The DES Sons Online Discussion Network: Critical Issues
and the Need for Further Research
by Scott Kerlin, Ph.D. and Dana Beyer, M.D.,
DES Sons' Online Discussion Network
Contacts: Scott Kerlin: skerlin@pacificcoast.net;
Dana Beyer: wbb3@cornell.edu
DRAFT Report (for reference and discussion only) Edition Update: August 2002
Introduction: Background of Available DES Research
During the 1980s and 1990s an increasing amount of public and scientific attention was paid to the health and medical problems of women whose mothers and grandmothers took diethylstilbestrol (DES). DES was the first available synthetic estrogenic drug, a sex hormone promoted by Sir E. Charles Dodds, professor of biochemistry at the University of London in 1938 (Apfel & Fisher, 1984; Orenberg, 1981). DES was prescribed by many doctors as a "wonder drug" for women, most notably for the prevention of miscarriages but also for a number of other health needs including treatment of menopausal symptoms. It was used chiefly during the years of 1941-1971 by millions of women in the U.S. and hundreds of thousands of women in other countries. At its height of popularity DES was manufactured by more than 200 companies (chief among them, Eli Lilly) under a wide variety of brand names (Martin v. Abbott Laboratories, 1984).
Though its efficacy was doubted by many researchers, DES became extremely popular during the early 1950s, when it is estimated that some medical centers in the U.S. gave the drug to as many as 5 to 7 percent of all pregnant mothers (Saunders, 1988). It remained on the market until the U.S. Food and Drug Administration (FDA) banned the drug following publication of research in the early 1970s identifying a link between DES and a rare form of vaginal cancer in females (commonly called "DES daughters") whose mothers used DES (Berkson, 2000; Braun, 2001). Tragically, some of these females died very young of the consequences of DES-induced cancer.
The discovery of the carcinogenic potential of DES in humans led to a broad public education campaign to reach individuals who had been exposed to DES, with the bulk of attention being focused on DES Daughters and mothers. It also heightened interest in the biomedical research communities about studying the short and long-term effects of DES exposure. The bulk of DES research has emphasized further study of its carcinogenic impact and its relationship to infertility and deformation of the female reproductive system in DES daughters (National Cancer Institute DES Research Update, 1999). Some effort has been made also to monitor health effects in mothers who were prescribed DES (DES mothers), including a heightened incidence of breast cancer.
Research on the continuing effects of DES has opened the door to serious study of the health and public policy implications of environmental estrogens and other toxins (Krimsky, 2000), in particular the prevalence of estrogen-mimics: substances which simulate natural estrogens. As attention to environmental health issues in the U.S. grew during the 1990s, some researchers advocated a broader investigation into the full impact of DES exposure on humans (Colborn, Dumanosky, & Myers, 1996; Cunha, et al., 1999; Solomon & Schettler, 2000). Long-time DES researcher and professor John McLachlan at the Center for Bioenvironmental Research at Tulane and Xavier Universities labeled DES as an environmental "endocrine disrupter" (McLachlan & Arnold, 1996; McLachlan, 1997; McLachlan, 2001; McLachlan et al., 2001).
Researcher D. Lindsey Berkson (2000), a DES daughter and consulting scholar at the Center for Bioenvironmental Research, describes hormone disruptors in her book Hormone Deception as "chemicals (or mixtures of chemicals) from outside the body that can interfere with the development or function of body systems in humans and wildlife, especially in their offspring, and may lead to irreversible adverse health effects" (Berkson, 2000, p. 14).
In documenting a range of issues associated with DES exposure in humans, Berkson urges others to consider fundamental questions about the impact of environmentally-produced estrogens and how they can affect not just our physical health, but also some of our most significant aspects of psychosocial human development, including the formation of gender identity, sexual orientation, and maintenance of reproductive health for both females and males. As an area of scientific inquiry, measuring the effects of endocrine disruptors tends to follow a "systems model" of thought: holistic, multifactoral, and multidisciplinary. It is rooted in investigation of developmental and evolutionary biology as well as in the medical field of endocrinology (McLachlan, 2001), and as such, provides the makings of a new paradigm for studying the workings of the human reproductive system and hormonal influences on human development.
Some of the most recent discoveries about the effects of DES have been in areas of genetics research. It has been recognized that DES suppresses the activity of particular genes which normally play a vital role in the development of the male and female reproductive tracts and in sexual differentiation (Block et al., 2000; Travis, 1999). Recent studies of male grandchildren of the women who took DES decades ago suggest they may be at greater risk for certain conditions such as hypospadias (Klip et al., 2001, 2002; Tunick, 2001).
One affected population which has received inadequate attention from the biomedical and health research community is DES-exposed males (the term "DES sons" is commonly used). It is estimated that up to 5 million mothers used DES in the U.S. (Giusti et al., 1995), and possibly as many as 2-3 million male offspring of these women were exposed in utero. Hundreds of thousands of DES sons were also born in other countries between the 1940s and 1970s.
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 research funding agencies.
The research studies on DES sons that have obtained greatest public attention have involved a handful of controlled "cohort" studies comparing exposed DES sons with unexposed peers. These studies each have involved a few hundred males and limited the scope of investigation to male infertility, increased potential for testicular cancer, and predicting the likelihood of genital malformations (Gershman & Stolley, 1988; Leary et al., 1984; Strohsnitter, et al., 2001; Wilcox et al. 1995). In most cases, researchers' findings from these studies were reported as "inconclusive", leaving many unanswered questions about whether DES is directly linked to any of these health conditions. Arguably, these cohort studies raise more questions than provide sufficient answers for the entire global population of exposed males. They represent the dominant trend in much of primary DES research: you get what you're looking for, nothing else. Because DES has been outlawed for prenatal use since the 1970s, no more controlled experiments can be developed for assessing the impact on human males or females. In experimental research with DES, only animal research is allowed.
In spite of the limited availability of large sample studies of DES sons, there is other documented evidence that DES has had detrimental health effects for a significant number of prenatally exposed males (Gill, et al., 1988; Giusti, et al., 1995; Laitman et al., 1997). These include increased risk of testicular cancer and a variety of structural abnormalities of the reproductive system such as epididymal (benign) cysts, hypoplastic testes or undescended testes (chryptorchidism), microphallus or underdeveloped penis which may be associated with an intersex condition, newly-identified "testicular dyssynergia", and hypospadias (opening of the penis is on the underside rather than at the end)(Klotz, L., 1999; Koskimäki, J. et al., 1999; Sharpe, R., 2001; Strohsnitter, et al., 2001). Recent research has also examined greater incidences of hypospadias among male offspring of DES daughters (Klip & Verloop, 2002). Studies documenting the physical effects to the reproductive systems of DES exposed males are the most common, and research on this subject is continuing in the 21st century, particularly in Europe.
A few studies have documented the therapeutic benefits of using DES for treatment of advanced prostate cancer (Agency for Health Care Policy and Research, 1999; Denis, 1998; Takezawa Y., et al., 2001), a practice that was fairly common until a few years ago. The principal benefit of using DES for such treatments is the rapid diminution of testosterone production, however its use for this treatment has also been associated with elevated blood pressure, impotence, depression, and feminization in males (BC Cancer Agency, 2001).
