=35) displayed uniformity in prescribing practices, despite a lack of local guidelines. We then investigated the effects of hormone therapy on cardiovascular risk and bone microstructure. Transgender individuals face higher metabolic risk due to sex hormone mediated changes in body composition and insulin resistance. Bone morphology may be compromised as estradiol is a key regulator of bone remodelling. Transgender adults on established hormone therapy, and control participants, underwent body composition scanning (dual energy X-ray absorptiometry) and quantification of bone microstructure (high-resolution peripheral quantitative CT). Trans men (n=43) had higher mean lean mass, +7.8kg (4.0, 11.5) p<0.001, similar total fat mass but higher android:gynoid fat ratio when compared to female controls (n=48). Insulin resistance was similar, indicating a protective effect of higher lean mass. Conversely, trans women (n=41) had lower mean lean mass, -6.9kg (-10.6, -3.1), p<0.001, higher fat mass, +9.8kg (3.9, 14.5), p=0.001, and lower android:gynoid fat ratio when compared to male controls (n=30). Although android fat correlated more strongly with insulin resistance, trans women had higher insulin resistance likely due to higher overall fat mass. Bone microarchitecture was not compromised in trans men (n=41), as aromatisation of administered testosterone to estradiol likely prevented bone loss. Trans men had higher distal tibial total volumetric bone density (vBMD), 0.71 SD (0.30, 1.12), p<0.01, preserved cortical morphology and trabecular bone volume fraction relative to female controls (n=71). Despite estradiol administration, trans women (n=40) were not protected from microarchitectural deterioration, indicating the dose was insufficient to offset reduced aromatisable testosterone. Trans women had -0.55 SD lower distal tibial total vBMD (-1.01, -0.08), p=0.02 due to higher cortical porosity, 0.63 SD (0.19, 1.07), p=0.01 and lower trabecular bone volume fraction relative to male controls (n=51). Our survey findings informed new Australian clinical practice guidelines and a new gender service. Our cross-sectional study not only provide new and important insights into sex hormone action but are also highly clinically significant, given proactive measures can be implemented to mitigate fat gain and bone loss, particularly in trans women.