The Riddle of Gender

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.”

In 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