Genetic or chromosomal sex

Chromosomal sex is determined during the fertilization which is typically XX for female and XY for male. In the early stages, the embryo has the capability to differentiate either to male or female. The embryo at this stage is morphologically bisexual. Later on, genetic sex code is the one which will code for primitive testes or primitive ovaries.

Gonadal sex

At around 5th week after fertilization, the gonadal ridge develops from the urogenital ridge and it remains undifferentiated till the 7th week. This stage of development is called the indifferent stage. From this point, male and female differentiation is distinct from each other. In a genetically male foetus, the differentiation is triggered by the sex determining region Y (SRY) gene in the Y chromosome which activates the testis determining factor (TDF). As a result of this, immature germ cells and somatic cells organize to form testicular cords. Some cells in the cord differentiate into Sertoli cells because of the influence by TDF and they secrete Mullerian inhibiting substance (MIS) which plays an important role in ductal differentiation (see below). Certain stromal cells differentiate into Leydig cells which are responsible for the production of testosterone from 10 weeks.

Female gonadal sex differentiation is as a result of the absence of SRY gene and consequently the absence of MIS and testosterone which leads to uninhibited differentiation into ovaries. Although a single X chromosome is sufficient for female sex differentiation, two X chromosomes are required to maintain the oocytes in ovaries. This pattern can be observed in patients with 45X where the oocytes become atretic after initial development.

Ductal differentiation

Wolffian or mesonephric ducts and Mullerian or paramesonephric ducts are the two paired sets of ducts involved in ductal differentiation and eventually forming the internal genital organs. Paired Wolffian ducts are responsible for the development of male internal genital organs such as seminal vesicles, epididymis, vas deferens and ejaculatory ducts on either side. Similarly, the paired Mullerian ducts are responsible for the development of female internal organs such as uterus, fallopian tubes and upper vagina. The choice of the future ductal system is determined by the gonadal sex and later on maintained by hormonal influence. In males, the MIS is responsible for the degeneration of Mullerian ducts. This inhibiting influence of MIS on the paired Mullerian ducts is believed to happen only on the ipsilateral side. Hence, MIS has to be produced on both sides for the complete degeneration of Mullerian structures in males. The surviving Wolffian ducts are later on maintained by testosterone. In females, the Mullerian ducts develop into the future female internal genital structures without inhibition due to the absence of MIS and the Wolffian structures do not develop because of the absence of testosterone.

External genital structures

The development of external genitalia begins in the 3rd week at which stage both the male and female external genital structures appear the same. The cloacal folds fuse in the cranial aspect to form the genital tubercle and caudally they form urethral and anal folds. Genital swellings develop on either side of the urethral folds. After this stage, the differentiation of genital tubercle into male or female structures happens around 9 to 12 weeks and is completely dependent on the effect of androgens. The testicular descent is also influenced by the circulating androgens. In females, the absence of androgens leads to the development of female genital structures. Even in males, if the sensitivity of the tissues towards testosterone is less, it can lead to feminization of external genitalia like in patients with androgen insensitivity syndrome (AIS).

The differentiation and development of male and female sex from a morphologically bisexual stage is a complex process influenced by genetic and hormonal factors. Any anomaly in this entire process can lead to DSD of varying severity.