In 2005, Dr. Scott Kerlin, DES Sons International Network, presented a breakthrough paper, with colleagues Dr. Dana Beyer and Milton Diamond, to the International Behavioural Development Symposium, delineating the impact DES has had in causing intersex and gender variations in human beings.
Paper prepared for the International Behavioral Development Symposium 2005, by Scott P. Kerlin, Ph.D., DES Sons International Network
For many years, researchers and public health specialists have been assessing the human health impact of prenatal exposure to the estrogenic anti-miscarriage drug, diethylstilbestrol (commonly known as DES or “stilbestrol”). The scope of adverse effects in females exposed to DES (often called “DES daughters”) has been more substantially documented than the effects in males (“DES sons”). This paper contributes three areas of important research on DES exposure in males:
an overview of published literature discussing the confirmed and suspected adverse effects of prenatal exposure in DES sons;
preliminary results from a 5-year online study of DES sons involving 500 individuals with confirmed (60% of sample) and suspected prenatal DES exposure;
documentation of the presence of gender identity disorders and male-to-female transsexualism reported by more than 100 participants in the study.
Introduction and Background
During the 1970s and 1980s an increased amount of public and scientific attention was paid to the health and medical problems of individuals whose mothers were prescribed diethylstilbestrol (DES). A potent synthetic nonsteroidal estrogen, 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. Though its efficacy had long been questioned by some in the medical community (Bambigboye and Morris, 2003; Dieckmann, 1953), DES remained popular with doctors until discovery in the early 1970s of an apparent association between prenatal exposure to DES and a rare form of vaginal cancer in females whose mothers used DES (Heinonen, 1973; Herbst and Bern, 1981). Subsequent research confirmed the transplacental mechanism of DES transmission (Maydl, et al., 1983) and classified DES as a carcinogen and teratogen (Mittendorf, 1995) as well as a mutagen (Roy and Liehr, 1999; Stopper et al., 2005).
While DES usage with pregnant women was banned by the FDA in 1971, the drug continued to be used in several European countries into the early 1980s (Schrager and Potter, 2004). DES remained a popular option for treatment of advanced prostate cancer in aging males due to its ability to inhibit luteinizing hormone secretion by the pituitary and thus inhibit testosterone secretion (Scherr and Pitts, 2003; Whitesel, 2003), despite reports that adverse effects from this treatment could include feminization in males (B. C . Cancer Agency, 2005). Through the 1970s DES was also prescribed as an estrogen supplement for treatment of male-to-female transsexuals (Kwan, 1985; Ober, 1976).
It has been estimated that as many as four to five million American women were prescribed DES during pregnancy. Estimates of the numbers of “DES daughters” and “DES sons” born in the U.S. are between one million and three million of each (Edelman, 1986). Hundreds of thousands of DES sons and daughters were also born in C anada, Europe and Australia between the 1940s and 1980s. Efforts to determine exact numbers of prenatally exposed individuals, and the dosage and exposure patterns, particularly during the years of prime DES popularity, 1947-55 in the U.S., have been largely unsuccessful (Duke, et al., 2000; Heinonen, 1973). Because DES proved popular as a growth-stimulant in the cattle industry (Raun and Preston, 2002) for more than forty years (McLachlan, 2001), many consumers have also been exposed to unknown amounts of DES as it entered the food chain through beef consumption.
Following the FDA restrictions on DES prescriptions in the U.S. in 1971, researchers began to document a range of confirmed and suspected adverse effects of prenatal DES exposure in females and males (Edelman, 1986). Compared with the volume of published research on adverse effects in DES daughters, however, relatively few primary studies of DES sons have been published. The scope of known and suspected health effects among DES sons discussed in literature published since the 1950s includes
reproductive tract abnormalities;
prostatic hyperplasia and cancer;
and effects on hemispheric laterality and spatial ability (Giusti et al., 1995; Pillard, et al., 1993; Reinisch and Sanders, 1992; Verdoux, 2004).
In 1959, a single case study of pseudohermaphrodism in a male with prenatal DES exposure was reported (Kaplan, 1959). Reports of urogenital abnormalities in DES sons first appeared in the medical literature during the 1970s (Andonian and Kessler, 1979; Bibbo et al., 1977; C osgrove et al., 1977; Gill et al., 1979; Gill, et al., 1988; Henderson et al., 1976), consistent with results of experiments with prenatal DES exposure in male mice reported by McLachlan et al. (1975) and Newbold et al. (1987). These effects include epididymal (benign) cysts, hypoplastic or undescended testes (chryptorchidism), microphallus or underdeveloped penis, and hypospadias. Using data from DES sons participating in the DES cohort studies funded by the National Cancer Institute (NC I), researchers have examined possible links between prenatal DES exposure and greater risk of male infertility but have reached inconclusive findings (Wilcox et al., 1995). Although heightened testicular cancer risk has long been associated with prenatal DES exposure in males, researchers using the NC I cohorts to track cancer outcomes among DES sons claim to have measured no statistically significant increases in testicular or other forms of cancer (Strohsnitter, et al. 2001).
John McLachlan (2001), a pioneering DES researcher whose studies have assessed the effects of DES exposure in laboratory animals and mechanisms of DES toxicity for the past three decades, was among the first researchers to classify DES within a broader family of chemical compounds called “environmental estrogens”, “xenoestrogens”, or “endocrine disrupting chemicals” because of their common ability to mimic and interfere with normal hormonal processes associated with reproductive development. He has observed:
Developmental feminization at the structural or functional level is an emerging theme in species exposed, during embryonic or fetal life, to estrogenic compounds. Human experience as well as studies in experimental animals with the potent estrogen diethylstilbestrol provide informative models (2001).
The evolving research on endocrine disruptors has implicated DES in a variety of sexual differentiation disorders of the brain and body in males (C olburn et al, 1993; McLachlan et al., 2001; Sharpe, 2001; 2004; Sultan et al, 2001; Toppari et al., 1996), including testicular dysgenesis syndrome (Boisen, et al., 2001; Skakkebæk, Meyts, and Main, 2001). In 1993, Sharpe and Skakkebæk observed:
Treatment of several million pregnant women between 1945 and 1971 with a synthetic oestrogen diethylstilbestrol (DES) is now recognized to have led to substantial increases in the incidence of cryptorchidism and hypospadias and decreased semen volume and sperm counts in the sons of these women. DES exposure may also increase the incidence of testicular cancer and cryptorchidism. The similarity between these effects and the adverse changes in male reproductive development and function over the past 40-50 years raises the question of whether the adverse changes are attributable to altered exposure to oestrogens during fetal development. This possibility is not unlikely given the view that ‘humans now live in an environment that can be viewed as a virtual sea of oestrogens’ (Sharpe and Skakkebæk, 1993).
