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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/cm3 (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/cm3 (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/cm2 (95% CI: 0.01 to 0.03), P = 0.01, and ultra-distal radius, MAD 0.01 g/cm2 (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: Indirect evidence suggests that the effects of testosterone on fat mass in men are dependent on aromatization to estradiol (E2). However, no controlled study has assessed the effects of E2 in the absence of testosterone., Design: Six-month randomized, placebo-controlled trial with the hypothesis that men randomized to E2 would reduce their fat mass., Methods: Seventy-eight participants receiving androgen deprivation therapy for prostate cancer were randomized to 0.9 mg of 0.1% E2 gel per day, or matched placebo. Dual x-ray absorptiometry body composition was measured at baseline, month 3, and month 6. The primary outcome was total fat mass., Results: Serum E2 increased in the estradiol group over 6 months compared to placebo, and mean-adjusted difference (MAD) was 207 pmol/L (95% CI: 123-292), P < 0.001. E2 treatment changed total fat mass, MAD 1007 g (95% CI: 124-1891), but not significantly, so P = 0.09. There were other consistent non-significant trends toward increased proportional fat mass, MAD 0.8% (95% CI: 0.0-1.6), P= 0.15; gynoid fat, MAD 147 g (95% CI: 2-293), P = 0.08; visceral fat, 53 g (95% CI: 1-105) P = 0.13; and subcutaneous fat, MAD 65 g (95% CI: 5-125), P = 0.11. Android fat increased, MAD 164 g (95% CI: 41-286), P = 0.04., Conclusion: Contrary to our hypothesis, we provide suggestive evidence that E2 acting in the absence of testosterone, may increase total and regional fat mass in men. Given the premature closure of clinical trials due to the COVID pandemic, this potentially important observation should encourage additional studies to confirm or refute whether E2 promotes fat expansion in the absence of testosterone.

Androgen deprivation therapy (ADT) is commonly given to men with prostate cancer. Both its benefits as well as its adverse effects are a direct consequence of sex steroid withdrawal. While ADT improves oncologic outcomes in appropriately selected men, it is associated with adverse effects, including accelerated bone loss leading to increased fracture risk, and with metabolically unfavorable body composition changes that predispose to diabetes and may increase cardiovascular risk. In this review, we will describe the pathophysiology behind these ADT-associated adverse effects, and discuss the clinical evidence guiding clinical assessment and management. A proactive approach is important to minimize ADT-associated adverse sequelae, so that the benefit-risk ratio of this treatment is optimized., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Androgen deprivation therapy (ADT) given to men with prostate cancer causes rapid and severe sex steroid deficiency, leading to increased bone remodeling and accelerated bone loss. To examine the effects of a single dose of zoledronic acid on bone microarchitecture, we conducted a 2-year randomized placebo controlled trial in 76 men, mean age (interquartile range [IQR]) 67.8 years (63.8 to 73.9) with non-metastatic prostate cancer commencing adjuvant ADT; 39 were randomized to zoledronic acid and 37 to matching placebo. Bone microarchitecture was measured using high-resolution peripheral quantitative computed tomography (HR-pQCT). Using a mixed model, mean adjusted differences (MAD; 95% confidence interval [95% CI]) between the groups are reported as the treatment effect at several time points. Over 24 months, zoledronic acid showed no appreciable treatment effect on the primary outcomes for total volumetric bone mineral density (vBMD); radius (6.7 mg HA/cm 3 [-2.0 to 15.4], p = 0.21) and tibia (1.9 mg HA/cm 3 [-3.3 to 7.0], p = 0.87). Similarly, there were no between-group differences in other measures of microarchitecture, with the exception of a modest effect of zoledronic acid over placebo in total cortical vBMD at the radius over 12 months (17.3 mgHA/cm 3 [5.1 to 29.5]). In contrast, zoledronic acid showed a treatment effect over 24 months on areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry (DXA) at all sites, including lumbar spine (0.10 g/cm 2 [0.07 to 0.13]), p < 0.001), and total hip (0.04 g/cm 2 [0.03 to 0.05], p < 0.001). Bone remodeling markers were initially suppressed in the treatment group then increased but remained lower relative to placebo (MADs at 24 months CTX -176 ng/L [-275 to -76], p < 0.001; P1NP -18 mg/L [-32 to -5], p < 0.001). These findings suggest that a single dose of zoledronic acid over 2 years is ineffective in preventing the unbalanced bone remodeling and severe microstructural deterioration associated with ADT therapy. © 2020 American Society for Bone and Mineral Research., (© 2020 American Society for Bone and Mineral Research.)

