My Academic Research Into Prenatal Hormonal Influences on Gender and Sexual Development in Men and Women, 1995 to 2021 (DES Research)
(Paper prepared for presentation to the December 2020 Conference Beyond Genes)
Scott P. Kerlin, PhD., M.S.
Overview: I have more than 25 years of interdisciplinary research into the effects of prenatal exposure to estrogenic and androgenic hormones on human behavioral development (including sexuality and gender identity), a field with extensive research investigation in the 1970s by Dr. June Reinisch, former director of the Kinsey Institute (see, for example, her 1984 journal article in Progress in Brain Research) and Dr. Dick Swaab of the Netherlands Institute for Neuroscience (see his co-authored 2010 article on Sexual Hormones and the Brain, published in the journal Pediatric Neuroendocrinology). My continued research was inspired by the lifetime work of Dr. Milton Diamond at the University of Hawaii. Dr. Diamond was a major advocate for my ongoing research.
Background of Existing Research on Prenatal Hormones and Psychosexual Development in Males and Females
Historically, there has been a significant body of literature on prenatal androgens and association with variations in gender and sexual development. Much of the existing published research on hormonal influences over gender identity development and the human brain focus only on impact of prenatal androgens and female development (for examples, see Berenbaum & Beltz, 2017, How Early Hormones Shape Gender Development, Hines, 2011, Annual Reviews on Gender Development and the Human Brain, and Hines, 2010, Sex-Related Variation in Human Behavior and the Brain from the journal Trends in Cognitive Sciences.)
There is far less long-term research on prenatal exposure to estrogens in males and psychosexual development (cite Yalom, Green and Fisk, 1973, Journal of the American Medical Association and Meyer-Bahlburg, 1978, published in the journal Pediatrics). This is an area that I have researched in depth from the 1990s onward.
The Diethylstilbestrol (DES) Story
DES, the abbreviation for “Diethylstilbestrol“, is a non-steroidal estrogenic drug and sex hormone that was given to millions of women in the U.S. and other countries during the 1940s to 1970s (and beyond) for management of pregnancy. An estimated 3 to 6 million “DES daughters” and “DES Sons” were born in the U.S. and many more in Canada, Europe, and Australia. DES is classified as an endocrine disruptor because of its detrimental effects on the development of the endocrine system.
A substantial array of adverse effects of DES has been documented in mothers and their offspring. The scope of reported effects has included cancer, physiological effects in daughters and sons, hormonal disorders, and psychiatric consequences. Additionally, several studies investigating the psychosexual effects of DES exposure in male and in females have been developed since 1959.
An extensive body of medical literature has been published about DES as early as 1939. The largest array of publications has been released since the early 1970s, when prenatal DES exposure in females was linked to a rare form of vaginal cancer. Here is an excellent, if somewhat dated research article from 2013:
- Exposure to Diethylstilbestrol During Sensitive Life Stages: A Legacy of Heritable Health Effects (November, 2013 full text), by Casey E. Reed and Suzanne E. Fenton, published in the journal Birth Defects Res C Embryo Today
DES has been extensively documented by the National Library of Medicine. For substantial reference on the biochemical makeup of DES and subsequent documentation of effects, see the National Library of Medicine’s Dictionary of Organic Compounds: DES directory. The summary entry for DES is the following:
Diethylstilbestrol is a synthetic, nonsteroidal form of estrogen. A well-known teratogen and carcinogen, diethylstilbestrol inhibits the hypothalamic-pituitary-gonadal axis, thereby blocking the testicular synthesis of testosterone, lowering plasma testosterone, and inducing a chemical castration.
[For a full summary of publications focusing on DES, see the APPENDIX A at the end of this paper.]
History of My Research Investigation Into Human Health Effects of Prenatal DES Exposure, 1995 to 2020
[December 2020 Update: I have summarized my key findings and observations of the DES story in a video presentation that I provided to the online academic conference Beyond Genes on December 4th, as part of a conference session on the “Heritable Impacts of Endocrine-Disrupting Compounds“. My presentation is available on youtube.]
As a verified DES Son, I have held long-standing interest in the array of adverse effects of prenatal DES exposure in males as well as in females, which I began to investigate in 1995.
When I first began to ask questions about the full scope of human effects, I learned that historically, DES-exposed females (i.e. “DES Daughters”) had a primary emphasis on the scope of research, particularly in the realm of cancer research. I became involved with the Montreal, Canada-based advocacy group DES Action Canada in 1997 as research specialist focusing on DES sons.
When I first organized the DES Sons’ International Research Network online in 1999, my aim was to document the full range of reportable adverse effects in males, including testicular cancer, infertility, hormonal disorders such as hypogonadism, and behavioral developmental effects. It is important to note that compared with DES Daughters, there were relatively few published studies that investigated the full range of adverse health effects in males.
Highlights and Timeline of My Initial Research Investigation
- In 1995, I began to investigate the historical published research on the adverse effects of prenatal exposure to diethylstilbestrol. I learned that in 1992, the U.S. National Toxicology Program’s Pub Chem database documented DES as having a variety of “health hazards.” These included causing “male impotence and transsexual changes”, along with “congenital malformation in the fetus.”
- In the mid 1990s I became an early adopter of using the Internet to conduct and develop investigative qualitative research. I have devoted many years to studying and developing the process of collecting qualitative data collection in online social communities. One article of more recent focus in this area is the article “Recommendations for Internet-Based Qualitative Health Research With Hard-to-Reach Populations”, by Michael Wilkerson, et al (2014), published in the journal Qualitative Health Research.
- Between 1999 and 2004, I documented the health history of more than 500 DES sons who participated in discussions in the DES Sons International Research Network. I conducted extensive interviews with network members during these years in order to verify likelihood or confirmation of prenatal DES exposure and subsequent developmental history (physical, physiological, and psychological).
- A core aspect of my utilization of Internet discussion network format was through developing focused discussions and emerging themes that evolved using rigorous qualitative research methods. The DES Sons network was designed to create a virtual “safe space” of an epidemiological nature, for disclosure of issues that had never before been explored in depth. Through the trust that I created as a leader of group discussions, insights were developed by participating members that led identification of a constellation of physiological and psychological effects traceable to the prenatal DES exposure.
A summary of my key findings from the 1999-2006 focus is available at Basic Statistics and Findings on DES Sons. The most frequently cited concerns among the study participants were (1) hormonal/endocrine health issues, especially hypogonadism; (2) gender identity and sexual health issues and (3) psychological/mental health issues including anxiety and depression.
Study Statistics and Preliminary Findings
This paper’s APPENDIX B 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 but was extended to 2006 in order to gather additional interview data. What follows is a brief summary of the results based on feedback from more than 500 initial study participants.
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 B, 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 B, 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 B, 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.
Initial Research Advancements/Conclusions – 1999-2006
- 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 individuals who have reported experiencing difficulties with gender dysphoria.
In my initial study begun in 1999, 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 male-to-female transsexuals and transgender 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.