However, in a recent Danish meta-review of published epidemiological studies involving the association of prenatal indicators of estrogen exposure (including prenatal DES) and the deleterious impact on human male reproductive health such as reduced sperm counts, cryptorchidism, hypospadias and testicular cancer, Storgaard et al. (2005) reached this conclusion:
With the possible exception of testicular cancer there is no strong epidemiological evidence to indicate that prenatal exposures to estrogen are linked to disturbed development of the male reproductive organs. It is unlikely that phytoestrogens and several environmental xenoestrogens play a role unless exposures are extremely high (which is not expected), the dose– response relation is U-shaped or mixtures of xenoestrogens have synergistic actions. Low exposure levels for xenoestrogens may, however, operate by means of other toxicological mechanisms (Storgaard, et al., 2005).
It has been hypothesized that prenatal DES exposure may also have led to behavioral effects in humans (Meyer-Bahlburg and Erhardt, 1986; Meyer-Bahlburg, et al., 1995). Primary studies exploring possible behavioral and psychiatric effects of prenatal DES exposure in males first appeared in the literature during the 1970s. DES exposure has been associated with increased potential for major depressive disorders and other psychiatric effects in males (Katz, et al., 1987; Meyer-Bahlburg et al., 1985; Pillard et al., 1993; Saunders, 1988; Vessey et al., 1983). Recent discussions of potential psychiatric effects of prenatal DES exposure, including gender-related effects and schizophrenia, have been presented by Verdoux (2000; 2004) and Boog (2004). Verdoux summarizes the research on DES in the psychiatric literature this way:
Sparse findings suggest that exposure to xenoestrogens such as diethylstilbestrol may be a risk factor for psychiatric disorders, mediated by a possible deleterious impact of the substances on foetal neurodevelopment, but this hypothesis is speculative owing to the small number of studies and their methodological limitations (Verdoux, 2004).
Among the possible effects associated with prenatal DES exposure that have been discussed in the literature is impact on psychosexual development (Giusti et al., 1995). Research investigating possible psychosexual impact in human males was first published in the 1970s (Yalom, Green, and Fisk, 1973). Studies by Kester et al. (1980), Reinisch and Sanders (1984; 1992) and Reinisch, et al., (1991) attempted to assess various dimensions of “masculine” and “feminine” behavior and spatial ability among DES sons. In their metaanalysis of 19 studies on the behavioral effects of prenatal exposure to hormones administered for the treatment of at-risk human pregnancy (including the Yalom et al., 1973 and Kester et al., 1980 studies of DES-exposed males), Reinisch et al. (1991) concluded:
The data on prenatal exposure to synthetic estrogen derive primarily from subjects exposed to diethylstilbestrol (DES). DES-exposed male subjects appeared to be feminized and/or demasculinized, and there is some evidence that DES-exposed female subjects were masculinized.
A study of “psychosexual characteristics” (limited to questions regarding “handedness”, “age at first sexual intercourse”, “number of sexual partners”, “percent having exclusively heterosexual partners”, “percentage ever married”) was conducted in 1994 with responses from DES sons and DES daughters participating in the National Cancer Institute’s long-term DES combined cohort studies (Titus-Ernstoff, et al. 2003). Although Udry (2003) critiques the Titus-Ernstoff study for not examining “gendered behaviors,” no primary research investigating gender-related outcomes of DES-exposed males has been published since the Reinisch et al. review of 1991.
While it is not possible in this paper to review the extensive array of experimental animal research involving prenatal and neonatal DES exposure, two recent wildlife studies of the effects of DES on the reproductive function and behavior of male Japanese quail are notable. One study by Halldin et al. (2004) included DES in a primary assessment of the effects of estrogenic chemicals administered during the sexual differentiation phase in Japanese quail. They summarize:
We conclude that the Japanese quail is well suited as an animal model for studying various long-term effects after embryonic exposure to estrogenic compounds. Depressed sexual behavior is proved to be the most sensitive of the variables studied in males and we find this endpoint appropriate for studying effects of endocrine modulating chemicals in the adult quail following embryonic exposure.
A separate study of sexual behavior in male quail by Viglietti-Panzica et al. (2004) led to the conclusion:
The present data demonstrate that embryonic treatment with diethylstilbestrol induces a full sex reversal of behavioral phenotype as well as a significant decrease of vasotocin expression in the preoptic-limbic region in male Japanese quail.
These findings are consistent with those of Walker and Kurth (1993), who experimented with DES in laboratory mice and concluded that abnormal sexual differentiation of the fetal hypothalamus is the most common by-product of DES exposure.
Many questions remain as to how extensively the results of wildlife and animal behavioral studies involving DES can be extrapolated to measurable effects in humans (Vandenbergh, 2003; Zala and Penn, 2004). Questions with regard to the full impact of prenatal DES exposure on the genetic aspects of sexual differentiation have also been raised in recent years (Fielden, et al., 2002; Mericskay et al., 2005). These issues validate the importance of continued study and documentation of the developmental effects of DES exposure in animals as well as humans.
Researching DES Sons: An Internet Study
In July 1999, the U.S. National Cancer Institute, National Institute of Environmental Health Sciences, Office of Research on Women’s Health and the Centers for Disease Control jointly sponsored a two-day conference, “DES Research Update 1999: Current Knowledge, Future Directions” (NC I, 1999). The event brought together leading DES research scientists, public health specialists, and DES-exposed advocacy group representatives for an evaluation of what was known and what still needed further investigation in the realm of human health effects of DES exposure. Among the notable conclusions of this conference was that DES sons had been insufficiently studied, and that more studies were needed to document the full range of adverse health consequences in DES sons.
This present study was initially conceptualized as an Internet-based outreach campaign for locating DES sons from around the world and inspired by the need for more primary research involving DES sons. During the same month as the NC I’s DES conference, the DES Sons online network was launched at http://health.groups.yahoo.com/group/des-sons. Scott Kerlin, a DES son born in 1953, founded the network after extensive review of existing DES research and following a series of discussions with DES Action USA, the largest advocacy group representing DES-exposed individuals in the United States. In 2003, the network’s name was updated to “DES Sons International Network” in order to reflect the inclusion of DES sons located in Canada, Europe, and Australia. An extensive online reference library was also developed and maintained.