Background: The role of testosterone in maintaining functional performance in older men remains uncertain., Methods: We conducted a 12-month prospective, observational case-control study including 34 men newly commencing androgen deprivation therapy for prostate cancer and 29 age-matched prostate cancer controls. Video-based motion capture and ground reaction force data combined with computational musculoskeletal modeling, and data were analyzed with a linear mixed model., Results: Compared with controls over 12 months, men receiving androgen deprivation therapy had a mean reduction in circulating testosterone from 14.1 nmol/L to 0.4 nmol/L, associated with reductions in peak knee extension torque, mean adjusted difference (MAD) -0.07 Nm/kg (95% confidence interval [CI]: -0.18, 0.04), p = .009, with a corresponding more marked decrease in quadriceps force MAD -0.11 × body weight (BW) [-0.27, 0.06], p = .045 (equating to a 9 kg force reduction for the mean body weight of 85 kg), and decreased maximal contribution of quadriceps to upward propulsion, MAD -0.47 m/s2 [-0.95, 0.02], p = .009. We observed between-group differences in several other parameters, including increased gluteus maximus force in men receiving androgen deprivation therapy, MAD 0.11 × BW [0.02, 0.20], p = .043, which may be compensatory., Conclusions: Severe testosterone deprivation over 12 months is associated with selective deficits in lower-limb function evident with an important task of daily living., (© The Author(s) 2019. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Context: Androgen deprivation therapy (ADT) for prostate cancer (PCa) leads to a selective loss of leg muscle function during walking. Rodent models of ADT have demonstrated that the levator ani is exquisitely androgen sensitive., Objective: To determine whether the high androgen responsiveness of the levator ani muscle documented in rodents is evolutionarily conserved and ADT is associated with a selective loss in leg muscle volume., Design: Prospective longitudinal case-control study., Setting: Tertiary referral hospital., Participants: Thirty-four men newly beginning ADT and 29 age-matched controls with PCa., Main Outcome Measures: The muscle volumes in liters of the levator ani and primary muscles involved in walking (iliopsoas, quadriceps, gluteus maximus, gluteus medius, calf)., Results: Compared with controls, during a 12-month period, men receiving ADT experienced a mean reduction in total testosterone from 14.1 to 0.4 nmol/L and demonstrated greater decreases in levator ani [mean adjusted difference (MAD), -0.005 L; 95% CI, -0.007 to -0.002; P = 0.002; -16% of initial median value], gluteus maximus (MAD, -0.032 L; 95% CI, -0.063 to -0.002; P = 0.017; -5% of initial median value), iliopsoas (MAD, -0.005 L; 95% CI, -0.001 to 0.000; P = 0.013; -5% of initial median value), and quadriceps (MAD, -0.050 L; 95% CI, -0.088 to -0.012; P = 0.031; -3% of initial median value). No substantial differences were observed in the gluteus medius and calf muscles., Conclusions: The androgen responsiveness of the levator ani appears to be evolutionarily conserved in humans. ADT selectively decreases the volume of muscles that support body weight. Interventional strategies to reduce ADT-related sarcopenia and sexual dysfunction should assess whether targeting these muscle groups, including the pelvic floor, will improve clinical outcomes., (Copyright © 2019 Endocrine Society.)

