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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: (1) an overview of published literature discussing the confirmed and suspected adverse effects of prenatal exposure in DES sons; (2) preliminary results from a 5-year online study of DES sons involving 500 individuals with confirmed (60% of sample) and suspected prenatal DES exposure; (3) documentation of the presence of gender identity disorders and male-to-female transsexualism reported by more than 100 participants in the study.
Prenatal Exposure to Diethylstilbestrol (DES)
in Males and Gender-Related Disorders:
Results from a 5-Year Study
Scott P. Kerlin, Ph.D.
DES Sons International Network
Vancouver, B.C., Canada
July 2005
Paper prepared for the
International Behavioral Development Symposium 2005
Minot, North Dakota
An earlier version of this paper was presented at
E.Hormone 2004, New Orleans
Prenatal Exposure to Diethylstilbestrol (DES)
in Males and Gender-Related Disorders:
Results from a 5-Year Study
Scott P. Kerlin, Ph.D.
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: (1) an overview of published literature discussing the
confirmed and suspected adverse effects of prenatal exposure in DES sons; (2)
preliminary results from a 5-year online study of DES sons involving 500
individuals with confirmed (60% of sample) and suspected prenatal DES
exposure; (3) documentation of the presence of gender identity disorders and
male-to-female transsexualism reported by more than 100 participants in the
Prenatal Exposure to Diethylstilbestrol (DES)
in Males and Gender-Related Disorders:
Results from a 5-Year 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 each (Edelman, 1986). Hundreds of
thousands of DES sons and daughters were also born in Canada, 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 (1) reproductive tract abnormalities; (2)
infertility; (3) testicular cancer; (4) prostatic hyperplasia and cancer; (5) psychosexual effects;
(6) psychiatric effects; and (7) 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;
Cosgrove 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 (NCI), 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 NCI 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 (Colburn 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
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.,
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 meta-analysis 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
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 (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” (NCI, 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 NCI’s DES conference, the DES Sons online
network was launched at 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 at
The perceived advantages of utilizing the Internet for conducting this study included:
o Opportunities for greater anonymity and privacy among participants
o 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
o 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,
o 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 (1) locating individual males who could confirm
their prenatal DES exposure (i.e., confirmation that they are “DES sons”); (2) documenting the
range of self-report indicators of lifetime health, medical, and behavioral concerns reported
directly by DES sons; (3) promoting interpersonal support among DES sons; (4) 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 NCI’s DES cohort studies.; (5)
attempting to document the length of prenatal drug exposure including determination of the
trimester of mother’s initial use of DES during pregnancy; and (6) 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 (NCI, 1999).
Sample Development
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
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 (1) evidence or confirmation of prenatal DES
exposure; (2) confirmation of birth between the late-1940s and early 1970s in all requests
from individuals born in the U.S.; (3) 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 DES-
exposed individuals (online at 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 (1)
documenting each member’s self-report indicators of critical health, medical, and
psychological events or issues across the lifespan; (2) periodic analysis and reporting of
statistical data summaries of leading health concerns reported by DES-exposed members; (3)
conducting several online surveys (open to network members only, and archived under the
“polls” section of the DES sons network web site at on issues of reported greatest concern
among network members; (4) 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.
Sample Size
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 post-operative,” (90 members),
“transgender” (48 members), “gender dysphoric” (17 members), or “intersex” (3
members). These statistics are taken from self-report 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 individuals 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 male-to-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-Cohen, 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 (EDCs) 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).
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.
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DES Sons International Network 5-Year Summary Statistics
I. Statistics on DES Sons Participating in the DES Sons International Network
Between 1999 and 2004
Online Study Dates: July 1999 to July 2004
(a) # of individuals requesting membership on DES Sons network listserv 600+
(b) # of individuals (after initial screening) with confirmed or “suspected”
prenatal DES exposure who were allowed to join DES sons network > 500
(c) % of (b) who confirmed prenatal DES exposure 60%
(d) % of (b) with “suspected” but unconfirmed prenatal DES exposure 40%
(e) % of (b) with direct access to mother’s medical records Unknown
1. In the five years since formation of the DES Sons network in July 1999, approximately 600
individuals requested 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 web site (
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.
