OBJECTIVE:Hyponatraemia is a common electrolyte disorder often driven by excess arginine vasopressin (AVP). Copeptin is a stable surrogate marker co-secreted with AVP. It is unclear whether treatment of hyponatraemia with tolvaptan, an AVP-V2 receptor antagonist, impacts copeptin. We aimed to assess the effects of tolvaptan on serum copeptin, compared to fluid restriction. DESIGN:Pre-specified secondary analysis of an open-label randomised trial comparing tolvaptan or fluid restriction for 3 days. PATIENTS:Hospitalised patients with plasma sodium (pNa) 115-130 mmol/L at a single-centre tertiary hospital in Melbourne, Australia. MEASUREMENTS:Copeptin measured at baseline and completion (Day 4, or discharge if sooner). RESULTS:Copeptin results were available in 45/54 participants, randomised to tolvaptan (n = 25) or FR (n = 20). Mean baseline copeptin was 10.4 pmol/L. pNa increased in both groups, significantly more with tolvaptan as previously reported. Copeptin remained stable after FR, but significantly increased after tolvaptan (mean adjusted difference between groups over 3 days 8.4 pmol/L, 95% CI 2.1-14.6, p = 0.01). Baseline copeptin did not predict rapid sodium rise. The rise in copeptin after tolvaptan may represent an exaggerated response to osmolality rise in these patients ('reset osmostat'), or feedback mechanisms from AVP blockade. CONCLUSION:Tolvaptan increased serum copeptin compared to fluid restriction. Further research is required to determine if there is clinical utility for measuring copeptin in hyponatraemia before it is adopted into practice. TRIAL REGISTRATION:ACTRN12619001683123.

CONTEXT:Current first-line therapy for hyponatremia, fluid restriction (FR), is often unsuccessful. Tolvaptan, an arginine vasopressin V2-receptor antagonist, is effective; however, concerns about plasma sodium (pNa) overcorrection risk have limited its uptake. OBJECTIVE:This work aimed to compare the efficacy of tolvaptan and FR, with a prespecified protocol for dextrose 5% intervention if sodium correction targets were exceeded. METHODS:An open-label, randomized trial was conducted at a single-center tertiary hospital, Austin Health, in Melbourne, Australia. Fifty-four hospitalized patients with pNa 115 to 130 mmol/L (mean 124 mmol/L) were enrolled and randomized to tolvaptan 7.5 mg oral daily or FR less than 1000 mL/day (1:1) for 3 days, with daily titration according to pNa response. Main outcome measures included plasma sodium change from day 1 to 4, requirement for intravenous 5% dextrose to prevent or treat overcorrection, symptom measures, and length of hospital stay. RESULTS:Plasma sodium concentrations increased more in the tolvaptan group, compared to FR, over 3 days (Poverall < .001). The mean adjusted difference in pNa between groups at days 2, 3, and 4 was 3.2 (95% CI, 1.6-4.7), 3.5 (95% CI, 1.9-5.2), and 2.5 mmol/L (95% CI, 0.8-4.2), respectively. Five tolvaptan recipients (19%) required dextrose 5% to treat rapid sodium increase. With this intervention, no patient had an Na increase more than10 mmol/L at 24 hours. There was no difference in length of stay or symptoms. CONCLUSION:Tolvaptan was superior to FR at raising pNa over 3 days. However, intervention was required to prevent overcorrection in some, with no benefit in secondary outcomes. This is the first prospectively validated protocol to detect and prevent tolvaptan-related overcorrection.

INTRODUCTION:Home continuous terlipressin infusion (CTI) is an emerging therapy for the treatment of portal hypertensive complications in decompensated cirrhosis. This study presents efficacy and safety data of long-term CTI in a longitudinal cohort. METHODS:All patients treated with at least 2 weeks of home CTI for portal hypertensive complications between 2013 and 2023 were included. Recorded data include handgrip strength (HGS), weight, serum biochemistry, and paracentesis frequency pre-CTI and during CTI. Adverse events related to CTI and unplanned readmissions before and during CTI were recorded. Patients were followed until liver transplantation, CTI cessation, death, or census date. RESULTS:One hundred and two transplant-eligible patients with median Model for End-Stage Liver Disease with sodium 24 (interquartile range 20-29) were treated with CTI for 84 (58-151) days. Compared with pre-CTI, HGS increased by 2.84 kg (95% confidence interval [CI] 1.89-3.80), while body weight reduced by 10.6 kg (95% CI -12.70 to -8.52) (both P < 0.0001). Paracentesis frequency reduced by 58% ( P = 0.006) and median creatinine by 0.61 mg/dL (95% CI -0.87 to -0.3) ( P < 0.001). Serum sodium did not significantly change. Over a cumulative total of 12,312 days, 49 treatment-related adverse events were recorded in 36 patients, 84% of which were central line related. There were no vascular events, episodes of pulmonary edema, or events requiring treatment cessation. DISCUSSION:This study demonstrates the safety of home CTI in a real-world cohort of over 100 well-selected transplant-eligible patients with decompensated cirrhosis. It confirms previous findings that long-term CTI is associated with increased HGS and reduced paracentesis, in addition to its established benefit on renal function. These data provide strong clinical rationale for further prospective randomized trials to investigate the use of CTI as a bridge to liver transplant.

