A New Era of Testosterone and Prostate Cancer: From Physiology to Clinical Implications

Abstract

Context

Decades-old beliefs regarding androgens and prostate cancer (PCa) have undergone dramatic shifts in light of modern evidence and new theoretical constructs, but considerable confusion remains on this topic, particularly with regard to the use of testosterone therapy in men with any history of PCa.

Objective

To review current literature regarding the relationship of serum testosterone on PCa and in particular the effect of testosterone therapy on PCa progression and recurrence.

Evidence acquisition

A Medline search 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.

Evidence synthesis

Contrary to traditional teaching, high endogenous serum testosterone does not increase the risk of developing PCa, and low serum testosterone does not protect against PCa. Although limited in size and duration, current studies similarly fail to indicate any increased risk of PCa in men receiving testosterone therapy. These results indicate a finite ability of androgens to stimulate PCa growth (the saturation model). A majority of studies demonstrate an association between low serum testosterone and poor prognostic features of PCa, including high-grade disease, advanced pathologic stage, and increased risk of biochemical recurrence following radical prostatectomy. The prostate-specific antigen-to-testosterone ratio predicted PCa risk in several biopsy studies. Multiple reports of testosterone therapy in men after treatment for localized PCa have shown low or absent recurrence rates. Some men with untreated PCa have received testosterone therapy without evidence for PCa progression.

Conclusions

The long-held belief that PCa risk is related to high serum androgen concentrations can no longer be supported. Current evidence indicates that maximal androgen-stimulated PCa growth is achieved at relatively low serum testosterone concentrations. It may therefore be reasonable to consider testosterone therapy in selected men with PCa and symptomatic hypogonadism.

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.