The perceived advantages of utilizing the Internet for conducting this study included:
Opportunities for greater anonymity and privacy among participants
Ability to include participants in research activities in a more convenient fashion (asynchronous, ongoing communication) than in traditional face-to-face interviews or one-time surveys
Ability to enroll study participants in a “virtual support group environment” (i.e., network-associated private discussion list) that enabled the researcher to present questions pertaining to DES exposure or effects which stimulated group discussion and deeper levels of self-disclosure than in traditional interview formats (Murray, 1997)
Opportunity for participants to develop a greater comfort level with participation in the research, which can lead to increased willingness to self-disclose about health, medical, or psychological issues of great sensitivity.
The network’s goals at the outset included
locating individual males who could confirm their prenatal DES exposure (i.e., confirmation that they are “DES sons”);
documenting the range of self-report indicators of lifetime health, medical, and behavioral concerns reported directly by DES sons;
promoting interpersonal support among DES sons;
expanding investigation of the confirmed and suspected adverse effects of prenatal DES exposure in males by surveying DES sons who had never participated in the NC I’s DES cohort studies.;
attempting to document the length of prenatal drug exposure including determination of the trimester of mother’s initial use of DES during pregnancy;
and assessing the level of public awareness about DES sons.
The revelation in the early 1970s of heightened cancer risk among DES daughters led to a public advocacy movement among DES daughters and their mothers for increased research on DES and women’s reproductive health concerns along with greater accountability among the drug companies (Seaman, 2003). However, DES sons have historically remained relatively isolated from one another and their health concerns have been largely unknown to the public. Among the activities of the DES Sons International Network was to document the most common patterns by which DES sons learned of their prenatal exposure. Researchers had long recognized that among DES daughters, the most common form of notification regarding DES exposure was from mothers (Apfel and Fischer, 1984; Seaman, 2003). Less has been known about communications and relationships between DES sons and their mothers although it is believed that lower percentages of DES sons than DES daughters have been informed of their exposure (NC I, 1999).
Upon launch of the DES Sons online network in 1999, announcements about the network were made through a variety of DES print and online outreach resources from DES Action USA, DES Action Canada, and DES Action Australia. Other announcements about the sons’ network and its web site were posted in male reproductive health resource networks where outreach was thought to provide greatest likelihood of reaching individual males with evidence of prenatal exposure.
Online requests for network memberships and listserv subscriptions became the mechanism by which, over time, the sample of DES sons was developed for the subsequent research study. Each request was carefully screened for
evidence or confirmation of prenatal DES exposure;
confirmation of birth between the late-1940s and early 1970s in all requests from individuals born in the U.S.;
confirmation that the subscriber was born as a male and thus qualified to be considered a “DES Son”.
There was no cost to participants who joined the network and all participation in subsequent interviews, surveys, and online discussions involved voluntary consent of the study participants. Members were asked to preserve the “closed” nature of all online discussions (i.e., access to list discussions was only for individuals who had become network members). In order to participate in the network’s discussion list, each membership applicant was asked by the researcher to provide a summary history of principal health, medical, and psychological issues that had occurred across the lifespan.
In accordance with recommended best practices in online health and medical research methodology, all health histories and online interview data gathered in this study were preserved confidentially offline and appropriate steps were followed to assure privacy (Duffy, 2002; Eysenbach, 2002; Sheehan and Hoy, 1999; Stone, 2003).
During 2003, the U.S. Centers for Disease Control and Prevention (CDC ) held a year-long “DES Update” public education and outreach campaign for providing information to DESexposed individuals. The DES Sons International Network served as a participating partner and was the largest organization of DES sons to join the campaign. As a result, nearly 100 DES sons ultimately joined the online network in subsequent months.
Primary research on DES sons’ health issues conducted through the network included
documenting each member’s self-report indicators of critical health, medical, and psychological events or issues across the lifespan;
periodic analysis and reporting of statistical data summaries of leading health concerns reported by DES-exposed members;
conducting several online surveys (open to network members only, and archived under the “polls” section of the DES sons network web site at http://health.groups.yahoo.com/group/des-sons/polls) on issues of reported greatest concern among network members;
follow-up interviews (open-ended) with individual DES sons, either online or by telephone when permission was granted for the researcher to make subsequent contact.
Reports of research findings were posted annually to the DES Sons International Network in order to keep members aware of the range of primary health and medical concerns raised by network subscribers. A preliminary report summarizing what had been learned from research with DES sons during the first three years of the study, 1999- 2002, was published by Kerlin and Beyer in 2003 (Kerlin and Beyer, 2003).
Study Statistics and Preliminary Findings
This paper’s Appendix presents an overview of statistics from initial analysis of data gathered during the primary study of DES sons discussed in this paper. The period of the full study spanned five years, from July 1999 to July 2004. What follows is a brief summary of the results that have been determined so far, based on feedback from more than 500 study participants. Data analysis will continue until 2006, when a full report will be released.
By July 2004, a sample of approximately 500 males with confirmed (60% of total) or “strongly suspected” DES exposure (40% of total) participated in the DES Sons International Network research and provided a summary of major health, medical, and psychological issues they had encountered across the lifespan. Among the 60% of participants who indicated they had confirmed their exposure, the majority of confirmations came from the mother’s verification of having been given DES at some time during the pregnancy. The total number of study participants who have confirmed their exposure through direct access to their mothers’ medical records continues to be investigated (see Appendix, Part I).
Nations of Origin
Approximately 85% of network members were born in the U.S., while 5% each indicated they were born in Canada, Europe (chiefly UK) or Australia.
Core Health Concerns of DES Sons
Based on preliminary analysis of critical health issues reported by individual DES sons in the network, the three topics most frequently listed among the sample of 500 individuals with confirmed or suspected prenatal DES exposure are (a) gender identity concerns (at least 150 reports); (b) psychological/mental health issues, especially depression and anxiety disorders (at least 100 reports); and (c) hormonal/endocrine health issues (at least 75 reports) (see Appendix, Part II).
