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Prenatal androgen exposure associated with male psychosexuality in disorders of sex development
Exposure to prenatal androgens, and not virilization of external genitalia, is associated with many psychosexual outcomes, including self-reported gender identity and sexual orientation, according to study findings published in The Journal of Clinical Endocrinology & Metabolism.
“The impacts of prenatal androgen exposure, appearance of the external genitalia, sex of rearing and [disorders of sexual development] etiology on human psychosexual development have not yet been fully established,” Rafael Loch Batista, MD, PhD, a physician researcher at the McKusick-Nathans Institute of Genetic Medicine at Johns Hopkins University, and colleagues wrote in the study background. “Such knowledge of the impact of these variables on human psychosexual development would be helpful for appropriated sex assignment in 46,XY [disorders of sexual development] patients and for a better comprehension of human psychosexual development.”
Batista and colleagues analyzed data from 144 adults with a clinical or molecular diagnosis of 46,XY disorders of sexual development (DSD; all with a 46,XY karyotype) followed at the developmental endocrinology unit at Hospital das Clinicas da Universidade de Sao Paulo. Researchers categorized patients according to sex assignment, degree of external genitalia virilization and prenatal androgen exposure. Additionally, patients were stratified by estimated prenatal androgen exposure based on specific DSD etiologies:
- patients without prenatal androgen exposure (n = 41), including those with complete androgen insensitivity syndrome (n = 24), complete gonadal dysgenesis (n = 7), Leydig cell hypoplasia (n = 7) and 17-alpha-hydroxylase deficiency with female external genitalia (n = 4);
- patients with intermediate androgen exposure (n = 70), including partial androgen insensitivity syndrome (n = 25), partial gonadal dysgenesis (n = 24), 3-beta-hydroxysteroid dehydrogenase type 2 deficiency (n = 3), 17-beta-hydroxysteroid dehydrogenase 3 deficiency (n = 15) and 17-alpha-hydroxylase deficiency (n = 3), all with atypical external genitalia; and
- patients with normal prenatal androgen exposure, including individuals with 5-alpha-reductase-2 deficiency (n = 32).
Researchers further stratified the group without prenatal androgen exposure into two subgroups: those with estrogen exposure (n = 31) and those with low or no estrogen exposure (n = 18). To evaluate whether the presence of androgens at puberty could influence psychosexual development, researchers stratified patients assigned as female into two groups according to age at gonadectomy ( age 12 years or age 16 years, with patients at pubertal age excluded). Gender role during childhood was defined by playmates, toy preference and gender behavior; gender identity and sexual orientation were assessed by self-report.
Within the cohort, 87% of participants were assigned female at birth.
Among patients assigned male at birth, partial androgen insensitivity syndrome was the most frequent 46,XY DSD diagnosis (47%), according to researchers, whereas 58% of participants assigned female at birth had typical female genitalia and 43% had variable degrees of genital undervirilization. Researchers observed no differences between patients with typical and atypical genitalia when considering self-reported gender role, preferred toys, playmates in childhood, gender identity, sexual orientation and frequency of gender change.
The researchers noted significant differences among the three groups according to prenatal androgen exposure in terms of gender role, gender identity, sexual orientation and frequency of gender change, and noted that normal prenatal androgen exposure was related to a higher frequency of male psychosexual outcomes.
In assessing patients with no prenatal androgen exposure who were exposed to prenatal estrogen (n = 24) or exposed to low or no prenatal estrogen (n = 18), researchers found no differences in psychosexual variables, including playmates, preferred toys, gender role in childhood, gender identity or sexual orientation. There were no cases of gender change in either group.
Within the cohort, 19% of participants (n = 27) underwent gender change, with 25 changing from female to male and two participants changing from male to female. There were no differences in social parameters among those who changed their gender vs. those who kept their assigned gender at birth, according to the researchers.
Additionally, the researchers wrote, the pubertal organizational effects of sex steroids were not enough to change psychosexual outcomes, suggesting that these effects are weaker than prenatal androgen exposure in human psychosexuality.
“In 46,XY DSD patients of both social sexes, the external genitalia appearance did not influence the psychosexual development,” the researchers wrote. “These results agree with the hypothesis that undervirilized external genitalia do not necessarily correspond to a nonvirilized central nervous system.”
The researchers noted that the discrepancy between brain and external genitalia virilization may be explained by sensitivity for androgens in both tissues occurring at different periods in pregnancy; virilization of external genitalia typically occurs at 6 to 8 weeks’ gestation, whereas brain virilization occurs typically in the second half of the pregnancy.
“We believe that our findings might help to guide the sex assignment of male newborns with atypical genitalia and to expand the knowledge on the influence of prenatal sexual steroids in the human psychosexuality,” the researchers wrote. – by Regina Schaffer
Disclosures: The authors report no relevant financial disclosures.