Some research has also investigated the neurological system links between DES exposure and increases in anxiety and depression in males as well as in females (Katz, et al., 1987; Meyer-Bahlburg, et al., 1985; Pillard et al., 1993; Saunders, 1988). A few reports have investigated possible associations between DES exposure in males and testosterone deficiency or hypogonadism (Hofnagel, D., 1976; Wortsman, J., Hamidinia, A., & Winters, S. J., 1989), but this topic needs more investigation in conjunction with recent studies of male andropause (Carruthers, M., 2001; Mailhot, J., 2001).
It has been recognized by some behavioral scientists and biomedical researchers that prenatal DES exposure in males and females may affect psychosexual development, sexual orientation, and sexual differentiation in later years (Amelsvoort, Compton, and Murphy, 2001; Bem, 1996; Gill, 1988; Gorski, 1998; Hines, 1982; Kohl, 1996; Meyer-Bahlburg et al., 1995; Reinisch, et al., 1991; Rogers, 1999; Solms & Turnbull, 2002; Toppari & Skakkebaek, 1998), in part because of its potential to alter the fragile hormonal balance between testosterone and estrogen levels, particularly in exposed males. Berkson (2000) contends that in humans, "for a male to become a male and a female to become a female, male and female hormones must be present in the mother in the right amount at the right time between fertilization and birth" (p. 42).
Berkson further states,
One cheeky irony of life is that how masculine a man is as an adult is partly the result of his having had the optimal amounts of estrogen in his brain at a certain time during his stay in the womb. Amazingly minute differences---parts per trillion of a few sex hormones---literally affect the making of men or women. Most certainly this new understanding of how estrogens work together emphasizes just how fundamental estrogen signals are in directing the development of life (p. 43).Berkson notes that endocrine disruptors such as DES can have "gender bending" effects in males: "too much estrogen (or not enough androgens) will cause de-masculinization in males" (pp. 130-131). Similarly, Toppari & Skakkebaek (1998) acknowledge that estrogenic substances such as DES have demasculinizing and feminizing effects in the developing human male fetus. Hines (1998a) demonstrates that prenatal exposure to DES is an influencing factor in sexual differentiation of human behavior, introducing effects on core gender identity and sexual orientation, and also playing a role in fostering intersexed conditions (i.e. ambiguous genitalia) in males and females.
In recent years, researchers have increasingly examined developments within the brain associated with gender identity and sexual differentiation in humans (Cardoso, 1997; Hines & Collaer, 1993; Hines, 1998a and 1998b; Matsumoto, 1999; Raloff, 1994; Rogers, 1999; Zhou, et al., 1995). Some research has been identified which examines the potential association between exposure to endocrine disruptors and increased likelihood of transsexualism or intersex conditions (Cohen-Kettenis & Gooren, 1999; Michel, et al., 2001; Slabbekoorn et al., 2000). The Endocrine Society in 2000 produced a patient fact sheet that associates DES exposure and feminization in males (Endocrine Society, 2000). One question that remains is whether scientists will eventually confirm a direct causal link between prenatal DES exposure and gender identity disorders and what would be the social, legal, and medical implications of doing so.
Although there has been limited ongoing research about the psychosexual impact of DES exposure in human males, studies examining possible feminizing effects were produced as early as the 1970s (Barr, 1973; Green, 1978; Kester et al., 1980). One probable reason for the limited availability of research documenting effects of DES exposure on male sexuality and gender identity is that most males afflicted have neither known of their exposure nor been aware of its potential effects. There have been few public educational campaigns about the impact of males' prenatal exposure to DES. In addition, many men feel uncomfortable discussing their health or medical questions with professionals (Meth & Pasick, 1990; Reese, 2000). Men are often more reticent about self-disclosure with their physicians, with therapists, and with one another than are females. It has taken great efforts to convince men to openly discuss issues such as depression and infertility let alone sexually related problems. It has required the potential of a huge market for the drug Viagra to stimulate public discussion of erectile dysfunction; it even required the development of the euphemism "erectile dysfunction" to replace "impotence" before some men became comfortable with the issue.
Among many males, discussions or honest admissions of feelings about masculinity, sexual orientation, and gender identity are very sensitive and often fraught with internalized conflict (Kimmel, 1996; Nardi & Schneider, 1998; Vance, 1995). Open discussion of these issues in our culture carries inherent risks among all men (Osherson, 1992) and thus they are more commonly withheld or repressed. This is particularly true among males who identify as gay, bisexual, or transgendered or who suffer from a range of gender identity concerns. For researchers interested in the full scope of effects of DES exposure on males this lack of forthrightness can be a formidable obstacle, not unlike the obstacles faced by researchers who seek to understand the diverse dimensions of human sexuality and behavior (Abramson & Pinkerton, 1995).
Formation of the DES Sons Online Discussion Network
In July 1999, Scott Kerlin, a DES son born in 1953, organized the DES Sons online discussion network following many years of investigative research about DES and its effects on males and females. The sons' network is an Internet-based discussion community of individuals who have joined after learning about the network through postings on the DES Action website and through a variety of other networks on health issues. As an interdisciplinary social science and biomedical researcher, Kerlin has taught social science and human development research courses to university undergraduates and graduate students in the U.S. and Canada and also has considerable experience with conducting online interviews, managing online academic discussion forums, and developing qualitative and quantitative research.
The creation of the DES sons' online network was an outgrowth of nearly 20 years of examination of research about human sexuality, gender issues, and reproductive health. It was developed with a number of primary goals in mind. Most importantly, it was formed to fill the need for greater interconnectedness among DES exposed males from around the world, since no large-scale communications network among DES sons had previously existed. By comparison, DES daughters have had the opportunity to interact via the DES Daughters discussion forum for many years, and the DES Cancer Network has long existed to fill the need for female victims of DES-related cancer.
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 has needed further investigation. To the extent that the DES Sons list has functioned as a "research forum", it has done so through providing an avenue for DES exposed individuals to discuss personal issues that have affected them via the online environment, which is a medium that often facilitates discussions of issues people feel are too sensitive in face-to-face environments.
The tools and features of online forums like the DES Sons discussion network provide the opportunity for conducting a type of qualitative research in health care (Pope & Mays, 2000) that enables a collective engagement of issues raised by participants and fresh insights for participants and researchers (see Fetterman, 1998 for a detailed focus on ethnographic research in online environments and Murray, 1997, for a discussion of using "virtual focus groups" in qualitative health research). Thanks to the Internet, a health researcher has the ability to study patient populations which, by virtue of a low incidence rate, were never able to be "gathered" in one place before.
Through a more qualitative emphasis in the online environment, a researcher can apply what Wildemuth (1993) describes as "the interpretive approach, with its goal of understanding the social world from the viewpoint of the actors within it, [which] is oriented toward detailed description of the actors' cognitive and symbolic actions, that is, the meanings associated with observable behaviors" (p. 451). This aspect of meaning-making among list participants has enabled exploration of health and identity issues among DES sons that may have eluded past researchers who have focused solely on using experimental or "case-control" methods to prove or disprove hypotheses about DES exposure. In this sense, it exemplifies a way that holistic qualitative inquiry can be used to match the systemic research paradigm needed for assessing the full impact of environmental endocrine disruptors-allowing new issues to emerge.