Additional Reported Adverse Health Effects
Though identified less frequently in overall health reports provided by study participants, several participants listed histories of infertility, reproductive tract abnormalities (including reports of ambiguous or underdeveloped genitalia), epididymal cysts, cryptorchidism, hypospadias, gynecomastia, and erectile dysfunction. Statistics on the full extent of reporting of these concerns are still undergoing analysis.
Prevalence of Male-to-Female Transsexual, Transgender, and Intersex Individuals
More than 150 network members with “confirmed” or “strongly suspected” prenatal DES exposure identified as either “transsexual, pre- or postoperative,” (90 members), “transgender” (48 members), “gender dysphoric” (17 members), or “intersex” (3 members). These statistics are taken from selfreport terms provided by individual participants in their health histories (see Appendix, Part III).
Low Cancer Prevalence
Only 7 individuals with confirmed or “strongly suspected” prenatal DES exposure have reported experiencing some form of cancer. Most were testicular cancer survivors.
Among 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 male-to-female transsexual or transgender, and indiv iduals who have reported experiencing difficulties with gender dysphoria.
In this study, more than 150 individuals with confirmed or suspected prenatal DES exposure reported moderate to severe feelings of gender dysphoria across the lifespan. For most, these feelings had apparently been present since early childhood. The prevalence of a significant number of self-identified maleto-female transsexuals and transgendered individuals as well as some individuals who identify as intersex, androgynous, gay or bisexual males has inspired fresh investigation of historic theories about a possible biological/endocrine basis for psychosexual development in humans, including sexual orientation, core gender identity, and sexual identity (Benjamin, 1973; Cohen-Kettenis and Gooren, 1999; Diamond, 1965, 1996; Michel et al, 2001; Swaab, 2004).
Mental health and psychiatric issues (including depression and anxiety disorders) are relatively significant among the population of DES sons participating in this research.
This study’s findings provide fresh evidence of psychiatric disturbances among individuals exposed to DES. It is hopeful that future research on human health effects of exposure to endocrine disrupting chemicals (i.e., assessing neurotoxicity) can include psychiatric disturbances such as major depression, anxiety disorders, eating disorders, and psychoses as potential endpoints for analysis of the long-term effects from prenatal exposure. 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.
Endocrine system disorders such as hypogonadotropic hypogonadism in DES sons have been among the more 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 epidemiological research on DES-exposed populations, both the Endocrine Society and the American Association of Clinical Endocrinologists (2002) have recognized prenatal DES exposure as a risk factor for endocrine disorders including hypogonadism. This study confirms that this issue needs further attention in future studies of DES sons.
Relative infrequency of reported cancer among the DES sons in this research is consistent with most existing long-term studies demonstrating limited cancer prevalence in males with prenatal DES exposure.
While the rate of total cancer occurrence among members of the DES Sons International Network is uncertain, numerous efforts have been made to generate discussion about cancer risks and in particular, to encourage dialogue regarding testicular cancer experiences. Approximately seven 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. (2001).
Based on the findings in this study, research into the human health effects of exposure to endocrine disrupting chemicals needs to focus on additional behavioral toxic endpoints besides those historically investigated.
Although the scope of documented human health effects from prenatal exposure to various endocrine-disrupting chemicals continues to expand, the study of human behavioral effects is still in relative infancy (Ferguson, 2002; Swaab, 2004). This study’s findings may offer new insights for the emerging field of neurobehavioral teratology relative to understanding disturbances of gender identity and sexual identity development.
Undoubtedly the results of this study–particularly the findings with regard to the prevalence of gender-related concerns among a significant number of individuals with confirmed and/or suspected prenatal DES exposure–will come as a surprise for some. It is worth noting that investigations regarding the possible effects of prenatal DES exposure on sexual differentiation (brain and body), and sexual orientation have been undergoing discussion for quite some time (Baron-C ohen, 2004; Hines, 1998; Hines 1999; Meyer-Bahlburg et al., 1995; Toppari and Skakkebæk, 1998), though more emphasis in the published research has tended to be placed on possible effects in DES daughters than in DES sons.
While prior to this current study there have been no primary research studies of DES sons which have documented the prevalence of transsexualism or other gender identity disorders, there are publications in which prenatal DES exposure is listed among the potential factors associated with transsexualism or sexual differentiation disorders. For example, Michel, Mormont, and Legros (2001) in their psycho-endocrinological overview of transsexualism observe the following:
Gender identity disorders may be the consequence of an atypical hormonal environment such as congenital adrenal hyperplasia, resistance to androgens or even exogenous hormonal impregnation (the absorption of diethylstilboestrol treatment during pregnancy). In the majority of cases, these subjects do not develop towards transsexualism (2001, p. 366).
In the 6th edition of the widely-consulted Dictionary of Organic Compounds (1996) the DES entry appears on pages 2175-2176 and includes within its array of documented adverse effects, “causes male impotence and transsexual changes particularly in offspring exposed in utero.” In the text, Human Embryology & Teratology, Second Edition (1996), O’Rahilly and Muller list DES among their directory of hormonal teratogens, stating, “Exposure of a female conceptus to DES, which can act as an estrogen, can lead to bisexuality. In a male conceptus, the secretion of testosterone can be suppressed, resulting in hypomasculinization.” (O’Rahilly and Muller, 1996, p. 111).
The term “gender-bending chemicals” has become relatively popular with the news media in their latest reports on the toxic effects of endocrine disrupting chemicals such as phthalates on male reproductive development (Sample, 2005; Swan et al., 2005). Scarcely more than a decade ago, the concept was almost unheard of. Its introduction into early news stories describing documented and suspected but unconfirmed effects of endocrine disrupting chemicals (EDC s) no doubt provoked both amusement and angst in the public imagination (see “Gender-Bending Pollution”, 1995). By the time the World Health Organization’s International Programme on Chemical Safety had released its “Global Assessment of the State-of-the-Science of Endocrine Disruptors” (IPCS, 2002), the story of DES had become part of the story of an entire group of environmentally-present toxic chemicals thought capable of creating a variety of reproductive abnormalities in humans as well as animal populations (“Alarm at Gender-Bending Chemicals”, 2002). In that same year, Dutch researchers studying male and female children’s play behavior documented apparent “feminizing” effects in boys resulting from perinatal exposure to PCBs and dioxins (Vreugdenhil, et al., 2002). Undoubtedly, the issue of endocrine disruption and potential impact on gender identity and sexual development is an issue that merits wider investigation in the future (Johnson, 2004).
