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Genitourinary Cancer Prostate Cancer Androgen Deprivation Therapy and the Re-emergence of Parenteral Estrogen in Prostate Cancer Iain Phillips, MBBS, MRCP, 1 Syed I A Shah, MBBS, 2 Trinh Duong, MSc, 3 Paul Abel, MB ChB, FRCS 4 and Ruth E Langley, MBBS, MRCP 5 1. Clinical Fellow, 3. Senior Statistician, 5. Medical Oncologist, Medical Research Council Clinical Trials Unit, University College, London, UK; 2. Clinical Research Fellow, 4. Professor and Honorary Consultant Urologist, Imperial College, London, UK Abstract Androgen deprivation therapy (ADT) resulting in testosterone suppression is central to the management of prostate cancer (PC). As PC incidence increases, ADT is more frequently prescribed, and for longer periods of time as survival improves. Initial approaches to ADT included orchiectomy or oral estrogen (diethylstilbestrol [DES]). DES reduces PC-specific mortality, but causes substantial cardiovascular (CV) toxicity. Currently, luteinizing hormone-releasing hormone agonists (LHRHa) are mainly used; they produce low levels of both testosterone and estrogen (as estrogen in men results from the aromatization of testosterone), and many toxicities including osteoporosis, fractures, hot flashes, erectile dysfunction, muscle weakness, increased risk for diabetes, changes in body composition, and CV toxicity. An alternative approach is parenteral estrogen, it suppresses testosterone, appears to mitigate the CV complications of oral estrogen by avoiding first-pass hepatic metabolism, and avoids complications caused by estrogen deprivation. Recent research on the toxicity of ADT and the rationale for revisiting parenteral estrogen is discussed. Keywords Prostate cancer, estrogen, testosterone, LHRH agonist, PATCH trial, androgen deprivation therapy (ADT) Disclosure: Paul Abel, MB ChB, FRCS, and Ruth E Langley, MBBS, MRCP, are co-chief investigators of the PATCH trial, which is an academic study funded by Cancer Research UK sponsored by the MRC Clinical Trials Unit at UCL. Iain Phillips, MBBS, MRCP, Syed I A Shah, MBBS, and Trinh Duong, MSc, have no conflicts of interest to declare. Received: January 23, 2014 Accepted: March 10, 2014 Citation: Oncology & Hematology Review, 2014;10(1):42–7 Correspondence: Ruth E Langley, MBBS, MRCP, Oncologist/Senior Scientist, MRC CTU at UCL, Aviation House, 125 Kingsway, London WC2B 6NH, UK. E: This review describes strategies for producing castrate levels of testosterone in men with androgen-sensitive prostate cancer (PC) and the associated toxicities, with particular focus on the re-emergence and potential benefits of parenteral estrogen. In the developed world, PC is the commonest malignancy and second commonest cause of cancer death affecting men. Its incidence is increasing with an aging population and frequent prostate-specific antigen (PSA) testing. 1 Almost 240,000 new cases of PC are diagnosed each year in the US and nearly 30,000 American men die from PC annually. 2 Androgen Deprivation Therapy The androgen dependence of PC has been recognized since the 1940s and remains a major component of the strategies used to manage PC today. Surgical Orchiectomy and Oral Estrogen Androgen deprivation therapy (ADT) was initially achieved by surgical orchiectomy, as the testes produce nearly 95 % of circulating androgens; the remaining 5  % is produced by the adrenal glands. 3 As surgical castration is invasive and can cause significant psychological trauma it became less common following the introduction of medical (also called chemical) ADT. Diethylstilbestrol (DES), a synthetic oral estrogen, 42 was the first pharmacological agent used as ADT for PC. The primary mechanism of action of DES involves a negative feedback loop affecting the hypothalamic–pituitary–testicular axis. 4,5 The pulsatile secretion of hypothalamic luteinizing hormone-releasing hormone (LHRH) stimulates the release of follicle stimulating hormone (FSH) and LH from the anterior pituitary, which then stimulates testicular Leydig cells to produce testosterone. DES remained an effective and low-cost option for ADT from the 1950s up to the 1980s, but its use was discontinued following findings of adverse cardiovascular system (CVS) outcomes from the Veterans Administrative Cooperative Urological Research Group (VACURG) trials. Initiated in the early 1960s, this series of randomized clinical trials compared DES with orchiectomy, placebo, DES plus orchiectomy, and placebo plus orchiectomy. Although DES improved PC outcomes, the DES groups were shown to have increased CVS toxicity (36 % increase in non- cancer-related deaths mostly CVS) with the highest risk in the first year of starting therapy. 6 Luteinizing Hormone-releasing Hormone Agonists and Anti-androgens Luteinizing hormone-releasing hormone agonists (LHRHa), also called gonadotrophin-releasing hormone analogs (GnRHa), were introduced © Tou c h ME d i ca l ME d ia 2014