The Riddle of Gender

by Deborah Rudacille

  Men are notoriously tight-lipped about health problems, and Kerlin was congratulating himself on having managed to create a safe, trusting environment in which list members felt comfortable discussing such personal concerns. Then, a new list member raised an issue that initiated a flood of responses, saying that he had, from his earliest youth, felt like a girl, and that he was, in fact, transsexual. Once the issue had been raised, it did not go away. Other list members began to speak about their own gender-identity issues, and “over subsequent months, these issues became more substantial in list discussions, at times becoming the dominant themes raised by members,” Beyer and Kerlin note in a 2002 paper. Some list members objected to the turn that the discussions were taking. They may have had reproductive health problems, but they were heterosexual men, and they were uncomfortable with the new focus on gender identity. Eventually, Kerlin and Beyer (who had become co-moderator of the group in 2001) set up a separate list (DES Trans) for list members who identified as trans-gender, transsexual, or intersexual.

  “About 50 percent of our two hundred people in the DES Sons Network exhibit some form of gender variance. Most of them joined us when we didn’t talk about gender variance at all,” says Beyer. “I would say about half of the people on our list came unknowing that

  DES was connected with gender.” In July 2004, on the fifth anniversary of the DES Sons Network, Kerlin reviewed his data and concluded that of the approximately six hundred individuals who had contacted the list for information or support in the previous five years, two-thirds of those who joined the list did not mention gender issues or concerns during their introductions, health histories, or subsequent postings. However, ninety-three individuals with confirmed prenatal DES exposure had indicated that they were either transsexual, trans-gendered, gender dysphoric, or intersexed. Another sixty-five individuals who “strongly suspect” DES exposure identified themselves using one of those four categories.

  Kerlin and Beyer are convinced that the DES Sons Network has broken the seal on the conspiracy of silence about the effects of DES exposure on sons, particularly its association with gender identity disorder in males. Not a single DES cohort study has explored this question. “It seems that the entire focus of any ongoing ‘cohort’ tracking for sons is to look for signs of cancer risk. Other health issues just don’t seem to be included,” Scott Kerlin told me during a series of e-mail and telephone conversations in 2002 and 2003. All current DES research is based on the DES Combined Cohort Studies (DCCS)— approximately five thousand women exposed to DES during pregnancy; four thousand unexposed (control) mothers; five thousand exposed and twenty-five hundred unexposed daughters; and two thousand exposed and two thousand unexposed sons. According to the U.S. Centers for Disease Control, “the goal of the DCCS is to determine whether the health risk of cancer among DES-exposed individuals is increased as a result of exposure to DES. Other health outcomes, such as infertility and pregnancy outcomes, are also being investigated through the DCCS.” It goes without saying, Kerlin and Beyer note, that there is no mention of gender variance in these studies. “Those studies are just not looking at the question of gender variance or anything remotely connected to it.”

  Kerlin has located a few articles raising the issue of prenatal DES exposure and feminization in males dating as far back as 1973, when researchers at Stanford found not only increased incidence of hypospa-dias but also “lower ratings on variables related to general masculinity, assertiveness and athletic ability” in twenty six-year-old boys whose mothers had taken DES, compared with a control group. A study published in 1992 by researchers at the Kinsey Institute shows significant differences in spatial ability between DES-exposed males and their brothers. The sample sizes in both studies were small (ten in the Kinsey group and forty in the Stanford study). However, when one considers that seven cases of clear cell adenocarcinoma in 1970 led to an investigation of the relationship between DES exposure and cancer in exposed females, one wonders why the investigation of the effects of DES on male psychosexual development and reproductive anomalies has been so muted. Even if the sample sizes have been small, “it’s not like the topic has never been examined,” says Scott Kerlin. “I’m beginning to think that sample size isn’t necessarily the most critical factor to consider when examining the published ‘findings’ of DES research.”

  Pat Cody, founder of DES Action, has responded to Kerlin’s persistent questioning about the lack of attention to these issues by that organization by noting that “this subject, as I don’t need to tell you, is one that no one wants to look at and therefore we do not have any good research with a large number of random subjects and equal number of controls.” Kerlin, who admits the limitations of existing studies, remains frustrated by the unwillingness of DES lobby groups and funding agencies to investigate further the concerns of DES sons. “Since we cannot create fresh studies of DES in humans and trace its effects from birth, we are pretty much forced to look at the existing adult populations. But it would be almost impossible to gather such a population in one place physically in order to verify who they are and whether they were, in fact, DES exposed. That is, unfortunately, one of the reasons that the control/cohort studies like the Dieckman cohort from the University of Chicago have continued to be used in CDC and other DES sons and other DES sons’ longitudinal tracking studies,” he says.