Objective: Hypogonadism from androgen deprivation therapy (ADT) for prostate cancer causes adverse body composition changes associated with insulin resistance and decreased quality of life (QoL). Our objective was to assess whether adverse body composition changes improve after cessation of ADT., Design: Prospective case-control study in a tertiary referral hospital. Thirty-four men newly commencing ADT (cases, median age: 67.6 years (interquartile range: 64.6-72.0)) and 29 age-matched (70.6 years (65.3-72.9)) prostate cancer controls not on ADT were assessed 2 years after cessation of ADT (median: 4.4 years)., Methods: Serum testosterone, body composition, handgrip strength, frailty and QoL were measured. Using a mixed model, the mean adjusted differences (MADs (95% CI)) between groups from baseline to study end are reported., Results: Twenty-seven cases and 19 controls completed the study. Median duration of ADT was 2.3 years (interquartile range: 1.8-3.1). Two years after cessation of ADT, total testosterone remained lower (MAD: -3.4 nmol/L (-6.3 to -0.5), P  < 0.022), fat mass (2214 g (490-3933), P  = 0.025) and insulin resistance (homeostasis model assessment of insulin resistance: 0.69 (0.31-1.07), P  < 0.001) remained higher in cases, whereas lean mass (-1450 g (-2259 to -640), P  < 0.001) and physical component of QoL remained lower than controls (-11.9 (-16.4 to -7.4), P  < 0.001)., Conclusion: Two years after ADT cessation, metabolically adverse changes in body composition, increased insulin resistance and reduced QoL persisted. This may be related to incomplete testosterone recovery. Persisting adverse effects need to be considered in the risk to benefit assessment of ADT and proactive mitigation should continue after cessation of treatment., (© 2018 European Society of Endocrinology.)

Objective: There is increasing recognition that, in men, some biological actions attributed to testosterone (TS) are mediated by estradiol (E2). This study used two low doses of daily transdermal E2 gel to assess the effects on circulating E2 concentrations in men with prostate cancer with suppressed endogenous E2 production arising from androgen deprivation therapy (ADT). Secondarily, we aimed to assess short-term biological effects of E2 add-back without increasing circulating TS., Design: 28-day randomised, placebo-controlled trial., Methods: 37 participants were randomised to either 0.9 or 1.8 mg of 0.1% E2 gel per day or matched placebo gel. Fasting morning serum hormones, quality of life questionnaires, and treatment side effects were evaluated at baseline, days 14 and 28. Hot flush diaries and other biochemical measurements were completed at baseline and study end., Results: Transdermal E2 significantly raised serum E2 from baseline to day 28 compared to placebo in the 0.9 mg dose group (median: 208 pmol/L; interquartile range: 157-332) and in the 1.8 mg dose group (median: 220 pmol/L; interquartile range: 144-660). E2 treatment reduced hot flush frequency and severity as well as beta carboxyl-terminal type 1 collagen telopeptide., Conclusion: In men with castrate levels of E2 and TS, daily transdermal E2: 0.9-1.8 mg increased median serum E2 concentrations into the reference range reported for healthy men, but with substantial variability. E2 treatment reduced hot flushes and bone resorption. Larger studies will be required to test whether low-dose E2 treatment can mitigate ADT-associated adverse effects without E2-related toxicity., (© 2018 European Society of Endocrinology.)