What has been learned so far from the DES Sons Discussion Network?
As of July 2002, the DES Sons online network included more than 130 active members, including Dr. Beyer, who joined the forum in 2000. Many list members have also corresponded privately and extensively with Kerlin or Beyer about issues they believe are related to the impact of DES exposure but that they felt were too sensitive to disclose to other members of the forum. A number of list members have participated in one or more of three private DES issues online "chats", each lasting 2.5 hours and conducted by Kerlin with Beyer's assistance. These chats have served as online equivalents of focus groups and have featured topics based on list members' requests (testosterone deficiency, cancer, depression, and gender/sexuality issues).
Initially, the sons' network was formed with no specific topical focus intended beyond providing a network for DES-exposed males. However, prior to approving a prospective list member's subscription, Kerlin requested that each applicant provide a brief overview of health concerns and past health issues as well as a confirmation of DES exposure. Most members who joined the network indicated that they had learned of their likely DES exposure either through a parent or sibling, but a few members could only speculate about, not confirm, their exposure.
Many of the issues and conversations on the DES sons list reveal the complexity of doing research on the effects of DES exposure in males. In an effort to assess the most critical factors concerning list members, Kerlin conducted a poll in early 2001 on the chief concerns of DES sons (see APPENDIX A) and nearly all members at the time (N=40 in February 2001) participated. Over a quarter had issues relating to sexuality, gender identity and reproductive health. These include transsexualism (another issue the medical establishment is not comfortable discussing), impotence, hypogonadism (low testosterone) and infertility. Nearly 20% had primary concerns with psychological and emotional health, particularly depression and anxiety, and 20% had primary concerns regarding their overall physical health including testicular cancer, hypospadias, and various urological malformations.
APPENDIX B contains the results of a survey conducted among a larger number of network members in August 2001 and indicates which issues are of greatest priority in future network discussions. Among nearly 45 respondents, the top five areas of concern were (in rank order): (1) Physical health concerns (e.g. hormones, infertility, erectile dysfunction, cancer); (2) gender issues (including gender identity, transgenderism, and transsexualism); (3) promoting more DES research in the future; (4) sexual identity issues (including sexual orientation and intersex); and (5) psychological and mental health issues (including anxiety and depression).
APPENDIX C provides an overview of the most recent poll of members of the DES Sons' network. Members were asked (anonymously) to indicate the one term pertaining to their gender or sexual identity or sexual orientation that they felt most described how they self-defined among their closest friends.
This poll demonstrated that among the 63 sons' network members who answered the question (approximately 70% of active network members at the time of that poll), the largest number (23, or 36.5% of respondents) identified as "transsexual" (pre- or post-op), while another 15% identified as transgendered, and 13% identified as "intersexed" or "androgynous." "Straight males" represented 17.5% of respondents (the second highest response group), while 13% identified as bisexual or gay males.
After approximately one year of the sons' network existing, some members began to raise issues with regard to sexuality, sexual orientation, and gender identity. Over subsequent months, these issues became more substantial in list discussions, at times becoming the dominant themes raised by members. As a result of significant attention to gender and sexual diversity issues among some network members, a support group (DES Trans) for these members was formed in January 2002. As of July 2002, more than 100 individuals voluntarily joined DES Trans, approximately 60 are also members of the DES Sons' network. This underscores the significance of gender identity and intersex condition as major concerns among a significant portion of persons who have been exposed to DES.
Many sons' network members have discussed a psychological experience of having felt "feminine" in their inner lives and had numerous challenges in managing relationships and social lives as a result. These members have attributed their personal experiences as linked to DES exposure and its attendant psychosexual side effects. However, this "feminization phenomenon" does not seem to be universally experienced by DES-exposed males within the network.
Conclusions
The DES Sons online network has provided fresh insights about the scope of experiences in DES-exposed males. It has led to new questions about the full impact of DES exposure on the health and well-being of males, extending beyond those issues at focus in the cohort studies of DES males published by Leary et al. (1984) and Wilcox et al. (1995) and the so-called "comprehensive" published review of research on effects of DES exposure in males by Laitman et al (1997). While network members do not necessarily represent a true "cross-section" of all exposed males, their most pressing concerns are supported in the broad body of published research on endocrine disruptors and DES.
Our findings suggest that new avenues and levels of sensitivity are needed among researchers who seek to uncover the continuing mysteries of DES exposure in humans. We believe that great benefit can occur through sharing of such research insights among biomedical researchers, health and medical professionals working directly with DES exposed daughters and sons. Much more compassion and outreach are needed among researchers wishing to further understand the scope of medical as well as the social and psychological impact of DES exposure in males. This suggests a collaborative role for social researchers (particularly researchers interested in issues of gender, sexuality, and male health) working with health and medical professionals and educators. Together they can work to raise consciousness about the potential psychosocial and emotional factors in DES exposed males and females which may be more difficult to detect and assess than physical symptoms.
We also believe strongly that the need exists for further research and educational outreach for DES sons (see questions we have proposed for guiding our further inquiry, listed in APPENDIX D). Many DES exposed males with the most significant problems reproductive system failures, gender identity issues, sexuality, infertility and depression - are likely unaware of any connection with DES. It may be that such knowledge will help provide a safe channel in which DES sons can find support to confront these very challenging and perplexing conditions.
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DES-Related Information and Research Websites
I. General DES Information Sources
A Brief History of DES (Diethylstilbestrol)
This timeline is provided by the DES Cancer Network for Women (http://www.descancer.org) and includes references to the range of companies that manufactured DES. http://www.descancer.org/timeline.html
ARC Known Carcinogens: Diethylstilbestrol
A report from the National Toxicology Program of the National Institute of Environmental Health Sciences describing in detail the carcinogenic impact of DES on animals and on humans.
DES Chemical Datasheet from the National Toxicology Program of the National Institute for Environmental Health Sciences (NIEHS)
This is a comprehensive fact sheet on DES, including various product names, effects on humans, and chemical/toxic makeup. Notable for its list of likely symptoms when taken orally by adults.
DES Action U.S.A.
A national, non-profit consumer organization dedicated to informing the public about DES and helping DES-exposed individuals. They publish a quarterly newsletter, The DES Action Voice, and many publications on various aspects of DES exposure. They also claim to provide a link between DES-exposed people and researchers and the medical community. Most of the emphasis is on DES exposed females, and outreach/support for DES sons is quite limited.
DES Action Canada
The official website for the office of DES Action Canada, with many helpful resources. http://www.web.net/~desact/
DES Sons' Information Page, from DES Action Canada
This is the most comprehensive summary on DES health issues for exposed males.
DES Research Update: Current Knowledge, Future Directions, 1999
This is the official website for the 1999 conference on DES Research that was held at the headquarters of the National Institutes of Health, Bethesda, Maryland. It shows the scope and limitations of current federally-funded (U.S.) research interests about the effects of DES exposure in humans.
