Estrogens: A Hidden Factor and New Target in Preventing Abnormal Growth of the Prostate.

For over 50 years urologists have used androgen ablation therapy to reduce normal and abnormal growth of the prostate. However, only limited attention has been given to the role of blocking estrogens in controlling the pathobiology of the prostate. A paradigm shift in our understanding of the importance of estrogens and how they may be regulated as both preventive and therapeutic agents in the control of prostate cancer, benign prostatic hyperplasia (BPH), and prostate inflammation is now occurring. Historically, urologists have focused only on one edge of estrogens’ double-edged sword. It was well known that estrogens strongly inhibited prostate growth by markedly lowering serum testosterone through blocking the hypothalamic-pituitary axis from releasing luteinizing hormone—a hormone essential for stimulating production of testosterone by the Leydig cells in the testes. In contrast, however, in the presence of androgens, estrogens strongly enhance abnormal growth of the prostate. In a classic study, Patrick C. Walsh and Jean D. Wilson1 administered both androgens and estrogens to castrated dogs and observed a massive overgrowth of the prostate to 4 times its normal size in non-castrated control animals. This estrogen-androgen synergy was confirmed and extended in a much larger study at Johns Hopkins.2 The massive overgrowth was produced by the combination of dihydrotestosterone (DHT) and estradiol. Estrogen increased the androgen receptor and induced inflammation and focal atrophy. A similar type of lesion, proliferative inflammatory atrophy (PIA), is now observed in human prostates and is proposed to be the first premalignant lesion that gives rise to prostatic intraepithelial neoplasia (PIN). In a recent classic review, Nelson and colleagues3 gave a comprehensive report on the steps in the pathobiology of prostate cancer. Earlier studies in rats indicated that estrogens could induce inflammation and that spontaneous inflammation could be reduced by administering a diet high in soy, which increases phytoestrogens in the blood. Phytoestrogens can function as both antiestrogens or weak estrogens, meaning that they can be both agonist or antagonist depending on the tissue in which they are located. It is known that both estrogen response and carcinogens are tissue-specific. Selective estrogen receptor modulators (SERMs), such as antiestrogens and phytoestrogens, function as agonists or antagonists in different tissues, depending on each tissue’s profile of coactivators or activators modulating the action of the receptor bound to the estrogen. This provides a unique opportunity to design antiestrogens with different properties to affect cancer only, while providing protection for normal tissue, such as bone tissue. This type of estrogen control has been successfully studied in breast cancer, and many of the principles will be applicable to the prostate, but the tissue specificity and role of androgens will have to be resolved. For example, estrogens are critical to both the etiology and therapeutic control of breast cancer, and antiestrogens (eg, tamoxifen, raloxifene, etc) have been added to the clinical armamentarium. It now appears that prevention and therapy are converging in breast cancer treatment.4 The role of androgens and estrogens in inducing BPH and inflammation in the dog and cancer and inflammation in the rat, combined with the appearance of early premalignant lesion such as PIA and PIN, strongly suggest that blocking estrogen function with antiestrogens and DHT formation with 5α-reductase inhibitors either alone or in combination may have a role in prevention or therapy. Preclinical experiments in animal models are supporting this approach, and mechanisms need to be elucidated. So far results from small clinical trials seem to be gaining attention, but much remains to be learned from the laboratory and clinic about these agents and their short-and long-term effects. In an effort to explore the current state of the art in prostate cancer prevention, we convened a roundtable in New York City on December 4, 2004 for a discussion of the use of pharmacotherapy in the prevention of prostate cancer. Five nationally recognized thought leaders in urology met and discussed and debated these issues as well as the potential to ameliorate the adverse events frequently associated with hormone therapy in general and gonadotropin-releasing hormone (GnRH) therapy, in particular. The topics covered included the mechanisms of estrogens in benign and malignant growth of the prostate, PIN as a precursor of prostate cancer, chemoprevention of prostate cancer, and ameliorating the side effects of GnRH agonists for prostate cancer. The following supplement to Reviews in Urology summarizes these discussions with the goal of helping clinicians recognize and understand the rationale for investigating antiestrogens (SERMs) as a chemopreventive strategy for prostate cancer with a focus on men with high-grade PIN (HGPIN). Maarten C. Bosland, DVSc, PhD, begins the supplement with a discussion of the association between estrogens and estrogen receptors in the development and progression of prostate cancer. Dr. Bosland then examines the rationale for using anti-estrogens as a chemotherapeutic and chemopreventive agent and summarizes the many studies in animal models supporting this strategy. Michael K. Brawer, MD, follows with an overview of PIN and the evidence indicating PIN is a premalignant lesion and therefore an appropriate chemoprevention target. Samir S. Taneja, MD, continues with a discussion of diagnosis and management of HGPIN. Dr. Taneja also discusses the latest clinical trial evidence demonstrating that the use of SERMs is a rational, although provocative, strategy for preventing prostate cancer. Matthew R. Smith, MD, PhD, concludes the supplement with a review of the evidence that estrogen deficiency rather than testosterone deficiency accounts for the adverse skeletal effects associated with the use of GnRH agonists to treat prostate cancer. The rationale for evaluating SERMs for prevention of treatment-related osteoporosis in men with prostate cancer is also presented and evaluated. Along with the significant progress in our understanding and treatment of men with prostate cancer has come an understanding of the importance of and need for preventive measures, both in relation to the disease itself and the effects of treatment. It is hoped that the information contained in this supplement will aid in understanding these issues, the current research activities and questions, and how to better serve the growing numbers of aging American men with or at significant risk of developing prostate cancer. PIA → PIN → PROSTATE CANCER