Gender identity disorders: a legacy of fetal exposition to Diethylstilbestrol, an Endocrine Disruptor Chemical
Main Article Content
Abstract
Several data analysed in the first part of this report demonstrate that fetal exposure to xenoestrogen Diethylstilbestrol could have a significant impact on the sexual orientation identity and gender-related behavior: for example, the increase of cases of male homosexuality and the decrease in cases of female homosexuality in US populations of children prenatally exposed to Diethylstilbestrol.
In the second part of this work, we report several cases from the French cohort HHORAGES of transgender identity change, Male to Female, of individuals formerly exposed in utero to Diethylstylbestrol. This high prevalence (1,58%) of male to female transgenderism on a cohort of 253 Diethylstilbestrol sons demonstrates for the first time that exposure to xenoestrogen during fetal life has an effect on male sex identity and behavior. Moreover, a qualitative study still in progress realized via the Association Diethylstilbestrol-Sons USA reveals a significant percentage of XY male-to-female transsexuals among a population in utero exposed to Diethylstilbestrol.
In the third part of this article, we report from a study of The University California Los Angeles, School of Law's Williams Institute, in 2022 and from a major IPSOS Institute survey in 2024 on the dramatic increase in gender dysphoria among adolescents identifying as “Trans” and whose number in the USA has doubled to 1.6 million during the 5 years between 2017 and 2022.
It is highly likely that other endocrine disruptors than Diethylstilbestrol, also mediated by the identical estrogen nuclear receptors ER α and ER β activity, may have the same effect on human sexual identity.
Keywords:
Synthetic sex hormones, Diethylstilbestrol, Fetal exposure, Sexual orientation identity, Endocrine Disruptor Chemical(s).
Article Details
How to Cite
SOYER-GOBILLARD, Marie-Odile; GASPARI, Laura; SULTAN, Charles.
Gender identity disorders: a legacy of fetal exposition to Diethylstilbestrol, an Endocrine Disruptor Chemical.
Medical Research Archives, [S.l.], v. 13, n. 3, mar. 2025.
ISSN 2375-1924.
Available at: <https://esmed.org/MRA/mra/article/view/6342>. Date accessed: 06 apr. 2025.
doi: https://doi.org/10.18103/mra.v3i3.6342.
Section
Research Articles
The Medical Research Archives grants authors the right to publish and reproduce the unrevised contribution in whole or in part at any time and in any form for any scholarly non-commercial purpose with the condition that all publications of the contribution include a full citation to the journal as published by the Medical Research Archives.
References
1. Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition, Text Revision (DSM-5-TR). American Psychiatric Association Publishing. 2024. 1,275 pp. https://Doi/book/10.1176/appi.books.9780890425787
2. Soyer-Gobillard MO, Gaspari L, Paris F et al. Effects of prenatal exposure to synthetic sex hormones on neurodevelopment: a biological mechanism. Front Mol Neurosci., 2023; 16 :12374 29. Doi: 10.3389/fnmol.2023.1237429.
3. Gaspari L, Soyer-Gobillard MO, Kerlin S et al. Early Female Transgender Identity after Prenatal Exposure to Diethylstilbestrol: Report from a French National Diethylstilbestrol (DES) Cohort. J Xenobiot. 2024; 14(1):166-175. Doi: 10.3390/jox14 010010.
4. Troisi R, Palmer JR, Hatch EE et al. Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol. Arch Sex Behav. 2020; 49(2): 447-454. Doi: 10.1007/s 10508-020-01637-7. Epub 2020 Jan 23.
5. Haney AF, Newbold RR, McLachlan JA. Prenatal diethylstilbestrol exposure in the mouse: Effects on ovarian histology and steroidogenesis in vitro. Biology of Reproduction 1984; 30: 471-478.
6. Adamson NA, Brokken LJ, Paranko J et al. In vivo and in vitro effects of flutamide and diethylstilbestrol on fetal testicular steroidogenesis in the rat. Reproductive Toxicology 2008; 25: 76-83. Doi :10.1016
7. Maimoun L, Philibert P, Cammas B, et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: An extensive international experience of 55 patients. J. Clin. Endocrinol. Metab. 2011; 96 : 296–307. Doi : 10.1210/jc.2010-1024. Epub 2010 Dec 8.
8. Sultan C Gaspari L Kalfa N et al. Chapter 16 Androgen insensitivity syndrome. In Genetic Steroid Disorders, 2nd ed.; New, M.I., Ed. Academic Press: San Diego CA USA 2023 pp. 327–341.
