Commentary: “Estrogenic and Anti-Androgenic Endocrine Disrupting Chemicals and Their Impact on the Male Reproductive System”

During the last two decades or so, endocrine-disrupting chemicals (EDCs) and their effects on human health have become one of the most researched and controversial topics in toxicology. There are a number of reviews on the health consequences of exposure to EDCs including a comprehensive report by the World Health Organization and the United Nations Environment Programme (1). Recently, De Falco et al. (2) addressed the impact of EDCs on male reproductive system, with special reference to the effects of bisphenol A (BPA), alkylphenols, and phthalates. Jeng (3) also reviewed the epidemiological data on the adverse effects of EDCs on male reproduction and experimental studies that could shed light on mechanisms (disruption of steroidogenesis, oxidative stress, and epigenetic changes) through which EDCs could impair male reproductive health. Both articles are essentially narrative reviews of the abundant and highly controversial literature on the health consequences of exposures to EDCs.

A key feature that distinguishes a narrative review from a systematic review is that the former review does not include a comprehensive and meticulous search of all potentially relevant articles on specified sources, and does not use explicit and reproducible criteria to selected articles for review (4). Compared to systematic reviews, narrative reviews of the literature are more likely to error and bias in the selection of relevant studies (4, 5). Moreover, if research designs, methods, and study characteristics do not undergo a critical appraisal, summary, and conclusions of literature reviews are even more prone to bias.

De Falco et al. were unable to convey to readers an unbiased review of the empirical evidence suggesting that environmental exposures to EDCs might affect male reproduction. The authors, for instance, did not disclose the conflicting evidence on the enlargement of prostate after developmental exposure to BPA. In the mid-1990s, a set of studies by vom Saal and coworkers showed that prenatal exposure to β-estradiol (EST), diethylstilbestrol (DES), or BPA led to enlarged ventral prostate in adult mice (6, 7). The observation that enlargement of prostate resulted from prenatal exposures to low doses of estrogenic compounds (e.g., supra-physiological levels of EST), and exhibited non-monotonic dose–response relationships, fueled considerable debate over the adverse health consequences of environmental exposure to EDCs. Several studies, however, failed to reproduce these findings not only with BPA but also with EST and DES (8–10). Although reproducibility is one hallmark of experimental sciences, the foregoing discrepancy between studies by different authors has remained unexplained (11).

Furthermore, authors’ statements that “…over 50 years, the global average sperm count dropped by half…” and that “studies of the last decade strongly support that male reproductive health has been deteriorating…” were unaccompanied by any reference to the conflicting evidence on this matter (2). The widespread notion that semen quality has decreased over the past decades stands on some retrospective studies [Ref. (12, 13), and others]. Nonetheless, results from a number of other studies (not cited by the authors) are inconsistent with this hypothesis. Most studies showing downward trends in sperm counts included samples coming from different populations and places that do not necessarily allow a valid comparison over time. For instance, a re-analysis of US data used by Carlsen et al. (12) found no decline in sperm counts when data from New York were excluded from the regression analysis (14). Therefore, apparent time trend toward lower concentrations reported by Carlsen et al. (12) resulted, in fact, from geographic variations in sperm counts (14, 15). Moreover, a longitudinal study of sperm concentrations for Danish military draftees (5000 men), collected annually for 15 years (1996–2010), found no indication that semen quality has changed during the monitoring period (16). Although several studies precipitated by reports on “downward temporal trends in sperm counts” refuted its existence, the “sperm crisis” notion is still a highly controversial issue in the literature (17–20). Temporal trends to increasing birth prevalence of male reproductive tract defects such hypospadias and cryptorchidism described by some authors are far from being a consistent finding among studies (21, 22).

The “endocrine disruptor hypothesis,” a landmark of which was the Wingspread Conference Statement in 1990s (23), fits like a glove to the beliefs of the public that pesticides and other manmade chemicals in the environment are undermining human health and fertility. Two seminal books by Rachel Carlson (Silent Spring, 1962) and Theo Colborn (Our Stolen Future, 1996) boosted considerably these concerns on the deleterious effects of environmental chemicals on human fertility and health. Notwithstanding the fact that ED hypothesis is instigating, the notion that “male reproductive health has been deteriorating,” as asserted by De Falco et al. (2) and others, lacks an unequivocal demonstration by soundly designed epidemiology studies. It is of note that, even if a temporal trend toward a worse male reproductive health had been demonstrated consistently, it would still be missing to prove that there is a causal link between EDCs, identified as such in experimental tests, and the incidence of the adverse health outcome in the human population. A step forward to identifying relevant research gaps and to unveiling the real impact of EDCs on male fertility and reproductive health would be to conduct less and less narrative and potentially biased reviews and more and more good quality systematic reviews of the literature on the topic. Finally, we highlight that a critical appraisal of the quality of original studies is required for both a good quality narrative and a good quality systematic review. If unbiased, good quality narrative reviews can also be helpful. Systematic reviews, however, are a more reliable approach to avoid bias in the selection of studies.

Conflict of Interest Statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.