  Because those studies have not posed any questions about subjects’ gender identity or sexual orientation, they provide no support for the contention that DES affects the psychosexual development of males exposed in utero. Even the evidence linking other reproductive effects in males (such as cryptorchidism, hypogonadism, and epididymal cysts) is considered inconclusive. Yet funding for further research on sons’ issues has been sparse. “Of course there are a handful of people saying, ‘Yes, we need more on sons.’ But when push comes to shove, sons’ issues, even the ones that are least threatening, are being ignored,” Kerlin notes. “Oh, maybe they’ll discuss the possibility of increased risk of testicular cancer later this year, when the CDC holds its teleconference on DES sons’ health, but I doubt much else is going to be addressed. It seems like this is an issue where the National Cancer Institute has been just so influential that other groups have been ignored.”

  The difficulties of researching the effects of DES on sons is acknowledged by the sexologist Milton Diamond, who told me that “the problem with DES is that there is no test that we can give today to determine if an individual has been exposed to DES. There are many individuals who say, ‘Well, my mother took DES,’ and you say, ‘How do you know?’ and they say that their mother told them or an aunt told them. Could have been, but there’s no proof.” In the larger population, there may well be DES children with gender issues, but “not only will the guys themselves be in the closet, but so will the physicians and parents.” “This is what we get from DES Action: ‘There’s no proof,’” adds Dana Beyer. “You know, there was no ‘proof that DES caused vaginal carcinoma either. There were seven cases. There was a cluster. But it scared the hell out of people that all these young women had cancer, so all of a sudden they accepted the fact that there was a correlation. But there’s never been any large randomized double-blind study. Nobody has yet found DES molecules in the cancerous cells. The technology just wasn’t there yet. But it’s accepted, so why not us?”

  Another body of research is beginning to provide support to DES sons who believe that their gender and/or reproductive anomalies may have been caused by prenatal exposure to an endogenous estrogen. In 2001, researcher Niels Skakkebaek and colleagues published an article in the journal Human Reproduction providing evidence of the link between exposure to estrogenic chemicals ubiquitous in the environment and a condition that the researchers have termed “testicular dysgenesis syndrome.” Epidemiologie evidence from around the world has shown a rise in testicular cancer, low and declining sperm quality, reproductive tract abnormalities, and abnormal sexual differentiation in humans—a collection of effects t
hat the authors attribute to prenatal exposure to chemicals that disrupt endocrine signaling. Such chemicals (collectively termed “endocrine disrupters” or EDCs) have become the target of major research programs in Europe and the United States. DDT, a potent endocrine disrupter, was banned in the United States following publication, in 1962, of Rachel Carson’s book Silent Spring, but many other chemicals in heavy use today also bind to hormone receptors, producing well-documented reproductive and other abnormalities in wildlife and laboratory animals. The publication of the book Our Stolen Future sounded the alarm in 1996 with its argument that some man-made chemicals disrupted chemical signaling in the body, creating myriad negative health effects. Subsequent studies have reinforced the environmental endocrine hypothesis advanced by the book’s authors: Theo Colborn, Dianne Dumanoski, and John Peterson Myers. Evidence has been steadily accumulating that the effects of endocrine-disrupting chemicals are not confined to wildlife. In fact, as the Skakkebaek article makes clear, many of the same effects are increasingly being observed in humans.

  In April 2002, the U.S. National Institute of Environmental Health Sciences and the World Health Organization released a joint document that concluded that “the biological plausibility of possible damage to certain human functions (particularly reproductive and developing systems) from exposure to EDCs seems strong when viewed against the background of known influences of endogenous and exogenous hormones on many of these processes. Furthermore, the evidence of adverse outcomes in wildlife and laboratory animals exposed to EDCs substantiates human concerns. The changes in human health trends in some areas (for some outcomes) are also sufficient to warrant concern and make this area a high research priority.”

  The environmental endocrine hypothesis was germinated in 1979, when researcher John McLachlan, at that time working in the Laboratory of Reproductive and Developmental Toxicology at the National Institute of Environmental Health Sciences, in Research Triangle Park, North Carolina, organized the first symposium on the effects of estrogenic chemicals in the environment. McLachlan had been studying DES since 1971 and he was using DES as a model for investigating the effects of DDT, on the basis of similarities in their chemical structure. At the 1979 meeting on “Endocrines in the Environment,” McLachlan and Retha R. Newbold presented data showing the effects of DES on the genital tract development of a mouse model. McLachlan and Newbold linked the effects of DES to those of industrial chemicals including bisphenol A, widely used in the production of plastics, and other environmental chemicals that exhibited estrogenic effects— essentially “tricking” the body into responding to them as estrogens. Bisphenol A (BPA) was developed in the laboratory of none other than Sir Charles Dodds, the man who developed DES. “It is somewhat ironic that two synthetic chemicals, the potent estrogen DES and the weak-acting estrogen BPA, which have been so important to our understanding of environmental estrogens, can be traced to one laboratory, that of Sir Charles Dodds,” McLachlan writes in a 2001 paper.

  In the early years of his research on the effects of environmental estrogens, McLachlan found it difficult to publish in mainstream scientific journals. “Reviewers considered the work metaphysical, pointing out that these compounds weren’t really hormones. According to McLachlan, his detractors claimed that he was stretching the limits of endocrinology and that his work was more like toxicology. He himself characterized his research as crossing the boundaries of endocrinology, developmental biology, and toxicology without fitting neatly into any of the disciplines,” Professor Sheldon Krimsky writes in Hormonal Chaos, a study of the scientific and social origins of the environmental endocrine hypothesis, published in 2000. “He and his colleagues were creating their own branch of science and it would take some years before it became accepted.”

