How Hormones Shape Sexual Development | Huberman Lab Essentials

Chromosomal sex (XX, XY, XXY, XYY) is only the starting point. Genes on the Y chromosome (e.g., SRY, the gene for Müllerian inhibiting hormone) influence gonadal sex by promoting testes and suppressing female reproductive structures (Müllerian ducts). Hormonal sex—patterns of testosterone, estrogen, DHT—and their receptor sensitivity then shape morphological sex (genitalia, body features) and brain organization, sometimes yielding discrepancies between chromosomes, gonads, anatomy, and identity.

In embryos with XY chromosomes and testes, testosterone is locally converted by 5-alpha-reductase into DHT in the genital tubercle, directing penis formation as a primary sexual characteristic. Later, during puberty, testosterone supports further genital growth and secondary traits (voice deepening, pubic hair), while DHT is the dominant androgen for aggression, strength, facial hair, and male pattern baldness. In 5-alpha-reductase deficiency (Guevedoces), lack of DHT causes babies to appear female at birth but develop male genitalia at puberty when testosterone surges.

Neuronally expressed aromatase converts testosterone to estrogen in the brain. This estrogen organizes neural circuits that underlie masculine sexual and territorial behavior repertoires. Later in life, circulating testosterone activates these preconfigured circuits, controlling the expression of those behaviors. Thus, testosterone and estrogen work in sequence: estrogen sets up the masculine brain circuitry; testosterone turns those circuits on when appropriate.

In androgen insensitivity syndrome (AIS), individuals with XY chromosomes and testes produce testosterone and have suppressed Müllerian ducts, but mutations in the androgen receptor prevent tissues from responding to testosterone. These individuals typically develop external female-appearing bodies, undescended internal testes, do not menstruate, and often subjectively experience themselves as female. This shows that hormone presence alone is insufficient; receptor function is essential for hormonal effects.

Atrazine, a widely used herbicide, causes severe testicular malformations and feminization in male frogs; large field surveys show 10–92% of males affected in some regions. Human data show major declines in sperm count and semen volume across decades (e.g., from ~113 million/mL in 1940 to ~66 million/mL in 1990 in the US and Western Europe), alongside disruptions in normal spermatogenesis. Such chemicals can alter testosterone- and estrogen-related pathways in both parents and offspring, likely contributing to fertility issues and shifted timing of puberty.