Prenatal Exposure to Diethylstilbestrol (DES) in Males and Gender-Related Disorders

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.

During the 1970s and 1980s an increased amount of public and scientific attention was paid to the health and medical problems of individuals whose mothers were prescribed diethylstilbestrol (DES). A potent synthetic nonsteroidal estrogen, DES was first developed in 1938 and initially became available in the U.S. for treating a range of gynecologic conditions in 1941 (Apfel and Fisher, 1984). A few years later its approval by the FDA was broadened to include treatment of pregnant women for the purpose of preventing miscarriages. Though its efficacy had long been questioned by some in the medical community (Bambigboye and Morris, 2003; Dieckmann, 1953), DES remained popular with doctors until discovery in the early 1970s of an apparent association between prenatal exposure to DES and a rare form of vaginal cancer in females whose mothers used DES (Heinonen, 1973; Herbst and Bern, 1981). Subsequent research confirmed the transplacental mechanism of DES transmission (Maydl, et al., 1983) and classified DES as a carcinogen and teratogen (Mittendorf, 1995) as well as a mutagen (Roy and Liehr, 1999; Stopper et al., 2005).

While DES usage with pregnant women was banned by the FDA in 1971, the drug continued to be used in several European countries into the early 1980s (Schrager and Potter, 2004). DES remained a popular option for treatment of advanced prostate cancer in aging males due to its ability to inhibit luteinizing hormone secretion by the pituitary and thus inhibit testosterone secretion (Scherr and Pitts, 2003; Whitesel, 2003), despite reports that adverse effects from this treatment could include feminization in males (B. C. Cancer Agency, 2005). Through the 1970s DES was also prescribed as an estrogen supplement for treatment of male-to-female transsexuals (Kwan, 1985; Ober, 1976).

It has been estimated that as many as four to five million American women were prescribed DES during pregnancy. Estimates of the numbers of "DES daughters" and "DES sons" born in the U.S. are between one million and three million of each (Edelman, 1986). Hundreds of thousands of DES sons and daughters were also born in 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.

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).

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.
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