2. 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
(Note: Figures are based on preliminary analysis of response data and will be
finalized in 2006)
Totals % of Total
(a) Number of DES sons (confirmed exposure) participating in the 300 60%
online study between 1999 and 2004
(b) Number of individual males with “suspected but unconfirmed” 200 40%
prenatal DES exposure participating in study
(c) Numbers of DES sons (confirmed and suspected) reporting various health and
medical concerns (percentages are of confirmed and suspected exposure):
Gender Dysphoria or Gender Identity Concerns 150+ 30%
Major depression and/or anxiety disorders 100+ 20%
Hypogonadism or other hormone-related disorders 75 15%
Infertility 30 6%
Testicular Cancer 7 1.4%
1. 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.
2. 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.
3. 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)
1. 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:
Confirmed DES-Exposed and Gender-Related Issues (N=93)
(1) Confirmed Exposed and Transsexual: 54 individuals
(2) Confirmed Exposed and Transgender: 26 individuals
(3) Confirmed Exposed and Gender Dysphoric: 10 individuals
(4) 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 either transsexual (male-to-female),
transgendered (male-to-female), “gender dysphoric,” or intersex. The distribution of
these 65 individuals is as follows:
Strongly suspected, not confirmed DES Exposed and Gender-Related Issues (N=65)
(1) Suspected Exposure and Transsexual: 36 individuals
(2) Suspected Exposure and Transgender: 22 individuals
(3) Suspected Exposure and Gender Dysphoric: 7 individuals
(4) Suspected Exposure and Intersex none reported
... Between 1939 and 1960, 2 million pregnant women in the United States and Europe were prescribed DES, an estrogen-like drug meant to prevent miscarriage. However, not only did DES not prevent miscarriage, but also it seems that male offspring of women exposed to DES during pregnancy had a higher prevalence of GD (Kerlin, 2005). It should be noted that there are some studies that did not find this relationship (Newbold, 1993;Titus-Ernstoff et al., 2003). ...
... Complete androgen insensitivity syndrome in XY individuals (female phenotype, female gender identity) (Wisniewski et al., 2000;Hines, 2008;Bao and Swaab, 2011) XY individuals with female gender identity DES? (Kerlin, 2005) [ incidence of GD in exposed male individuals? Immunological ...
Sexual differentiation of the brain, gender identity (an individual's perception of being male or female), and sexual orientation (heterosexuality, homosexuality, bisexuality, and pedophilia) is orchestrated and determined in our brain during early development. Sexual differentiation of the brain is determined by a series of events, starting with the influence from the SRY gene on the Y chromosome, followed by the influence of sex hormones regulated by different mechanisms, through different paths and with different endpoints, including epigenetic modifications. These complex mechanisms ensure the variability, necessary from an evolutionary perspective; however, it also provides multiple points where it may be disrupted or modified, and therefore influence sexual behaviors. This chapter will review the literature regarding the genetic, postmortem, and in vivo scanning observations that support the neurobiological theory about the origin of our gender identity and sexual orientation. In humans, there is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity and sexual orientation.
... DES turned out to increase the likelihood of bisexuality and homosexuality in the daughters of women given this drug (Ehrhardt et al., 1985). In addition, a high prevalence of gender identity problems has been reported in DES sons (Kerlin, 2005). A formal study of these alarming data is certainly warranted. ...
Gender identity (an individual's perception of being male or female) and sexual orientation (heterosexuality, homosexuality, or bisexuality) are programmed into our brain during early development. During the intrauterine period in the second half of pregnancy, a testosterone surge masculinizes the fetal male brain. If such a testosterone surge does not occur, this will result in a feminine brain. As sexual differentiation of the brain takes place at a much later stage in development than sexual differentiation of the genitals, these two processes can be influenced independently of each other and can result in gender dysphoria. Nature produces a great variability for all aspects of sexual differentiation of the brain. Mechanisms involved in sexual differentiation of the brain include hormones, genetics, epigenetics, endocrine disruptors, immune response, and self-organization. Furthermore, structural and functional differences in the hypothalamus relating to gender dysphoria and sexual orientation are described in this review. All the genetic, postmortem, and in vivo scanning observations support the neurobiological theory about the origin of gender dysphoria, i.e., it is the sizes of brain structures, the neuron numbers, the molecular composition, functions, and connectivity of brain structures that determine our gender identity or sexual orientation. There is no evidence that one's postnatal social environment plays a crucial role in the development of gender identity or sexual orientation.