Background and aims Pooling of blood in the splanchnic circulation due to cirrhotic portal hypertension reduces effective circulating blood volume and activates the renin-angiotensin-aldosterone system (RAAS). This study investigates the effects of long-term continuous terlipressin infusion (CTI) on the RAAS in patients with decompensated cirrhosis. Methods 30 participants with cirrhosis and ascites were enrolled in a prospective crossover study comparing 12 weeks of home CTI to observation. Analysis of plasma renin concentration, aldosterone, ACE and ACE2 activity was performed. Results The median age of participants was 62 years (IQR 57-64), median model for end-stage liver disease-Na was 16 (12.3-20.8) and 73% (n=22) were male. Plasma renin decreased by a mean adjusted difference (MAD) of 479.25 mIU/L (95% CI -652.11 to -313.18, p<0.0001), and aldosterone decreased by a MAD of 698.26 pmol/L (95% CI -1009.28 to -396.30, p<0.0001) on CTI compared with observation. Serum ACE2 activity significantly increased by a MAD of 13.71 pmol/mL/min (95% CI 5.88 to 21.92, p=0.001) on CTI compared with observation, and ACE/ACE2 ratio decreased by a MAD of -0.34 (95% CI -0.52 to -0.17, p<0.0002). Conclusion This study demonstrates for the first time a significant attenuation of the classical RAAS and increase in ACE2 activity in patients with decompensated cirrhosis treated with long-term CTI, confirming the physiological mechanism of action of terlipressin in improving ascites and renal function in these patients. Further studies are required to explore the effect of CTI on the alternate RAAS and to determine whether long-term CTI can modulate the clinical progression of decompensated cirrhosis and prevent the development of complications including hepatorenal syndrome. Trial registration number ACTRN12619000891123.

BACKGROUND:Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population. AIMS:We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis. METHODS:We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures. RESULTS:A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045). CONCLUSION:BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

CONTEXT:Menopause is associated with changes in musculoskeletal, body composition, and metabolic parameters that may be amplified in premenopausal women receiving estradiol suppression for breast cancer. Denosumab offsets deleterious skeletal effects of estradiol suppression and has been reported to have effects on body composition and metabolic parameters in preclinical and observational studies, but evidence from double-blind randomized controlled trials is limited. OBJECTIVE:To assess the effect of denosumab on body composition and metabolic parameters. METHODS:In a prespecified secondary analysis of a 12-month randomized, double-blind, placebo-controlled trial, 68 premenopausal women with breast cancer initiating ovarian function suppression and aromatase inhibition were randomized to denosumab 60-mg or placebo administered at baseline and 6 months. Outcome measures were total and regional fat and lean mass (DXA), body mass index (BMI), waist and hip circumference, fasting glucose, HOMA-IR, and lipid profile. Using a mixed model, between-group mean adjusted differences over time are reported. RESULTS:Over 12 months, relative to placebo, android and gynoid fat mass decreased in the denosumab group (-266 g [95% CI -453 to -79], P = .02, and -452 g [-783 to -122], P = .03, respectively). Total fat mass and waist circumference were lower in the denosumab group but not significantly (-1792 g [-3346 to -240], P = .08 and (- 3.77 cm [-6.76 to -0.79], P = .06, respectively). No significant treatment effects were detected in lean mass, BMI, hip circumference, fasting glucose, HOMA-IR, or lipid profile. CONCLUSION:In premenopausal women receiving estradiol suppression, denosumab decreases some measures of fat mass with no detectable effects on other measures of body composition or metabolic parameters.

