Initial Evidence from a 5-Year Study
by Scott P. Kerlin, Ph.D., DES Sons International Network,
Presented at 6th Annual E-Hormone Conference, New Orleans, October 27-30, 2004
Introduction and Background
During the 1970s and 1980s an increasing amount of public and scientific attention was paid to the health and medical problems of women and men whose mothers and grandmothers took diethylstilbestrol (DES) for prevention of miscarriage. A potent estrogenic chemical, DES was first developed in 1938 and initially became available in the U.S. for treating a range of gynecologic conditions in 1941 (Apfel and Fisher, 1984). A few years later its approval by the FDA was broadened to include treatment of pregnant women for the purpose of preventing miscarriages (spontaneous abortions). Though its efficacy had long been doubted by some in the medical community (Bambigboye and Morris, 2003; Dieckmann, 1953; Edelman, 1986), DES remained popular until publication of research in the early 1970s identifying an apparent association between prenatal exposure to DES and a rare form of vaginal cancer in females (commonly called “DES daughters”) whose mothers used DES (Giusti, Iwamato, and Hatch, 1995; Heinonen, 1973; Herbst and Bern, 1981).
It is estimated that as many as five to ten million Americans received DES during pregnancy or were exposed to the drug in utero between the late 1940s and early 1970s (Giusti, Iwamoto, and Hatch, 1995). The numbers of male offspring exposed in utero to DES (“DES sons”) have been estimated at between one and three million in the U.S. (Laitman, Jonler, and Messing, 1997) and similar estimates exist for the numbers of American females exposed in utero (Edelman, 1986). Hundreds of thousands of DES sons and daughters were also born in Canada, Europe and Australia during a similar period.
Compared with the history of research on the range of health effects of DES daughters, there are relatively few published medical research studies conducted with DES sons. And yet, the finding that prenatal DES exposure also led to detrimental effects for a number of exposed males has existed since the 1970s (Andonian and Kessler, 1979; Bibbo et al., 1977; Gill et al., 1979; Gill, et al., 1988; Laitman et al., 1997). These effects include 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, and hypospadias (opening of the penis is on the underside rather than at the end). Although DES exposure has been suspected as a possible source of male infertility and testicular cancer (Giusti, Iwamato, and Hatch, 1995, it is still uncertain whether prenatal DES exposure has led to increased risk of infertility (Wilcox et al., 1995) or increased rates of testicular cancer as well as other types of cancer in males (Strohsnitter, et al. 2001).
While published primary studies of other health issues among males with prenatal exposure to DES are not numerous, there is some available research investigating possible links between DES exposure and increased potential for major depressive disorders and other psychiatric effects (Katz, et al., 1987; Meyer-Bahlburg and Ehrhardt, 1986; 1987; Pillard et al., 1993; Vessey et al., 1983). More recent discussion of possible psychiatric effects of prenatal DES exposure, including gender-related effects, has been forwarded by Verdoux (2000; 2002) and Boog (2004). Research investigating possible psychosexual impact of DES exposure in human males (feminization and demasculinization) has been published since the 1970s (Dorner, 1985; Green, 1978; Kester, Green, Finch, and Williams, 1980; Reinisch and Sanders, 1984; Reinisch, Ziemba-Davis, and Sanders, 1991; Yalom, Green, and Fisk, 1973), while research on endocrine disruptors which includes discussion of DES as a possible link in a variety of sexual differentiation disorders in humans has been produced more recently (Boisen, et al., 2001; Gupta, 2000; McLachlan, 2001; McLachlan et al., 2001; Sharpe, 2001; 2004; Skakkebk, Meyts, and Main, 2001; Sultan et al, 2001; Swaab et al., 2002; Toppari and Skakkebk, 1998).
This study was initially conceptualized as a one-year (1999-2000) virtual (online) focus group of DES sons from around the world, with the basic purpose being discussion and documentation of the range and history of reported adverse health effects among DES sons. Virtual focus groups are online discussion communities or support groups which, when effectively designed and moderated, enable investigation of a particular issue (for example, adverse health effects) from the perspective of the individuals who are most directly affected (Murray, 1997). The tools and features of online forums like the DES Sons International Network enable a collective engagement of issues raised by participants and fresh insights for participants and researchers.
The DES Sons International Network was developed with a number of primary goals in mind: to bring together an expanding range of individuals born as males who were exposed prenatally to DES, to expand awareness of the range of existing research about DES and male health, and to explore other issues affecting the physical, mental, and reproductive health of DES sons. Most important, it was meant to further investigate still unresolved questions regarding DES sons, consistent with recommendations issued by the National Cancer Institute and National Institutes of Health (National Cancer Institute, 1999).