Androgen deprivation therapy (ADT) decreases muscle mass and function but no human studies have investigated the underlying genetic or cellular effects. We tested the hypothesis that ADT will lead to changes in skeletal muscle gene expression, which may explain the adverse muscle phenotype seen clinically. We conducted a prospective cohort study of 9 men with localised prostate cancer who underwent a vastus lateralis biopsy before and after 4 weeks of ADT. Next-generation RNA sequencing was performed and genes differentially expressed following ADT underwent gene ontology mining using Ingenuity Pathway Analysis. Differential expression of genes of interest was confirmed by quantitative PCR (Q-PCR) on gastrocnemius muscle of orchidectomised mice and sham controls (n=11/group). We found that in men, circulating total testosterone decreased from 16.5±4.3nmol/L at baseline to 0.4±0.15nmol/L post-ADT (p<0.001). RNA sequencing identified 19 differentially expressed genes post-ADT (all p<0.05 after adjusting for multiple testing). Gene ontology mining identified 8 genes to be of particular interest due to known roles in androgen-mediated signalling; ABCG1, ACTC1, ANKRD1, DMPK, THY1, DCLK1, CST3 were upregulated and SLC38A3 was downregulated post-ADT. Q-PCR in mouse gastrocnemius muscle confirmed that only one gene, Actc1 was concordantly upregulated (p<0.01) in orchidectomised mice compared with controls. In conclusion, given that ACTC1 upregulation is associated with improved muscle function in certain myopathies, we hypothesise that upregulation of ACTC1 may represent a compensatory response to ADT-induced muscle loss. Further studies will be required to evaluate the role and function of ACTC1., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Objective: Recent evidence suggests that androgens either directly or via aromatisation to oestradiol may regulate telomere length, hence providing a mechanism whereby reproductive steroids are linked to biological ageing in men. Using men with prostate cancer initiating androgen deprivation therapy (ADT), we tested the hypothesis that severe sex steroid deprivation would accelerate telomere shortening., Design: We conducted a secondary analysis of a 2-year prospective controlled study among 65 men with nonmetastatic prostate cancer newly commencing adjuvant ADT (n=40) and age- and radiotherapy-matched prostate cancer controls (n=25)., Methods: We measured leucocyte telomere length (LTL) expressed as telomeric/single copy control gene (T/S) ratio at baseline, 6, 12 and 24 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up., Results: Compared to controls over 24 months, men receiving ADT had no change in LTL, MAD for T/S ratio (0.105 [-0.004; 0.213], P=.235)., Conclusions: Using men with prostate cancer receiving ADT as a model we found no evidence that prolonged and profound sex steroid deprivation is associated with accelerated telomere shortening. Larger studies will be required to confirm or refute these findings., (© 2017 John Wiley & Sons Ltd.)

Prostate cancer (PCa) is the second most commonly diagnosed cancer in men. Conventional endocrine treatment for PCa leads to global sex steroid deprivation. The ensuing severe hypogonadism is associated with well-documented adverse effects. Recently, it has become apparent that many of the biological actions attributed to androgens in men are in fact not direct, but mediated by estradiol. Available evidence supports a primary role for estradiol in vasomotor stability, skeletal maturation and maintenance, and prevention of fat accumulation. Hence there has been interest in revisiting estradiol as a treatment for PCa. Potential roles for estradiol could be in lieu of conventional androgen deprivation therapy or as low-dose add-back treatment while continuing androgen deprivation therapy. These strategies may limit some of the side effects associated with conventional androgen deprivation therapy. However, although available data are reassuring, the potential for cardiovascular risk and pro-carcinogenic effects on PCa via estrogen receptor signalling must be considered., (© 2017 Society for Endocrinology.)

Objective: While androgen deprivation therapy (ADT) has been associated with decreased quality of life (QoL), controlled prospective studies are lacking. We aimed to assess QoL during ADT using two validated questionnaires and determine contributing factors., Design: Prospective controlled study., Patients: Sixty-three men with nonmetastatic prostate cancer newly commencing ADT (n = 34) and age- and radiotherapy-matched prostate cancer controls (n = 29)., Measurements: QoL was measured by Short-Form 12 version 2 survey (SF-12) and Aging Males' Symptoms (AMS) score at 0, 6 and 12 months. Generalized linear models determined the mean adjusted difference (MAD) (95% confidence interval) between groups during follow-up., Results: Compared to controls over 12 months, men receiving ADT had decreased SF-12 physical component score [MAD -3·61 (-6·94, -0·29), P = 0·013] reflecting worsening QoL but no change in the mental component (P = 0·74). Total AMS score increased [MAD 9·35 (5·65, 13·07), P < 0·001], reflecting worse QoL. Both SF-12 and AMS changes were greater than reported minimum clinically important differences. AMS sub-domains showed increased somatic [MAD 3·96 (1·94, 5·99), P < 0·001] and sexual [MAD 3·80 (2·16, 5·44), P < 0·001] components but not psychological (P = 0·19). Decrements were related to an increase in hot flushes (P = 0·016) but not haemoglobin decrease (P = 0·46)., Conclusions: Within 12 months, ADT is associated with clinically significant decreased QoL, particularly physical and sexual aspects, independent of the confounding effects of a cancer diagnosis or radiotherapy. As QoL is a crucial aspect of prostate cancer treatment, addressing hot flushes, sexual dysfunction and exercise may potentially improve outcomes for men undergoing ADT., (© 2016 John Wiley & Sons Ltd.)

