Fertility & the Modern Male: Still More Questions than Answers

While some think that male reproduction is another endocrine function that could be adversely affected by endocrine-disrupting chemicals, not everybody is convinced. Does a solid link between male hormones and EDCs truly exist?

The effects of chemicals like phthalates and bisphenol A (BPA) continue to grab headlines, as do stories blaming them for potential declines in fertility. This attention may lead more patients to ask their physicians whether environmental exposures could be causing their fertility problems.

And the answer still seems to be that although studies continue to illustrate ways that endocrine-disrupting chemicals (EDCs) can perturb reproductive systems, definitive answers are elusive, and many skeptics question whether the disruptions are strong enough to cause measurable consequences.

One of the latest examples of this new evidence is a study associating phthalate levels in men with a longer time to pregnancy in their partners. The phthalate family of plasticizers has come under scrutiny because they are ubiquitous, used in products ranging from plastic bottles and cosmetics to meats, cheeses, and some medical devices.They are metabolized much more slowly than another chemical that has faced scrutiny lately, namely BPA.

Phthalates and Fecundity

In a prospective study published in Fertility and Sterility, researchers led by Germaine Buck Louis, PhD, of the National Institutes of Health, enrolled 501 couples in Michigan and Texas who were planning a pregnancy. The researchers tested the urine of both the male and female partners for 14 phthalate metabolites and BPA, then followed the couples’ success at attaining pregnancy. They found that in males, high levels of three phthalates were associated with a longer time to pregnancy. Th e researchers described this effect as a 20% drop in fecundity, which refers to the probability of becoming pregnant in a single menstrual cycle. Buck Louis puts that effect in context by noting it “is pretty much what we see with cigarette smoking.”

But in females, high levels of two of the 14 phthalates were associated with shorter times to pregnancy, and there was no association of BPA levels in either males or females.

Sheela Sathyanarayana, MD, MPH, assistant professor of pediatrics at the University of Washington in Seattle, said that the study stands out from others because it involved both members of a couple, rather than just the female or male. And the couples were from the general population, rather than pre-selected for infertility problems.

A phthalates expert, Sathyanarayana says that the results make sense “because phthalates have a direct anti-androgenic effect on male testes. There have been several studies that show that phthalates lead to low testosterone and changes in sperm quality and function. The evidence for phthalates is actually quite good when you look at male fertility, that phthalates are true anti-androgens and can adversely affect male reproductive outcomes.”

Phthalates and Reduced Testosterone

However, a recent study in the Journal of Clinical Endocrinology & Metabolism does seem to show a link between EDCs and reduced testosterone levels in not just men, but women and children as well. In a cross-sectional study of the general U.S. population from 2011 to 2012, data from the U.S. National Health and Nutrition Examination Survey showed that multiple phthalates were associated with significantly reduced testosterone in both males and females regardless of age.

Since various animal and cellular studies have shown that some phthalates block the effects of testosterone, study authors John D. Meeker, MS, ScD, and Kelly K. Ferguson, PhD, of the Department of Environmental Health Sciences at the University of Michigan in Ann Arbor set out to prove if the same was true in humans. These compounds are commonly used in plastics and personal care products, items that everyone uses on a regular basis with few exceptions.

Not Everyone is Convinced

But it’s these kinds of studies that will add to the conviction of those concerned about EDCs, but do little to change the minds of those who remain skeptical of any clear and present danger. Stephen Safe, PhD, a distinguished professor and director of the Center for Environmental and Genetic Medicine at Texas A&M University, says that many studies of the effects of EDCs tend to cherry-pick their results, and he wonders how much significance to assign to a survey of a large number of chemicals, most of which had no effect: “The study by Buck Louis and coworkers found a very small correlation with males and a 20% reduction in fecundity and nothing else.”

Safe says that such studies are important, but “let’s see if this is repeatable” before drawing any conclusions. He notes that the effects of the potent estrogenic endocrine disruptor diethylstilbestrol (DES) were evident in every human study, but the effects of phthalates and other EDCs being studied today give variable results.

Bald Eagles as Poster Children

That endocrine disruptors can have devastating effects on reproduction was demonstrated by the effects of the pesticide DDT on bald eagles. Bald eagles once seemed to be on a fast road to extinction, but have been repopulating the country since DDT was banned.

As top predators, they were repositories for the persistent DDT, but so far there is no DDT-like chemical in humans. And even as evidence mounts for EDC effects on endocrine systems, any signal would be diffi cult to spot amidst other changes over time that could adversely affect reproduction, such as more couples postponing child-bearing until later in life, the increase in obesity, and dietary changes.

Are Sperm Counts Dropping?

One of the primary measures proposed for male reproductive capacity has been sperm and semen quality, and a key paper on the topic was published in 1991 by a team lead by Niels Skakkebaek of the University of Copenhagen. That meta-analysis touched off years of debate over its thesis that sperm counts were dropping globally while testicular cancer, hypospadia, and cryptoorchidism were increasing. The paper was criticized for many methodological flaws and eventually largely discredited, says Brad Anawalt, MD, a professor of medicine at the University of Washington in Seattle. And later studies on sperm counts and quality have had inconsistent results. “On the basis of the conflicting results of studies to date, it is difficult to make any firm conclusions about whether there is a global trend toward decreased average sperm counts in humans,” Anawalt wrote in the Asian Journal of Andrology. In fact, one of the authors of that original Skakkebaek article, Richard Sharpe, PhD, of the University of Edinburgh in Scotland, has since all but repudiated his positions, becoming a skeptic of the evidence of strong effects of endocrine disruption.

Skakkebaek himself continues to be one of the leading proponents of the dangers of EDCs. His team recently published an in vitro study in EMBO Reports recounting that a variety of EDCs applied at concentrations present in bodily fluids interfered with sperm functions.

Endocrine Society Statement on EDCs

Endocrine Society leaders are concerned enough about the potential problems from EDCs that the Society published a scientific statement described as “an exhaustive summary of the scientific background that justifies concern for the effects of EDC exposures to humans and wildlife.” It stresses that “in the absence of direct information regarding cause and effect, the precautionary principle is critical to enhancing reproductive and endocrine health.”

Andrea Gore, PhD, one of the authors of the Endocrine Society scientific statement and editor of the journal Endocrinology, recommends an abundance of caution regarding exposure to EDCs, especially for both men and women planning a family. Many of the precautions sound a lot like the advice physicians generally give: Live a healthy lifestyle, and eat thoroughly washed fresh fruits and vegetables. Buy organic if you can afford it, especially for vegetables with large surface areas like lettuce and spinach. Avoid canned foods and foods stored in plastics, and don’t use plastic in the microwave.

And as for the patient who asks whether phthalates or other environmental exposures could be causing a fertility problem, Anawalt advises: “I think that the take-home message for clinicians needs to be that there is not enough evidence that that is the cause. There is a possibility that EDCs could affect male reproductive function, but the evidence is inconclusive. Until we can reassure patients that it does not appear to be the likely explanation, it is sensible to avoid prolonged exposure to potential toxins.”

— Seaborg is a freelance writer based in Charlottesville, Va. He
wrote about endocrinologists’ influence in the June issue.

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