Upon creation of the DES Sons Online Network (now the DES Sons International Network) in 1999, announcements about the online network were made on a variety of online DES and reproductive health information networks. Subscription requests were carefully screened for
- evidence or confirmation of the likelihood of prenatal DES exposure;
- confirmation of birth between the late-1940s and early 1970s which was the critical “window” during which DES was administered as an anti-miscarriage drug;
- confirmation that the subscriber was born as a male and thus qualified to be considered a “DES Son”.
Although a few other individuals whose exposure status was unknown were permitted to join the Network they are not included in the statistical analysis that is covered in this report.
Data-gathering within this study has used the principles of grounded theory in qualitative analysis which involves a process of continuous expansion and refinement of issues in online discussions, combined with ethical principles of precaution around network members’ identities and privacy. As individuals joined the DES Sons International Network, they provided (privately to the researcher and on occasion in the support group discussions) an overview of health and medical histories as well as other questions or issues surrounding their DES exposure. Primary research on DES sons’ health issues included open-ended questions, occasional surveys or polls of members, periodic online chats (conducted in “real time”) to answer questions on particular health questions such as DES exposure and infertility, and the sharing and posting of relevant published DES research studies in order to generate discussion and further awareness. Summary results from most of the available text-based data are being analyzed using sophisticated qualitative data analysis software.
Within the first year of Network discussions, 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. The Network continued to attract interest and new members after the first year and it was decided to continue the Network indefinitely. By the summer of 2004, the DES Sons International Network had more than 200 active subscribers.
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 2004, more than 130 individuals had joined DES Trans. This underscores the significance of gender identity and intersex conditions as major concerns among a significant portion of persons who have been exposed to DES.
This section presents an introduction to some of the key findings from research conducted with the members of the DES Sons International Network between July 1999 and July 2004. A more comprehensive summary of the full scope of findings will be completed in 2005.
Gender Identity, Sexual Orientation, and Sexual Diversity of DES Sons provides an overview of a January 2002 poll of members of the DES Sons International Network when its total membership was just over 100. Members were asked 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. What is significant among the findings of this poll is that among the 63 network members who answered the question (approximately 70% of active network members), 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 “intersex” or “androgynous.” “Straight males” represented 17.5% of respondents (the second highest response group), while 13% identified as bisexual or gay males.
APPENDIX B – DES Sons International Network 5-Year Summary Statistics: First Findings
- 1. Basic Statistics and Findings on DES Sons Participating in the DES Sons International Network Between 1999 and 2004
- 2. DES Sons and the Significance of Gender Identity: Statistics of Individuals with Gender-related Issues or Outcomes Among Network Members
- 3. Statistics of Prevalence of Transsexualism, Transgenderism, Gender Dysphoria, or Intersex Among “Likely Exposed” DES 46XY Individuals Contacting or Joining the Network (N=158)
presents an overview of the range of issues raised by the approximately 500 members of the DES Sons International Network during its first five years. (Note re sample size: as of spring 2004, the number of individuals with known or likely DES exposure who have joined the Network since 1999 reached 500 (base sample size = 500). Issues raised by Network members include:
- Principal Reported Health Concerns of DES Sons
Based on results from a variety of assessments of individual DES sons in the Network, the three health areas of greatest concern among Network members are (a) hormonal/endocrine health issues; (b) gender identity and sexual health issues; and (c) psychological/mental health issues including anxiety and depression.
- Additional Reported Adverse Health Effects
Members identified a range of adverse health effects including autoimmune disorders, infertility, reproductive tract abnormalities, ambiguous or underdeveloped genitalia, epididymal cysts, testicular cancer, and erectile dysfunction.
- Significant Gender Dysphoria Prevalence
Somewhere between one-quarter and one-third of members of the DES Sons’ network since 1999 have indicated that gender dysphoria, transsexual outcomes, and/or sexual health issues were among their top concerns.
- Relatively High Prevalence of Transsexual, Transgender, and Intersex
More than 150 network members with “confirmed” or “strongly suspected” prenatal DES exposure status indicated they are either transsexual (pre- or post-operative, 90 members), transgender (48 members), “gender dysphoric” (17 members), or intersex (3 members).
- Low Cancer Prevalence
Only a small number of DES sons contacting the network have reported experiencing any type of cancer-related health problems (primarily testicular cancer during younger years).
