The Riddle of Gender

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 that 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