Historically, in the case of news stories about DES and its cancer-causing effects in DES daughters, many revelations first occurred in the 1970s (Berkson, 2000; Krimsky, 2000), but publicity regarding DES sons remained largely absent. And yet, there was no lack of recognition in the published medical literature that historically, at least some males prenatally exposed to DES were born with “structural and functional disorders of the reproductive tract” (Cosgrove, et al., 1977) or suffered psychiatric effects (Pillard et al, 1993).
If the results of this current study have pointed out anything significant, it is that we cannot relegate DES to the dustbin of “cancer-causing drugs no longer being used and therefore unworthy of continued investigation.” And we cannot afford to limit the scope of our vigilance and public health information regarding long term effects of DES to cancer outcomes (Schrager and Potter, 2004).
A recent Cochrane Library Review of proposed medical protocols for evaluating future research identifying the relative risks and benefits (if any) of treating preterm infants with estrogens and progestins in order to prevent morbidity and mortality (Hunt et al., 2005) has recognized the history of adverse effects of prenatal DES exposure in sons and daughters. In discussing the history of adverse events associated with previous medical uses of estrogenic drugs for treatment of pregnancies, the authors observe:
Administration of sex steroids is not without risk. In the 1960’s, women with high risk pregnancies were treated with diethylstilbestrol (DES). Epidemiological studies have since demonstrated strong associations between such therapy and abnormalities in the offspring of these pregnancies.
Perhaps most important relative to the findings presented in this current study of DES sons is the recommendation by Hunt et al. (2005) that future studies of preterm infants treated with estrogens and progestins need to carefully observe “evidence of any adverse events from hormone administration”. Hunt et al. recognize two indicators of adverse events in this area:
feminisation of males
long term psychological morbidity, defined as any psychological disorder that meets diagnostic criteria of DSM-IVR.
DES Sons International Network 5-Year Summary Statistics
I. Statistics on DES Sons Participating in the DES Sons International Network Between 1999 and 2004
In the five years since formation of the DES Sons network in July 1999, approximately 600 individuals requested information or support through e-mail followup requests and/or requests to join the network. This is over and above all information that is freely available for visitors to the Network’s web site (http://health.groups.yahoo.com/group/des-sons) which provides substantial information and resources on DES without subscription. Because the DES Sons International network does not maintain statistics on total Internet traffic to its web site, there is no accurate method to gauge how many other affected individuals may be utilizing this information.
Of the 600 individuals who have sought further DES information, approximately 500 indicated at the time of my initial screening that they had either actual confirmation (from mother, or direct access to medical records) or strong suspicions (based on unconfirmed information from other family members) that they had been exposed to DES in utero. These 500 individuals with confirmed or suspected prenatal DES exposure were members of the network sometime between 1999 and 2004.
II. DES Sons Reported Health and Medical Concerns: Frequency of Reporting
Based on health history summaries received by the DES sons network between 1999 and 2004 from individuals with confirmed and suspected DES exposure, the three areas of greatest health concern among DES sons in the network appear to be (a) gender identity disturbances; (b) psychological/mental health issues including anxiety and depression; and (c) hormonal/endocrine health issues, especially hypogonadism. More than 150 members (all individuals who were born male) described histories of significant feelings of gender discomfort, and more than 90 identified as male-tofemale transsexuals. More than 100 members described lifetime experiences with depression and/or anxiety disorders.
Somewhat lower proportions of members indicated concerns regarding autoimmune disorders, infertility, reproductive tract abnormalities, ambiguous or underdeveloped genitalia, epididymal cysts, testicular cancer, and erectile dysfunction. Because not every individual member has necessarily disclosed the full range of health issues or medical concerns by which he or she has been affected, the relative significance of reported health concerns among DES sons in this research study is an approximation, based on preliminary textual analysis of information which has freely volunteered by network members.
Cancer reports among DES sons were relatively rare (7 reported cases of testicular cancer).
III. Statistics of Prevalence of Transsexualism, Transgenderism, Gender Dysphoria, or Intersex Among “Confirmed” and “Suspected” DES Exposed Individuals (N=158)
Among the population of DES sons joining the network who have discussed a history of gender identity concerns, personal stories and/or introductions have been received from more than 150 individuals with either confirmed or “strongly suspected” DES exposure.
Responses were received from at least 93 individuals with confirmed prenatal DES exposure who self-identify as either transsexual (male-to-female), transgendered (male-to-female), “gender dysphoric,” or intersex. The distribution of these 93 individuals is as follows:
There have been at least 65 individuals with “strongly suspected but not yet confirmed” exposure who indicated they are either either transsexual (male-to-female), transgendered (male-to-female), “gender dysphoric,” or intersex. The distribution of these 65 individuals is as follows:
I wish to thank Milton Diamond, Ph.D., University of Hawaii, John McLachlan, Ph.D., Center for Bioenvironmental Research at Tulane/Xavier Universities, Dana Beyer, M.D., (DES Sons International Network), Kathy Cochrane, and Christine Johnson for their helpful comments, suggestions and generous support.
Scott P. Kerlin, Ph.D. DES Sons International Network , Vancouver, B.C ., Canada, August 2005.
What Do Animal Research Findings Reveal About Future DES Health Effects?
This excerpt is from a teleconference with Dr. John McLachlan, a long time researcher on the effects of DES exposure, and Scott P. Kerlin, Ph.D., DES Sons International Network,
CDC’s DES Update – TELECONFERENCE TRANSCRIPT
Abstract (pages 17 to 20)
” Dr. McLachlan, it’s Scott Kerlin from the DES Sons Network. Good to make a connection with you here. I appreciate your presentation on many different levels, but I’ll try to be fairly specific on my own topic question. Our network in the past year did a poll to try to find out what were the leading concerns of DES sons and, as you’ve pointed out and other’s have, there’s a lot less research that has documented the effects on DES sons than on daughters.
We learned quite a bit though from network members that: endocrine system problems, gender identity problems, and mental health problems seem to be among the top three areas, closely followed by cancer. I wonder if you could just briefly comment from your own long-term research about two somewhat questionable or controversial topics; one being feminization in males, and the other being various endocrine disorders in males, particularly hypogonadism, and whether you’ve seen linkages in your research over the years in animal research that might point to a significant predominance of hypogonadatropic hypogonadism, I guess is what it would be called.
