Medicine (Austin & Northern Health) - Theses
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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.