Modus Operandi of an Infamous Drug: Diethylstilbestrol
An article originally published in Science News Online in 1999, this full-text reproduction discusses the genetic impact of DES and provides links to additional full-text articles covering DES.
Questions and Answers about DES: Cancer Facts
From the National Cancer Institute's CancerNet website, this information focuses chiefly on the potential for cancer in DES daughters but also briefly discusses cancer potential for DES sons. http://www.meb.uni-bonn.de/cancernet/600034.html
The Story of DES: A Cautionary Tale
This revealing timeline of DES development and the discoveries (much later) of its dangerous effects is excerpted from Women and the Crisis in Sex Hormones, by Seaman and Seaman, 1971. http://www.oxford.net/~tishy/des.html
II. DES Research: Effects on Human Health, Sexuality, and Gender Development
Chemicals Linked to Declining Male Reproductive Health
A 1996 article by Jorma Toppari et al, "Male Reproductive Health and Environmental Xenoestrogens" published in Environmental Health Perspectives is discussed in this paper, which includes a focus on the impact of DES exposure on males. http://www.monitor.net/rachel/r514.html
Chemical Profile for Diethylstilbestrol
A very comprehensive fact sheet of hazardous potential of DES, produced by Environmental Defense.
Development of the Cerebral Cortex: Sexual Differentiation of the Central Nervous System, by Dr. Roger Gorski, Source: Journal of the American Academy of Child & Adolescent Psychiatry, 37(12): 1337-1339, 1998. This article contains many references to the impact DES may have on sexual differentiation in humans.
Do Environmental Estrogens Have Negative Effects on the Human Reproductive System?
This article by Jessica Spencer of the Emory University Department of Chemistry examines the chemical structure and the research covering effects of DES and other "environmental estrogens."
Effects of Estrogen Treatment on Sexual Behavior in Male-to-Female Transsexuals: Experimental and Clinical Observations, by Marie Kwan, Judy VanMaasdam, and Julian M. Davidson
This article discusses various treatments of transsexuals with hormone therapy and the resulting effects; one client is included who was given DES as a primary estrogen. http://www.transgender.at/nettext/te-effec.html
Endocrine Disruptors: The State of the Science (1997)
This report by Ted Schettler MD, MPH of the Greater Boston Physicians for Social Responsibility defines what endocrine disruption is, and contains many references to the effects of DES. http://www.psr.org/tedfs.htm
Endocrinology and Environmental Estrogens
A fact sheet from the Endocrine Society that discusses the impact of synthetic estrogens (including DES) on the endocrine system.
Endocrine active environmental chemicals and sexual differentiation of central nervous system and reproductive organs: Steroid hormone-regulated gene expression (research proposal)
This proposal is from Prof. W. Lichtensteiger and Dr. M. Schlumpf of the University of Zurich, and includes significant focus on DES and possible effects.
Environment and Health: Endocrine Disruption and Potential Human Health Implications
This study by Gina M. Solomon and Ted Schettler was published in 2000 in the Canadian Medical Association Journal and discusses the effects in humans and animals of exposure to DES and other environmental hormone system (endocrine) disruptors. http://www.cmaj.ca/cgi/content/full/163/11/1471
Environmental and Occupational Hazards and Male Infertility
A guide to various causes of male infertility, diminished libido, and other hormonal effects of environmental estrogens such as DES, sponsored by the Department of Urology of the State University of New York, Stony Brook. http://www.uhmc.sunysb.edu/urology/male_infertility/Environmental_and_Occupational_Hazards.html
Environmental Effects on Reproductive Health: The Endocrine Disruption Hypothesis
Article by Dore Hollander reproduced from the March/April 1997 issue of Family Planning Perspectives, this includes a section covering the effects of DES.
Estrogen Actions in the Brain: A Symposium to Honor the Contributions of Roger Gorski
An article from CNS Drug Reviews, Vol. 5 (1), 77-82 available in pdf format.
Evidence of Endocrine Disruptors Impact on Human Health
This paper was produced by Professor Stephen Safe, a Distinguished Professor of Veterinary Physiology & Pharmacology at Texas A&M University, and presented for the Center for Health Effects of Environmental Contamination at the University of Iowa. It contains significant discussion about the potential effects of DES exposure in humans. http://www.cheec.uiowa.edu/conferences/edc_2000/safe.html
Exotic Becomes Erotic: A Developmental Theory of Sexual Orientation, by Daryl J. Bem, Cornell University
The full text of a major research study on the impact of various factors (including the possible effects of DES exposure) on the development of sexual orientation in humans. http://www.psych.cornell.edu/dbem/ebe_theory.html
Hormonally Active Agents in the Environment, by the National Research Council and Commission on Life Sciences
This full-text reproduction of the 2000 book is available on the web as part of the National Academy Press online publications collection (www.nap.edu) and contains substantial discussion of DES and other environmental hormone disruptors. Highly-recommended for serious researchers! http://www.nap.edu/catalog/6029.html
Human (DES) Exposures and Human Health Effects
A paper by Dr. Richard Miller on the effects of DES and other hormone disruptors in humans, provided by McMaster University (Canada) Department of Biology.
Human Pheromones: Mammalian Olfactory, Genetic, Neuronal, Hormonal, and Behavioral Reciprocity and Human Sexuality
An article originally published by James Vaughn Kohl in the journal Advances in Human Behavior and Evolution, which includes reference to research on DES exposure and sexual orientation.
Human Sexual Differentiation: Overview
This paper was authored by P.C. Sizonenko of the Department of Pediatrics at University Cantonal Hospital, Geneva, Switzerland. It covers the basic aspects of biological differentiation of the human male and female, and includes reference to effects of DES in relation to intersexuality and testosterone deficiency.
Involvement of Insulin-Like Factor 3 (Insl3) in Diethylstilbestrol-Induced Cryptorchidism, by Judith M. A. Emmen, Anke McLuskey, Ibrahim M. Adham, Wolfgang Engel, Miriam Verhoef-Post, Axel P. N. Themmen, J. Anton Grootegoed and Albert O. Brinkmann
An article published in Endocrinology, 2000, Vol. 141, No. 2 p. 846.
Male Reproductive Health and Environmental Exposures
This summary, which includes a discussion of DES exposure and urogenital abnormalities, discusses issues of male infertility and testicular cancer. Provided by the Mount Sinai School of Medicine Center for Children's Health and the Environment.
Mortality and Morbidity in Transsexual Patients With Cross-Gender Hormone Treatment by H. Asscheman, L.J.G. Gooren, and P.L.E. Eklund
This research study focuses on uses of various estrogenic products for assisting male-to-female transsexuals in transitioning, and describes the uses of DES as such a product until around 1980 (source of original information unknown)
Neurotransmitters and the Control of Hypophyseal Gonadal Functions: Possible Implications of Endocrine Disruptors (pdf document)
Published by F. Piva and L. Martini of the University of Milano (Italy) Department of Endocrinology in the journal Pure & Applied Chemistry, Vol. 70 (9), pp. 1647-1656, 1998, this paper discusses the potential effects of DES and other endocrine disruptors on development of the neuroendocrine system in humans. http://www.iupac.org/publications/pac/special/0998/pdfs/109.pdf
New Approaches for Estimating Risk from Exposure to Diethylstilbestrol (1999)
This is the abstract for an article published by Gerald R. Cunha et al. in Environmental Health Perspectives
Volume 107, Supplement 4, August 1999, which outlines a multidisciplinary research approach to identifying the effects of human exposure to DES.