Background: Although muscle mass declines with testosterone deficiency in men, previous studies of muscle function have not demonstrated consistent deficits, likely due to relatively insensitive methodology. Our objective was to determine the effects of testosterone deprivation on the biomechanical function of individual lower-limb muscles., Methods: We conducted a 12-month prospective, observational case-control study of 34 men newly commencing androgen deprivation treatment (ADT) for prostate cancer and 29 age-matched prostate cancer controls. Participants were assessed at 0, 6, and 12 months while walking in a biomechanics laboratory. We combined video-based motion capture and ground reaction force data with computerized musculoskeletal modelling to assess the following primary outcomes: (i) peak joint torques at the hip, knee and ankle, and corresponding individual muscle forces; (ii) individual muscle contributions to acceleration of the body's centre of mass; and (iii) walking speed, stride length, and step width. A linear mixed model was used to compare mean differences between groups., Results: Compared with controls over 12 months, men receiving ADT had a mean reduction in total testosterone level from 14.1 to 0.4 nmol/L, and demonstrated more marked decreases in peak hip flexor torque by 14% [mean difference -0.11 N/kg (-0.19, -0.03), P = 0.01] and peak knee extensor torque by 16% [-0.11 N/kg (-0.20, -0.02), P = 0.02] of the initial mean value. Correspondingly, iliopsoas force decreased by 14% (P = 0.006), and quadriceps force decreased by 11%, although this narrowly missed statistical significance (P = 0.07). Soleus decreased contribution to forward acceleration of the body's centre of mass by 17% [mean difference -0.17 m/s 2 (-0.29, -0.05), P < 0.01]. No significant changes between groups were observed in other joint torques or individual muscle contributions to acceleration of the body. Step width increased by 18% [mean adjusted difference 1.4 cm (0.6, 27.4), P = 0.042] in the ADT group compared with controls, with no change in stride length or walking speed., Conclusions: Testosterone deprivation selectively decreases lower-limb muscle function, predominantly affecting muscles that support body weight, accelerate the body forwards during walking, and mediate balance. Future exercise and pro-myogenic interventional studies to mitigate ADT-associated sarcopenia should target these deficits., (© 2016 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.)

Objective: While androgen deprivation therapy (ADT) has been associated with insulin resistance and frailty, controlled prospective studies are lacking. We aimed to examine the relationships between insulin resistance and frailty with body composition and testosterone., Design: Case-control prospective study., Methods: Sixty three men with non-metastatic prostate cancer newly commencing ADT (n=34) and age-matched prostate cancer controls (n=29) were recruited. The main outcomes were insulin resistance (HOMA2-IR), Fried's frailty score, body composition by dual x-ray absorptiometry and short physical performance battery (SPPB) measured at 0, 6 and 12months. A generalised linear model determined the mean adjusted difference (95% CI) between groups., Results: Compared with controls over 12months, men receiving ADT had reductions in mean total testosterone level (14.1-0.4nmol/L, P<0.001), mean adjusted gain in fat mass of 3530g (2012, 5047), P<0.02 and loss of lean mass of 1491g (181, 2801), P<0.02. Visceral fat was unchanged. HOMA2-IR in the ADT group increased 0.59 (0.24, 0.94), P=0.02, which was most related to the increase in fat mass (P=0.003), less to lean mass (P=0.09) or total testosterone (P=0.088). Frailty increased with ADT (P<0.0001), which was related to decreased testosterone (P=0.028), and less to fat mass (P=0.056) or lean mass (P=0.79). SPPB was unchanged., Conclusions: ADT is associated with increased insulin resistance and frailty within 12months of commencement, independently of confounding effects of cancer or radiotherapy. Insulin resistance appears to be mediated by subcutaneous or peripheral sites of fat deposition. Prevention of fat gain is an important strategy to prevent adverse ADT-associated cardiometabolic risks., (© 2016 European Society of Endocrinology.)

