The Riddle of Gender

by Deborah Rudacille

  Beginning in the early forties, DES was also used in commercial agriculture, added to the feed given to livestock and chickens in pellets—a practice given added impetus when, in 1947, researchers at the Purdue University Agricultural Station discovered that DES was a potent growth stimulant in cattle. In 1959, high levels of DES in meat were discovered to produce “disturbing symptoms” in agricultural workers and consumers, including sterility, impotence, and gyneco-mastia (breast growth) in men. As a result, the FDA banned the use of DES pellets in chicken and lamb feed in 1959. However, the use of DES in cattle feed was not prohibited by the USDA until 1979, after nearly a decade of wrangling between cattle breeders and regulatory agencies.

  The number of people exposed to DES through meat consumption from 1941 to 1979 is incalculable. The effects of this secondary exposure are unknown, though recent data on the epigenetic effects of maternal diet on fetal development make the subject well worth investigating. Epigenetics is a relatively new science that investigates how environmental factors such as diet, stress, and maternal nutrition can change gene function without altering DNA by inducing mutations. Genes can be activated or inactivated by a process called meth-ylation, in which a group of four atoms (methyl group) attaches itself to a gene at a specific point and relaxes or tightens the coiled strands of DNA, regulating gene expression. Methylation is critically important during prenatal and postnatal development, silencing some genes and activating others—one of the two X chromosomes in female cells, for example, is “turned off” by methylation. The mixture of genetic traits inherited from one’s parents is controlled by this process, and the process is highly vulnerable to environmental influences. “Fleeting exposure to anything that influences methylation patterns during development can change the animal or person for a lifetime,” the science writer Sandra Blakeslee reports in an article describing the impact of maternal diet on fetal development published in the New York Times in October 2003. “Methyl groups are entirely derived from the foods people eat…. Maternal diet during pregnancy is consequently very important, but in ways that are not yet fully understood.”

  DES had one other major use—it was used to treat prostate cancer in men by suppressing the production of testosterone, which stimulates tumor growth in the prostate. “DES also feminizes these patients,” Apfel and Fisher note. A fact sheet on DES produced by the National Toxicology Program notes transsexualism as one of many effects of DES, and the Dictionary of Organic Compounds, a standard reference book for organic chemists, notes that DES “causes male impotence and transsexual changes particularly in offspring exposed in utero.” Far more potent than natural estrogen, DES was sometimes prescribed to induce feminization in male-to-female transsexuals. This super-potency has ominous implications for those exposed in utero. In recent decades, researchers have learned that “fetal tissues are even more sensitive to DES than to natural estrogens because the fetus has to use other biochemical pathways to deactivate the synthetic substance,” say Drs. Apfel and Fisher in To Do No Harm.

  The chemical structure of DES is very different from the chemical structure of natural estrogens, and metabolizing DES thus forces fetal tissue to perform a task for which it is not naturally primed. Even more important, researchers have discovered that “the fetus probably becomes sensitized to all estrogens by DES exposure, a sensitization that may become important later in life.” In other words, DES exposure in utero causes the fetus (whether male or female) to become more than usually responsive to the effects of later estrogen or estrogen-mimicking substances. Prenatal exposure to DES primes an individual to be supersensitive to estrogens, whether endogenous (produced within the body) or exogenous (outside the body) for the remainder of his or her life. This sensitivity has major implications for DES mothers and daughters, who are exposed to their own (endogenous) estrogens throughout most of their lives and who may also be exposed to exogenous estrogens through the use of birth control pills and hormone replacement therapy in menopause.