Reproductive Malformation of the Male Offspring Following Maternal Exposure to Estrogenic Chemicals by Dr. Chhanda Gupta
This paper by Dr. Gupta of the University of Pittsburgh's School of Pharmacy contains extensive references to the effects of prenatal DES exposure on male and was published in the Proceedings of the Society for
Experimental Biology and Medicine in July 2000.
Relative Effectiveness and Cost-Effectiveness of Methods of Androgen Suppression in the Treatment of Advanced Prostatic Cancer: Summary Evidence Report/Technology Assessment: Number 4, January 1999
This study was developed by the U.S. Agency for Healthcare Research and Quality (AHRQ) and assesses the relative benefits and disadvantages of using DES to treat advanced prostate cancer because of its function as an "androgen blockade" (i.e. testosterone suppressant).
Sex Steroids and Human Behavior: Implications for Developmental Psychopathology
This article, published by Gerianne M. Alexander, PhD, and Bradley S. Peterson, MD in CNS Spectrums 2001;6(1), pp. 75-88, explores a summary of research investigating hormonal influences on human behavior. Using an association between patterns of sexual differentiation and specific forms of psychopathology it suggests novel avenues for assessing the effects of sex steroids (including DES) on brain structure and function in males and females.
Testicular Dysgenesis Syndrome: An Increasingly Common Developmental Disorder with Environmental Aspects
This article by N.E.Skakkebæk, E.Rajpert-De Meyts and K.M.Main of Copenhagen University Hospital, Denmark, was produced in the July 2001 issue of Human Reproduction v. n.5 pp. 972.-978, and discusses a wide range of male reprodutive health problems including the newly defined testicular dysgenesis syndrome (TDS) which the authors attribute largely to environmental influences.
That Feminine Touch: Are Men Suffering from Prenatal or Childhood Exposures to "Hormonal" Toxicants?
An article by J. Raloff published January 1994 in Science News that discusses the potential effects of prenatal exposure to DES and other sex hormones on gender and sexual differentiation for males.
III. Sites Providing Glimpses of Direct Effects of DES on Gender and Sexuality
About Diethylstilbestrol; About Gender
This comment page on diethylstilbestrol and gender is excerpted from the evolving online text, "About Gender" (www.gender.org.uk/about/), which features many psychological, biological, and sociological examinations of gender development. DES exposure is discussed in chapter 5 on "the developing embryo".
Hormone Therapy FAQ Guide, from the Society for Human Sexuality
This comprehensive guide is a part of the SHS website www.sexuality.org and includes tips on all aspects of sex hormones including a reference to DES and its historical use for the treatment of transsexuals under the estrogens section.
Mikki's Miracle Missive on the World Wide Web: Mikki's Hormones Get FAQ'd
See reference to DES under available estrogens for transitioning males, question "What are the types, names, of popular drugs employed in M2F transition and available in the U.S.?"
Transsexual and Transgender Health Information, from Gay Community News (Ireland)
This site provides information on which hormones are available and most useful in Ireland for assisting transsexuals with hormone therapy. There is significant reference to DES, particularly under the section on which hormones are available in Ireland. It is quite clear that DES is being included here as an option.
Transgender Q&A Guide: Diethylstilbestrol
This page has limited information but is revealing of some of the previous inquiries about the uses of DES to assist in the feminization process for M to F transsexuals.
Willow Firesong's Circle of Firelight in the Grove of Information
This site is for Pagans as a reference regarding sex and sexuality. Under the section entitled "what is your belief about transsexualism?" is the following: "Male to Female transsexualism is often associate with the use of DiEthylStilbestrol, or DES, by their mothers prenatally; this is a female hormone sometimes used as a fertility drug." http://members.tripod.com/~Willow_Firesong/Tradtion/sex.html
APPENDIX A
Survey Results from DES Sons Online Discussion Network, 2001 (N=40 list subscribers received survey)
Method: During January 2001, a survey was posted to the polls section of the DES Sons discussion network website. At that time, the list had 40 active participants. The survey asked list members, "What topics are most important to you as a member of this discussion forum?" List members were given one month to submit their responses. The poll listed the following choices and responses are included:
Issue Responses % of Total
Responses % of Total- Physical health issues 8 20.51%
8 20.51% - Psychological/emotional health issues 7 17.95%
17.95% - Sexuality, gender identity, and
reproductive health 11 28.21%
11 28.21% - Latest research on DES 6 15.38%
6 15.38% - Support or advice and information 3 7.69%
3 7.69% - Outreach work for locating more DES
exposed individuals 2 5.13%
2 5.13% - Help in working with medical or health
professionals 2 5.13%
2 5.13% - Other 0 0.00%
0 0.00% TOTAL 39 100%
39 100%APPENDIX B
Results of Survey of DES Sons Discussion Network Member Concerns
September 1, 2001
Background:
The following question was posted as a "poll" for network members on July 14, 2001 and respondents were allowed until August 31, 2001 to respond:
As the DES Sons Discussion Network enters its third year, what issues do you feel need the most attention and support in our continuing list discussions around the possible effects of DES exposure? (choose up to 3 selections)
The responses were as follows:
*******************************************************************************
Responses Issue/Topic
Issue/Topic20 Physical health concerns (e.g. hormones, infertility, erectile dysfunction, cancer)
17 Gender issues: gender identity, transgender and transsexualism
13 Promoting more DES research in the future
13 Sexuality issues: sexual orientation, intersex
12 Psychological/mental health issues (anxiety, depression)
11 Immune system problems (e.g. autoimmune disorders)
10 Learning more about the medical world and which specialists may be most helpful to you (e.g. Urologists, Endocrinologists)
9 Locating more sources of research about DES
3 Obtaining support from other network members for your DES-related concerns
3 Developing strategies for reaching more DES exposed persons to join our network
3 Learning about public DES education campaigns in the U.S. or elsewhere
2 Seeking legal advice and attorney referrals with respect to DES
TOTAL: 116 Responses out of 80 subscribers (Approximately 45 participants 65% response rate--out of an estimated 70 active list subscribers in August 2001)
APPENDIX C
Gender Identity, Sexual Orientation, and Sexual Diversity of DES Sons:
January 2002 Poll of DES Sons Network Members
Background:
The following question was posted as a "poll" for network members on December 22, 2001 and respondents were allowed until January 13, 2001 to respond:
If you were talking with your closest friend who likes you "just as you are,"
what term would you use to represent how you define yourself at the present time? (choose one)
The responses were as follows:
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Responses Issue/Topic % of Respondents11 Straight Male 17.5 6 Gay Male 9.5 2 Bisexual Male 3.1 9 Transgendered 14.3
Transgendered 14.3 23 Transsexual (pre- or post-op) 36.5
Transsexual (pre- or post-op) 36.5 2 Intersex 3.1 6 Androgynous 9.5 1 Female 1.5
Female 1.5 1 Eunuch 1.5
Eunuch 1.5 2 Other 3.1
Other 3.1TOTAL: 63 Individual Responses from 102 subscribers (Approximately 65-70% response rate for an estimated 90-95 active list participants in January 2002)
APPENDIX D
Questions and Issues Needing Further Research, Inquiry, and Discussion
1. In medical research about humans, what scientific methods are typically used for assessment of "gender" and "gender purity" in modern times?