Androgen deprivation therapy (ADT) is a highly effective treatment used in ∼30% of men with prostate cancer. Adverse effects of ADT on muscle are significant with consistent losses in muscle mass. However, effects of ADT on muscle strength and physical function, of most relevance to the patient, are less well understood. This is in part due to the fact that muscle effects of ADT at the cellular, genetic and protein level, critical to the understanding of the pathophysiology of sarcopenia, have come into focus only recently. This review highlights the complexity of androgen-dependent signaling in muscle with an emphasis on recent findings in the regulation of muscle growth and muscle atrophy pathways. Furthermore, the effects of ADT and testosterone on skeletal muscle histology, gene expression and protein transcription are discussed. A better mechanistic understanding of the regulation of muscle mass and function by androgens should not only pave the way for developing targeted promyogenic interventions for men with prostate cancer receiving ADT but also may have wider implications for age-associated sarcopenia in the general population., (© 2016 Society for Endocrinology.)

Prostate cancer and treatment with androgen deprivation therapy (ADT) affect significant numbers of the male population. Endocrine effects of ADT are a critical consideration in balancing the benefits and risks of treatment on long-term survival and quality of life. This review highlights the latest advances in androgen manipulation in prostate cancer with an emphasis on the effects of ADT on muscle and bone, which universally affects the health and well-being of men undergoing ADT for prostate cancer. Muscle mass declines with ADT; however, the evidence that this correlates with a decrease in muscle strength or a decrease in physical performance is discordant. Cortical bone decay also occurs in association with an increase in fracture risk, hence optimization of musculoskeletal health in men undergoing ADT is crucial. The role of exercise, and current and emerging anabolic therapies for muscle as well as various new strategies to prevent loss of bone mass in men undergoing ADT are discussed. Future well-designed, prospective, controlled studies are required to elucidate the effects of ADT on physical performance, which are currently lacking, and larger randomized controlled trials are required to test the efficacy of medical therapies and exercise interventions to target proven deficits and to ensure safety in men with prostate cancer., (© 2014 Society for Endocrinology.)

Our objective was to evaluate the effectiveness of implementing standardized guidelines to mitigate metabolic and bone side effects of androgen deprivation therapy (ADT) in men with non-metastatic prostate cancer. We conducted a 2-year prospective cohort study at a tertiary referral teaching hospital. Overall, 236 men (mean age 69.8 ± 7.1) commencing ADT for non-metastatic prostate cancer attended a baseline clinic visit between 2007 and 2011, and 153 men were eligible for follow-up after 2 years of continuous ADT. Of these, 113 men had data available for analysis at 2 years. At baseline, 87% of the men were overweight or obese, 61% had hypertension, 56% had hypercholesterolaemia, 27% prior cardiovascular disease, 11% osteoporosis and 40% osteopaenia. After 2 years of ADT, there was an increase in waist circumference (+2.8 ± 6.3 cm, p = 0.002), and, in men without diabetes, in HbA1c (+0.13 ± 0.34%, p = 0.019). Despite this, due to treatment, there were significant reductions in total cholesterol (-0.35 ± 1.00 mmol/L, p < 0.001), and blood pressure (systolic -7.6 ± 19.3 mmHg; diastolic -4.7 ± 11.6 mmHg, p < 0.001). After 2 years, men not receiving anti-resorptive therapy experienced a significant decline in lumbar spine (-0.042 ± 0.134 g/cm(2) , p = 0.012) and total hip bone mineral density (BMD) (-0.026 ± 0.036 g/cm(2) , p < 0.001), whereas bisphosphonate treatment maintained stable BMD. Prevalence of anaemia increased from 13.8 to 32.5%. Older age independently predicted a greater drop in haemoglobin (p = 0.005). We conclude that a structured approach to assess and treat men undergoing ADT effectively improves cardiovascular risk factors and prevents bone decay. Larger studies are needed to determine effects on cardiovascular outcomes, fracture prevention and survival., (© 2013 American Society of Andrology and European Academy of Andrology.)