Radioiodine treatment (RIT) has a high success rate in both the treatment of hyperthyroidism and improving the quality of life (QoL) of symptomatic patients. In asymptomatic patients with subclinical hyperthyroidism thyroid related QoL outcomes are less well known.METHODS:Study aim was to evaluate thyroid-related QoL in patients with subclinical hyperthyroidism mostly due to toxic nodular goitre undergoing RIT, compared to a control group of euthyroid subjects. Study design was monocentric, prospective, controlled. Fifty control subjects were enrolled and 51 RIT patients. Most subjects were examined at least twice at an interval of 6 months, with visits immediately before and 6 months after treatment in the RIT group. QoL was estimated with the ThyPRO questionnaire, using its composite scale as primary outcome. Treatment effect was the mean adjusted difference (MAD) between groups over time, using repeated? measures mixed? effects models.RESULTS:TSH concentrations were lower in the RIT group prior to treatment and recovered thereafter slightly above the level of the control group. Correspondingly, QoL improved significantly after 6 months from a worse level in the RIT group, compared to controls (MAD -10.3 [95% CI -14.9, -5.7], p<0.001). QoL improvements were strong for general items, but less pronounced for the hyperthyroid domain. Compared to controls, thyroid volume, thyroid functional capacity (SPINA-GT) and deiodinase activity (SPINA-GD) were significantly reduced in the RIT group.CONCLUSION:Patients with subclinical hyperthyroidism improve both biochemically and in their QoL after RIT, compared to controls. QoL assessment should have a wider role in clinical practice to complement biochemical tests and help with treatment decisions.

Objective: To determine the relationship between ambient air temperature and the incidence of hyponatremia in a heat-prone region. Methods: We conducted a retrospective study that correlated serum sodium concentrations documented at the Austin Hospital in Melbourne over 10 years from January 2014 to December 2023 with publicly available temperature data from the Australian Bureau of Meteorology. The main outcome measures were serum sodium concentrations and incidence of hyponatremia admissions when correlated to temperature, and, following heatwave events, defined as temperature above 30 degrees C over 5 consecutive days. Results: Over this period, 45 718 low serum sodium results were identified from 26 557 unique patients. Serum sodium concentrations in January (Australian summer) were 0.55 mmol/L lower (95% CI 0.36 to 0.77, P < .001) than in September (Australian early spring). Women had lower sodium concentrations than men (-0.21 mmol/L, 95% CI -0.29 to -0.12, P < .001), as did patients older than 80 years when compared with those younger than 65 years (-0.39 mmol, 95% CI -0.50 to -0.29, P < .001). Hospital admissions with hyponatremia were more frequent during summer months. Profound hyponatremia admissions (sodium <= 125 mmol/L) were more frequent following a heatwave than without (7.6% vs 6.5%, P = .04). Conclusion: Our study demonstrates that serum sodium concentrations are lower and profound hyponatremia-related hospital admissions higher when ambient temperatures are warmer. This suggests that hyponatremia is a climate-associated health issue. Local public health advice for water consumption during heatwaves should consider this risk, and prompt action to limit climate change is required to mitigate this risk.

Background and Aims: Observational studies suggest a beneficial effect of continuous terlipressin infusion (CTI) on ascites and sarcopenia in decompensated cirrhosis with portal hypertension. Approach and Results: This single-center, prospective, cross-over study randomized 30 patients with cirrhosis, ascites, and sarcopenia to commence on 12 weeks of home CTI or 12 weeks of observation prior to cross-over. The co-primary outcomes were change in handgrip strength and paracentesis volume. Secondary outcomes included quality of life, sarcopenia measures, renal function, safety, and hospitalization. The median age of participants was 62 years (IQR: 57–64), the median Model for End-Stage Liver Disease-Sodium was 16 (12.3–20.8), and 22 (73%) were male. Handgrip strength increased by a mean adjusted difference (MAD) of 3.09 kg (95% CI: 1.11–5.08 kg) between CTI and observation ( p =0.006); an 11.8% increase from baseline. The total volume of ascites drained decreased by a MAD of 11.39L (2.99–19.85, p =0.01), with 1.75 fewer episodes of paracentesis (0.925–2.59, p <0.001) on CTI. Serum creatinine decreased, urinary sodium excretion increased, and quality of life was significantly higher on CTI (all p <0.001), with an increase in Chronic Liver Disease Questionnaire score of 0.41 points (0.23–0.59). There were 7 minor line-related complications but no cardiac events or pulmonary edema. Conclusions: This novel study demonstrates a significant increase in handgrip strength, reduction in paracentesis volume, and improved quality of life in patients with decompensated cirrhosis treated with continuous terlipressin infusion. These findings provide a strong rationale for the use of ambulatory CTI in appropriately selected patients with cirrhosis.