... Brain's sexual differentiation starts with a complicated pre-hormonal, gene-orchestrated process (Lentini et al. 2013;Ngun et al. 2011), followed by sex hormoneorchestrated brain differentiation. During embryonic development, external sex hormone exposure can lead to variations in biological sex and gender identity development: 1) Iatrogenic diethylstilbestrol exposed genetic males show higher prevalence of transgender identity (Kerlin 2005); 2) Sexual development variations can cause discordant external genitalia and chromosomal sex, which can then lead to incongruence between gender identity and chromosomal sex and/or biological sex (Bailey et al. 2000;Coolidge et al. 2002;Heylens et al. 2012); 3) External genitalia may not fit in the binary gender classification (male vs. female), a condition known as intersex (Hughes et al. 2006). Intersex conditions can present with different variations of internal and external genitalia and gender identity, which may or may not be congruent with the chromosomal and/or biological sex. ...
Full-text available
Gender identity development is complex and involves several key processes. Transgender people experience incongruence between their biological and identified gender. This incongruence can cause significant impairment in overall functioning and lead to gender dysphoria (GD). The pathophysiology of GD is complex and is poorly understood. A PubMed search based on predetermined eligibility criteria was conducted to review neuropsychiatric articles focused on neurological, biological and neuroimaging aspects of gender development, transgender identity and GD. The information obtained from the literature was then used to formulize a GD model. Distinct gray matter volume and brain activation and connectivity differences were found in individuals with GD compared to controls, suggesting a neurobiological basis of GD; which leads to the concept of brain gender. Individuals with GD encounter a recurrent conflict between their brain gender and the societal feedback; which causes recurrent and ongoing cognitive dissonance, finally leading to GD and functional connectivity and activation changes in the transgender brain. GD has neurobiological basis, but it is closely associated with the individuals’ interaction with the external world, their self-perception and the feedback received in return. We propose a novel model where the development of GD includes cognitive dissonance, involving anterior cingulate cortex and ventral striatum as the key brain structures. This model can be used to generate testable hypotheses using behavioral and neuroimaging techniques to understand the neuropsychobiology of GD.
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Durante el siglo pasado, los profesionales de la medicina intentaron aliviar las tensiones internas de los transexuales ajustando su apariencia externa a sus identidades de género preferidas. En repetidos estudios se constató una reducción de la disforia de género mediante cirugías de reasignación de sexo y terapias hormonales. Aunque bienintencionados, estos esfuerzos fueron por sí solos insuficientes para aliviar la angustia subyacente causada por la disforia de género. Además, las personas transexuales, incluso después de los procedimientos de reasignación de sexo, tienen mayores riesgos de mortalidad, neoplasias, comportamientos suicidas y morbilidad psiquiátrica que la población general. Las terapias de conversión basadas en la fe duplican las tasas de morbilidad de los individuos transgénero. Un enfoque religioso no basado en la ciencia médica produce peores resultados que no proporcionar ningún tipo de apoyo. La falta de apoyo familiar y comunitario a los jóvenes transexuales conduce a un aumento de la falta de vivienda, la prostitución y el abuso de sustancias. El enfoque intransigente y de amor-duro no conduce a resultados positivos para muchos jóvenes transexuales. Las pruebas médicas de la década anterior sugieren una causa del neurodesarrollo para las identidades transgénero; sin embargo, los estudios sobre la disforia de género de inicio rápido apuntan a causas sociales para el pico de adolescentes que se identifican como transgénero. Mientras que las altas tasas de niños preadolescentes diagnosticados como transgénero desisten de su disforia, algunos estudios han demostrado que los adolescentes que toman bloqueadores hormonales no desisten hasta los veinte años. Se necesitan estudios de seguimiento a más largo plazo para conocer los efectos que tienen los bloqueadores hormonales en el desistimiento cuando se prescriben a tiempo. Los teóricos nominalistas del género han integrado las identidades transgénero en su ideología, según la cual el cuerpo, la mente y el espíritu no están esencialmente unidos. Aunque estas ideologías intentan liberar a los individuos de las restricciones del realismo biológico, esta ideología no ha ofrecido a las personas transgénero una sensación de paz interior. Según un estudio de la Campaña de Derechos Humanos de 2018, los individuos que se identifican como no binarios y otras identidades de género recién nombradas sufren los niveles más altos de depresión, ansiedad e intentos de suicidio. Bajo el paraguas transgénero se encuentran tres grupos de personas: (1) los que tienen disforia de género de inicio temprano, (2) los que tienen disforia de género de inicio rápido y (3) los teóricos del género que forman parte de la 4ª ola del feminismo. Las personas con disforia de género de inicio temprano padecen una condición médica que desiste en un 80% en la adolescencia; el 20% que persiste se beneficia de alguna forma de transformación social en el sexo opuesto. La gran mayoría de las personas que se autodenominan transgénero pertenecen a la segunda categoría, que son principalmente mujeres adolescentes. Al igual que las autolesiones y los trastornos alimentarios, este contagio social alcanza su punto álgido a los diecisiete años, desistiendo en la edad adulta. Los jóvenes autistas están muy afectados. Este grupo busca principalmente una identidad y una comunidad de apoyo. El teórico del género ha aprovechado este caos y ha presentado eficazmente la identidad transgénero como una forma de reinvención. Las personas con disforia de género necesitan apoyo, las que tienen confusión de género necesitan orientación y los teóricos del género necesitan ser desafiados filosóficamente. El realismo tomista ofrece recursos adicionales para los individuos transgénero, que la ciencia secular no puede ofrecer por sí sola. El tomismo abarca todas las disciplinas de la ciencia y las humanidades para presentar una expresión holística de la verdad. La heurística tomista utiliza la ciencia médica y busca restaurar la naturaleza por los medios menos invasivos, al tiempo que depende de las virtudes y la gracia para proporcionar sabiduría y carácter para superar los obstáculos. Este libro sostiene que el uso de una heurística tomista en consonancia con la enseñanza de la Iglesia es mejor que las terapias médicas por sí solas, la terapia de conversión basada en la fe o la adopción de una ideología de teoría de género basada en el nominalismo.