Comment on the Emergence of Gender-Related Concerns Among DES Network Members
- Within the first few months of my formation of the DES Sons’ network, more than 250 individuals expressed interest in joining the private discussion network. Before admitting members, I interviewed and surveyed each applicant to determine (1) likelihood of confirmed prenatal DES exposure; (2) health history and evidence of any documented physiological or mental health difficulties.
- Between the years of 1999 and 2003, I conducted a series of surveys of members in order to determine which issues were most prevalent in areas of concern. My own investigation revealed patterns and outcomes in many DES sons that paralleled what was documented in published research. Documentation of my full research and data collection process was retained within the DES Sons’ research network archives that I maintained from 1999 to 2020.
- What I learned very soon after launching the original DES Sons’ network email discussion list on Yahoo (DES-Sons) in 1999, was that a significant number of new members who introduced themselves to the group and/or to me in private communications described a history of gender dysphoria and other gender and sexuality related issues.
- During conversations among network participants, several members reported a variety of issues and concerns related to gender identity, gender dysphoria, and transgenderism. Because of the sensitive nature of this topic, it took several months for members to self-disclose their history of gender-related concerns. These were provided to me in most cases privately.
- In 2001 I formed a separate discussion list called DES-Trans Support Group. There was a substantial amount of discussion activity on DES-Trans that truly underscored for me the importance of further exploring a possible link between prenatal DES exposure and psychosexual issues.
- Through my extensive experience with conducting qualitative research in an online environment, I was able to develop an environment of trust and respect for all members, allowing me to ask questions that further probed the nature and history of gender dysphoria and transgender identity among DES Trans members. The evolution of this topic is reported on DES Sons and the Significance of Gender Identity.
- During the next several years, discussions on the DES-Sons tended to focus on cancer concerns and other physiological effects in exposed males, while DES-Trans tended to focus on psychosexuality and gender identity.
- In fall of 2002 I was interviewed by a member of the DES-Trans support group for a program she produced for radio station KBOO in Portland, Oregon, which was entitled “Under Our Skins: The Hidden Story About DES and Transgenderism.”
- In 2002, I was interviewed on the program GenderTalk Radio regarding my first discoveries of a possible link to transsexualism resulting from hormonal disturbances in males at birth. I coauthored with Dr. Dana Beyer an article entitled “The DES Sons’ Online Discussion Network” for the Winter 2002 issue of the journal Transgender Tapestry
- In the years 2002-2004 I participated as a Visiting Research Scholar in Psychology at the University of Victoria (Canada). During this period I conducted a scholarly literature investigation about hormones and human sexual behaviour, focused on the biological and psychological frames of reference for conducting scientific studies of human sexual development. I produced a thesis at UVic entitled “Hormones, Sexual Behavior, and Gender Identity in Human Development.” My investigative research continued during 2005-06 at the University of British Columbia in Vancouver.
- In March 2003, I participated in a transcribed telephone interview with DES researcher Dr. John McLachlan on the topic of feminization of males exposed to DES in-utero during the DES Update of the Centers for Disease Control (CDC).
- In 2003, I identified several historical medical research studies of transsexual patients (male to female) who were treated with DES, a practice that apparently was quite common in gender transition clinics prior to 1980. One example of such a study is “Mortality and Morbidity in Transsexual Patients with Cross-Gender Hormone Treatment“, by H. Asscheman, L.J.G. Gooren, and P.L.E. Eklund.
- Formulating a DES Research Hypothesis: In 2003, following extensive interviewing and surveying of members of the DES Sons and DES Trans groups, I decided to pose a fomal research hypothesis: If DES was at one time considered an effective estrogen for supporting gender transition for male-to-female transsexuals, could prenatal exposure of the male fetus to DES also be implicated in subsequent gender variance during adulthood?
- During 2003-5, I received invaluable support and consultation from the world-renowned sexologist Dr. Milton Diamond, who indicated through email and telephone conversations that he had “long suspected that prenatal DES exposure had significant developmental effects on gender and sexuality.” His advice was of tremendous assistance in helping to develop an action plan for making my research more visible to an international research community.
- In 2004, at the invitation of DES researcher Dr. John McLachlan at Tulane University, I presented preliminary findings from 5 years of research into prenatal exposure to the estrogenic drug DES (diethylstilbestrol) to the annual E.Hormone academic conference at Tulane University. A slideshow of this presentation is available, entitled “The Presence of Gender Dysphoria, Transsexualism, and Disorders of Sexual Differentiation in Males Prenatally Exposed to Diethylstilbestrol: Initial Evidence of a 5-Year Study.”
- In 2004, I served as a member of the faculty research committee for Christine Johnson, a master’s degree recipient at the Evergreen State University in Olympia, Washington. Johnson is a DES-Son who transitioned to female in her 20s. Johnson’s thesis is entitled Transsexualism: An Unacknowledged Endpoint of Developmental Endocrine Disruption? The full 212-page thesis is available here.
- In 2005 I presented an invited research paper Prenatal Diethylstilbestrol Exposure and Gender-Related Disorders: Results from a 5-Year Study to the International Behavioral Development Symposium which was consulted and supported by renowned sexologist Dr. Milton Diamond of the University of Hawaii School of Medicine and Dr. John McLachlan of Tulane University School of Medicine. I also participated in a radio interview on my research for KWMR Radio.
- An article which highlights my research was published in 2006 by Ernie Hood in Environmental Health Perspectives, “Are EDCs Blurring Issues of Gender?”
- In 2006, Deborah Rudacille published The Riddle of Gender with a chapter summarizing my ongoing DES research. The chapter is titled “The Fear of a Pink Planet”. Several members of the DES Sons network, along with Dr. Milton Diamond, were interviewed for her book.
- In 2006, the Gender Identity Research and Education Society (GIRES) of the UK recognized prenatal DES exposure as a contributing factor in gender-related disorders in its comprehensive overview Atypical Gender Development–A Review.
Continuing Investigation into 2021
The initial findings from my research, presented to international conference (International Behavioral Development Symposium in Minot, North Dakota) in 2005, provided the opportunity to further explore the validity of a hypothetical correlation between prenatal DES exposure in males and females and variations in core gender identity and sexual development across the lifespan. Meanwhile, the DES Sons Research Network and its companion DES-Trans Transgender Support Group have continued to be active into 2020.
For several years subsequently, the question of whether prenatal estrogenic hormone exposure in males can be directly linked to major psychiatric disorders, gender dysphoria, transexualism, transgenderism, intersex, and variations in sexual orientation has been further investigated by others, and I have continued my own investigation through interviews and surveys with DES Sons and DES Trans discussion group members and extensive review of contemporary related research literature/publications.
Though no definitive conclusion regarding the role of prenatal DES exposure (or other EDCs exposure) in shaping psychosexual development in males and females has yet been reached, 25 years since beginning my own research investigation there is now (2020) compelling empirical data and a much broader array of promising investigative studies devoted to this question. I find this truly encouraging.
