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Association between repeat number polymorphisms of sex hormone-related genes and gender phenotype variations in

Mizuho Igarashi^1,2, Yuko Katoh-Fukui¹, Atsushi Hattori¹

¹Department of Molecular Endocrinology, National Research Institute for Child Health and Development, Tokyo 157-8535, Japan.

Sexual Medicine

|August 19, 2025

Abstract

Background:

Although common repeat number polymorphisms in 3 hormone-related genes (AR, CYP19A1, and ESR2) have been implicated in the variations in several sexually dimorphic phenotypes, their contributions to the variations in gender identity (GI) and sexual orientation (SO) remain to be clarified.

Aim:

To clarify the possible association between the repeat number polymorphisms and gender phenotype variations in the general population.

Methods:

We used paper-based questionnaires to select 80 individuals with atypical gender phenotypes (the case group) and 114 control individuals (the control group) from 736 university students. The case group was further divided into two subgroups: one consisted of individuals with low GI scores (the atypical GI subgroup), and the other consisted of individuals with non-heterosexual orientation (the atypical SO subgroup). Repeat numbers of the longer and shorter alleles in each participant (Alleles 1 and 2) were examined through microsatellite analysis. Repeat numbers of AR in females were adjusted for the X chromosome inactivation status.

Outcomes:

We examined the statistical differences in the repeat numbers between the case and control groups, and between each subgroup and the control group.

Results:

The overall differences between the case and control groups and between each subgroup and the control group were small. However, the repeat numbers of AR in males of the case group were larger than those of the control group (P = 0.049), and the repeat numbers of ESR2 Allele 1 were larger in males of the atypical GI subgroup than in those of the control group (P = 0.046). In addition, females in the atypical SO subgroup had smaller repeat numbers of CYP19A1 Allele 2 than control females (P = 0.011).

Clinical Implications:

These results indicate the complex genetic basis of gender phenotype variations.

Strengths & Limitations:

This is the first study that addresses the possible association between common polymorphisms in hormone-related genes and gender phenotypes in the general population. Given the small number of our subjects and the modest differences in the repeat numbers between the case and control groups, our results await further validation.

Conclusion:

The results indicate that the contribution of repeat number polymorphisms of the 3 genes to gender phenotype variations in the general population is small, although the repeat numbers of AR and ESR2 are potentially associated with atypical gender phenotypes in males.

Keywords:

androgen estrogen gender identity polymorphism sex hormone receptor sexual orientation

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