Dr. McLachlan : Right. Hypogonadatropic hypogonadism, is a low level of pituitary hormone telling the testicle, the gonad, to make testosterone and sperm. It is something that has been seen occupationally in men who have acute exposure to DES. So if an adult male takes estrogen or is exposed to estrogen, the obvious results will be gynecomastia (enlarged breasts),, and hypogonadotropic hypogonadism, (small testicles, low libido).
I haven’t seen the same kind of thing reported from prenatal exposure to DES. Mice that get treated with DES prenatally have a smaller than normal testicular size and a lower than normal sperm count that’s dose related. Testosterone levels in these mice are pretty much normal, although estrogen levels are higher than normal. I don’t know of any comparable studies that have been done in humans, but you might know.
Scott Kerlin : I’ve been looking hard.
Dr. McLachlan : The other issue you mentioned was feminization. All mammals – mice, rats, and humans – as fetuses start out as bisexed beings. We have a gonad that’s going to be either a testis or an ovary, depending on the genetics. Once that happens that little organ secretes some things that do one of two things.
In the case of a genetic male, the testis will start making testosterone, which keeps the male reproductive system intact during fetal life. They also make another protein called Mullerian inhibiting substance, which is specifically set to wipe out the female reproductive system that the fetus has at this time.
If there is no genetically determined male gonad that makes androgen to keep the male tract alive, and then makes this other inhibitor to kill the female tract, invariably you end up with a female. There are genetic disorders or genetic syndromes where those things can change resulting in a genetic male that may have a complete functioning cervix or uterus. This could happen, it seems in mice or humans exposed to DES, though it hasn’t been shown clearly in many human cases. In a mouse whose mother is given DES, you feminize the reproductive system such that a genetically born male, has testis, is usually not making as many sperm as normal, has slightly lower androgen levels, and has higher estrogen levels. That male mouse will have a prostate seminal vesicle, all the other plumbing to get the sperm from the gonad out, but it will also literally have a functioning set of fallopian tubes, uterus, cervix, and an upper portion of the vagina.
The penis of this mouse is also feminized to the extent that there is a higher prevalence of a condition called hypospadias, which is a congenital defect wherein the penis doesn’t totally close in the right way. There is an opening that might be along the shaft of the penis or is often at the end of the penis where there’s almost another kind of — I hate to use the term because it’s not scientific — quasi-vaginal like orifice. It means that estrogen has prevented the total masculinization of what could just as easily end up being the clitoral structure and vaginal structure.
Scott Kerlin : Right.
Dr. McLachlan : We also know that femininization can even happen inside a cell, and from a molecular level there’s a kind of feminization that we and others have shown in mice.
Coming back to one of the earlier questions about hormonal changes in the brain and how this might relate to gender identity. That’s been a really tough one for a lot of people. In the mouse and rat you can certainly do prenatal or neonatal treatment with estrogens or androgens to feminize or masculinize behavior. But in humans it’s very controversial and unknown as to whether this can happen at all. It seems as if the network is hardwired in a different way. Having said that, I’m not sure if anybody is really dealing directly with this.
Scott Kerlin : I will let go at this point so everyone else can ask their questions, but one of the documents that we have actually posted to our Sons Network home page is from the National Toxicology Program fact sheet on DES. I was intrigued when I read the list of symptoms from physical exposure taken by adults. It says right in the text, not only can it cause male impotence, but it can cause transsexual changes, and it indicates it can cause gynecomastia.
Dr. McLachlan : This is in adults though, right?
Scott Kerlin : I think so as best as I can tell. My understanding was that if one time DES was used for male to female transsexuals who were transitioning.
Dr. McLachlan : It is actually
Scott Kerlin : Is it? Okay.
Dr. McLachlan : Yes.
Scott Kerlin : But the prenatal exposure and transsexual effects, that has never been clear to me exactly how that works.
Dr. McLachlan : Yes. We are talking about, in both humans and mice, a feminization of structures. An example in terms of the genital tract is that with undescended testicles the male gonads stay right where they were when they were both male and female. But again, even though animal studies suggest that you can feminize male rats or mice with developmental exposure to estrogens or androgens, this is not clearly the same case, and I think is pretty much considered impossible, with humans. I don’t think that has really been tested in all of the kinds of subtlety that would be required when one considers the complexity of an issue like gender identity.
Scott Kerlin : Yes, that would concur. Thank you so much. “
Thesis for the Master of Environmental Studies Degree, Christine Johnson, 2004
Johnson is interviewed in Deborah Rudacille’s book The Riddle of Gender. She was born a DES son but transitioned to female (m to f) in her 20s. Scott Kerlin served on her Master’s degree thesis committee at Evergreen State University in Washington and this thesis contained extensive evidence of prenatal exposure to DES, DDT, PCBs, and other endocrine disrupting substances on gender identity and gender development.
In recent years, evidence has accumulated demonstrating that endocrine disrupting chemicals (EDCs) have the potential to alter sexual development at the organizational and functional level in many species, including humans, indicating that this class of chemicals may play a role in the etiology of transsexualism. Although transsexualism has historically been attributed to social or psychological causes, little data exists to support these claims, thus requiring a closer examination of the evidence regarding changes in sexual development due to EDCs. Toward that end, this thesis considers data from studies examining hormonal signaling mechanisms and changes in sexual development observed in wildlife, laboratory animals, and humans exposed to EDCs, all providing a consistent picture that sex hormones and their receptors are highly conserved evolutionarily, finding similar effects of disruption in many species.
Transsexualism: An Unacknowledged Endpoint of Developmental Endocrine Disruption? by Christine Johnson, A Thesis: Essay of Distinction Submitted in partial fulfillment of the requirements for the degree, Master of Environmental Studies, The Evergreen State College, antijen.org, June 22 2004.
In order to place the data in context, a number of historical threads are examined, including: the use of chemicals in agriculture, the use of the pesticide DDT and the pharmaceutical drug diethylstilbestrol (DES), the intertwined relationship between chemical manufacturers and the military, and the history of transsexualism since 1950. The operation and function of the endocrine system is reviewed in order to provide the background to properly interpret findings from endocrine disruptor studies, focusing particularly on the hypothalamic-pituitary-gonadal (HPG) axis. Recent physiological data regarding the vomeronasal organ (VNO) is reviewed, demonstrating that the VNO is the organ responsible for detecting pheromones, or sexually-relevant chemically-based cues, and that exposure of the VNO to extremely low levels of putative sex hormones causes numerous autonomic system responses, including alterations in endocrine function in males. It is therefore suggested that the VNO plays a central role in the circuitry involving sexual development, and a hypothetical framework for testing this concept is provided.