9. Soyer-Gobillard MO, Paris F, Gaspari L et al. Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children. Gynecol Endocrinol. 2016; 32(1): 25- 29. Doi: 10.3109/09513590.2015.1063604. Epub 2015 Jul 14.
10. Soyer-Gobillard MO, Gaspari L, Yao P, Sultan Ch. Prenatal exposure to progestins: impact on neurodevelopment of the child. (25 pp., 2 Figs., 5 Tables). In: C. Martin, V.R. Preedy & R. Rajendram (Eds), Factors affecting Neurodevelopment 2021 Academic Press London/Elsevier Inc. 34, pp. 395-408.
11. Soyer-Gobillard MO, Sultan Ch. Behavioral and Somatic Disorders in Children exposed in utero to Synthetic Hormones: A Testimony-Case Study in a French Family Troop. In: “State of the Art of Therapeutic Endocrinology”, Sameh Magdeldin Ed, Niigata University, Japan. InTech, 2012, pp. 67-86.
12. Soyer-Gobillard M.-O, Gaspari L, Sultan C. Some Insights into the Impact of Exposure to Synthetic Sex Hormones on the Human Cen¬tral Nervous System: A Never-Ending Story. J Sexual Med Reprod Health 2024; 5: 7.
13. Palmer JR, Wise LA, Hatch EE et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarker Prev. 2006; 15 :1509-1514. Doi: 10.1158/1055-9965.EPI-06-0109.
14. Tournaire M, Devouche E, Epelboin S et al. Diethylbestrol exposure: evaluation of the doses received in France. Eur. J. of Epidemiology 2012; 27 (4): 315-318. Doi: 10.1007/s10654-012-9677-7
15. Frisen L, Söder O, Rydelius PA. Dramatic increase of gender dysphoria in youth. Lakartidningen. 2017; 114: EFMY
16. Di Ciglie D. Autonomy and decision-making in children and young people with gender dysphoria. In: Shaw M & Bailey S (Eds) Justice for children and families: A development perspective 2018 pp.145-153. Cambridge UK: Cambridge University Press.
17. UCLA School of Laws’s Williams Institute. Report on Trangenders, 2022. California, USA.
18. IPSOS LGBT+ PRIDE REPORT 2024. A 26-Country Ipsos Global Advisor Survey. June 2024 © Ipsos | LGBT+ Pride 2024.
19. Dodds EG, Goldberg L, Larson W et al. Oestrogenic activity of certain synthetic compounds. Nature. 1938 ; 141 : 247-248.
20. Lacassagne A. The appearance of mammary adenocarcinomas in male mice treated by a synthetic estrogenic substance. Weekly reports of the Society of Biology and its affiliates. 1938; 12 : 641-643.
21. Tournaire M, Epelboin S, Devouche E. Histoire du Diethylstilbestrol. Therapie. 2014 ; 69 : 101-114.
22. Kebir O, Krebs MO. Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights. World J Biol Psychiatry. 2012; 13(2): 84-95. https://Doi.org/10.3109/15622975.2011.560280
23. Quenneville S, Verde G, Corsinotti A et al. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011 ;44(3) :36172. https://Doi.org/10.1016/j.molcel.2011. 08.032 PMID :22055183
24. Lemarchant S, Pruvost M, Montaner J et al. ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation. 2013; 10: 133. https:// Doi.org/10.1186/1742-2094-10-133.
25. Mittaz L, Russell DL, Wilson T, et al. ADAMTS-1 is essential for the development and function of the urogenital system. Biol Reprod. 2004; 70: 1096-1105 https://Doi.org/10.1095/biolreprod.103.023911.
26. Rivollier F, Chaumette B, Bendjemaa N, et al. Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol. PloS One. 2017; 12 (4): 1–18.
https://Doi.org/10.1371/journal.pone.0174783. e0174783.
27. Kioumourtzoglou MA, Coull BA, O'Reilly ÉJ et al. Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits. JAMA Pediatr. 2018; 172(7):670-677. Doi: 10.1001/jamapediatrics.2018.0 727.PMID : 29799929.
28. Gaspari L, Soyer-Gobillard MO, Paris F et al. Multigenerational endometriosis: Consequence of fetal contamination by DES in an informative family. Environmental Health. 2021; 20(1): 96. ff10.1186/s12940-021-00780-5ff. ffhal- 03338915
29. Soyer-Gobillard MO, Gaspari L, Paris F et al. Prenatal contamination by DES and multigenerational transmission of psychiatric disorders in an informative family. International Journal of Environmental Research and Public Health. 2021; 18 (19): 9965, https://Doi.org/10.3390 /ijerph 1819996.
