Background: Brain sexual differentiation is a process that results from the effects of sex steroids on the developing brain. Evidence shows that epigenetics plays a main role in the formation of enduring brain sex differences and that the estrogen receptor a (ESR1) is one of the implicated genes. Aim: To analyze whether the methylation of region III (RIII) of the ESR1 promoter is involved in the biological basis of gender dysphoria. Methods: We carried out a prospective study of the CpG methylation profile of RIII (À1,188 to À790 bp) of the ESR1 promoter using bisulfite genomic sequencing in a cisgender population (10 men and 10 women) and in a transgender population (10 trans men and 10 trans women), before and after 6 months of gender-affirming hormone treatment. Cisgender and transgender populations were matched by geographical origin, age, and sex. DNAs were treated with bisulfite, amplified, cloned, and sequenced. At least 10 clones per individual from independent polymerase chain reactions were sequenced. The analysis of 671 bisulfite sequences was carried out with the QUMA (QUantification tool for Methylation Analysis) program. Outcomes: The main outcome of this study was RIII analysis using bisulfite genomic sequencing. Results: We found sex differences in RIII methylation profiles in cisgender and transgender populations. Cismen showed a higher methylation degree than ciswomen at CpG sites 297, 306, 509, and at the total fragment (P .003, P .026, P .001, P .006). Transmen showed a lower methylation level than trans women at sites 306, 372, and at the total fragment (P .0001, P .018, P .0107). Before the hormone treatment, transmen showed the lowest methylation level with respect to cisgender and transgender populations, whereas transwomen reached an intermediate methylation level between both the cisgender groups. After the hormone treatment, transmen showed a statistically significant methylation increase, whereas transwomen showed a non-significant methylation decrease. After the hormone treatment, the RIII methylation differences between transmen and transwomen disappeared, and both transgender groups reached an intermediate methylation level between both the cisgender groups. Clinical Implications: Clinical implications in the hormonal treatment of trans people. Strengths & Limitations: Increasing the number of regions analyzed in the ESR1 promoter and increasing the number of tissues analyzed would provide a better understanding of the variation in the methylation pattern. Conclusions: Our data showed sex differences in RIII methylation patterns in cisgender and transgender populations before the hormone treatment. Furthermore, before the hormone treatment, transwomen and

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The most probable cause of the inadequate TSH suppression in our patients was the reduction in bioavailability in certain batches of Levothroid, although we are unable to rule out the possibility that the results obtained after the changeover to Dexnon were due to its greater bioavailability. Simple changes in the manufacture of levothyroxine tablets may produce important variations in their bioavailability, having an adverse effect on the clinical control of the patients, and causing extra expense by the need for repeated patient visits and thyroid function tests.

Introduction Gender incongruence defines a state in which individuals feel discrepancy between the sex assigned at birth and their gender. Some of these people make a social transition from male to female (trans women) or from female to male (trans men). By contrast, the word cisgender describes a person whose gender identity is consistent with their sex assigned at birth. Aim To analyze the implication of the estrogen receptor α gene ( ESR1 ) in the genetic basis of gender incongruence. Main Outcome Measures Polymorphisms rs9478245, rs3138774, rs2234693, rs9340799. Method We carried out the analysis of 4 polymorphisms located at the promoter of the ESR1 gene (C1 = rs9478245, C2 = rs3138774, C3 = rs2234693, and C4 = rs9340799) in a population of 273 trans women, 226 trans men, and 537 cis gender controls. For SNP polymorphisms, the allele and genotype frequencies were analyzed by χ 2 test. The strength of the SNP associations with gender incongruence was measured by binary logistic regression. For the STR polymorphism, the mean number of repeats were analyzed by the Mann–Whitney U test. Measurement of linkage disequilibrium and haplotype frequencies were also performed. Results The C2 median repeats were shorter in the trans men population. Genotypes S/S and S/L for the C2 polymorphism were overrepresented in the trans men group ( P = .012 and P = .003 respectively). We also found overtransmission of the A/A genotype (C4) in the trans men population ( P = .017), while the A/G genotype (C4) was subrepresented ( P = .009]. The analyzed polymorphisms were in linkage disequilibrium. In the trans men population, the T(C1)-L(C2)-C(C3)-A(C4) haplotype was overrepresented ( P = .019) while the T(C1)-L(C2)-C(C3)-G(C4) was subrepresented ( P = .005). Conclusion The ESR1 is associated with gender incongruence in the trans men population. Fernández R, Delgado-Zayas E, Ramírez K, et al. Analysis of Four Polymorphisms Located at the Promoter of the Estrogen Receptor Alpha ESR1 Gene in a Population With Gender Incongruence. Sex Med 2020;8:490–500.