Using this framework, a mechanism for the development of gender identity is proposed, suggesting that gender identity is determined via pheromones by comparing the self with others at an unconscious level. One consequence of this mechanism is that messages conveyed by pheromones can be regarded as signals that can be in contradiction from messages from society, leading to a paradoxical double bind, or a logical contradiction between messages that exist on different logical levels. Another consequence is that there may exist a class of chemicals, pheromone disruptors, that could interfere with pheromones in a manner analogous to endocrine disruptors. Further research must be performed to test this hypothesis since little data exists on pheromones in humans, but early data suggests chemicals may be found that interfere with normal pheromone function.
The prevalence of transsexualism is examined, finding that prevalence differences reported in various countries are not well explained by social factors. Also, it is observed that existing studies have reported the prevalence of transsexuals seeking treatment over a specific time period, but this reporting method is not a measure of the number of transsexuals for each country, which is what the term implies to most people. Several recent epidemiological studies that address sexual changes from endocrine disruption are critiqued, finding that they are plagued with methodological weaknesses and contain a number of errors in interpretation. It is argued that instead of using epidemiological techniques, a more useful approach would be to perform demographic studies that map the birthplace of transsexuals in space and time to determine any patterns that may be related to environmental conditions. The lack of detailed data on transsexual demographics, especially in the United States where such data are completely lacking, has left a void where a lack of data has been interpreted incorrectly as a lack of effect.
The fundamental assumptions used in risk analysis and toxicology are reviewed in the context of recent findings that the effects of a chemical may be larger at low doses than at high doses and that thresholds for the endocrine system must be determined empirically, rather than by assumption of a dose-response curve and extrapolation from an observed toxicological endpoint. The use of invalid techniques by toxicologists has thus invalidated claims of chemical safety, and indicates that public policy based on these techniques are insufficiently protective of public health. Because few things are more important to the continuity of cultures than sexuality and social relations, a number of areas requiring further research are identified, and the need for education of the public is emphasized. I conclude that the existing evidence points towards chemical causes of transsexuality rather than social or psychological causes, requiring a shift in research priorities away from psychosocial studies towards physiological studies of transsexuals.
Hormones, Sexual Development, and Transsexualism
… “this observation raises questions about the validity of existing methods of assessment for studying questions of gender identity development in general. This problem is particularly relevant for offspring of mothers prescribed DES during their pregnancy, since no studies have been performed that specifically asked about changes in gender identity due to these known prenatal exposures to an estrogenic substance.”…
… “The first study was a cohort study of men and women exposed in utero to DES; the study collected demographic data including: age, education, and ethnicity, and psychosexual characteristics including: handedness, sex partner choice, marital status, age at first intercourse, and number of partners.
Interestingly, one finding that reached statistical significance was that DES sons had a higher frequency of left-handedness, which the authors associated with complications during pregnancy; other authors have found that transsexuals also have a higher frequency of left-handedness, suggesting that questions explicitly asking about gender identity status would be appropriate to add to all future studies examining these relations.
However, there are several problems with the study. The format of the study was a survey questionnaire mailed to exposed and unexposed groups, but ultimately, 49% of men and 50% of women from the cohort could not be located, were dead, or chose not to participate in the survey. Consequently, sampling may be biased to an unknown degree because there is no method of determining if those responding are representative of the whole group. Other problems are that all children exposed to DES in utero are assumed to be similarly affected, but because the endocrine disruption thesis suggests that dose and timing is important with regard to outcomes, it is necessary to distinguish when and in what amounts the DES was present in the fetus during critical stages of sexual development. Because the study lacks empirical data regarding prenatal DES exposure, this dramatically weakens the ability of the study to detect differences. Because sexual development proceeds in a number of stages, the timing of the dose is critically important to detecting differences statistically. By considering all those exposed to DES as a homogenous group, effects deriving from exposures during critical periods are obscured, because those exposed outside of these critical windows do not show effects, and therefore they dilute the statistical power of the study. This could be repaired by stratifying the groups by ‘period of exposure’.
Another serious problem with the study is that there is no person in the United States that can be considered a control. As mentioned in the history section, DES was widely used for cattle, thus to a greater or lesser degree, everyone in the U.S. was exposed. Additionally, many other endocrine disrupting chemicals exist, limiting the utility of using a single marker of exposure as an independent variable for changes in sexuality. When these factors are taken into account: high non-response rate, treating all DES exposed persons as a group, and the lack of a proper control, the lack of significance should not be taken as evidence of the lack of an effect.
In a recent teleconference addressing issues of concern to DES sons, Dr. Titus Ernstoff was asked if there were any plans to study gender identity outcomes associated with DES exposure; she replied saying that their study did not have sufficient statistical power to study “rare” outcomes such as transsexuality. However, the DES Sons’ International Network, an internet based research, education, and advocacy group, has found that transsexualism is a common outcome of fetal exposure to DES among sons, indicating that studies on DES exposed persons should be examining endpoints related to altered sexual development. Of their total membership of 600 genetic males, among those who could verify their DES exposure, 52 (8.7%) consider themselves to be transsexual, 26 (4.3%) are transgendered, 9 (1.5%) are gender dysphoric, and 3 (0.5%) are intersex. When all these conditions are considered together, the total rate is 15%, indicating that for DES sons, the frequency of gender identity issues cannot be considered rare. When those who strongly suspect, but who are unable to confirm DES exposure are included, the total number of people who self-identify using one the above categories is 153, or 25% of the network membership.
If the rate of transsexuality in the U.S. is assumed to be 1 in 100,000, and if the number of DES exposed mothers ranges from 3-5 million, the number of transsexuals expected in the entire DES sons population would be 15-25, assuming that DES did not increase the probability of developing transsexualism compared to the general public. Since the DES Sons’ International Network already has double that number of transsexuals alone, this is evidence that among DES sons, the condition is not as rare as Titus-Ernstoff claims, and therefore failure to study the problem may have reasons other than a lack of statistical power – i.e. the decision not to examine the issue may be politically motivated.
