Editorial
Secular Decline in Male Reproductive Function: Is Manliness Threatened?
Shalender Bhasin
- Author Affiliations
Section of Endocrinology, Diabetes, and Nutrition, Boston University School of Medicine, Boston Medical Center, Boston, Massachusetts 02118
In this issue of JCEM, Travison et al. (1), using data from the Massachusetts Male Aging Study (MMAS), report that circulating testosterone concentrations in men are in an age-independent, secular decline. This population-level decline in testosterone concentrations in men is not explained fully by the usual suspects: increasing body mass index and prevalence of obesity, certain other co-morbid conditions, or decreasing incidence of smoking. Although the analysis by Travison et al. did reveal significant age-related increases in adiposity and medication use and a welcome decline in smoking, the age-matched decline in testosterone concentrations persisted even after adjusting for these variables. These data are important because they add to the concern raised by earlier reports of the population-level decline in sperm counts and increasing incidence rates of certain reproductive disorders in men, especially in some Northern European countries (2, 3). How much credence should we ascribe to these reports and what public health implications, if any, do they have for the welfare of the human race?
Several retrospective analyses have suggested that average sperm concentrations and motility and the percentage of morphologically normal spermatozoa in fertile men have been declining steadily over the past 50 yr (2, 3). However, these earlier reports had generated skepticism because other studies did not confirm this secular decline (4, 5, 6). Furthermore, substantial regional differences in semen quality and time trends have been reported (e.g. Refs. 4 and 5). Consequently, thoughtful commentators, citing methodological limitations of these initial analyses, have discounted these concerns about population-level decline in reproductive function (6, 7).
In the midst of this contentious debate, some additional trends in male reproductive health have emerged. The incidence of congenital urogenital tract abnormalities, such as hypospadias and cryptorchidism, has been reported to be rising (8, 9). Data collected by the International Clearinghouse for Birth Defects Monitoring Systems show increasing incidence of hypospadias in Sweden, Norway, Denmark, England, Hungary, and the United States (9). However, problems with ascertainment and incomplete reporting of these two conditions to the International Registry make its data suspect (9). Most remarkable perhaps is the consistent observation that the incidence rates of testicular cancer have been rising worldwide, although these trends are most pronounced in Northern Europe. Skakkebaek (10) has suggested that these three conditions–cryptorchidism, hypospadias, and testicular cancer–share common pathogenic mechanisms and has proposed the term “testicular dysgenesis syndrome” to describe them.
Several prenatal and postnatal factors have been invoked to explain the increasing incidence rates of reproductive disorders in men. Prenatal exposure to environmental and dietary estrogens has received the most visibility. Indeed, habitat contamination by pesticidal chlorinated hydrocarbons and organophosphates that have estrogenic or growth inhibitory activities played an important role in driving populations of California condors and other birds of prey to near extinction in several parts of the United States (11). In the 1970s, occupational exposure of industrial workers to 1,2-dibromo-3-chloropropane was associated with a high frequency of infertility (12). Humans ingest small quantities of estrogenic and antiestrogenic compounds daily in their diets. For instance, bioflavinoids widely distributed in plant products and chlorinated hydrocarbon pesticides and phenolic compounds that have weak estrogenic activity regularly find their way into the human food chain. Other plant products such as indole-3 carbinol found in cruciferous vegetables and some aromatic hydrocarbon combustion products exhibit antiestrogenic activity. Although there is little evidence that humans are being exposed to substantially increased net levels of estrogenic activity, we do not know whether modest increases in estrogen exposure in utero and early postnatal life could have a lasting deleterious epigenetic effect on reproductive function in men. Some investigators have argued that even small amounts of estrogenic compounds such as bisphenol A could potentially exert clinically important biological effects (12, 13, 14). Others such as Handelsman (6) have pointed out that neither fertility nor sperm output are adversely affected in offspring of mothers exposed to high doses of diethylstilbestrol during pregnancy, although the offspring have higher frequency of urogenital malformations.
The current MMAS data (1) showing a secular, age-independent decline in testosterone levels in men over the past two decades are important because they provide independent support for the concerns raised earlier about the reproductive health of men. Undoubtedly, the age-matched differences in testosterone levels between the cohorts were small and may not be clinically significant in any one individual. However, from evolutionary and ecological perspectives, this magnitude of change over such a short period of time is disquieting. Although increasing adiposity and lifestyle factors that were recorded in the MMAS could not account for the secular trends in testosterone level, it is possible that other lifestyle factors, such as increasing use of tight-fitting underwear, increasing room temperatures in American homes and offices over the past three decades, decreased physical activity with increasing body mass indices, and decreased smoking, could have contributed to the declining testosterone levels in men. To be sure, there are some inherent limitations to this study. It would have been interesting to measure plasma estrogenic activity in men participating in the MMAS. Also, the MMAS surveyed men in a limited geographic region of the United States; it remains to be determined whether similar trends in testosterone levels are apparent in other parts of the United States and the world. Needless to say, further confirmation of this trend in other cohorts of men is needed. Although prospective longitudinal studies of the reproductive function of human populations are desirable, their design and execution is inherently complex and difficult. It is unclear how best to design population-based, prospective studies of the effects of environmental exposures, especially to estrogenic compounds, on human reproductive function. Combined application of multiple experimental models and epidemiological approaches including the use of biomarkers, as has been suggested previously (14), should help confirm the existence and magnitude of these changes and determine the significance of these trends. Although it is premature to raise alarm, it would also be unwise to dismiss these reports as mere statistical aberrations because of the potential threat these trends–if confirmed–pose to the survival of the human race and other living residents of our planet.
Regards
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