REVIEW Androgen deprivation therapy and estrogen deficiency induced adverse effects in the treatment of prostate cancer SJ Freedland 1 , J Eastham 2 and N Shore 3 1 Departments of Surgery (Urology) and Pathology, Durham VA Medical Center and Duke Prostate Center, Duke University School of Medicine, Durham, NC, USA; 2 Memorial Sloan-Kettering Cancer Center—Urology, New York, NY, USA and 3 Atlantic Urology Clinics/Carolina Urologic Research Center, Myrtle Beach, SC, USA Androgen deprivation therapy (ADT) is the standard of care for metastatic prostate cancer and is increasingly used to treat asymptomatic patients with prostate-specific antigen recurrence after failed primary therapy. Although effective, ADT is associated with multiple adverse effects, many of which are related to the estrogen deficiency that occurs as a result of treatment. These include increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss. By providing clinicians with a greater awareness of the estrogen deficiency induced adverse effects from ADT, they can proactively intervene on the physical and psychological impact these effects have on patients. Prostate Cancer and Prostatic Diseases (2009) 12, 333–338; doi:10.1038/pcan.2009.35; published online 1 September 2009 Keywords: adverse effects; androgen deprivation; estrogen; side effects; testosterone Introduction In 2008, prostate cancer was estimated to account for 25% of all new cancer cases and 10% of all cancer deaths in men. 1 Common treatment options for localized prostate cancer include active surveillance, radical prostatectomy, radiation therapy and cryosurgery. 2 Some patients may experience an eventual increase in PSA or biochemical failure necessitating additional treatment. Androgens and the functional status of androgen receptors are considered integral to both normal prostate development and prostate cancer progression; 3 con- sequently, androgen deprivation therapy (ADT) is a common treatment for prostate cancer. Although ADT is the standard of care for symptomatic and metastatic disease, 4 its use has expanded to include patients who show evidence of increased PSA recurrence or biochem- ical failure. 5 Although the mortality rates for prostate cancer have been steadily decreasing since 1994 (whether a result of improved screening, diagnosis or therapy), the fact that the aging male population is increasing along- side a longer duration of survival is estimated to result in an increase in the number of men with prostate cancer by more than 50% over the next 20 years. 6 Consequently, the number of patients receiving ADT is likely to see an increase. Androgen deprivation therapy is typically performed through medical castration and, less frequently, surgical castration. Although there are several methods of medical castration (Table 1), it is most commonly achieved through the use of gonadotropin-releasing hormone (GnRH) agonists (for example, leuprolide, goserelin and triptorelin). 7 GnRH is secreted by the hypothalamus and leads to the pulsatile release of follicle-stimulating hormone and luteinizing hormone by the pituitary gland. The release of follicle-stimulating hormone and luteinizing hormone promotes testosterone secretion by Leydig cells of the testes. High continuous exposure to GnRH, such as that which occurs through treatment with GnRH agonists, causes downregulation of receptors in the pituitary gland, leading to decreased pituitary hormone production and ultimately a decrease in the production of testosterone. 8 Although ADT is effective in treating prostate cancer, it is associated with adverse effects, some of which are due to a deficiency in testosterone levels (Figure 1). However, because estrogens are derived in men through the aromatization of testosterone, the reduction in testoster- one due to ADT also decreases the levels of estrogen. 9 This can lead to a number of estrogen deficiency induced side effects, including increased fracture risk, hot flashes, gynecomastia, serum lipid changes and memory loss (Figure 1). Although some of these estrogen related ADT side effects have been reviewed previously, 10 it is important to revisit and update the issue given the projected increase in the number of patients with Received 28 April 2009; revised 22 June 2009; accepted 25 June 2009; published online 1 September 2009 Correspondence: Dr SJ Freedland, Departments of Surgery (Urology) and Pathology, Duke University School of Medicine, Box 2626 DUMC, 551 Research Drive, Room 475, Durham, NC 27710, USA. E-mail: steve.freedland@duke.edu Prostate Cancer and Prostatic Diseases (2009) 12, 333–338 & 2009 Nature Publishing Group All rights reserved 1365-7852/09 $32.00 www.nature.com/pcan