  Part of the problem in gaining scientific acceptance for the environmental endocrine hypothesis was that it challenged the prevailing paradigm in toxicology, which linked potency to dose. The foundational assumption of toxicology, unchanged since its inception, was “it’s the dose that makes the poison.” The focus of testing was to determine at which dose a particular chemical would cause death (acute toxicity) or produce various types of morphologically apparent damage to experimental animals, especially carcinoma. Upping the dose of a toxin was expected to produce increasingly pernicious (and quickly observable) effects. “The higher the dose, the greater is the expected effect. However, in dealing with hormones and hormone mimics, small quantities might yield an effect, whereas large quantities of the same compound might shut the system off entirely, producing no effect,” says Krimsky Professor Milton Diamond, whose early experiments with guinea pigs showed the gender-bending effects of androgens on female fetuses, told me that when the research team attempted to feminize males with similarly large doses of estrogens, “we couldn’t do it. We got ioo percent abortions.”

  Another difficulty encountered by the early exponents of the environmental endocrine hypothesis was that effects manifested themselves not in adult animals exposed to the chemicals, but in their offspring, and in many cases the effects were delayed. The authors of a 2000 paper published in the Quarterly Review of Biology contrasted the traditional toxicological approach based on carcinogenesis and acute toxicity, with the endocrine-disrupter approach, which “relies on a developmental model and delayed dysfunction.” A fetus exposed to an endocrine disrupter might not show any effect at all until puberty— like the first cases of cancer in DES daughters. The delayed effects of DES, DDT, and other estrogenic compounds allowed potential problems to escape detection for many years. Not until the mid-eighties did scientists begin to link the kinds of reproductive anomalies that had been observed for years in wildlife with possible human health effects. In 1990, pharmacist-turned-zoologist Theo Colborn published the results of an extensive literature search on the Great Lakes ecosystem, which revealed signs of reproductive anomalies in eleven of the fourteen species previously identified to be declining in population. Colborn found that though adult animals seemed unharmed by pollutants, “some of their offspring were not surviving, and those that did were afflicted with a variety of abnormalities of reproduction, metabolism, thyroid function, and sexual development.”

  Around the same time, a reproductive physiologist named Frederick vom Saal published studies on what he called “the positioning effect,” showing that male mice positioned in the womb between two female fetuses receive extra doses of estrogen, and female fetuses positioned between two males receive extra doses of testosterone just prior to delivery, as the hormone circulates in the amniotic fluid. “The differences in hormone exposure caused by the positioning effect of the mice in the uterus were quite small, yet the behavioral and physiological effects were nonetheless significant,” writes Krimsky in Hormonal Chaos. “Some animals that experienced the positioning effect become more aggressive and territorial—the result of one-time exposures to additional estrogen (or testosterone) that seemed to have made imprints in their brains. These experiments revealed that even minute changes in the hormone exposure of the developing fetus during certain sensitive stages could result in measurable effects.”

  Colborn, vom Saal, and other researchers began sharing data, “a unique cross-fertilization of scientific disciplines,” says Krimsky, which soon produced provocative results. Toxicologists were forced to rethink the dose-response paradigm and to consider the possibility that barely detectable doses of estrogenic chemicals could disrupt the functioning of the exquisitely sensitive, self-regulating endocrine system—a system that engages in “cross talk” with every other system in the body, including the nervous system. In July 1991, researchers from a number of different disciplines met at a seminal scientific meeting to discuss “Chemically Induced Alterations in Functional Development: The Wildlife/Human Connection” at the Wingspread Conference Center in Racine, Wisconsin. The consensus statement signed by twenty-one scientists at the meeting laid the groundwork for future research and marked the start of public debate on the subject of environ
mental estrogens.

  This debate was given added impetus by Danish researcher Niels Skakkebaek and British researcher Richard Sharpe, who, working independently, had both identified spiking rates of male reproductive problems. Together, the two wrote a paper, published in the British medical journal The Lancet in 1993, linking fetal exposure to estrogens or estrogen mimics to declining sperm counts, sperm quality, and motility. The threads of the environmental estrogen hypothesis began coming together in the mid-nineties, as scientists in various disciplines who had been working separately began meeting and pooling their data. Funding agencies, too, began taking notice, and as more money became available to study the problem, generating more data, the environmental endocrine hypothesis achieved a greater degree of scientific legitimacy. “Additional research funds to study different components of the environmental endocrine hypothesis soon became available. Scientists in a variety of subfields of molecular and cellular biology, toxicology, and enviromental sciences, taking notice of the new funding opportunities, began to reorient their model systems to compete for a share of the newly available grant money,” writes Krim-sky. “Once it enters America’s network of biomedical and environmental funding streams and is incorporated within program requests for proposals, a scientific hypothesis gains new constituencies.”