  To understand how DES produces this range of effects requires a brief lesson in embryology and endocrinology. The human embryo, like that of other mammals, has the potential to become either male or female. Each embryo develops two paired sets of germinal ducts—the mullerian duct and the wolffian duct. Without the influence of the Y chromosome and its chemical messengers, the wolffian ducts will begin to regress in the sixth week of pregnancy, and the primitive gonad will differentiate into an estrogen-producing ovary. Under the influence of the Y chromosome (and the androgen receptor gene on the male fetus’s X chromosome), the mullerian ducts will atrophy, and the gonads differentiate into androgen-producing testicles. The sexual differentiation of a fetus is an exquisitely choreographed ballet, and the Balanchine directing this intricate dance is the endocrine system. Testis-determining factor is released on day fifty-six of human gestation. As researcher Lindsey Berkson notes in her book Hormone Deception, “If the timed sequence of hormone signals is disrupted, development of the male reproductive organs can be skewed, resulting in undescended testicles or other problems.”

  It is often said that the “default” sex in mammals is female, because even in the absence of ovaries, the fetus will develop a female reproductive anatomy unless exposed to sufficient levels of circulating testosterone. Many women object to this way of phrasing the biological reality that females are the basic model and males the frill. “The term default sex has such a passive ring to it, suggesting that girls just happen, that making them is as easy as unrolling a carpet downhill; you don’t even have to kick it to get it going,” science journalist Natalie Angier writes in Woman: An Intimate Geography. “A number of women in biology have objected to the terminology and the reasoning behind it…. Just because hormones don’t appear to be responsible for female sex determination doesn’t mean that nothing is responsible; other signaling systems exist and participate in fetal growth, though they’re harder to find and study than a sharp and unmistakable burst of androgens.” Despite dislike of the bias implicit in the notion of a “default sex,” no one seriously questions the fact that without that “sharp and unmistakable burst of androgens” in development, fetuses develop in the female direction. All the evidence from animal, in vitro, and clinical studies points to the critical importance of circulating testosterone in establishing a male reproductive anatomy and brain structure.

  Doctors often prescribed massive doses of DES to prevent miscarriage in the first trimester of pregnancy—but as researcher Lindsey Berkson discovered, even a single shot of DES in the first trimester could have devastating results. The protocol recommended by Smith and Smith “began during weeks 5 and 6 of fetal life and the dosage increased until the 36th week of pregnancy.” Thus, precisely at the crossroads when the developing embryo begins to differentiate sexually, the children of DES mothers were subjected to a barrage of synthetic estrogen. “Most of the first trimester, when embryonic development is most active and differentiation of structures is rapid, was blanketed by DES,” say Apfel and Fisher. “The dosage schedules used in other studies varied somewhat but all included significant doses during the first trimester and increasing doses until at least mid-pregnancy” DES was administered in pills, injections, vaginal suppositories, and vitamins. The DES Cancer Network estimates that approximately ten million mothers and unborn children were exposed to DES from 1941 to 1971. A great many of these individuals, both mothers and children, have no idea that they were unwitting participants in the DES experiment. “Many of these people are not aware that they were exposed,” the National Cancer Institute admits on its website. Lindsey Berkson says that the estimate of ten million Americans exposed to DES either during pregnancy or in utero “probably underestimates the number of in utero exposures of DES since many private physicians administered the drug and hospitals often did not keep records of ‘enhancement’ treatments. Even if they did not receive direct injections of DES, many of our mothers ate contaminated food before and during their pregnancies.”

  I
n April 1971, a paper published in the New England Journal of Medicine noted the appearance of a rare form of vaginal cancer among very young women. Though the first case of clear cell adenocarcinoma (CCA) had been diagnosed in 1961, doctors at Massachusetts General Hospital stumbled on a cluster—eight women under the age of twenty—with a disease that normally manifested itself only in much older women, and then quite rarely. One of the mothers wondered if her daughter’s cancer could be related to the DES she took during her pregnancy. It was a smart guess; a search of medical records revealed that seven of the eight young women treated at Mass General had been exposed to DES in utero. Those seven cases were followed by others. By November 1971, twenty-one cases had been reported. The snowballing cases led to an FDA bulletin to all physicians in the United States, warning them that the use of DES was “contraindicated in pregnancy.”