2. How are the concepts of "masculinity", of "femininity", of "feminization of males" and "masculinization of females" assessed in "scientific" terms?
3. If humans are exposed prenatally to environmental estrogens like DES that have been found to alter, or the potential of altering the natural patterns of sexual development/differentiation in animals, how is this "alteration" measured, identified, or validated in scientific or medical terms?
4. Based on the previous question, what "alterations" in various animal species have been scientifically identified? Are they somatic only (gonadal, etc.), or also behavioral (same-sex attractions; male of species demonstrating female behavior, etc.). How would we assess "alterations" in interpersonal behavior among animals that have been "gender-altered" by exposure to DES or other synthetic estrogens?
5. What research currently exists that measures the neurological differences and stages of neurological development in males and female humans?
6. What available research examines the neurological and hormonal differences among transsexuals, homosexuals, and heterosexuals (both male and female)?
7. What theories exist for explaining why some members of each sex identify strongly with (or wish to become) the opposite sex more than their own sex?
8. What training do medical practitioners, researchers, and specialists typically receive in understanding (a) sexual orientation and transsexualism/transgenderism; (b) gender identify formation; and (c) psychosexual development? Has this training improved over the last 20 years?
9. How do researchers distinguish forms of depression that derive from social (or environmental) circumstances from those that are caused by neurological disturbances?
10. How do endocrine disruptors alter the normal patterns of neurological development and sexual differentiation of male and female humans? What consequences have been "measured"?
11. Are there any examples of other drugs that have ever been "proven" to modify the normal patterns of gender identity formation and sexual differentiation of males and females who are exposed to these drugs in utero, or are we dealing (in researching DES impact) in purely "uncharted territory" in raising the questions we have about the effects of DES exposure?
12. How do we scientifically assess the differences between "typical" and "atypical" patterns of gender and sexual differentiation in humans?
13. (Politics of DES and similar research) What role have homophobia and denial (or pathologization) of gender dysphoria played in the shaping of medical and biomedical research historically? Put another way: are there questions about atypical gender and sexual differentiation that have been under-explored (or unexplored) by the medical and scientific community because of homophobia or denial of gender dysphoria?
14. How have the parameters of existing DES research questions been defined (and limited) over the years, and why?
15. How have these factors affected the evolution and types of questions that researchers have asked about DES exposure in humans since 1971?
16. Are males with relatively low levels of testosterone and relatively high levels of estrogen more likely to experience "feeling feminine" and/or homosexual/bisexual orientation?
17. In existing published "cohort tracking" research about DES exposure in males, are transsexual/transgendered or homosexual/bisexual males likely to be statistically underrepresented from most samples, and if so, what are the implications of "generalizations" made from the existing studies of DES sons?
18. If DES does feminize some males psychologically, is it not likely that a majority of those who are feminized (or feel feminized, even if only psychologically) will either (a) try to deny it; (b) experience depression from not "fitting in" with others; or (c) live lives characterized by gender identify confusion and associated self-destructive or self-denigrating behaviors? If any of these are true, how would a researcher assess for these, and how would a medical professional typically respond if such males self-disclosed these feelings?
19. If DES exposed males (even a small percentage) have been "feminized" by prenatal exposure, how can this issue be accepted within the broader medical, biomedical, and health communities as an issue of equal concern as cancer, genital malformation, or reproductive problems? The Endocrine Society has recognized the relationship between DES exposure and feminization in males; see http://www.endo-society.org/pubrelations/patientInfo/estrogens.htm
20. Why was DES used as a hormone replacement of estrogen in male to female transsexuals (historically), and what are the implications for its possible effects in utero in altering hormone balances in humans?
21. "First Do No Harm" Principle: Should it be formally acknowledged within the medical and biomedical community that a drug which has the potential of altering the masculinity and femininity of humans if they are exposed involuntarily constitutes significant harm to humans? Is this an issue that needs to be settled in the courts?
22. Who and which professionals (areas of specialization) within the medical and scientific community are most resistant, and who is most receptive (or least resistant) to a theory that prenatal DES exposure can have direct impact on gender identity formation, sexual orientation, neurological development, and psychological health of males?
23. What biases or beliefs about males and male health might be responsible for the limited research about DES exposed males historically? Is the overall lack of public funding for health research on males accountable for the poor supply of studies of DES-exposed males, or are the DES advocacy communities more responsible for failing to raise public awareness about the effects of DES on male health?
24. Why are there no registries for DES exposed males similar to the University of Chicago registry for DES exposed females who have developed clear cell cancer?
25. What are the most commonly believed "causes" of gender dysphoria in males and females within the contemporary medical community?
26. How do researchers distinguish the causes of early-onset versus late-onset gender dysphoria?
27. For transsexuals, how do synthetic estrogens used for gender reassignment function in altering the endocrine system and what other biological and behavioral mechanisms are altered by these estrogens?
28. What is the reason for the dearth of research in the social science, gender studies, and human development communities about the human effects and consequences of environmental estrogens and endocrine disruptors like DES?
29. If a doctor is confronted with a DES-exposed individual who does demonstrate gender dysphoria, what medical response is most common and what "causality" is most typically assessed?
30. Is there a common agreement within the medical and biomedical community about the effects in males of exposure to excess estrogens both prenatally and later?
31. How have the courts generally handled suits against DES manufacturers brought by DES sons? Who has usually won the suits, and what have been the principal issues involved when DES exposed individuals win?
32. Given that studies have identified a relationship between DES exposure and higher rates of anxiety, depression, and eating disorders, why hasn't more research been conducted about the effects of DES on the central nervous system of humans?
33. Has it been confirmed that prenatal exposure to DES in males can contribute to unusually lowered testosterone levels after birth and in later years, or is this a subject that needs further research?
34. Should we conclude that even if we can produce evidence that DES feminizes at least some exposed males, the mainstream (non-naturopathic) medical and scientific community and the public health establishment (CDC, NIH, NIEHS, DES Action, etc.) would typically prefer to look the other way rather than to recognize this is a bona-fide medical or public health problem (diagnosis and treatment of both intersexuality and gender dysphoria)? Why?
35. If most medical researchers and practitioners are trained and oriented toward understanding the physiological and neurological aspects of human beings, where is the best available research bridge to the psychological, social, and behavioral study of humans?
36. What role may have been played by the large pharmaceutical corporations (particulary those based in the U.S. which produced DES during its years of greatest popularity) in influencing or shaping the public research and education agenda around the effects of DES?