The fundamental models underlying hormonal physiological regulation and homeostasis remain poorly understood. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones. We studied the slopes of correlations between concentrations of circulating free thyroxine and thyrotropin, calcium and parathyroid hormone, hemoglobin and erythropoietin, and glucose and insulin in such population data, as well as the slopes of the limbs of various feedback loops estimated empirically and by reverse engineering of the population data. We used computer simulations to model the factors that influence the slopes derived from the population data, and then matched these simulations with the empirically derived slopes. Our simulations showed that changes to the population distribution of feedback loop limbs may alter the slopes of correlations within population data in specific ways. Non-random (interdependent) associations of the limbs of feedback loops may also have this effect, as well as producing discrepancies between the slopes of feedback limb loops determined experimentally and the same slopes determined by derivation from population data. Our corresponding empirical findings were consistent with the presence of such interdependence in the free thyroxine/thyrotropin, hemoglobin/erythropoietin, and glucose/insulin systems. The glucose/insulin data provided evidence consistent with increasing interdependence with age in childhood. Our findings therefore provide strong evidence that the interdependence of the limbs of feedback loops is a general feature of endocrine homeostatic regulation. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages.

PURPOSE Suppression of ovarian function and aromatase inhibition (AI) increases disease-free survival in premenopausal women with estrogen receptor (ER)-positive early-stage breast cancer but accelerates bone loss. We therefore hypothesized that suppressing bone remodeling using denosumab (DMAB) would prevent bone loss in these women. METHODS In a 12-month double-blind randomized trial, 68 women with ER-positive early-stage breast cancer commencing ovarian function suppression and AI were randomly assigned to 60 mg DMAB (n = 34) or placebo (PBO; n = 34) once every 6 months (at 0 and 6 months). Volumetric bone mineral density (BMD), microarchitecture, and estimated bone strength of the distal tibia and distal radius were measured using high-resolution peripheral quantitative computed tomography, and spine and hip BMD were measured using dual-energy X-ray absorptiometry at 0, 6, and 12 months. The primary end point and treatment effect was the mean adjusted between group difference (MAD; [95% CI]) in distal tibial total volumetric BMD over 12 months, with a single P value tested over all time points. The study is registered with the Australian New Zealand Clinical Trials Registry (anzctr.org.au; identifier: ACTRN12616001051437). RESULTS Intention-to-treat analysis included all 68 randomly assigned women. Over 12 months, compared with PBO, DMAB prevented the decrease in distal tibial total BMD (MAD, 20.8 mg HA/cm(3) [95% CI, 17.3 to 24.2]), cortical BMD (42.9 mg HA/cm3 [95% CI, 32.1 to 53.9]), trabecular BMD (3.32 mg HA/cm3 [95% CI, 1.45 to 5.20], P = .004), estimated stiffness (11.6 kN/m [95% CI, 7.6 to 15.6]), and failure load (563 N [95% CI, 388 to 736]). Findings were similar at the distal radius. Decreases in BMD at the lumbar spine (MAD, 0.13 g/cm(2) [95% CI, 0.11 to 0.15]), total hip (0.08 g/cm(2 )[95% CI, 0.07 to 0.09], and femoral neck (0.06 g/cm(2) [95% CI, 0.05 to 0.07]) were also prevented. All P < .001 unless otherwise noted. CONCLUSION Treatment with DMAB at commencement of estradiol suppression therapy preserves BMD, bone microarchitecture, and estimated strength, and is likely to increase fracture-free survival.