30. Zou Y, Lu Q, Zheng et al. Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. Molecular Autism. 2017; 8: 1–16. https://Doi.org/ 10.1186/s13229-017-0159-3.
31. Kniper GG, Carlsson B, Grandien K et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogenreceptors alpha and beta. Endocrinology. 1997; 138: 863-870.
32. Meyer-Bahlburg HF, Ehrhardt AA, Feldman JF et al. Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol. Psychosomat Med. 1985 ; 47 (6) :497-511.
33. Ehrhardt AA, Feldman JF, Rosen LR, et al. Psychopathology in prenatally DES-exposed females current and life-time adjustement. Psychosomat Med. 1987; 49 (2):183-196.
34. Newbold RR. Gender related bahavior in women exposed to Diethylstilbestrol. Env Health Perspectives. 1993 ; 101 (3) : 208-213.
35. Meyer-Bahlburg HFL, Ehrhardt AA, Rosen LR et al. Prenatal estrogens and the development of homosexual orientation. Developmental Psychology. 1995; 31(1): 12–21. https://Doi.org/10.1037/0012-1649.31.1.12
36. Titus-Ernstoff L, Perez K, Hatch EE et al. Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol. Epidemiology. 2003; 14: 155–160.
37. Leary F, Resseguie L, Kurland L et al. Males exposed in utero to diethylstilbestrol. J. of American Medical Association. 1984; 252: 2984-2989.
38. Özel1 F, Rüegg J. Exposure to endocrine-disrupting chemicals and implications for neurodevelopment. Dev Med Child Neurol. 2023; 65:1005–1011. Doi : 10.1111/dmcn.15551.
39. Ramírez V, Gálvez-Ontiveros V, González-Domenech PJ et al. Role of endocrine dirupting chemicals in children neurodevelopment. Environmental Research. 2022; 203: 111890. https://Doi.org/10.1016/j.envres.2021.111890
40. Yang Z, Zhang J, Wang M et al. Prenatal endocrine-disrupting chemicals exposure and impact on offspring neurodevelopment: a systematic review and meta-analysis. NeuroToxicology. 2024; 103: 335-357. PMID :39013523 Doi: 10.1016/j.neuro.2024.07.006
41. Foreman M, Hare L, York K et al. Genetic Link Between Gender Dysphoria and Sex Hormone Signaling. J. Clin. Endocrinol. Metab. 2019; 104: 390–396. Doi: 10.1210/jc.2018-01105.
42. Robotti S. The heritable legacy of diethylstilbestrol: a bellwether for endocrine disruption in humans. Biol Reprod, 2021; Sep 14 ;105(3): 687-689. https://Doi: 10.1093/biolre/ioab146.
43. Titus L. Evidence of intergenerational transmission of diethylstilbestrol health effects: hindsight and insight. Biol Reprod. 2021; 105(3) : 681-686. Doi: 10.1093/biolre/ioab153.
2. Soyer-Gobillard MO, Gaspari L, Paris F et al. Effects of prenatal exposure to synthetic sex hormones on neurodevelopment: a biological mechanism. Front Mol Neurosci., 2023; 16 :12374 29. Doi: 10.3389/fnmol.2023.1237429.
3. Gaspari L, Soyer-Gobillard MO, Kerlin S et al. Early Female Transgender Identity after Prenatal Exposure to Diethylstilbestrol: Report from a French National Diethylstilbestrol (DES) Cohort. J Xenobiot. 2024; 14(1):166-175. Doi: 10.3390/jox14 010010.
4. Troisi R, Palmer JR, Hatch EE et al. Gender Identity and Sexual Orientation Identity in Women and Men Prenatally Exposed to Diethylstilbestrol. Arch Sex Behav. 2020; 49(2): 447-454. Doi: 10.1007/s 10508-020-01637-7. Epub 2020 Jan 23.
5. Haney AF, Newbold RR, McLachlan JA. Prenatal diethylstilbestrol exposure in the mouse: Effects on ovarian histology and steroidogenesis in vitro. Biology of Reproduction 1984; 30: 471-478.
6. Adamson NA, Brokken LJ, Paranko J et al. In vivo and in vitro effects of flutamide and diethylstilbestrol on fetal testicular steroidogenesis in the rat. Reproductive Toxicology 2008; 25: 76-83. Doi :10.1016
7. Maimoun L, Philibert P, Cammas B, et al. Phenotypical, biological, and molecular heterogeneity of 5α-reductase deficiency: An extensive international experience of 55 patients. J. Clin. Endocrinol. Metab. 2011; 96 : 296–307. Doi : 10.1210/jc.2010-1024. Epub 2010 Dec 8.