Here are some representative examples of others’ investigations and findings.
- New Research Indicates a Connection Between Genes, Hormones, and Gender Dysphoria (2020) from Newsweek, with the full research study published in the journal Nature: The Use of Whole Exome Sequencing in a Cohort of Transgender Individuals to Identify Rare Genetic Variants, (2019), by J. Graham Thiesen, et al.
- Neuroimaging Gender Dysphoria: A Novel Psychobiological Model (2019), by Murat Altinay & Amit Anand, published in the journal Brain Imaging and Behavior
- The Dissolution of Gender: The Role of Hormones (2019), by Robert J. Hedaya MD, DLFAPA, ABPN, CFM, published in Psychology Today
- Biology of Gender Identity and Gender Incongruence (2019)
- Healthcare of the Transgender Patient, by Dr. William Powers (M.D.) (2019), presented during the 2019 Medical Education Week for Oakland University William Beaumont School of Medicine
- Did DES Cause People to Be Transgender? (2018), published in Patheos.com
- The Possible Link Between DES and Being Transgender in Later Life (2017)
- Thousands of People Believe DES is the Reason They are Transgender (2017 video news story)
- Endocrine Considerations in Transgender Youth (2016), by Deanna W. Adkins, MD, Duke University Children’s Hospital
- Sexual Identity and Sexual Orientation (2016), by Laura Castellanos, Ai-min Bao, and Dick Swaab, published in the textbook Hormones, Brain and Behavior, 3rd edition
- Special Report: Sexuality and Gender: Findings from the Biological, Psychological, and Social Sciences (2016), by Lawrence S. Mayer, MD and Paul R. McHugh, MD, of the Johns Hopkins University Medical School Department of Psychiatry
- Brody: Transgender Identity May Form in the Womb (2016), by Jane Brody, published in the International Herald Tribune
- Between (Gender) Lines: The Science of Transgender Identity (2016), by Katherine J. Wu, Harvard University Medical School
- A DES Victim Tells the Story of the Largest Drug Disaster in History (2016)
- Petition Asking the FDA to Recognize That Hormone Treatment During Pregnancy Can Cause Intersex and Transgender(2014)
- Gender Identity and DES Exposure (2011), from Diethylstilbestrol.UK
- DES’ Other Daughters, by Dana Beyer, M.D. (2008)
- Finger Length (2D:4D) in Adults with Gender Identity Disorder (2007), by Bernd Kraemer, et.al, published in the Archives of Sexual Behavior
- Endocrine Disruption and Male Reproductive Health (2005), by Philippa D. Darbre, published in the text Endocrine Disruption and Human Health (2005, P. Darbre ed.)
- Gender Identity Disorder: General Overview and Surgical Treatment for Vaginoplasty in Male-to-Female Transsexuals(2005), by Gennaro Selvaggi, MD, et al., published in the journal Plastic Reconstructive Surgery
- (Historical) He and She: The Sex Hormones and Behavior(1972), by Maggie Scarf, published in the New York Times
Other Published Research Into Prenatal and Biological Influences on Sexual Orientation and Gender Identity:
Recent Studies (2013 to 2020)
- A Short Review of Biological Research on the Development of Sexual Orientation (2020), by Anthony F.Bogaert and Malvina N.Skorska, published in Hormones and Behavior
- Etiology of Gender Dysphoria, by Randi Ettner (2020), published the text Gender Confirmation Surgery (ed. by
- Gender Dysphoria: Definitions, Classifications, Neurobiological Profiles and Clinical Treatments (2020), by Giulio Perrota, published in the International Journal of Sexual and Reproductive Health Care
- Brain Sex Differences Related to Gender Identity Development: Genes or Hormones? (2020), by Jiska Ristori et. al, published in the International Journal of Molecular Sciences
- Sex, Gender and Gender Identity: A Re-evaluation of the Evidence (2020), by Lucy Griffin, et. al, published in the journal BJPsychBulletin
- Neuroscience and Sex/Gender: Looking Back and Forward (2020), by Melissa Hines, published in the Journal of Neuroscience
- Sexual Orientations: A Critical Review of Psychological, Clinical, and Neurobiological Profiles. Clinical Hypothesis of Homosexual and Bisexual Positions (2020), by Guilio Perrotta, published in the International Journal of Sexual and Reproductive Health Care
- Sexual Partner Preference in Animals and Humans (2020), by Jacques Balthazart, published in the journal Neuroscience and Biobehavioral Reviews
- StatPearls: Gender Dysphoria (2020), from the U.S. National Library of Medicine
- Gender Fluidity and Hormone Disruptors: Hormone Disrupting Chemicals May Increase Gender Dysphoria (2019), by Nigel Barber, Ph.D, published in Psychology Today
- Genetic Link Between Gender Dysphoria and Sex Hormone Signaling (2019), by Madeleine Foreman, et. al, published in the Journal of Clinical Endocrinology & Metabolism
- Neuroendocrine Influences on Human Sexuality (2019), by Ashlyn Swift-Gallant and S. Marc Breedlove, published in the Oxford Research Encyclopedia: Neuroscience
- Individual Differences in the Biological Basis of Androphilia in Mice and Men (2019), by Ashlyn Swift-Gallant, published in the journal Hormones and Behavior
- Biological Origins of Sexual Orientation and Gender Identity: Impact on Health (2018), by Katherine O’Hanlan, Jennifer C. Gordon, and Mackenzie W. Sullivan, published in the journal Gynecologic Oncology
- Beyond the Binary: Gender Identity and Mental Health Among Transgender and Gender Non-Conforming Adults, 2018, by Chassity N. Fiani, Ph.D. dissertation completed at City University of New York (CUNY)
- Neurobiology of Gender Identity and Sexual Orientation(2018), by C. E. Roselli, published in the Journal of Neuroendocrinology
- The Molecular Mechanisms of Sexual Orientation and Gender Identity (2018), by Allessandra D. Fisher, et. al, published in the journal Molecular and Cellular Endocrinology
- The Evolution of Human Female Sexual Orientation (2018), by Austin John Jeffery, et.al, published in the journal Evolutionary Psychological Science
- The Biological Contributions to Gender Identity and Gender Diversity: Bringing Data to the Table (2018), by Tinca J.C. Polderman, et. al, published in the journal Behavior Genetics
- Molecular Basis of Gender Dysphoria: Androgen and Estrogen Receptor Interaction (2018), by Rosa Fernandez, et. al, published in the journal Psychoneuroendocrinology
- Prenatal Androgen Exposure Associated with Male Psychosexual Development in Disorders of Sexual Development (2018), by R.L. Batista, published in the Journal of Clinical Endocrinology & Metabolism
- The Future of Sex and Gender in Psychology: Five Challenges to the Gender Binary (2018), by Janet Shibley Hyde, et. al, published in American Psychologist
- The Evolution of Human Female Sexual Orientation (2018), by Austin John Jeffery, et al., published in the journal Evolutionary Psychological Science
- Prenatal Influences on Human Sexual Orientation: Expectations versus Data (2017), by Marc S. Breedlove, published in Archives of Sexual Behavior
- Prenatal Exposure to Progesterone Affects Sexual Orientation in Humans (2017), by June M. Reinisch, Erik Lykke Mortensen & Stephanie A. Sanders, published in the Archives of Sexual Behavior