  Because the first victims were young women, and because the health effect that was first identified was a rare carcinoma, DES very quickly became a story about mothers, daughters, and cancer. The DES narrative shaped by the media (and by women’s health advocates) was in many respects a product of the 1970s and two of that decade’s major preoccupations—the plight of women under patriarchy and the carcinogenic potential of chemicals. First (and most explicitly) DES illustrated the evils of medical paternalism. The first visible victims were very young women, whose sexuality, fertility, and very lives were threatened by an awful, disfiguring disease. The CCA daughters and their heartbroken mothers were an appealing patient group whose plight would move the hardest of hearts. DES was viewed as a textbook example of the male medical establishment’s abuse of women, its lack of concern for women’s health, and its tendency to pathologize female bodies and view natural functions and women’s life passages such as pregnancy and menopause as illnesses requiring treatment.

  The ability of DES to cause cancer was also discovered at a time when carcinogenicity was a primary focus of toxicological testing. The Delaney Amendment to the Food, Drugs and Cosmetic Act, passed by the U.S. Congress in 1958, required manufacturers to furnish data establishing the carcinogenic potential of a product prior to its marketing. From the fifties through the eighties, carcinogenicity was a primary concern of regulatory agencies worldwide. DES was a known cancer promoter, as were natural estrogens. As early as 1938, studies showed that mice and rats exposed to DES developed mammary tumors. However, DES was approved by the FDA seventeen years before the passage of the Delaney Amendment. In 1941, all but four of the fifty-four academic experts who had reviewed the data submitted by twelve pharmaceutical companies wishing to market the drug approved DES as a “safe” drug. This despite the existence of a 1939 editorial in the Journal ofthe American Medical Association, titled “Estrogen Therapy: A Warning,” cautioning against the “long continued and indiscriminate therapeutic use of estrogens…. The possibility of carcinoma induced by estrogens cannot be ignored,” the author of the editorial writes. This Cassandra-like prophecy was ignored. However, by 1971, when DES was proved to be the cause of vaginal cancer in young women who had been exposed to DES in utero, the carcinogenic potential of xenobiotics had become the primary concern of toxicologists and regulatory agencies. DES thus fit perfectly into the “cancer” paradigm of the toxicologists as well as the “evils of medical patriarchy” paradigm of women’s health advocates. An advocacy group, DES Action, was formed in 1975 by a DES mother, Pat Cody, and in 1982 the DES Cancer Network, “an international, non-profit, consumer organization that addresses the special needs of women who have had clear cell adenocarcinoma of the vagina or cervix,” was founded. These advocates worked hard to spread the news about DES and lobbied for research funding to study its effects. “DES was one of the prime movers behind the nascent women’s health movement back in the seventies. Our Bodies, Ourselves, that kind of thing,” says Dana Beyer. “DES Action was formed as the political clout of women was beginning to change, in the seventies, so they focused on women’s health. It was conceived as a mother-daughter thing because of the cancer—vaginal cancer, which is not common. That’s what was weird and caused people to make the connection. If it had been a slight increase in uterine cancer, it would have gone unnoticed. So that was lucky, I guess. So they formed this organization and they’ve worked very hard, lobbying Congress and drafting female representatives who support them, getting House appropriations to get the National Cancer Institute to fund this [DES research]. That’s where the activism has been.”

  The bulk of the educational efforts were directed at mothers and daughters, and focused on cancer risk. Women who knew that they had been exposed to DES were told to inform their health care providers, particularly gynecologists, about their exposure, and obstetricians and family practitioners who had administered DES to pregnant women were asked to inform their patients that they and their children had been exposed. Many failed to do so. Apfel and Fisher attribute the “subdued, even paralyzed responses of practicing physicians” to the “fear of facing their own mistakes, of failing in the eyes of peers and younger colleagues, of being criticized, regulated and even sued.” They conclude that “most doctors go out of their way to avoid concluding that a patient’s problem has been iatrogenically induced.” In the case of DES, that resistance to assuming responsibility has been shared by the pharmaceutical companies that produced the drug, and by the research establishment as a whole, which continues to resist a full investigation of the tragedy. Half of the fetuses exposed to DES in utero were male, subjected to a barrage of synthetic estrogen during the period of sexual differentiation, chemically primed to be exquisitely sensitive to estrogen and estrogen-mimicking chemicals for the remainder of their lives. Their stories remain untold, and no one—not DES Action, not the Centers for Disease Control, not the National Cancer Institute, not the drug companies that manufactured DES— wants to hear them.