8. Sultan C Gaspari L Kalfa N et al. Chapter 16 Androgen insensitivity syndrome. In Genetic Steroid Disorders, 2nd ed.; New, M.I., Ed. Academic Press: San Diego CA USA 2023 pp. 327–341.
9. Soyer-Gobillard MO, Paris F, Gaspari L et al. Association between fetal DES-exposure and psychiatric disorders in adolescence/adulthood: evidence from a French cohort of 1002 prenatally exposed children. Gynecol Endocrinol. 2016; 32(1): 25- 29. Doi: 10.3109/09513590.2015.1063604. Epub 2015 Jul 14.
10. Soyer-Gobillard MO, Gaspari L, Yao P, Sultan Ch. Prenatal exposure to progestins: impact on neurodevelopment of the child. (25 pp., 2 Figs., 5 Tables). In: C. Martin, V.R. Preedy & R. Rajendram (Eds), Factors affecting Neurodevelopment 2021 Academic Press London/Elsevier Inc. 34, pp. 395-408.
11. Soyer-Gobillard MO, Sultan Ch. Behavioral and Somatic Disorders in Children exposed in utero to Synthetic Hormones: A Testimony-Case Study in a French Family Troop. In: “State of the Art of Therapeutic Endocrinology”, Sameh Magdeldin Ed, Niigata University, Japan. InTech, 2012, pp. 67-86.
12. Soyer-Gobillard M.-O, Gaspari L, Sultan C. Some Insights into the Impact of Exposure to Synthetic Sex Hormones on the Human Cen¬tral Nervous System: A Never-Ending Story. J Sexual Med Reprod Health 2024; 5: 7.
13. Palmer JR, Wise LA, Hatch EE et al. Prenatal diethylstilbestrol exposure and risk of breast cancer. Cancer Epidemiol Biomarker Prev. 2006; 15 :1509-1514. Doi: 10.1158/1055-9965.EPI-06-0109.
14. Tournaire M, Devouche E, Epelboin S et al. Diethylbestrol exposure: evaluation of the doses received in France. Eur. J. of Epidemiology 2012; 27 (4): 315-318. Doi: 10.1007/s10654-012-9677-7
15. Frisen L, Söder O, Rydelius PA. Dramatic increase of gender dysphoria in youth. Lakartidningen. 2017; 114: EFMY
16. Di Ciglie D. Autonomy and decision-making in children and young people with gender dysphoria. In: Shaw M & Bailey S (Eds) Justice for children and families: A development perspective 2018 pp.145-153. Cambridge UK: Cambridge University Press.
17. UCLA School of Laws’s Williams Institute. Report on Trangenders, 2022. California, USA.
18. IPSOS LGBT+ PRIDE REPORT 2024. A 26-Country Ipsos Global Advisor Survey. June 2024 © Ipsos | LGBT+ Pride 2024.
19. Dodds EG, Goldberg L, Larson W et al. Oestrogenic activity of certain synthetic compounds. Nature. 1938 ; 141 : 247-248.
20. Lacassagne A. The appearance of mammary adenocarcinomas in male mice treated by a synthetic estrogenic substance. Weekly reports of the Society of Biology and its affiliates. 1938; 12 : 641-643.
21. Tournaire M, Epelboin S, Devouche E. Histoire du Diethylstilbestrol. Therapie. 2014 ; 69 : 101-114.
22. Kebir O, Krebs MO. Diethylstilbestrol and risk of psychiatric disorders: a critical review and new insights. World J Biol Psychiatry. 2012; 13(2): 84-95. https://Doi.org/10.3109/15622975.2011.560280
23. Quenneville S, Verde G, Corsinotti A et al. In embryonic stem cells, ZFP57/KAP1 recognize a methylated hexanucleotide to affect chromatin and DNA methylation of imprinting control regions. Mol Cell. 2011 ;44(3) :36172. https://Doi.org/10.1016/j.molcel.2011. 08.032 PMID :22055183
24. Lemarchant S, Pruvost M, Montaner J et al. ADAMTS proteoglycanases in the physiological and pathological central nervous system. J Neuroinflammation. 2013; 10: 133. https:// Doi.org/10.1186/1742-2094-10-133.
25. Mittaz L, Russell DL, Wilson T, et al. ADAMTS-1 is essential for the development and function of the urogenital system. Biol Reprod. 2004; 70: 1096-1105 https://Doi.org/10.1095/biolreprod.103.023911.