- Endocrine Treatment of Gender-Dysphoric/Gender-Incongruent Persons: An Endocrine Society Clinical Practice Guideline (2017), by Wylie C Hembree, et. al, published in the Journal of Clinical Endocrinology & Metabolism
- The Biologic Basis of Transgender Identity: 2D:4D Finger Length Ratios Implicate a Role for Prenatal Androgen Activity (2017), by Matthew Leinung, MD & Christina Wu, published in the journal Endocrine Practice
- Prenatal Influences on Human Sexual Orientation: Expectation vs. Data (2017), by S. Marc Breedlove, published in the Archives of Sexual Behavior
- Prenatal Androgens in Men’s Sexual Orientation: Evidence for a More Nuanced Role?(2016), by Malvina N. Skorska & Anthony F. Bogaert, published in the Archives of Sexual Behavior
- Gonads and Strife: Sex Hormones Vary According to Sexual Orientation for Women and Stress Indices for Both Sexes (2016), by Robert-Paul Juster, et al, published in the journal Psychoneuroendocrinology
- Sexual Orientation, Controversy, and Science (2016), by J. Michael Bailey, et al., published in Psychological Science in the Public Interest
- Early Androgen Exposure and Human Gender Development (2015), by Melissa Hines, Mihaela Constantinescu & Debra Spencer, published in the journal Biology of Sex Differences
- Evidence Supporting the Biologic Nature of Gender Identity (2015), by Aruna Saraswat, Jamie Weinand, and Joshua Safer, published in the journal Endocrine Practice
- Gender Identity Development in Adolescence (2013) by Thomas D. Steensma et. al, published in the journal Hormones and Behavior
- Update on the Biology of Transgender Identity (2013), by Laura Erickson-Schroth MD MA, published in the Journal of Gay and Lesbian Mental Health
Foundational Studies (2000 to 2012)
- Gender Development and the Human Brain (2011), by Melissa Hines, published in Annual Review of Neuroscience
- Prenatal Endocrine Influences on Sexual Orientation and on Sexually Differentiated Childhood Behavior, 2011, by Melissa Hines, published in Frontiers in Neuroendocrinology
- Mini-Review: Hormones and Human Sexual Orientation, 2011, by Jacques Balthazart, published in the journal Endocrinology
- Sexual Differentiation of the Human Brain: Relation to Gender Identity, Sexual Orientation, and Neuropsychiatric Disorders, 2011, by Ai-MinBao & Dick F.Swaab, published in Frontiers in Neuroendocrinology
- Biological and Psychosocial Correlates of Adult Gender-Variant Identities: New Findings, 2010, by Jaimie F.Veale, David E.Clarke, & Terri C.Lomax, published in the journal Personality & Individual Differences
- Prenatal Testosterone and Gender-Related Behavior (2006), by Melissa Hines, published in the European Journal of Endocrinology
- Sexual Differentiation of the Human Brain: Relevance for Gender Identity, Transsexualism and Sexual Orientation (2004), by D.F. Swaab, published in Gynecological Endocrinology
- Prenatal Sex Hormone Effects on Child and Adult Sex-Typed Behavior: Methods and Findings (2003), by Celina C.C. Cohen-Bendahan, Cornelieke van de Beeka, and Sheri A. Berenbaumc, published in Neuroscience and Biobehavioral Reviews
- Prenatal Hormone Exposure and Sexual Variation, 2003, by John Vandenbergh, published in American Scientist
2020: Newest published cohort study of prenatally DES-exposed males and females:
Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol (2020), by Rebecca Troisi, et al., published in the Archives of Sexual Behavior.
My Observations on this Publication:
(1) The timing and the motivating influences behind the publication of this study, 2020, have really intrigued me. What issues other than a desire to refute any theories of prenatal DES having psychosexual effects in offspring males and females?
(2) The study was based on a single-question demographic category identification methodology in mailed follow-up surveys using the long-term DES Combined Cohort Study of DES Sons and DES Daughters, funded by the National Cancer Institute. The NCI-funded research has historically emphasized an effort to statistically measure trends in cancer prevalence in DES Sons, DES Daughers, and DES Mothers. To the best of my knowledge, the Combined Cohorts are the only current population samples of DES Sons and DES Daughters in the U.S. that are still being monitored systematically.
(3) In the combined-cohort study, initial surveys were mailed in 1994 to approximately 1700 DES Sons and 4500 DES Daughters and subsequent surveys to this same population approximately every five years between 1994 and 2016. The population in this study was from a single large fertility clinic (unidentified) in the U.S.
(4) As with most research on DES Combined Cohorts, this study does not have a sophisticated foundational understanding of prenatal hormones and psychosexual development.
(5) In measuring the survey respondents’ “sexual orientation”, data analysis was based on single questions in the 2016 surveys which asked respondents to check a box on “how do you identify: (a) gay or lesbian; (b) straight; or (c) other;” [sexual orientation].
(6) Though this study purports to measure “gender identity” of DES-exposed Sons and Daughters, a standard question was asked on the questionnaire, “Which of the following best represents how you currently think of yourself: “Woman”, “Man”, “Other”, and “Prefer not to respond.” This could easily have been inferred by most respondents as a standard “what sex are you?” kind of question. Indeed, more than 99% of respondents among both DES Daughters and DES Sons classified themselves as “female” and “male” respectively.
(7) Among the 900+ DES Sons participating in these studies, the researchers report that DES Sons had a slightly higher likelihood of reporting being “non-heterosexual”,”gay”,”bisexual”, or “other” than did DES Daughters (5.5% vs. 3.5%).
(8) The study reports that “very few individuals think of themselves as a ‘gender other than that assigned at birth.'” And yet, the authors confirm that gender identity is a complex construct, and may not be effectively assessed through the questionnaire format they utilized.
(9) To quote the authors of this study in their conclusion (page 453):
“Although our study was large and has documented DES exposure status, it has limited power to assess associations with rare outcomes such as transgender identity. Despite limitations, these are unique data on a group of individuals exposed to high doses of synthetic estrogen during a particularly important development period.”
(10) In conclusion, I believe that this 2020 publication does not measure the full scope of complex psychosexual effects of prenatal DES exposure in males and females, many of which are not easily measured from demographic data questionnaires. In particular, the research lacked in-depth analysis of gender identity issues, despite the inclusion of this item in the paper’s title. My own research study has filled this gap, and it forwards evidence of significant positive correlation between prenatal DES exposure and gender variance in DES Daughters and DES Sons.