37. Is it possible that much more is known about the full range of negative effects of DES by its main manufacturers than has heretofore been made public?
38. What impact may these companies have had in influencing the focus or areas of further research about DES of U.S. public health research agencies such as the National Institutes of Health, National Institute of Environmental Health Sciences, and National Cancer Institute? See, for example, this information about chemical industry influence over the NIEHS research on endocrine disruptors: http://www.mapcruzin.com/news/news072801a.htm
39. Which health agencies in the U.S. in the year 2002 are still actively promoting ongoing investigation into the effects of DES on the original exposed populations, and what is the scope of research included in their agendas?
40. What is the status of the recommendations and available public funding for further research and findings and assessment of impact of DES on males, recommended by the 1999 NIH-sponsored event on DES research? (see program posted at http://searchosp1.nci.nih.gov/whealth/DES/index.html )
41. In light of the substantial increase of evidence of detrimental effects of endocrine disruptors such as DES on male reproductive health, does this not cast a cloud of doubt on the validity and adequacy of existing DES sons' "cohort studies" such as that published by Wilcox et al. in 1995? Would it not make more sense to use other holistic research methodologies such as those suggested by Krimsky, McLachlan, and others who support the environmental endocrine hypothesis for documenting the full range of health effects of DES on exposed males born to DES mothers between the 1940s and 1970s?
42. What other broad public health policy implications are raised by the findings in this immediate study of DES sons, and what steps need to be taken to bring this information to more potentially interested individuals and organizations?
43. Given the current political climate in the United States, how do we weigh the risks raised by drawing attention to the more controversial findings from our research such as the association between DES and transgenderism against the potential benefits for DES exposed persons and their families? Are there ethical considerations that need to be addressed as we continue our research in this area?
44. Is there data available from the birth defects registries around the U.S. that documents the numbers of DES-exposed males born with various reproductive or other physical ailments? Is there any way to pool this data on a national scale to determine how widespread certain conditions such as chryptorchidism, hypospadias, intersex are among DES-exposed males?
45. Are there currently efforts under way to promote broad studies of male reproductive health in Europe and other portions of the world in which there have been direct links identified between declines in male health and exposure to DES and other endocrine disrupting chemicals? Would these provide effective models for future public health research and policy initiatives in the U.S?
Excerpts about the history of DES from The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth, by Barbara Seaman (2003, Hyperion Books)
I. Introductory Comments (pp. 4-6)
“The experiment began in England in 1938, and has continued for sixty-five years. A British biochemist, desperate to prevent Nazi Germany from cornering the world market on synthetic sex hormones, published his formula for cheap and powerful oral estrogen. Within months, thousands of doctors and scores of drug companies around the world were working with this formula.
That opened the Greatest Experiment. Products made from chemicals that mimicked the feminizing effects of a woman’s natural secretions were marketed fresh out of the lab. They were prescribed and sold for a host of concerns—to slow and prevent aging, to stop flashes, to avoid pregnancy or miscarriage, and as a morning-after contraceptive.
I call the marketing, prescribing, and sale of these drugs an experiment because, for all these years, they have been used, in the main, for what doctors and scientists hope or believe they can do, not for what they know the products can do. Medical policy on estrogens has been to “shoot first and apologize later”—to prescribe the drugs for a certain health problem and then see if there is a positive result…
The risks of these drugs have been known and documented from the start. The British doctor [Sir Charles Dodds] who published his estrogen formula in 1938 spent many years thereafter warning the world that these drugs, although containing great promise, put women at serious peril for endometrial and breast cancer… We have known since day one that these drugs posed threats. And since then science has added to, not subtracted from, the list of estrogen’s problems.
If doctors and scientists have known these dirty secrets for so long, why is the bad press so recent? That is an essential question right now, and this book seeks to present the answer. Part of the answer lies in the vigorous efforts by drug companies to protect an invaluable market. These efforts have included underwriting studies and subsidizing doctors, participating in medical school curriculums, advertising heavily in medical journals, and seeing that continuing medical education is directed by doctors on the drug industry’s payroll. They have also entailed one of the most elaborate promotion and advertising campaigns in the history of the media not only in America but worldwide.”
II. On Sir Charles Dodds and the Origins of DES (pp. 32-36)
“In 1938, the opening year of the greatest experiment ever performed on women, Winston Churchill was out on a limb in England, warning his countrymen that Hitler intended war. Few paid attention, even though the fuhrer already held Austria and was poised to take Czechoslovakia. Recovering from the trauma of World War I, struggling to come out of an economic depression, the British weren’t in a mood to hear Churchill’s message, preferring instead to support Prime Minister Neville Chamberlain’s doomed appeasement policies.
There were exceptions, of course, among them a tiny corps of distinguished chemists, including Sir Charles Dodds, director of the Courtald Institute of Biochemistry at Middlesex General Hospital in London and the father of diethylstilbestrol or DES, the first synthetic estrogen to make a huge commercial splash the world over. Affable and kindly, a regular at international chemistry events, Charles Dodds frequently received ominous news from Germany. He was often reminded that German chemistry, dangerously ahead of Britain’s on many frontiers, was being conscripted in the service of Hitler’s most evil fantasies. Dodds often discussed his fears and worries with his eminent colleague and friend Dr. Robert Robinson, director of the Dyson Perrins Laboratory at Oxford University. They pooled their information and passed it on to Churchill, providing the background for the future prime minister to cry out against the ‘perverted science’ of the Third Reich. As Dodds and Robinson were doing research in sex hormones, they were particularly interested in [German biochemist Adolph Friedrich Johann] Butenandt’s work and in the uses [German chemical manufacturer] Schering made of it. They were concerned that Schering had major ties to I.G. Farben, a German cartel of five large corporations that deal with all sorts of chemicals, including poison gases and rocket fuels, and which, drawn by free labor to the death camps, would soon build an industrial complex at Auschwitz for the production of synthetic rubber and oil.
At war’s end, General Dwight D. Eisenhower assigned a team of civilian and military experts to make an exhaustive investigation of Farben’s contribution to the Nazi effort. When members of Germany’s industrial elite were tried at Nuremberg, the key role that chemistry had played in the Third Reich was underlined by the name applied to these criminals: ‘the Devil’s Chemists.’
The Devil’s Chemist Dodds feared most was Butenandt. Perhaps he and Robinson were a little bit envious, for no other steroid chemist in the world had such achievements to his credit. On the other hand, these Englishmen were not engaged in heads-on professional competition, for they were on a different track, trying to develop what are called nonsteroidal estrogens, in contrast to Butenandt’s, which were steroidal.
The nonsteroidal estrogen is simpler. It lacks the four interlocking carbon rings that characterize the natural steroidal hormones and their derivatives. Dodds and Robinson, working separately, were aiming for a simpler compound—a compound without the rings of carbon, completely synthetic,unrelated to any natural substance, strong enough to take by mouth, stable, and very inexpensive. And oh yes—it would have to deliver all the same benefits as existing steroidal estrogens.
