Low Perinatal Androgens Predict Recalled Childhood Gender Nonconformity in Men

Abstract

The contributions of gonadal hormones to the development of human behavioral sex differences are subjects of intense scientific and social interest. Isolated gonadotropin-releasing-hormone deficiency (IGD) is a rare endocrine disorder that can reveal a possible role of early gonadal hormones. IGD is characterized by low or absent gonadal hormone production after the first trimester of gestation, but external genitalia and hence gender of rearing are concordant with chromosomal and gonadal sex. We investigated recalled childhood gender nonconformity in men (n = 65) and women (n = 32) with IGD and typically developing men (n = 463) and women (n = 1,207). Men with IGD showed elevated childhood gender nonconformity, particularly if they also reported undescended testes at birth, a marker of low perinatal androgens. Women with IGD did not differ from typically developing women. These results indicate that early androgen exposure after the first trimester contributes to male-typical gender-role behaviors in childhood.

Keywords: androgens; childhood gender nonconformity; isolated gonadotropin-releasing-hormone deficiency; open data; open materials; sex differences; sex hormones.

Fig. 1.

Some putative causes of sex differences in behavior and possible combinations of external anatomy and perinatal testosterone exposure. Behavioral sex differences may result from direct effects of gonadal hormones on patterns of gene expression in the developing brain (a, top row) and/or effects on external anatomy, which influences interactions with the environment, including gender socialization (a, bottom row). These factors can be partially disentangled by examining individuals whose perinatal testosterone exposure differs from that of typically developing individuals with similar external anatomy (unshaded cells in b). XX IGD = females with isolated gonadotropin-releasing-hormone deficiency; XY IGD = males with isolated gonadotropin-releasing-hormone deficiency; XX CAH = females with congenital adrenal hyperplasia; XY GR = males whose gender was reassigned to female in infancy.

Fig. 2.

Approximate human chorionic gonadotropin (hCG) and gonadal sex-steroid production in males (upper graph) and females (lower graph). In typical males, androgen production begins at roughly the 8th week of gestation with the differentiation of the bipotential gonads into testes (Negri-Cesi et al., 2004; Pardue & Wizemann, 2001; Siiteri & Wilson, 1974) and persists until the 24th week (Forest et al., 1973). In typical females, estrogen levels progressively increase across gestation, peaking perinatally, although ovarian activity transiently ceases in the immediate postpartum period between birth and the onset of minipuberty (Lanciotti et al., 2018). In individuals with isolated gonadotropin-releasing-hormone deficiency (IGD), gonadal hormone production declines as circulating hCG levels wane. Figure adapted from Lanciotti et al. (2018). FSH = follicle-stimulating hormone; LH = luteinizing hormone.

Fig. 3.

Mean childhood gender-nonconformity scores in men. Comparisons are shown separately for (a) the two groups who had isolated gonadotropin-releasing-hormone deficiency (IGD) and the control group, (b) the control group and individuals born with and without cryptorchidism (cryp+ and cryp–, respectively), and (c) the control group and individuals born with and without microphallus (micro+ and micro–, respectively). Larger symbols with white shading and associated error bars show group means and 95% confidence intervals, respectively. Smaller symbols show individual scores, and the width of the shaded areas indicates the density of the data. Vertical and horizontal jitter were added to individual points to aid in data visualization. Significance values are shown in (a) between the control group and the two IGD groups together and between the two IGD groups only and in (b) and (c) for both linear and quadratic effects.

Fig. 4.

Mean childhood gender-nonconformity scores in women, separately for the two groups who had isolated gonadotropin-releasing-hormone deficiency (IGD) and the control group. Larger symbols with white shading and associated error bars show group means and 95% confidence intervals, respectively. Smaller symbols show individual scores, and the width of the shaded areas indicates the density of the data. Vertical and horizontal jitter were added to individual points to aid in data visualization. Significance values are shown between the control group and the two IGD groups together and between the two IGD groups only.