Concluding Observations: Implications of My Research Findings
- I have chosen to treat my 25-year study as primarily investigative in nature and not yet reaching definitive conclusions about the full scope of possible effects attributable to prenatal DES exposure. Further interviews and direct assessment of DES-exposed individuals are strongly recommended. Nevertheless, I believe my own discoveries through many years of connection with the DES sons community and the transgender-identified members brought me keen insights about the nature of human sexual variation, and the role that hormones play in shaping behavior and identity.
- In total, I estimate that 1000+ individuals have participated in the DES Sons network discussions during the period of 1999 through 2020.
- In my research interactions (through meetings, interviews, surveys) with the individuals who participated in the DES Sons network, it was not possible to independently verify that prenatal exposure to DES had definitely occurred, except in the cases when the individuals’ medical records were actually located. However, I utilized rigorous screening methods to verify likelihood of prenatal exposure before permitting DES Sons to participate.
- Verification of DES exposure status has always been a challenge, though many members were trained in ways of establishing verification through access to their medical records or through direct conversations with their parents or immediate family members.
- The initial findings in my surveys of individual DES-exposed persons born or raised as males (conducted during the period of 1999 through 2006) revealed a significant prevalence of hormonal disorders such as hypogonadism (testosterone deficiency), which is consistent with findings suggested in the early 2000s by the American Association of Clinical Endocrinologists (AACE).
- In my own deep quantitative and qualitative research with DES sons over the period of 1999 to 2020, I learned that many of them described a history of suffering from gender dysphoria that is not easily measured by a simple question in a survey.
- The emergence of discussions of gender identity-related concerns among participants in the DES Sons network (late 1999 and onward through early 2000s during my initial investigation period) was not expected or predicted ahead of time.
- The prevalence of gender dysphoria among many participants in this study lends evidence to the finding of Ettner in Etiology of Gender Dysphoria (2020), who observes that “Early hormonal influences on the brain appear to account for different brain phenotypes and may ultimately provide answers to the origins of gender incongruence.” (In L. Schecter, Gender Confirmation Surgery, (2020) pp. 21-28)
- As noted above, there were relatively few reported instances of DES sons developing or experiencing cancer that was potentially linkable to their prenatal exposure. However, approximately 10 individuals reported a history of testicular cancer diagnosis and treatment.
- Several individuals I encountered who had verified prenatal DES exposure reported congenital deformities of the male reproductive system including hypospadias, cryptorchidism, and epididymal (benign) cysts.
- Throughout my years of study of the health effects of DES Sons since my initial formation of the DES Sons International Research Network, it has become clear that males are typically reluctant to discuss their health challenges and concerns. This has made it a continual challenge for me as primary researcher when attempting to validate individual stories relative to likelihood of prenatal DES exposure.
- I am heartened to learn of major psychiatric research with DES Sons and Daughters from France published in 2018 by research scientists Marie-Odile Soyer-Gobillard, Laura Gaspari, Charles Sultan, in a chapter entitled, “Evidence for link between mental disorders and in utero exposure to synthetic hormones: A long and crucial history”. The authors measured a truly alarming level of major behavioral and psychiatric disorders and suicidality among a large portion of prenatally-exposed DES Sons and DES Daughters, an issue which several members of my DES Sons International Network raised in communications with me and in group discussions in the DES-Sons and DES-Trans groups.
Many of the issues raised within my study of DES-exposed males tended to go to the heart of previous research investigations into factors that shape psychosexual development. The original motivation for my investigative study of DES-exposed males (1999) was not meant to establish or argue for a “causal link” between prenatal DES exposure and potential impact on the development of core gender identity, although I did have many questions stemming from early DES studies of psychosexual development such as Yalom et al, 1973. Nevertheless, in my early years of investigating the published DES literature stemming from the 1960s onward, it became apparent that other research scientists have also asked questions that go to the heart of the hormonal impact on human sexual development.
- Over the range of time in history since the earliest investigations (1960s) into the human health effects of prenatal DES exposure in males and in females, the scientific notions of hormonal influences over core gender identity have significantly evolved.
- In my extensive literature review into DES psychological effects, I encountered a major literature review completed in 2001 a published study by Michel, Mormont, and Legroes in the European Journal of Endocrinology, “A Psycho-endocrinological Overview of Transsexualism,” in which the authors suggested prenatal exposure to DES as a contributing factor in males gender-identity disorders and in some cases, transsexualism.
- By the early 2000s, psychologists were recognizing that prenatal hormones could play a prominent role in sexual differentiation of the human brain and concomitant impact on gender-specific behavioral development. Cambridge University psychologist Simon Baron-Cohen, in his 2003 Guardian article “They Just Can’t Help It” observed: Some of the most convincing evidence for biological causes [of sexual differentiation of brain and behavioral tendencies] comes from studies of the effects of hormones. There was a time when women were prescribed a synthetic female hormone (diethylstilbestrol), in an attempt to prevent repeated spontaneous miscarriages. Boys born to such women are likely to show more female-typical, empathising behaviours, such as caring for dolls. And if a female rat is injected at birth with testosterone, she shows faster, more accurate maze learning, compared with a female rat who has not been given such an injection.
- At the heart of my study of DES sons and the nature of historical research into hormonal influences over the development of core gender identity in humans, I found it tremendously valuable to ground my findings in the studies of Dr. Milton Diamond. I was strongly influenced by his 2009 article in Hormones and Behavior, “Clinical Implications of the Organizational and Activational Effects of Hormones.“
- In developing my framework for further analysis of the gender identity issues raised by many members of my DES Sons network, I found it informative to consult references from the evolving body of literature associated with the fields of Transgender Health, as informed by participants in the World Professional Association for Transgender Health (WPATH).
- In my continuing investigation into the evolving research theories about gender identity formation, I have found the WPATH guidelines particularly beneficial in providing definitions of key constructs in transgender health. One contemporary reference that is of great assistance is the chapter on Language and Terminology in Transgender Health (2020) by Dr. Gail Knudson of the University of British Columbia Canada Faculty of Medicine, from the textbook Gender Confirmation Surgery. Knudson defines “gender dysphoria” this way:
Gender Dysphoria: Refers to discomfort or distress that is caused by a discrepancy between a person’s gender identity and that person’s sex assigned at birth (and the associated gender role and/or primary and secondary sex characteristics). Only some gender-noncomforming people experience gender dysphoria at some point in their lives.
- There are several key references that underscore the core aspects of prenatal hormonal influences on the development of gender dysphoria. For example, Capetillo-Ventura et al, in Gender Dysphoria: An Overview (2014), Medicina Universitaria state:
Various authors conclude that the factors which affect gender during early development are prenatal hormones and the components that change these hormone levels (p.56).