Background: Thyroid hormones are controlled by the hypothalamic–pituitary–thyroid (HPT) axis through a complex network of regulatory loops, involving the hormones TRH, TSH, FT4, and FT3. The relationship between TSH and FT4 is widely used for diagnosing thyroid diseases. However, mechanisms of FT3 homeostasis are not well understood. Objective: We used mathematical modelling to further examine mechanisms that exist in the HPT axis regulation for protecting circulating FT3 levels. Methods: A mathematical model consisting of a system of four coupled first-order parameterized non-linear ordinary differential equations (ODEs) was developed, accounting for the interdependencies between the hormones in the HPT axis regulation. While TRH and TSH feed forward to the pituitary and thyroid, respectively, FT4 and FT3 feed backward to both the pituitary and hypothalamus. Stable equilibrium solutions of the ODE system express homeostasis for a particular variable, such as FT3, if this variable stays in a narrow range while certain other parameter(s) and system variable(s) may vary substantially. Results: The model predicts that (1) TSH-feedforward protects FT3 levels if the FT4 production rate declines and (2) combined negative feedback by FT4 and FT3 on both TSH and TRH production rates keeps FT3 levels insensitive to moderate changes in FT4 production rates and FT4 levels. The optimum FT4 and FT3 feedback and TRH and TSH-feedforward ranges that preserve FT3 homeostasis were found by numerical continuation analysis. Model predictions were in close agreement with clinical studies and individual patient examples of hypothyroidism and hyperthyroidism. Conclusions: These findings further extend the concept of HPT axis regulation beyond TSH and FT4 to integrate the more active sister hormone FT3 and mechanisms of FT3 homeostasis. Disruption of homeostatic mechanisms leads to disease. This provides a perspective for novel testable concepts in clinical studies to therapeutically target the disruptive mechanisms.

Purpose: We previously demonstrated that 12 months of aromatase inhibitor (AI) treatment was not associated with a difference in body composition or other markers of cardiometabolic health when compared to controls. Here we report on the pre-planned extension of the study. The pre-specified primary hypothesis was that AI therapy for 24 months would lead to increased visceral adipose tissue (VAT) area when compared to controls. Methods: We completed a 12-month extension to our prospective 12-month cohort study of 52 women commencing AI treatment (median age 64.5 years) and 52 women with breast pathology not requiring endocrine therapy (63.5 years). Our primary outcome of interest was VAT area. Secondary and exploratory outcomes included other measures of body composition, hepatic steatosis, measures of atherosclerosis and vascular reactivity. Using mixed models and the addition of a fourth time point, we increased the number of study observations by 79 and were able to rigorously determine the treatment effect. Results: Among study completers (AI = 39, controls = 40), VAT area was comparable between groups over 24 months, the mean-adjusted difference was -1.54 cm(2) (95% CI: -14.9; 11.9, P = 0.79). Both groups demonstrated parallel and continuous increases in VAT area over the observation period that did not diverge or change between groups. No statistically significant difference in our secondary and exploratory outcomes was observed between groups. Conclusions: While these findings provide reassurance that short-to-medium-term exposure to AI therapy is not associated with metabolically adverse changes when compared to controls, risk evolution should be less focussed on the AI-associated effect and more on the general development of cardiovascular risk over time.

Abstract The fundamental models of physiological regulation and homeostasis remain uncertain and controversial. We aimed to derive quantitative evidence regarding these models from the study of population data of balance points of different parameters and their respective controlling hormones in terms of the slopes of correlations between parameters and controlling hormones, and the slopes of derived estimates of the physiological responses of parameters to their respective regulating hormones. Our simulations showed that changes to the population distribution of, or dependence between, feedback loop limbs alter these slopes of population data derived correlations and estimates in specific ways. Our corresponding empirical findings were similar across multiple systems and support a general model of regulation whereby the balance points of parameters are generated peripherally under the influence of feed-back loops, both limbs of which may interdependent. This interdependence potentially bestows evolutionary homeostatic and regulatory advantages.

ThyroidAhead of Print Re: "Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status" by Van Uytfanghe et al.Stephen P. Fitzgerald, Henrik Falhammar, and Rudolf HoermannStephen P. FitzgeraldAddress correspondence to: Stephen P. Fitzgerald, MBBS, The Department of General Medicine, The Royal Adelaide Hospital, Adelaide, SA 5000, Australia E-mail Address: [email protected]https://orcid.org/0000-0002-9755-2316Department of General Medicine, The Royal Adelaide Hospital, Adelaide, South Australia.Department of Endocrinology, The Royal Adelaide Hospital, Adelaide, South Australia.Discipline of Medicine, Adelaide Medical School, University of Adelaide, Adelaide, Australia.Search for more papers by this author, Henrik Falhammarhttps://orcid.org/0000-0002-5622-6987Department of Endocrinology, Karolinska University Hospital, Stockholm, Sweden.Department of Molecular Medicine and Surgery, Karolinska Institutet, Stockholm, Sweden.Search for more papers by this author, and Rudolf Hoermannhttps://orcid.org/0000-0002-1326-4270Department of General Medicine, Gastroenterology and Endocrinology, Klinikum Lüdenscheid, Lüdenscheid, Germany.Yandina, Australia.Search for more papers by this authorPublished Online:17 Nov 2023https://doi.org/10.1089/thy.2023.0496AboutSectionsView articleView Full TextPDF/EPUB Permissions & CitationsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookXLinked InRedditEmail View article"Re: "Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status" by Van Uytfanghe et al.." Thyroid, , pp. FiguresReferencesRelatedDetails Volume 0Issue 0 InformationCopyright 2023, Mary Ann Liebert, Inc., publishersTo cite this article:Stephen P. Fitzgerald, Henrik Falhammar, and Rudolf Hoermann.Re: "Thyroid Stimulating Hormone and Thyroid Hormones (Triiodothyronine and Thyroxine): An American Thyroid Association-Commissioned Review of Current Clinical and Laboratory Status" by Van Uytfanghe et al..Thyroid®.ahead of printhttp://doi.org/10.1089/thy.2023.0496Online Ahead of Print:November 17, 2023Online Ahead of Editing: October 26, 2023PDF download