Androgen deprivation therapy (ADT) has been associated with a plethora of adverse effects, consistent with the androgen dependency of multiple reproductive and somatic tissues. One such tissue is the hemopoietic system, and one of the most predictable consequences of ADT is the development of anemia. Although anemia caused by ADT is rarely severe, ADT is often given to frail, elderly men with increased susceptibility to anemia due to multiple other causes. ADT-associated anemia may contribute to fatigue and reduced quality of life (QoL) in such men, although this requires further study. While anemia is an independent risk factor of mortality in men with prostate cancer, it is not known whether treatment of ADT-associated anemia alters clinically important outcomes, or whether treatment affects mortality. Awareness of the phenomenon of ADT-induced anemia should avoid unnecessary work-up in mild cases of normocytic normochromic anemia. However, assessment and treatment of more severe anemia may be required. This should be determined on an individual basis. In contrast to the well-described actions of ADT on erythropoiesis, its effect on other hemopoietic lineages has been less well elucidated. While preclinical studies have found roles for androgens in maturation and differentiated function of neutrophils, lymphocytes and platelets, the implications of these findings for men with prostate cancer receiving ADT require further studies.

Androgen deprivation therapy (ADT) is a major component of the contemporary management of prostate cancer. ADT's use is increasing rapidly. The side effects of this therapy include loss of bone mass and fractures, increase in fat mass, and worsening of insulin resistance, the metabolic syndrome, diabetes and cardiovascular risk, and anemia and loss of muscle. Neuropsychological and sexual symptoms are common. The impact of these side effects is often overlooked or underestimated in decisions about prostate cancer therapy. This review surveys the data relating to the side effects of ADT and provides recommendations regarding their minimization and management., (Copyright © 2011. Published by Elsevier Inc.)

Androgen deprivation therapy (ADT) in men with prostate cancer increases the risk of osteoporotic fractures, type 2 diabetes and, possibly, cardiovascular events. There is considerable uncertainty about the risk-benefit ratio of ADT in non-palliative treatment; the benefits of ADT in treating non-metastatic prostate cancer need to be carefully weighed against the risks of ADT-induced adverse events. Baseline assessment of bone health at the initiation of ADT should include measurement of bone mineral density (BMD) by dual energy x-ray absorptiometry and, in men with osteopaenia, a thoracolumbar spine x-ray. General measures to prevent bone loss, including regular physical activity, as well as ensuring calcium and vitamin D sufficiency, should be instituted routinely. All men with a previous minimal trauma fracture should receive pharmacological therapy unless contraindicated; for those who have not sustained a minimal trauma fracture, treatment is advised if the BMD T score is ≤ - 2.0, or if the 10-year risk of a major osteoporotic fracture exceeds 20%. Men with prostate cancer who are receiving ADT should be closely monitored for weight gain and diabetes; intensive lifestyle intervention is recommended to prevent ADT-induced weight gain and insulin resistance. Management of the metabolic sequelae of ADT includes optimal reduction of cardiovascular risk factors, with particular attention to weight, blood pressure, lipid profile, smoking cessation, and glycaemic control.

