Hair, Hormones, and High-Risk Prostate Cancer

Prostate cancer remains one of the most prevalent cancers in the world and the second leading cause of cancer death in men in the United States. A major issue in addressing the disease is avoiding overtreatment of less aggressive tumors while targeting higher risk situations with appropriate therapy. It is critical to distinguish overall incidence from incidence of clinically relevant or aggressive prostate cancer, given the heterogeneity of the disease and the huge increases in the diagnosis of indolent prostate cancer with the implementation of prostate-specific antigen (PSA) screening starting in the early 1990s. With screening now controversial and limited by many guideline committees to men with an affected first-degree relative, as well as African Americans, the question arises as to whether certain groups can be identified who definitely should be screened, such as those with a first-degree relative with a history of prostate cancer, and so on. Such an approach would reduce the burden of screening, enrich the pool of those screened with those at true risk of dying as a result of prostate cancer, and may lead to the development of a screening approach that is logical, feasible, and, most importantly, saves lives. In the article that accompanies this editorial, Zhou et al contribute provocative information that may aid in the identification of patients who could be targeted for screening and possible early intervention: men with frontal and vertex baldness between age 40 and 50 years. Using a prospective cohort of approximately 39,000 men enrolled onto the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial, they report an analysis of the association of male pattern baldness to aggressive, and therefore clinically significant, prostate cancer risk. They hypothesizedthat thetwooutcomesshareacommonpathogenesis that is related to cumulative lifetime exposure to androgens. Although previous reports have also evaluated this hypothesis, this study was one of the largest to date that had the ability to focus on more clinically relevant disease. There were more than 39,000 men in the analysis population, with 1,138 prostate cancers observed, including 571 diagnoses of aggressive disease. The authors were able to consider several potential confounding factors, such as race, education, marital status, cigarette smoking, body mass index at age 50 years, regular aspirin use, history of diabetes, history of myocardial infarction, family history of prostate cancer in first-degree relative(s), history of enlarged prostate, screening assignment (from the original trial), and screening center. Intriguing aspects of the results include the specific association of only frontal plus moderate vertex baldness with aggressive disease but not with nonaggressive prostate cancer. Furthermore, there was lack of evidence for any association of other types of baldness (eg, frontal only, frontal plus mild vertex, frontal plus severe vertex baldness) and either prostate cancer outcome. The results shown in the Data Supplement (Supplemental Table 2) further suggest that the results were stronger for frontal plus moderate vertex baldness when applying a definition of aggressiveness that was restricted to higher grades of prostate cancer (eg, Gleason sum 8). It is nevertheless slightly curious that mild vertex baldness and severe vertex baldness were not associated with prostate cancer risk, whereas moderate vertex baldness was, although there were fewer men in the severe vertex baldness group. As the authors point out, these data could be confounded by the elimination of patients diagnosed with prostate cancer before entering the screening study, as well as those with a history of cardiac disease, a condition also associated with baldness. The fact that only a particular type of baldness carries this association argues against baldness being an epiphenomenon of a particular lifestyle or environmental process, such as diet, lack of exercise, and so on. Vertex baldness has similarly been associated with increased coronary heart disease, likely because of a link between reduced arterial blood flow in scalp skin, mirroring the same in the coronary arteries. Androgen exposure may underlie both events in the vertex, as it has been observed that minoxidil, a vasodilator, is effective in curtailing the progression of vertex, but not frontal, hair loss. Incidentally, the link between androgens and coronary events has, in effect, been prospectively demonstrated in the context of androgen replacement therapy, wherein an increase in cardiac events was noted. Much like prostate cancer cells themselves, hair follicles can be classified as androgen dependent (beards), androgen independent (eyebrows), or androgen sensitive (scalp hair). The difference is likely the result of variable expression of sex steroid–producing and –converting enzymes, as well as the androgen receptor (AR), in the nearby skin and follicle itself. It is the latter type, androgen sensitive, for which the link to baldness emerges, given that chronic exposure to androgens, through lower levels of sex hormone–binding globulin or higher expression of 5-alpha reductase, leads to a shortening of the anagen phase and eventual thinning and shortening of the hair produced. Androgenetic alopecia (AGA) affects men of all genetic backgrounds but is far more common in white men, affecting approximately 50% of the population, than in men of African or Asian descent. Beyond epidemiologic associations, there are now genetic links to baldness. Two unique genetic loci have been associated with baldness. One of them, EDA2R, is located on the X chromosome in close proximity to the AR itself. The other, a single-nucleotide polymorphism (SNP) recently identified on chromosome 20, leads to a seven-fold risk of alopecia when coexistent with an SNP in AR. These findings have the potential for implications along three fronts JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 33 NUMBER 5 FEBRUARY 1