Genetic and endocrine bases of the development of sexual identity. Transsexuality

Sexual identity is a complex process that begins at conception and continues through adolescence, with genetic, endocrine, and environmental implications.

Joaquín Díaz Atienza

 

INTRODUCTION

I have finished reading an article by Rosa Mª Fernández García and Eduardo Pasaro Méndez published in Bioethics Notebooks.¹ It presents, in a way accessible to a non-specialized audience, the research carried out to date on the development of sexual identity.

In this post I intend to summarize the knowledge presented in the article, but in a way that is even more accessible to a general audience.

1. 1. The three sexes: chromosomal, gonadal, and cerebral

In cases of normality during fertilization (if no anomalies occur that give rise to any intersexuality), the chromosomal sex in the embryo. It will be a male embryo if it has 46, XY and it will be a female embryo if it has 46, XX.

Similarly, if normal embryonic and fetal development occurs, due to genetic conditioning, the undifferentiated gonads, will transform into testicles in case 46, XY (male) or ovaries In case 46, XX (women). This is what is called the gonadal sex.

Finally, the hormonal action of androgens and estrogens during critical developmental periods will give rise to cerebral sexual differentiation, which under normal circumstances is congruent with gonadal differentiation. Therefore, the brain sex This is due to the direct action of sex hormones, with genetics playing an indirect role.

It is very important to differentiate these three sexes because they will follow a different temporal sequence, although the interaction between them is evident.

2. 2. Biological development of sexual differentiation

Both the brain and the gonads originate from bipotential organs. What determines sexual dimorphism (that is, testes in men or ovaries in women) is the genetic result derived from the presence of the 46,XY karyotype in men or the 46,XX karyotype in women, along with the presence of... SRY gene which is found only on the Y chromosome. Specifically, it is the presence of the SRY gene that causes the testes to develop in men from undifferentiated gonads. In women, who do not have the SRY gene, the undifferentiated gonads develop into ovaries.

The testicles begin to synthesize testosterone from the second trimester of pregnancy, while the ovaries remain inactive until the perinatal period.

Let's look at how the masculinization and feminization of the brain occur.

a)  Brain masculinization

The key hormone for masculinization, both of the male sex organs and brain, is testosterone, derived from a aromatization process.

The process is as follows:

1. 1. During embryogenesis, aromatase (CYP19A1) produces aromatization of brain testosterone, transforming it into estradiol.

1. 1. Estradiol binds to estrogen receptors (ER), contributing to the masculinization and feminization of specific brain areas.

1. 1. In short, the action of estradiol is to promote male circuits and suppress female ones.

1. 1. Elevated estrogen levels, through the aromatization of testosterone, contribute to brain masculinization.

1. 1. Both fetal environmental conditions and genetics contribute to greater or lesser brain masculinization.

b) Cerebral feminization

It usually occurs during a critical period of development and happens under the following circumstances:

1. 1. The existence of excessively low levels of steroids for brain masculinization to occur.

1. 1. During the critical period the ovaries remain inactive.

1. 1. Alpha-fetoprotein protects the brain from masculinization by preventing estrogen from entering the brain.

1. 1. Therefore, as we can deduce from the above, the female phenotype is not the isolated result of the presence of the SRY gene, but also requires low levels of estrogen during the critical perinatal period.

1. 1. Therefore, if a fetus with a female karyotype is exposed to high levels of testosterone or estradiol during the critical perinatal period, its brain will become masculinized despite its female karyotype.

1. 1. Biological bases of gender dysphoria (302.6 – F64.2 – DSM 5)

The etiopathogenesis of gender dysphoria (GD) It is multifactorial, with some factors being more important than others. For some, gender dysphoria arises from the discrepancy between gonadal sex and brain sex. They support their explanation with the proven fact that the brain morphology of transgender men and women differs from that of non-transgender individuals.

Other arguments would be based on the probable abnormal action of sex hormones in specific brain areas.

What is well known is that androgen receptors (AR) and estrogen receptors alpha and beta (ERα and ERβ) are involved in the defeminization of the brain. Similarly, ERα is directly involved in brain masculinization, while ERβ is involved in defeminization.

a) Brain action of estrogens at the cellular level

1. 1. Estrogens enter the cell by specifically binding to their receptor, alpha or beta.

1. 1. Dimerization occurs, resulting in a conformational change (Figure 4).

1. 1. Next, the hormone-receptor complex enters the cell nucleus and binds to specific DNA sequences located near promoter regions.

1. 1. This is followed by a cascade transcription process of the genes related to sexual development.

Given the above, it is believed that AR receptors, ER alpha and beta, and aromatase are the factors directly involved in the development of brain sex and indirectly involved in its genetic basis.

b) Main molecular results

Every day, the molecular mechanisms that give rise to gestational diabetes are being understood with greater precision. Science transcends ideologies and highlights the objectivity of what is happening in this field, which is so steeped in prejudices of all kinds.

• • Female-to-Male (FtoM) Transsexuality

The involvement of ER alpha and ER beta receptors as a genetic basis for gestational diabetes (GD) has been confirmed. A greater number of ER beta repeats is associated with greater susceptibility to GD. ER alpha and beta receptors appear to be independently associated with GD.

• • Male/Female (MtoF) Transsexuality

The AR receptor (androgen receptor) is involved in gestational diabetes (GD), although it is not entirely determining but is necessary. What increases the risk of GD is the combination of specific forms of AR and ER beta, or the combination of ER beta and aromatase.

Conclusion

The researchers FHernández García and Pásaro Méndez They conclude that:

"1. Sexual identity is not a choice, but is configured prenatally.

2. 2. It is an integral part of our innermost self.

2. 2. Although social, educational, and psychological influences cannot be excluded, sexual identity is genetically determined and has a very important hormonal component.

2. 2. Its foundation is not ideological, but cerebral.

2. 2. Science supports the existence of sexual dimorphism.

2. 2. Although the first symptoms of DG appear during early childhood, its semiology may disappear in puberty, perhaps due to the profound hormonal changes that occur during it.

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