Adverse effects of androgen deprivation therapy (ADT) are a consequence of the induced sex steroid deficiency. ADT increases fat mass leading to insulin resistance and diabetes, and accelerates bone loss causing increased fracture risk. Given the high prevalence of cardiovascular disease and reduced bone density in ADT-naïve men with prostate cancer, the benefits of ADT have to be carefully weighed against its side effects, especially as a diagnosis of prostate cancer does not alter the life expectancy for most men. Men commencing ADT should be counselled about and be carefully monitored for these and other ADT-induced complications, which include fatigue, sexual dysfunction, hot flushes and anaemia. ADT-associated side effects should be prevented and treated in order that ADT-induced toxicity does not outweigh its benefits. Future clinical trials are needed: first, to better define the effects of ADT on survival in men with localized prostate cancer or with biochemical prostate-specific antigen recurrence; second, to delineate ADT-associated harm, especially with respect to cardiovascular events and fractures; and third, to test the efficacy of interventions designed to minimize ADT-related adverse outcomes. Such information will be essential to better quantify the risk-benefit ratio of ADT in the individual man with prostate cancer., (© 2011 Blackwell Publishing Ltd.)

Objective: Androgen deprivation therapy (ADT) for prostate cancer is associated with increases in fat mass and risk of type 2 diabetes; however, the relationship between sex steroid deficiency and abdominal fat distribution remains controversial., Design: We conducted a 12-month prospective observational study at a tertiary referral centre., Patients and Measurements: We investigated changes in abdominal fat distribution and insulin resistance in 26 men (70.6±6.8 years) with nonmetastatic prostate cancer during the first year of ADT., Results: Twelve months of ADT increased visceral abdominal fat area by 22% (from 160.8±61.7 to 195.9±69.7 cm(2) ; P<0.01) and subcutaneous abdominal fat area by 13% (from 240.7±107.5 to 271.3±92.8 cm(2) ; P<0.01). Fat mass increased by 14% (+3.4 kg; P<0.001) and lean tissue mass decreased by 3.6% (-1·9 kg; P<0.001). Insulin resistance (HOMA-IR) increased by 12% (2.50±1.12 to 2.79±1.31, P<0.05). There was no change in fasting glucose or glycated haemoglobin levels. Total testosterone (TT) was inversely associated with visceral fat area independent of oestradiol (E2), but E2 was not associated with visceral fat area independent of TT. Visceral fat area, not TT or E2, was independently associated with insulin resistance., Conclusions: ADT for prostate cancer results in accumulation of both visceral and subcutaneous abdominal fat. Increased visceral fat area appears more closely linked to testosterone than oestradiol deficiency. Increased insulin resistance may arise secondary to visceral fat accumulation, rather than as a direct result of sex steroid deficiency., (© 2011 Blackwell Publishing Ltd.)

Context: Androgen deprivation therapy (ADT) used in the treatment of prostate cancer reduces bone mineral density (BMD) and predisposes to fractures. The structural basis of the BMD deficit and bone fragility is uncertain., Objective and Patients: We investigated changes in bone microarchitecture in 26 men (70.6±6.8 yr) with nonmetastatic prostate cancer during the first year of ADT using the new technique of high-resolution peripheral quantitative computed tomography., Design and Setting: We conducted a 12-month prospective observational study in the setting of a tertiary referral center., Results: After 12 months of ADT, total volumetric density decreased by 5.2±5.4% at the distal radius and 4.2±2.7% at the distal tibia (both P<0.001). This was due to a decrease in cortical volumetric BMD (by 11.3±8.6% for radius and 6.0±4.2% for tibia, all P<0.001) and trabecular density (by 3.5±6.0% for radius and 1.5±2.3% for tibia, all P<0.01), after correcting for trabecularization of cortical bone. Trabecular density decreased due to a decrease in trabecular number at both sites (P<0.05). Total testosterone, but not estradiol, levels were independently associated with total and corrected cortical volumetric BMD at the tibia., Conclusions: Sex steroid deficiency induced by ADT for prostate cancer results in microarchitectural decay. Bone fragility in these men may be more closely linked to testosterone than estradiol deficiency.