- A notable study, The Future of Sex and Gender in Psychology: Five Challenges to the Gender Binary (2018), by Janet Shibley Hyde, et. al, published in American Psychologist and a highlight of the 2020 annual conference of the American Psychological Association, notes:
For more than a century, psychological scientists have relied on the gender binary in research. Recent empirical findings stemming from multiple disciplines provide fundamental challenges to the notion that humans can be understood as belonging to only two categories: women and men. This evidence includes neuroscience findings that refute gender/sex dimorphism of the human brain; behavioral endocrinology findings that challenge the notion of biologically fixed, gender dimorphic hormonal systems; psychological findings that highlight the similarities between males and females; psychological research on transgender and nonbinary individuals’ identities and experiences; and developmental research suggesting that the tendency to view gender/sex as a meaningful, binary category is not innate but instead is culturally determined and malleable. Furthermore, societal changes in the ways that laypersons think and feel about gender/sex are increasingly incompatible with the gender binary.
- In the text The Plasticity of Sex: The Molecular Biology and Clinical Features of Genomic Sex, Gender Identity and Sexual Behavior (2020), the authors of Chapter 8 on the Biological Basis of Gender Identity, Alessandra Daphne and Fisher Carlotta Cocchetti summarize:
Core gender identity (the sense of whether one is male or female) is one of the most sexually differentiated traits in humans. In the past, gender identity was thought to be influenced only by social and familial factors. However, growing evidence has led to a new conception of psychosexual development as a result of genetic, hormonal, and psychosocial influences. Recent studies have shown the possible role and interaction of neuroanatomic, hormonal, and genetic factors. The sexually dimorphic brain is considered the anatomical substrate of psychosexual development, on which genes and gonadal hormones—both during intrauterine and pubertal periods—have a shaping effect. Future studies are needed to better clarify the complex interaction between genes, anatomy, and hormonal influences on psychosexual development.
- Perhaps most essentially notable is a recent special article published in BJ Psych Bulletin (2020, July), Sex, Gender and Gender Identity: A Re-Evaluation of the Evidence by psychiatrists Lucy Griffin, Katie Clyde, Richard Byng, & Susan Bewley. The authors observe:
Definitions have evolved beyond those included in the 1992 ICD-10 under ‘gender identity disorders’, with which psychiatrists might be familiar. Transsexualism was widely understood to mean ‘a desire to live and be accepted as a member of the opposite sex, and an accompanied discomfort of one’s anatomic sex’. Underlying mechanisms are poorly understood, although there are similarities and overlaps with both body dysmorphia and body integrity identity disorder. Sufferers might embark on social and medical intervention to help them ‘pass’ as the opposite sex. Historically, a diagnosis of gender dysphoria would have been required for doctors to intervene in this group.
Transgender, however, has become a much broader category. New terminology reflects a conceptual shift from clinical disorder to personal identity. Crucially, gender dysphoria is no longer integral to the condition. The World Health Organization has renamed ‘gender identity disorder’ as ‘gender incongruence’ and reclassified it as a ‘condition related to sexual health’ rather than retaining it in the chapter pertaining to ‘mental and behavioural disorders’, a somewhat discrepant placement, reflecting a political rather than scientific decision-making process.
Definitions are inadequate in explaining how anyone experiences the gender of the opposite sex. Without further explanation of ‘toys, games or activities’ that are typical of each sex, this is left to parents, teachers and doctors to determine. The inference might be that gender-congruent behaviours have some objective existence and not fulfilling them might indicate a ‘trans’ identity. Children who do not conform to social norms and expectations come to dislike their sexual characteristics: that embodiment of their gender dissonance.
There is a lack of consensus demonstrated as to the exact nature of the condition. Questions remain for psychiatrists regarding whether gender dysphoria is a normal variation of gender expression, a social construct, a medical disease or a mental illness. If merely a natural variation, it becomes difficult to identify the purpose of or justification for medical intervention.
APPENDIX A: Literature Review: Human Health Effects of Diethylstilbestrol Exposure in Males and Females
Here is a portion of the published research that I reviewed in my initial background investigation and continued assessments.
General DES References 1939-2020
- Effects of the Therapeutic Use of Diethylstilbestrol, 1939, by C.L. Buckston and Earle T. Engel, published in the Journal of the American Medical Association (JAMA)
- Therapeutic Trials of Diethylstilbestrol, 1939, by Alfred E. Loeser, M.D., published in The British Medical Journal
- On the Toxicity of Oestrogens with Special Reference to Diethylstilbestrol, 1939, published in the Canadian Medical Association Journal
- The Synthetic Estrogen Diethylstilbestrol: Clinical and Experimental Studies, 1941, by Cyril MacBride, et al., published in the Journal of the American Medical Association (JAMA)
- Does the Administration of Diethylstilbestrol During Pregnancy have Therapeutic Value?, 1953, by W.J. Dieckmann, et al., published in the American Journal of Obstetrics and Gynecology
- The Stilbestrol Story, 1974, by Albrecht W. Schmitt, M.D, published in the Bulletin of the Society of Pharmacological and Environmental Pathologists
- Follow-up Study of Male and Female Offspring of DES-Exposed Mothers, 1977, by M. Bibbo et al, published in the Journal of Obstetrics and Gynecology
- Pathological Semen and Anatomical Abnormalities of the Genital Tract in Human Male Subjects Exposed to Diethylstilbestrol in Utero, 1977, by W.R.Gill, G.F.B.Schumacher, and M.Bibbo, published in the Journal of Urology
- Male Genitourinary Abnormalities and Maternal Diethylbestrol, 1977, by M.D. Cosgrove, et al, published in the Journal of Urology
- Association of Diethylstilbestrol Exposure in Utero with Cryptorchidism, Testicular Hypoplasia, and Semen Abnormalities, 1979, by W.B. Gill, et. al, published in the Journal of Urology
- Randomized Trial of High Doses of Stilbestrol and Ethisterone Therapy in Pregnancy: Long-term Follow-up with the Children, 1981, by Valerie Beral and Linda Colwell, published in the Journal of Epidemiology and Community Health
- A Randomized Double-blind Controlled Trial of the Value of Stilbestrol Therapy in Pregnancy: Long-term Follow-up of Mothers and their Offspring, 1983, by M.P. Vessey, et al., published in the British Journal of Obstetrics and Gynecology