Even if a much higher rate of transsexualism in the U.S. is assumed, the numbers do not change very much. For example, if the prevalence of transsexualism in the U.S. is assumed to be the same as in the Netherlands, there should be between 126 and 210 transsexuals in the U.S. due to DES exposure. Because the DES Sons International Network already has 52 transsexuals in their network, this would mean that they have found between 25 and 41% of all transsexuals whose transsexuality can be attributed to DES. Given the membership totals only 600, this seems extremely unlikely, and instead suggests that DES is capable of causing transsexualism, thus explaining the dramatic increase in the frequency of transsexualism in the DES sons group compared to the general public.” …
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
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.
DES Sons International Network Statistics of Individuals with Gender-related Issues or Outcomes Among Network Members
Scott Kerlin, 5-Year Research Summary Update, October 2004
Among the population of DES sons in our network who have raised gender-related questions and experiences, I have received personal stories and/or introductions from more than 150 individuals with either confirmed or “strongly suspected” DES exposure. Among 158 “likely DES-exposed” persons (confirmed or suspected), their summary descriptions of identity and/or experiences reflected the following.
There have been at least 93 individuals with confirmed prenatal DES exposure who indicated they are either transsexual, transgendered, gender dysphoric, or intersex. (These terms come from individuals’ self-description of their identities or primary health concerns.) Here is the distribution of those 93 individuals:
Confirmed DES-Exposed and Gender-Related Issues (N=93)
Confirmed Exposed and Transsexual: 54 individuals
Confirmed Exposed and Transgender: 26 individuals
Confirmed Exposed and Gender Dysphoric: 10 individuals
Confirmed Exposed and Intersex: 3 individuals
There have been at least 65 individuals with “strongly suspected but not yet confirmed” exposure who indicated they are either transsexual, transgendered, gender dysphoric, or intersex. Here is the distribution of those figures:
Strongly suspected, not confirmed DES Exposed and Gender-Related Issues (N=65)
Suspected Exposure and Transsexual: 36 individuals
Suspected Exposure and Transgender: 22 individuals
Suspected Exposure and Gender Dysphoric: 7 individuals
DES Sons International Network Statistics of Individuals with Gender-related Issues or Outcomes Among Network Members
Scott Kerlin, 5-Year Research Summary Update, October 2004
Within a few months of the formation of the Network in 1999, several members raised issues regarding gender dysphoria as among their (apparent) side effects. Over time this issue became more common in private disclosures to me by members, as well as online group discussions. Over time, gender identity issues and transsexualism emerged in discussions among regular DES Sons International Network members. Ultimately because of the sensitivity of many gender-related discussions, some members wished to have a more private discussion environment separate from the main DES Sons International Network. In January 2002 I formed the DES-Trans Gender Support Group (DES-Trans) for more extensive discussions of these issues.
Somewhere between one-quarter and one-third of members of the DES Sons International Network since 1999 have indicated (through my private surveys and/or interviews of members, membership poll responses, or through personal introductions and subsequent discussion postings to the Network) that gender identity and/or sexuality issues were among the most significant issues they needed to understand or seek further support.
The majority of individuals who joined the Network (i.e. somewhere between 2/3 and 3/4 of the total, or about 350 persons) did not mention gender issues or concerns during their personal introductions, health histories, or subsequent Network discussions. I have no way of knowing how many of these individuals may also have gender-related issues, unless at a subsequent time they have chosen to raise them (as some have in private correspondence with me). I suspect there are others for whom it is an underlying concern but not an easy for them to articulate without fear of ridicule or dismissal from others.
DES Sons International Network 5-Year Summary Statistics: First Findings on DES Sons Participating in the DES Sons International Network Between 1999 and 2004
Scott Kerlin, 5-Year Research Summary Update, October 2004
In the five years since formation of the DES Sons Network in July 1999, approximately 600 individuals have requested more information or support through e-mail follow-up requests and/or requests to join the Network. This is over and above all information that is freely available for visitors to the Network’s website which provides substantial information and resources on DES without subscription. Because the DES Sons International Network does not maintain statistics on total Internet traffic to its website, there is no accurate method to gauge how many other affected individuals may be utilizing this information.
Of those 600 individuals who have sought further DES information, approximately 500 are 46XY males who indicated at the time of my initial Network subscription screening that they had either strong suspicions (based on evidence from family members) or actual confirmation (from mother, or direct access to medical records) that they had been exposed to DES in utero. These 500 individuals with confirmed or likely prenatal DES exposure have been members of the network sometime between 1999 and 2004. For this reason I consider our study’s base sample size to have attained a total of 500 DES sons as of spring 2004.
The vast majority of individuals whom I have allowed to join the Network had either “confirmed” (i.e. directly through medical records access or indirectly through personal conversation with mother) or “strongly suspected” (i.e. all evidence points in that direction, but medical records access and/or contact with mother not possible) prenatal DES exposure. However, a few (less than 50 altogether since the Network was formed) who had no way of confirming their exposure also were permitted to join in order to assist them with unanswered questions.
Based on responses between 1999 and 2004 to Network surveys, responses from individual online or telephone interviews, and follow-up discussions with DES sons members, the three areas of greatest health concern among DES sons in the DES sons’ network appear to be
Somewhat lower proportions of members indicated concerns regarding autoimmune disorders, infertility, reproductive tract abnormalities, ambiguous or underdeveloped genitalia, epididymal cysts, testicular cancer, and erectile dysfunction. Because not every individual member has necessarily disclosed the full range of health issues or medical concerns by which he or she has been affected, the relative significance of reported health concerns among DES sons in this research study is an approximation, based on rigorous qualitative analysis of information which has freely volunteered by network members.
Despite exhaustive efforts to clarify the history of health issues experienced by DES sons, it appears that only a small number of DES sons contacting our Network have suffered from any type of cancer-related health problems (primarily testicular cancer during younger years). The Network continues to raise awareness among members regarding potential cancer risks. These efforts include participation in the annual prostate cancer awareness month activities of the National Cancer Institute and membership subscription to monthly online alerts from the International Society for Men’s Health and Gender (ISMH). Despite my numerous inquiries, no case of prostate cancer has been disclosed by network members as of July 2004.
Background: The following question was posted as a “poll” for network members on December 22, 2001 and respondents were allowed until January 13, 2002 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:
* TOTAL: 63 Individual Responses from 102 network subscribers. Response rate approximately 65-70% based on an estimated 90-95 active list participants receiving the survey in January 2002; estimated 10 additional members received survey but were not accessing their computers during the survey period of December 22, 2001 and January 13, 2002.