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Throughout the previous century, medical professionals aimed to ease the inner tensions found within transgender individuals by conforming their outer appearances to their preferred gender identities. Repeated studies have found a reduction of gender dysphoria through sex reassignment surgeries and hormone therapies. Although well-intentioned, these efforts were on their own insufficient for relieving the underlying distress caused by gender dysphoria. Moreover, transgender individuals, even after sex reassignment procedures, have higher risks of mortality, neoplasms, suicidal behaviors, and psychiatric morbidity than the general population. Faith-based conversion therapies double the morbidity rates of transgender individuals. A religious approach not based on medical science produces worse outcomes than providing no support at all. A lack of family and communal support of transgender youths leads to increased homelessness, prostitution, and substance abuse. The uncompromising, tough-love approach does not lead to positive outcomes for many transgender youths. Medical evidence from the previous decade suggests a neurodevelopmental cause for transgender identities; however, studies on Rapid-Onset Gender Dysphoria point to social causes for the spike of adolescents identifying as transgender. While high rates of pre-adolescent children diagnosed as transgender desist in their dysphoria, some studies have shown that adolescents who take hormone blockers do not desist into their early twenties. Longer-term follow-up studies are needed to know the effects hormone blockers have on desisting when prescribed early. Nominalist gender theorists have integrated transgender identities into their ideology, whereby the body, mind, and spirit are not essentially united. Although these ideologies attempt to liberate individuals from restrictions of biological realism, this ideology has not offered transgender people an inner sense of peace. According to a 2018 Human Rights Campaign study, individuals who identify as non-binary and other newly named gender identities suffer from the highest levels of depression, anxiety, and suicide attempts. Under the transgender umbrella are three groups of people: (1) those with early-onset gender dysphoria, (2) those with Rapid Onset Gender Dysphoria, and (3) gender theorists who are part of the 4th wave of feminism. Those with early-onset gender dysphoria suffer from a medical condition that desists at a rate of 80% by adolescence—the 20% who persist benefit from some form of social transformation into the opposite sex. The vast majority of people calling themselves transgender are from the second category who are mostly adolescent females. Like self-harm and eating disorders, this social contagion peaks at seventeen years of age, desisting in adulthood. Autistic young people are significantly affected. This group is primarily looking for an identity and supportive community. The gender theorist has capitalized on this chaos and effectively presented the transgender identity as a way of reinvention. Those with gender dysphoria require support, those with gender confusion need guidance, and gender theorists need to be philosophically challenged. Thomistic realism offers additional resources for transgender individuals, which secular science cannot offer on its own. Thomism embraces all disciplines of science and the humanities to present a holistic expression of the truth. The Thomistic heuristic utilizes medical science and seeking to restore nature by the least invasive means while depending on virtues and grace to provide wisdom and character to overcome obstacles. This book argues that using a Thomistic heuristic in line with church teaching is better than medical therapies alone, faith-based conversion therapy, or adopting a nominalist-based gender theory ideology.