  “For a very long time, we’ve been battling with the forces that would try to keep the DES radar screen narrowly focused on cancer and, in particular, on vaginal and cervical cancer alone,” says social scientist Scott Kerlin. A DES son, Kerlin founded DES Sons Network in 1999, an online support and advocacy group for the XY children exposed to DES in utero. For years, Kerlin has been fighting the perception that DES is a women’s health issue. “Compared with research on DES daughters, there is a paucity of published research studies and public awareness focusing directly on the health effects of DES sons. The reasons for this remain at question, although evidence points in part to a history of inadequate commitment to male reproductive and sexual health issues by the DES-exposed victims advocacy groups which first called for public investigation about the effects of DES in the 1970s. It is also quite possible that the level of public awareness and U.S. governmental funding for further DES research was kept deliberately narrow (i.e., focusing on “known” effects such as vaginal cancer), and other areas of potential health effects were simply not addressed by public health funding agencies.”

  Kerlin says that the latest round of research and educational materials produced by the U.S. Centers for Disease Control will not change the perception that DES is primarily a women’s health concern. “I’ve gotten advance looks at the CDC materials and it goes without saying, sons’ issues are really being neglected. It seems that this is the biggest obstacle we are facing; DES is not just about increased cancer risk or infertility, but our ‘advocates’ would never want you to know that.” Kerlin himself suffers from hypogonadism, or testosterone deficiency. Hypogonadism is one of the “unproven” effects of DES in exposed males, though animal research has shown that DES exposure causes imbalances in fetal hormone levels and impairment of normal functioning in hormone receptors. Other structural effects of exposure to DES and other estrogenic chemicals in males include epididymal (tes-ticular) cysts; hypoplastic (small) testicles; undescended testicles, or cryptorchidism; microphallus (abnormally small penis); and testicular varicoceles (irregularly swollen veins on the testicle). These enlarged veins produce a higher-than-norm
al temperature in the testicles and can, over years, lower sperm count, resulting in sub-fertility Hypospa-dias, a condition in which the opening of the penis is located on the underside rather than at the tip; and urethral meatal stenosis, a narrowing of the opening of the penis, have also been noted in DES sons. Gy-necomastia, enlargement of the male breast, has been noted not only in DES sons but also in adult male agricultural workers exposed to the chemical.

  Scott Kerlin stumbled onto another potential outcome of DES exposure in sons when his DES Information Network was a few months old. Kerlin had created the online discussion group to fill the need for “greater interconnectedness” and communication among DES sons. Mothers and daughters had being doing so for years, online and at meetings. DES sons, by contrast, were a mostly silent, mostly invisible group. By creating a forum for the men to discuss their concerns, Ker-lin hoped to prod the DES advocacy groups and government funding agencies to recognize the wide range of health effects experienced by sons and the lack of attention to their needs. “The DES Sons Online Network was also formed to expand awareness about the range of existing research about DES and males’ health and to explore other issues affecting the physical, mental, sexual, and psychosexual health of DES sons—particularly issues which had been suggested in previous existing research studies about DES and males but which need further investigation,” Kerlin says. For that reason, he asked all new subscribers to the online group to submit a brief overview of their health concerns and past health issues as well as a confirmation of DES exposure. Over a quarter of the first forty members of the list noted concerns about issues relating to sexuality and reproductive health.