- Males Exposed in Utero to Diethylstilbestrol, 1984, by Frank J. Leary et al., published in the Journal of the American Medical Association
- Hormonal Risk Factors in Testicular Cancer: A Case-Control Study, 1986, by Andrew Moss, et al., published in the American Journal of Epidemiology
- Effects on Human Males of in-utero Exposure to Exogenous Sex Hormones, by W.B. Gill 1988. In T. Mori and H. Nagasawa (eds.), Toxicity of Hormones in Perinatal Life (Boca Raton: CRC Press), p. 161
- Psychopathology and Social Functioning in Men Prenatally Exposed to Diethylstilbestrol, 1993, by R.C. Pillard, et. al, published in Psychosomatic Medicine
- Fertility in Men Exposed Prenatally to Diethylstilbestrol, 1995, by Allen Wilcox, MD, et al., published in the New England Journal of Medicine
- Diethylstilbestrol Revisited: A Review of the Long-term Health Effects, by R.M. Giusti, et al., 1995, published in the Annals of Internal Medicine
- Do Environmental Estrogens Contribute to the Decline in Male Reproductive Health? 1995, by Tina Kold Jensen, Jorma Toppari, Niels Keiding, and Niels Enk Skakkebaek, published in the journal Clinical Chemistry
- Intrauterine Exposure to Diethylstilbestrol: Long-term Effects in Humans, 2000, by Shanna Swan, published in the journal APMIS
- Cancer Risk in Men Exposed in utero to Diesthylstilbestrol, 2001, by William Strohsnitter, et al., published the Journal of the National Cancer Institute
- Reproductive Outcomes in Men with Prenatal Exposure to Diethylstilbestrol, 2005, by Kimberly M. Perez, et al., published in the journal Fertility and Sterility
- Quantitative Meta-Analysis, 2008, by Olwenn Martin, et al, published in the journal Environmental Health Perspectives
- Testicular Dysgenesis Syndrome and the Estrogen Hypothesis: A Quantitative Meta-Analysis, 2008, by Olwenn V. Martin, et al., published in Environmental Health Perspectives
- Urogenital Abnormalities in Men Exposed to Diethylstilbestrol in Utero: A Cohort Study, 2009, by Julie R. Palmer, et al., published in the journal Environmental Health
- Diethylstilbestrol Exposure in Utero and Depression in Women, 2010, by Éilis J. O’Reilly et. al, published in the American Journal of Epidemiology
- Adverse Health Outcomes in Women Exposed in Utero to Diethylstilbestrol, 2011, by Robert N. Hoover, et al., published in the New England Journal of Medicine
- Diethylstilbestrol and Risk of Psychiatric Disorders: A Critical Review and New Insights, 2012, by Oussama Kebir & Marie-Odile Krebs, published in the journal The World Journal of Biological Psychiatry
- Diethylstilbestrol in Castration-Resistent Prostate Cancer, 2012, by Anna Wilkins, et al., published in the journal Urological Oncology
- Effects of Diethylstilbestrol Exposure During Gestation on Both Maternal and Offspring Behavior, 2015, by Kazuya Tomihara, et al., published in the journal Frontiers of Neuroscience
- Male Reproductive Disorders and Fertility Trends: Influences of Environment and Genetic Susceptibility, 2016, by Niels E. Skakkebaek, et al., published in the journal Physiology Review
- The Testis and Male Hypogonadism, Infertility, and Sexual Dysfunction (2016), by RS Swerdloff & C Wang
- The Epidemiologic Evidence Linking Prenatal and Postnatal Exposure to Endocrine Disrupting Chemicals with Male Reproductive Disorders: A Systematic Review and Meta-analysis, 2016, by Jens Peter Bonde, et al., published in the journal Human Reproduction Update
- Evidence for Link Between Mental Disorders and in Utero Exposure to Synthetic Hormones: A Long and Crucial History, 2018, by Marie-Odile Soyer-Gobillard, Laura Gaspari and Charles Sultan, published online in the open-acess text Psychopathology: An International and Interdisciplinary Perspective, (2018), edited by Robert Woolfolk, Lesley Allen, and Frederico Durbano
- Current Perspective of Diethylstilbestrol (DES) Exposure in Mothers and Offspring, 2017, by Taher Al Jishi and Consolato Sergi, published in the journal Reproductive Toxicology
- Prenatal Diethylstilbestrol Exposure and Cancer Risk in Women, 2017, by Rebecca Troisi et. al, published in the journal Environmental and Molecular Mutagenesis
- Systematic Review and Meta-Analysis of Testicular Germ-cell Tumors Following in utero Exposure to Diethylstilbestrol, 2019, by Marianne Hom, et. al, published in the JNCI Cancer Spectrum
- Prenatal Diethylstilbestrol Exposure: A Harbinger of Future Testicular Cancer Incidence?, 2019, by William Strohsnitter, published in the JNCI Cancer Spectrum
- Prenatal Diethylstilbestrol Exposure and Risk of Diabetes, Gallbladder Disease, and Pancreatic Disorders and Malignancies, (2020), by Rebecca Troisi, et al., published in the Journal of Developmental Origins of Health and Disease
Psychosexual and Behavioral Developmental Effects, 1959-2020
- Male Pseudohermaphrodism–Report of a Case, with Observations on Pathogenesis, 1959, Norman M. Kaplan, published in the New England Journal of Medicine
- Masculinization of the Female Infant Associated with Estrogenic Therapy Alone During Gestation: Four Cases, 1959, by A.M. Bongiovani, A.M. DiGeorge, and M.M. Grumbach, published in the Journal of Clinical Endocrinology and Metabolism
- Male Pseudohermaphrotitism with Female Chromosomal Constitution, 1965, by W.M. Cleveland and G.C.H. Chang, published in the journal Pediatrics
- Prenatal Exposure to Female Hormones: Effect on Psychosexual Development in Boys, 1973, by Irvin D. Yalom, MDRichard Green, MDNorman Fisk, MD, published in the Archives of General Psychiatry
- Prenatal Exposure to Synthetic Progestins and Estrogens: Effects on Human Development, 1977, by June Reinisch & William Karow, published in the Archives of Sexual Behavior
- Behavioral Effects of Estrogen Treatment in Human Males, 1978, by Heino Meyer-Bahlburg, published in the journal Pediatrics
- Prenatal ‘Female Hormone’ Administration and Psychosexual Development in Human Males, 1980, by Patricia Kester, et al, published in the journal Psychoneuroendocrinology
- Prenatal Gonadal Steriod Influences on Gender-Related Behavior, 1984, by June Reinisch & Stephanie Saunders, published in the journal Progress in Brain Research
- Sexual Orientation after Prenatal Exposure to Exogenous Estrogen, 1985, by Anke A. Ehrhardt Ph.D, et al., published in the journal Archives of Sexual Behavior
- Effects of Estrogen Treatment on Male-to-female transsexuals: Experimental and Clinical Observations, 1985, by Marie Kwan, et al, published in the Archives of Sexual Behavior
- Psychosis and Prenatal Exposure to Diethylstilbestrol, 1987, by David L. Katz, et al, published in the Journal of Nervous and Mental Disease
- The Development of Gender-Related Behavior in Females Following Prentatal Exposure to Diethylstilbestrol (DES), 1989, by Anke A. Ehrhardt, et. al, published in Hormones and Behavior
- Gender-Related Behavior Development in Females Exposed to Diethylstilbestrol (DES) in Utero: An Attempted Replication, 1991, by Jennifer D. Lish, et al, published in the Journal of the American Academy of Child & Adolescent Psychiatry