Discussion and Implications
During the first five years of research within the DES Sons International Network some important accomplishments and discoveries have occurred. These will be more thoroughly detailed when a subsequent edition of this paper is completed in 2005. Accomplishments and a brief examination of the implications include the following: through the first five years of this study a base sample of 500 individuals with confirmed or “suspected” DES exposure from a wide range of locations around the world has been obtained.
Historically, research with DES sons has often entailed relatively low numbers of individuals, making it difficult to extrapolate from one study to broader populations of DES sons. The research in the DES Sons International Network, while involving relatively low levels of researcher control over issues of geographic location or dosage/timing of exposure, has enabled deeper exploration of issues of common life experience and human development among DES sons. Grounded Theory (Glaser and Strauss, 1967), as a rigorous method of qualitative inquiry in which theory is developed inductively from a corpus of data, was used in this study to enable issues to emerge that otherwise might be overlooked in study designs involving greater levels of control.
Endocrine system disorders such as hypogonadotropic hypogonadism in DES sons have been among the most common reported adverse health effects in this research study.
Although the prevalence of endocrine system disorders among DES sons has not been discussed in any of the existing published research on DES-exposed populations, both the Endocrine Society and the American Association of Clinical Endocrinologists (2002) have recognized prenatal DES exposure as a potential risk factor for endocrine disorders including hypogonadism. Our research confirms that this is an issue that needs further attention in future studies of DES sons.
Mental health and psychiatric issues (including depression and anxiety disorders) are relatively significant among the population of DES sons participating in this research.
Our findings support the efforts, most recently by Verdoux (2000, 2002), to obtain better understanding about the risks and causes (if any exist) of psychiatric disturbances among DES-exposed individuals. It is hopeful that future research on human health effects of exposure to endocrine disrupting chemicals (i.e. assessing neurotoxicity) will include psychiatric disturbances such as major depression, anxiety disorders, eating disorders, and psychoses as potential endpoints for analysis. Additional questions may be explored as to whether psychiatric conditions such as increased depression and/or anxiety disorders in DES sons have a foundation in primary endocrine system disorders.
Relative infrequency of reported cancer among the DES sons in this research is consistent with most existing long-term studies demonstrating there is limited cancer risk in males directly due to prenatal DES exposure.
While the rate of total cancer occurrence in the DES Sons International Network could not be rigorously measured, numerous efforts have been made to generate discussion about cancer risks and in particular, to encourage dialogue regarding testicular cancer experiences. Approximately five members of the network between the study years of 1999 and 2004 indicated some past or present experience with testicular cancer. It appears that overall cancer outcomes among network members have been low, a finding consistent with research by Strohsnitter et al. in 2001.
One of the most significant findings from this study is the high prevalence of individuals with confirmed or strongly suspected prenatal DES exposure who self-identify as transsexual, transgender, intersex, or who have identified serious difficulties with gender dysphoria.
Throughout this study, the issue of gender dysphoria (Colucciello, 1996) and the prevalence of a significant number of self-identified male-to-female transsexuals (Cohen-Kettenis and Gooren, 1999) and transgendered individuals (Conway, 2004) as well as some individuals who identify as intersex, androgynous, gay and bisexual has raised fresh awareness of historic theories of a possible biological/endocrine foundation to variations in psychosexual development in humans (including sexual orientation, core gender identity, and sexual identity). Some of these theories were first forwarded in the 1960s by experts in sexual medicine (Benjamin, 1966,
1973; Diamond, 1965, 1996) and have been further refined relative to the role of hormones in shaping gender-based behavior and sexual orientation (Dorner, 2001; Friedman and Downey, 2002; Wilson, 1999; Michel, Mormont and Legros 2001; Rudacille, 2005). The discoveries in this study suggest that gender dysphoria and transsexual changes may be a plausible toxic endpoint for future exploration of the human health effects of exposure to endocrine disruptors. Further, they call into question the accuracy and adequacy of previous research and conclusions by Titus-Ernstoff et al. (2003) in which they conclude that there is little support for a hypothesis that prenatal DES exposure influences psychosexual development in males and females (Udry, 2003).
The findings in this study relative to developmental abnormalities of the male reproductive tract substantiate previous research on prenatal DES exposure and various structural deformities in some DES sons and lend new support for the hypothesis that endocrine disruptors may have substantial negative effects in human males.
In underscoring the human health effects of prenatal exposure to DES in males, the findings in this study are consistent with McLachlan’s (2001) proposition that DES be considered as a model for developmental estrogenization.
This paper has provided a brief encapsulation of the leading trends and outcomes from a preliminary review of results from a five-year study of DES sons. Many of the issues and questions deriving from this study will be further examined and refined during 2005. Interested researchers are invited to join the DES Research online group located here.
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