Quality of life decrements in men with prostate cancer undergoing androgen deprivation therapy.

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.

Actin alpha cardiac muscle 1 gene expression is upregulated in the skeletal muscle of men undergoing androgen deprivation therapy for prostate cancer.

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.

Targeting muscle signaling pathways to minimize adverse effects of androgen deprivation.

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.