- Hormonal Contributions to Sexually-Dimorphic Behavioral Development in Humans (1991), by June MachoverReinisch, MaryZiemba-Davis, & Stephanie A.Sanders, published in the journal Psychoneuroendocrinology
- Prenatal Exposure to Diethylstilbestrol (DES): Childhood Play Behavior and Adult Gender-Role Behavior in Women, 1992, by Jennifer D. Lish, et. al, published in the Archives of Sexual Behavior
- Gender-Related Behavior in Women Exposed Prentally to Diethylstilbestrol, 1993, by Retha Newbold, published in the journal Environmental Health Perspectives
- A Psycho-Endocrinological Overview of Transsexualism (2000), by A Michel, C Mormont, and J J Legros, with reference to prenatal DES exposure, published in the European Journal of Endocrinology
- Long-term Psychiatric and Behavioural Consequences of Prenatal Exposure to Psychoactive Drugs, 2002, by Helene Verdoux, published in the French journal Therapie
- Prenatal Hormone Exposure and Sexual Variation, 2003, by John Vandenbergh, published in American Scientist
- Serious Psychiatric Outcome of Subjects Prenatally Exposed to Diethylstilbestrol in the E3N Cohort Study, 2007, by Hélène Verdoux, et al., published in the journal Psychological Medicine
- Impact of Prenatal Exposure to Diethylstilbestrol (DES) on Psychological Outcome: A National Survey of DES Daughters and Unexposed Controls, 2017, by Helene Verdoux, et al., published in the journal Archives of Women’s Mental Health
- Neurobiology of Gender Identity and Sexual Orientation, 2018, by C.E. Roselli, published in the Journal of Neuroendocrinology
- Evidence for Link Between Mental Disorders and in Utero Exposure to Synthetic Hormones: A Long and Crucial History, 2018, by Marie-Odile Soyer-Gobillard, Laura Gaspari and Charles Sultan (book chapter)
- American Association of Clinical Endocrinologists Medical Guidelines for Clinical Practice for the Evaluation and Treatment of Hypogonadism in Adult Male Patients, 2019 update, by the AACE Hypogonadism Task Force
- Sexual Orientations: A Critical Review of Psychological, Clinical, and Neurobiological Profiles: Clinical Hypothesis of Homosexual and Bisexual Positions, 2020, by Giuilo Perrotta, published in the International Journal of Sexual and Reproductive Health Care
There are several books devoted to the legacy of DES in humans. I especially recommend these texts:
- Toxic Bodies: Hormone Disruptors and the Legacy of DES, by Nancy Langston, 2010
- Hormonal Chaos: The Scientific and Social Origins of the Environmental Endocrine Hypothesis, by Sheldon Krimsky, 2003
- To Do No Harm: DES and the Dilemmas of Modern Medicine, by Roberta Apfel and Susan Fisher, 1986
Research into the possible inherited effects of prenatal DES exposure for third-generation “DES grandchildren” has also been published since 2000:
DES Third-Generation Effects Literature, 1992-2020
- The DES Product Liability Story in America: The Third Generation in Litigation, 1992, by William J. Curran, published in the International Journal of Risk & Safety in Medicine
- Hypospadias and Endocrine Disruption: Is There a Connection? (2001), by Laurence S. Baskin, Katherine Himes, & Theo Colborn, published in Environmental Health Perspectives
- Hypospadias in the Sons of Women Exposed to Diethylstilbestrol in Utero: A Cohort Study, 2002, by Helen Klip, et al., published in the journal The Lancet
- Hypospadias: A Transgenerational Effect of Diethylstilbestrol?, 2006, by M.M. Brouwers, et. al, published in the journal Human Reproduction
- Esophogeal Atresia and Tracheosophogeal Fistula in Children of Women Exposed to Diethylstilbestrol in Utero, 2007, by Janine F. Felix, et. al, published in The American Journal of Obstetrics and Gynecology
- Birth Defects in the Sons and Daughters of Women who were Exposed in utero to Diethylstilbestrol (DES), 2010, by Linda Titus-Ernstoff, et al., published in the journal International Journal of Andrology
- Hypospadias: Risk Factor Patterns and Different Phenotypes, 2010, by Marijn M. Brouwers, et. al, published in the journal BJU International
- Prevalence of Hypospadias in Grandsons of Women Exposed to Diethylstilbestrol During Pregnancy: A Multigenerational National Cohort Study, 2011, by Nicholas Kalfa et al., published in the journal Fertility and Sterility
- Transgenerational Neuroendocrine Disruption of Reproduction, 2011, by Deena M. Walker and Andrea C. Gore, published in Nature Reviews: Endocrinology
- Exposure to Diethylstilbestrol During Sensitive Life Stages: A Legacy of Heritable Health Effects, 2013, published in the journal Birth Defects C Embryo Today
- Diethylstilbestrol (DES) Also Harms the Third Generation (2016), published in the French medical journal Prescrire International
- Adverse Health Effects in Children of Women Prenatally Exposed in utero to Prenatal Diethylstilbestrol (DES) (2016), by Michel Tournaire et al., published in the French journal Pharmacoepidemiology
- Birth Defects in Children of Men Exposed in utero to Diethylstilbestrol, 2017, by Michel Tournaire, et al., published in the French journal Pharmacovigalence
- Association of Exposure to Diethylstilbestrol During Pregnancy with Multigenerational Neurodevelopmental Deficits (2018), by Marianthi-Anna Kioumourtzoglou, ScDBrent A. Coull, PhDÉilis J. O’Reilly, ScD, published in the journal JAMA Pediatrics
- Genital Tract and Reproductive Characteristics in Daughters of Women and Men Prenatally Exposed to Diethylstilbestrol (DES) (2019), by Anne Waultier, et al., published in the journal Therapies
- Reproductive and Hormone-Related Outcomes in Women whose Mothers were Exposed in utero to Diethylstilbestrol (DES): A Report from the U.S. National Cancer Institute DES Third Generation Study (2019), by Linda Titus, Ph.D. et al., published in the journal Reproductive Toxicology
Pregnancy Drugs, Fetal Germline Epigenome, and Risks for Next‐generation Pathology: A Call to Action, 2019, by Jill Escher and Suzanne Robotti, published in the journal Environmental and Molecular Mutagenesis
- “Idiopathic” Partial Androgen Insensitivity Syndrome in 11 Grandsons of Women Treated by Diethylstilbestrol During Gestation: A Multi-Generational Impact of Endocrine Disruptor Contamination? (2020), by L. Gaspari, et. al, published in the Journal of Endocrinological Investigation
Genital Tract and Reproductive Characteristics in Daughters of Women and Men Prenatally exposed to Diethylstilbestrol (DES), 2020, by Anne Wautier, et al., published in the journal Therapies
Diethylstilbestrol Exposure During Pregnancy with Primary Clear-Cell Carcinoma of the Cervix in a 8-Year-Old Granddaughter: A Multi-generational Effect of Endocrine Disruptors?, 2021, by Laura Gaspari, et.al, published in the journal Human Reproduction
APPENDIX B: DES Sons International Network 5-Year Summary Statistics 1999-2004
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-to female 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.
- 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.