Dodds had been working hard on this since 1934 and was almost there, but one or two final mysteries remained for him to unlock, a term he often used to convey the challenges of chemistry.
Some day around New Year’s Day 1938, Dodds and Robinson called a hasty meeting to discuss the latest rumor from Berlin. Schering had applied for a patent on estradiol. Dodds and Robinson agreed this was absurd and unethical. Estradiol is not a patentable substance. Estrogen molecules belong to nature. They belong to God. They belong to—women…
‘Such products must stay in the public domain,’ Dodds insisted, referring to synthetic estrogen. ‘Those Germans are trying to corner the entire field of sex hormones, and use the profits to fund Hitler,’ Robinson added. They were told that estradiol might be used as a weapon, but they didn’t know for what. Would this be a means to Hitler’s ‘final solution’ to sterilize and eliminate Jews, Gypsies, cripples, and maybe the British one day?
…Robinson’s nonsteroidal research was at an earlier stage than Dodds’s, but he had some excellent ideas and offered to help cheer Dodds to the finish line. They would pool their resources. Their labs would work together. Maybe some of their countrymen didn’t know it, but this was war. For a suitable crash effort, they would enlist all workers at both facilities, even the undergraduate students. Dodds could keep the principal credit, but Robinson and his people would give their all—for Dodds, for the King, for England. Schering was about to make a killing with its patented ethinyl estradiol. If Dodds and Robinson hurried, they might stop the private ownership of estrogen molecules in its tracks.
Very soon thereafter, Wilfred Lawson, a chemist on Dodds’s staff, scribbled a new formulation on the back of an envelope. Leon Goldberg, an Oxford student of Robinson’s, performed the actual synthesis of diethylstilbestrol by heating one gram of a similar substance to 205 degrees C. All at once, it was done. The formula worked. Dodds rushed the experiment into publication in the form of a fifteen-paragraph article in the magazine Nature on February 15, 1938.
This would give the world a cheap and powerful estrogen everyone could use. Any of Schering’s hopes for a big export business in estradiol were dashed, along with plans to control the world’s hormone markets. The estrogen diethylstilbestrol could be taken in liquid form or as a pill and – a sensational bargain – would cost only $2 a gram, compared to estradiol’s $300. It came to be known as DES in the United States and stilbestrol in England.
DES was a novel and daring product, constructed entirely from a chemical base. It produced the same feminizing effects as estrogens derived from animals and plants but was three times more powerful. Anyone could make it, because in publishing his formula Dodds threw away his own patent rights.”
III. On the Rush to get FDA Approval of DES in the U.S. (pp. 43-46)
“As soon as Dodds’s formula appeared in Nature, free to copy by all comers, a plethora of American drug companies, most notably Eli Lilly and Squibb, but also Abbott Laboratories, Sharp & Dohme, and Upjohn, were distributing samples to doctors and seeking instructions from the FDA on how to get approval. Lilly launched its own research program, under the direction of Dr. Don Carlos Hines, while Squibb’s Dr. Sidney Newcomer called on interested physicians, encouraging them to do research that Squibb would help them prepare for publication.
But alarm bells were ringing, and it wasn’t just DES that set them off. Dodd’s estrogen was the newest addition to a family of drugs already indicted for causing cancer. Back in 1932, Antoine Lacassagne, who would one day win the coveted UN Prize for Cancer Research, gave Butenandt’s estrogens to mice and induced mammary cancer. By the end of the 1930s, Shimkin, Dodds, and anyone else who wanted to check this out at a medical library would have been startled at the sheer weight of the warnings already published in prestigious journals. Furthermore, on rumors that requests to market DES were pouring into the FDA, the Journal of the American Medical Association (JAMA) published a powerful editorial against the drug on December 23, 1939, entitled ‘Estrogen Therapy—A Warning?’
[excerpted from the JAMA editorial] ‘Regarding conflicting reports about DES… a thorough investigation of this compound is in order before it can be prescribed for routine therapy… The possibility of carcinoma cannot be ignored… it appears likely that the medical profession may be importuned to prescribe to patients large doses of high potency estrogens, such as stilbestrol, because of the ease of administration of these products.’
In that same issue, the Council on Pharmacy and Chemistry (which included George N. Papanicolaou, originator of the Pap smear) cautioned that ‘because the product is so potent and because the possibility of harm must be recognized, the Council is of the opinion that it should not be recognized for general use at the present time… and that its use by the general medical profession should not be undertaken until further studies have led to a better understanding of the functions of the drug.’
Nonetheless, by the end of 1940, a dozen drug companies had asked the FDA for approval to market diethylstilbestrol. The agency made it known that it would turn down any application but that the companies had the right to protest, fearing that if the press got wind of the situation, it would bring the cancer fears to public attention. The manufacturers, rather than fighting the decision, met together and decided to withdraw their applications, and to regroup.
The regrouping that followed was a blueprint for joint spin doctoring by the drug companies and it laid down the bases for the formation of Big Pharma, the powerful industry lobby that would officially start business in 1951. Meanwhile, under tight discipline, the companies agreed to pool their resources to construct a ‘master file’ on DES. Four companies, which became known as the Small Committee, would do the lion’s share of the work. Lilly’s Don Carlos Hines was the head of the group. Winthrop and Upjohn were members, and Dr. J.A. Morrell of Squibb contributed a most impressive collection of articles. (Impressive, that is, to the FDA perhaps, but it horrified Dodds, who recalled the dreaded ‘master file’ to me with bitter emotion twenty-five years later.) That file contained 257 articles on the successful uses of DES.
There were two divisions in the DES army. The drug-company doctors, Hines and Morrell, led the first; the second was headed by a dynamic Washington lobbyist-publicist, Carson P. Frailey, the executive vice president of a trade group, the American Drug Manufacturers Association.
Frailey’s campaign opened on January 28, 1941, when he was host to a meeting at the Washington Hotel. He explained his scheme to round up doctors across the country and enlist them to write to the FDA. Fifty-four doctors cooperated, describing their experiences with more than 5000 patients. Only four doctors felt that DES should not be approved.
By May 12, Frailey announced that a nearly done deal. He sent a letter to the Small Committee with good news: ‘The time now seems propitious to suggest that you re-file your new drug application for stilbestrol. I am making no commitments that the application will be permitted to become effective, but the suggestion offered has official background.’
The drug-company physicians understood from the letter that someone in power at the FDA was on their side of the battle. On September 19, 1941, the fall of the Japanese attack on Pearl Harbor, the FDA officially approved the use of stilbestrol for the treatment of menopause symptoms, menstrual disorders, and other problems.
The FDA’s capitulation to a slick campaign and its failure to heed the warnings of cancer experts marked a most shameful day in the agency’s history. It is estimated that in the yeas from 1941 to 1971, over four million pregnant women in the United States were treated with nonsteroidal synthetic estrogen on the contention that it would prevent miscarriages and ensure their babies’ health. Pearl Harbor was not the only cruel and tragic trick played on the American people in the autumn of 1941.” Excerpts about the history of DES from The Greatest Experiment Ever Performed on Women: Exploding the Estrogen Myth, by Barbara Seaman (2003, Hyperion Books)