Objective: In men, many effects of testosterone (T) on the skeleton are thought to be mediated by estradiol (E2), but trial evidence is largely lacking. This study aimed to determine the effects of E2 on bone health in men in the absence of endogenous T. Design: This study is a 6-month randomized, placebo-controlled trial with the hypothesis that E2 would slow the decline of volumetric bone mineral density (vBMD) and bone microstructure, maintain areal bone mineral density (aBMD), and reduce bone remodelling. Methods: 78 participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel daily or matched placebo. The outcome measures were vBMD and microarchitecture at the distal tibia and distal radius by high-resolution peripheral quantitative CT, aBMD at the spine and hip by dual-energy x-ray absorptiometry, and serum bone remodelling markers. Results: For the primary endpoint, total vBMD at the distal tibia, there was no significant difference between groups, mean adjusted difference (MAD) 2.0 mgHA/cm(3) (95% CI: -0.8 to 4.8), P = 0.17. Cortical vBMD at the distal radius increased in the E2 group relative to placebo, MAD 14.8 mgHA/cm(3) (95% CI: 4.5 to 25.0), P = 0.005. Relative to placebo, E2 increased estimated failure load at tibia, MAD 250 N (95% CI: 36 to 465), P = 0.02, and radius, MAD 193 N (95% CI: 65 to 320), P = 0.003. Relative to placebo, E2 increased aBMD at the lumbar spine, MAD 0.02 g/cm(2) (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm(2) (95% CI: 0.00 to 0.02), P = 0.01, and reduced serum bone remodelling markers. Conclusion: Relative to placebo, E2 treatment increases some measures of bone density and bone strength in men and reduces bone remodelling, effects that occur in the absence of endogenous T.

OBJECTIVE:Most men undergoing androgen deprivation therapy (ADT) for prostate cancer experience hot flushes. Current treatments have low or limited evidence of efficacy. It is likely that oestradiol depletion is the mediator of these hot flushes, and transdermal oestradiol might be an effective treatment.DESIGN:This is a 6-month randomised, placebo-controlled trial with the hypothesis that oestradiol would reduce hot flush frequency and intensity and improve quality of life (QoL).METHODS:Seventy-eight participants receiving ADT were randomised to 0.9 mg of 0.1% oestradiol gel per day or matched placebo. Hot flush frequency and severity were assessed by 7-day diary at baseline, month 1, month 3, and month 6. QoL was assessed by validated questionnaire.RESULTS:Oestradiol reduced daily hot flush frequency, with a mean adjusted difference (MAD) of -1.6 hot flushes per day (95% CI: -2.7 to -0.5; P = 0.04). The effect on weekly hot flush score was non-significant, with a MAD -19.6 (95% CI: -35.5 to -3.8; P = 0.11). On per protocol analysis, E2 significantly reduced daily hot flush frequency, with a MAD of -2.2 hot flushes per day (95% CI: -3.2 to -1.1; P = 0.001), and weekly hot flush score, with a MAD of -27.0 (-44.7 to -9.3; P = 0.02). Oestradiol had no significant effect on QoL.CONCLUSION:We confirmed our hypothesis of a clinical effect of assignment to oestradiol to reduce hot flush frequency in men with castrate testosterone due to ADT. Transdermal oestradiol could be considered for men with burdensome hot flushes in whom other treatments have failed as long as the risk of breast effects and fat gain are considered.