Levels of sexual differentiation: chromosomal, gonadal, and phenotypic

The Chromosomal Basis and the Bipotential Phase

Human primary sexual development begins with the genetic makeup established at the precise moment of fertilization. The presence or absence of specific chromosomes determines the initial genetic sex.

However, during the first six weeks of gestation, the embryonic body structure is completely undifferentiated and bipotential.

During this period, the embryo possesses the anatomical capacity to develop into any phenotype.

There is a common gonadal ridge and two pairs of internal rudimentary ducts known as the Wolffian and Müllerian ducts.

Furthermore, the external genital primordia remain identical in all human cases.

This shared anatomical template demonstrates that the biological construction of the body does not follow mutually exclusive pathways from the outset.

Subsequent anatomical divergence will depend on precise chemical and genetic signals that coordinate the activation or suppression of preexisting structures at this early embryonic stage.

Gonadal Determination and Genetic Cascades

Around the seventh week of development, the decisive shift toward gonadal formation occurs.

If the genetic makeup includes the male chromosome, the master SRY gene is activated, encoding the testis-determining factor.

This event stimulates the formation of male gonads composed of Sertoli and Leydig cells.

Conversely, in the absence of the SRY gene, an active transcriptional cascade is triggered, coordinated by specific genetic factors such as WNT4, DAX1, and FOXL2.

This molecular circuit actively blocks the testicular pathway and drives tissue differentiation toward female gonads composed of granulosa and theca cells.

Therefore, gonadal sex determination is not a passive, default event, but rather a genuine, regulated genetic contest.

The resulting gonadal structures will become the key endocrine centers responsible for orchestrating the differentiation of the rest of the organism through hormone synthesis.

The Expression of the Somatic and Genital Phenotype

The final level corresponds to phenotypic sex, divided into internal structures and external genitalia.

The male gonads secrete anti-Müllerian hormone via Sertoli cells, causing the Müllerian ducts to regress.

Simultaneously, testosterone secreted by Leydig cells rescues the internal Wolffian ducts, developing them into seminal vesicles and vas deferens.

In the absence of these masculinizing substances, the Müllerian ducts persist, forming the uterus, the fallopian tubes, and the upper vagina, while the Wolffian ducts atrophy.

Furthermore, the formation of the external genitalia begins in the ninth week from the genital tubercle, folds, and protrusions.

The local conversion of testosterone to dihydrotestosterone by the enzyme 5-alpha-reductase fully masculinizes the tissues, forming the penis and scrotum.

Without this potent androgen, the clitoris and labia develop, demonstrating the clear tissue homology among the different anatomical structures.

Summary

Sexual differentiation is a sequential biological process structured into three interconnected stages. It begins with chromosomal determination at conception and proceeds through an undifferentiated embryonic period of shared potential prior to gonadal development.

Gonadal determination occurs between the sixth and seventh weeks through active genetic networks. The SRY gene induces testis formation, while specific genes promote ovarian development, dispelling the notion that ovarian development is passive.

Finally, phenotypic sex shapes the internal reproductive tracts and external genital anatomy. This process is guided by the action—or absence—of key hormones and enzymes that determine the homologous male or female structures.