26. Rivollier F, Chaumette B, Bendjemaa N, et al. Methylomic changes in individuals with psychosis, prenatally exposed to endocrine disrupting compounds: Lessons from diethylstilbestrol. PloS One. 2017; 12 (4): 1–18.
https://Doi.org/10.1371/journal.pone.0174783. e0174783.
27. Kioumourtzoglou MA, Coull BA, O'Reilly ÉJ et al. Association of Exposure to Diethylstilbestrol During Pregnancy With Multigenerational Neurodevelopmental Deficits. JAMA Pediatr. 2018; 172(7):670-677. Doi: 10.1001/jamapediatrics.2018.0 727.PMID : 29799929.
28. Gaspari L, Soyer-Gobillard MO, Paris F et al. Multigenerational endometriosis: Consequence of fetal contamination by DES in an informative family. Environmental Health. 2021; 20(1): 96. ff10.1186/s12940-021-00780-5ff. ffhal- 03338915
29. Soyer-Gobillard MO, Gaspari L, Paris F et al. Prenatal contamination by DES and multigenerational transmission of psychiatric disorders in an informative family. International Journal of Environmental Research and Public Health. 2021; 18 (19): 9965, https://Doi.org/10.3390 /ijerph 1819996.
30. Zou Y, Lu Q, Zheng et al. Prenatal levonorgestrel exposure induces autism-like behavior in offspring through ERβ suppression in the amygdala. Molecular Autism. 2017; 8: 1–16. https://Doi.org/ 10.1186/s13229-017-0159-3.
31. Kniper GG, Carlsson B, Grandien K et al. Comparison of the ligand binding specificity and transcript tissue distribution of estrogenreceptors alpha and beta. Endocrinology. 1997; 138: 863-870.
32. Meyer-Bahlburg HF, Ehrhardt AA, Feldman JF et al. Sexual activity level and sexual functioning in women prenatally exposed to diethylstilbestrol. Psychosomat Med. 1985 ; 47 (6) :497-511.
33. Ehrhardt AA, Feldman JF, Rosen LR, et al. Psychopathology in prenatally DES-exposed females current and life-time adjustement. Psychosomat Med. 1987; 49 (2):183-196.
34. Newbold RR. Gender related bahavior in women exposed to Diethylstilbestrol. Env Health Perspectives. 1993 ; 101 (3) : 208-213.
35. Meyer-Bahlburg HFL, Ehrhardt AA, Rosen LR et al. Prenatal estrogens and the development of homosexual orientation. Developmental Psychology. 1995; 31(1): 12–21. https://Doi.org/10.1037/0012-1649.31.1.12
36. Titus-Ernstoff L, Perez K, Hatch EE et al. Psychosexual characteristics of men and women exposed prenatally to diethylstilbestrol. Epidemiology. 2003; 14: 155–160.
37. Leary F, Resseguie L, Kurland L et al. Males exposed in utero to diethylstilbestrol. J. of American Medical Association. 1984; 252: 2984-2989.
38. Özel1 F, Rüegg J. Exposure to endocrine-disrupting chemicals and implications for neurodevelopment. Dev Med Child Neurol. 2023; 65:1005–1011. Doi : 10.1111/dmcn.15551.
39. Ramírez V, Gálvez-Ontiveros V, González-Domenech PJ et al. Role of endocrine dirupting chemicals in children neurodevelopment. Environmental Research. 2022; 203: 111890. https://Doi.org/10.1016/j.envres.2021.111890
40. Yang Z, Zhang J, Wang M et al. Prenatal endocrine-disrupting chemicals exposure and impact on offspring neurodevelopment: a systematic review and meta-analysis. NeuroToxicology. 2024; 103: 335-357. PMID :39013523 Doi: 10.1016/j.neuro.2024.07.006
41. Foreman M, Hare L, York K et al. Genetic Link Between Gender Dysphoria and Sex Hormone Signaling. J. Clin. Endocrinol. Metab. 2019; 104: 390–396. Doi: 10.1210/jc.2018-01105.
42. Robotti S. The heritable legacy of diethylstilbestrol: a bellwether for endocrine disruption in humans. Biol Reprod, 2021; Sep 14 ;105(3): 687-689. https://Doi: 10.1093/biolre/ioab146.
43. Titus L. Evidence of intergenerational transmission of diethylstilbestrol health effects: hindsight and insight. Biol Reprod. 2021; 105(3) : 681-686. Doi: 10.1093/biolre/ioab153.