Collaborative Review – AndrologyA New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications
Introduction
Over the past 15 yr, there has been growing recognition of the benefits of testosterone therapy for men with testosterone deficiency, also termed hypogonadism. These benefits include improved sexual interest and performance, improved mood and energy, increased muscle and bone density, decreased fat, and possibly improved longevity [1]. The new interest in testosterone therapy has precipitated reexamination of traditional assumptions regarding the relationship between testosterone and prostate cancer (PCa) [2], leading to a fundamental paradigm shift. This shift is at odds with longstanding beliefs and has resulted in controversial new practices, such as offering testosterone therapy to men with PCa.
The belief that androgens cause de novo PCa or accelerate its growth has been called the androgen hypothesis. The androgen hypothesis arose from reports beginning in the 1940s in which men with metastatic PCa demonstrated clinical and biochemical improvement with androgen deprivation via castration or estrogen treatment and conversely demonstrated rapid PCa progression with testosterone administration [3], [4]. Medical students and physicians have been taught for years that high testosterone promotes the development of PCa, low testosterone is protective, and the administration of testosterone to a man with existing PCa is like “feeding a hungry tumor” or “pouring gasoline on a fire.” An international survey revealed that the most common concern about testosterone therapy among physicians is the risk of PCa [5].
Today, the androgen hypothesis has been seriously challenged, as overwhelming evidence contradicts its basic principles [6]. Men with high serum testosterone are not at increased risk of developing PCa, low serum testosterone provides no protection against the development of PCa, and some men with untreated PCa have received testosterone therapy without evidence of PCa progression [7], [8], [9]. The androgen hypothesis has therefore been replaced by the saturation model [10] to accommodate the dual observations that PCa is (1) exquisitely sensitive to variations in androgens at low concentrations and (2) indifferent to variations at normal and high concentrations. The simple yet profound paradigm change is that androgens appear to have a finite ability to stimulate PCa growth. This creates opportunities for new clinical uses of testosterone therapy.
The purpose of this review is to synthesize historical and modern evidence to provide an objective and up-to-date basis for clinical decision making. Indications for testosterone therapy in men include low testosterone levels in combination with signs and symptoms of testosterone deficiency, such as fatigue, erectile dysfunction, depression, decreased libido, and decreased muscle mass. Although any history of PCa has been a longstanding contraindication for testosterone therapy, there may now be circumstances where this is a reasonable therapeutic choice, as we discuss below.
Section snippets
Evidence acquisition
A Medline search from 1940 to 2013 was conducted to identify all original and review articles assessing the effect of androgens on the prostate and the use of testosterone in men with a history of treated and untreated PCa. Key words used were testosterone, androgens, prostate cancer, saturation, and prostate specific antigen.
Physiology of androgens and the prostate
Testosterone is the principal circulating androgen in males. Approximately 90% of testosterone is synthesized from testicular Leydig cells and 10% from the adrenals. Androgens induce differentiation of the Wolffian ducts, prostate, and male genitalia. Within the prostate, the primary androgen is 5α-dihydrotestosterone (DHT), metabolized intracellularly from testosterone by the 5α-reductase (5-AR) enzyme. The androgen receptor (AR) binds both testosterone and DHT but has greater affinity for
Conclusions
New scientific evidence over the past 15 yr has resulted in a revolutionary shift in understanding regarding the relationship of androgens and PCa, with important clinical implications. The key conceptual change is that there appears to be a limit to the ability of androgens to stimulate PCa growth, termed the saturation model. In addition, accumulating data indicate an important association between low testosterone concentrations and worrisome aspects of PCa. Given the established benefits of
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