This review summarizes current knowledge of the genetic and hormonal control of sexual differentiation of the reproductive system, brain and brain function. While the chromosomal regulation of sexual differentiation has been understood for over 60 years, the genes involved and their actions on the reproductive system and brain are still under investigation. In 1990, the predicted testicular determining factor was shown to be the SRY gene. However, this discovery has not been followed up by elucidation of the actions of SRY, which may either stimulate a cascade of downstream genes, or inhibit a suppressor gene. The number of other genes known to be involved in sexual differentiation is increasing and the way in which they may interact is discussed. The hormonal control of sexual differentiation is well-established in rodents, in which prenatal androgens masculinize the reproductive tract and perinatal oestradiol (derived from testosterone) masculinizes the brain. In humans, genetic mutations have revealed that it is probably prenatal testosterone that masculinizes both the reproductive system and the brain. Sexual differentiation of brain structures and the way in which steroids induce this differentiation, is an active research area. The multiplicity of steroid actions, which may be specific to individual cell types, demonstrates how a single hormonal regulator, e.g. oestradiol, can exert different and even opposite actions at different sites. This complexity is enhanced by the involvement of neurotransmitters as mediators of steroid hormone actions. In view of current environmental concerns, a brief summary of the effects of endocrine disruptors on sexual differentiation is presented.
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Diethylstilbestrol (DES) has been widely used around the word in pregnancy care until the discovery in the early 1970s of the teratogenic and carcinogenic effects of this drug. The genital and obstetrical iatrogenic effects of the intrauterine exposure to DES are now well established. However, the potential impact of the DES and related xenoestrogen on the foetal neurodevelopment are poorly known. It has been suggested that prenatal DES exposure may modify the cerebral lateralisation. A more speculative issue with regard to the possible neurodevelopmental consequences of DES exposure is the possible impact on gender-identity and gender-related behavior. Prenatal DES exposure may be also a risk factor for psychiatric disorder in adulthood. This increased liability can not be totally explained by the genital and reproductive consequences of DES exposure, since it can also be found before the appearance of such complications and/or in subjects unaware of their exposure to DES, and also exists in DES-exposed sons who do not present with somatic complications. Most previous studies have assessed the links between perinatal DES exposure and increased risk of depression. A few reports also suggest that subjects exposed to DES may be at greater risk of eating or psychotic disorders. Further research on the neurodevelopmental consequences of xenoestrogen exposure is required from an aetiological perspective, but also from a preventive point of view.
Conference Paper
Growing evidence from clinical and epidemiological studies points to a synchronized increase in the incidence of male reproductive problems, such as genital abnormalities, testicular cancer, reduced semen quality, and subfertility. Together these mate reproductive problems may reflect the existence of one common entity, a testicular dysgenesis syndrome (TDS). Experimental and epidemiological studies suggest that TDS Is a result of disruption of embryonal programming and gonadal development during fetal life. The recent rise in the prevalence of TDS may be causally linked to endocrine disrupters affecting genetically susceptible individuals. We recommend that future epidemiological studies on trends in male reproduction do not focus on one symptom only, but take all aspects of TDS into account. The potential Impact of adverse environmental factors and the role of genetic polymorphisms involved in gonadal development requires further research.
Numerous reports have recently focused on various aspects of adverse trends in male reproductive health, such as the rising incidence of testicular cancer; low and probably declining semen quality; high and possibly increasing frequencies of undescended testis and hypospadias; and an apparently growing demand for assisted reproduction. Due to specialization in medicine and different ages at presentation of symptoms, reproductive problems used to be analysed separately by various professional groups, e.g. paediatric endocrinologists, urologists, andrologists and oncologists. This article summarizes existing evidence supporting a new concept that poor semen quality, testis cancer, undescended testis and hypospadias are symptoms of one underlying entity, the testicular dysgenesis syndrome (TDS), which may be increasingly common due to adverse environmental influences. Experimental and epidemiological studies suggest that TDS is a result of disruption of embryonal programming and gonadal development during fetal life. Therefore, we recommend that future epidemiological studies on trends in male reproductive health should not focus on one symptom only, but be more comprehensive and take all aspects of TDS into account. Otherwise, important biological information may be lost.
In psychobiological research on sexual orientation, the prenatal hormone theory has a central position. This article examines the hypothesis that prenatal estrogens contribute to the development of human sexual orientation. Several groups of women with a history of prenatal exposure to diethylstilbestrol (DES), a nonsteroidal synthetic estrogen, were compared with several samples of control women in the context of a comprehensive study of the psychiatric and psychologic effects of prenatal DES. Various aspects of sexual orientation were assessed by systematic interview. Consistently across samples, more DES-exposed women than controls were rated as bisexual or homosexual (scores 2-6 on Kinsey-format scales ranging from 0 to 6). The data are compatible with the hypothesis that prenatal estrogens may play a role in the development of human sexual orientation.