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II. Normal Sex Differentiation

Human sexual differentiation is a complicated process. In a simple manner, one can describe four major steps which constitute normal sexual differentiation. These four steps are:

  1. Fertilization and determination of genetic sex
  2. Formation of organs common to both sexes
  3. Gonadal differentiation
  4. Differentiation of the internal ducts and external genitalia

Step 1: Fertilization and Determination of Genetic Sex

The first step of sex differentiation takes place at fertilization. An egg from the mother, which contains 23 chromosomes (including an X chromosome), is combined with a sperm from the father, which also contains 23 chromosomes (including either an X or Y chromosome). Therefore, the fertilized egg has either a 46,XX (genetic female) or 46,XY (genetic male) karyotype.

Step 1 in sex differentiation:
Determination of genetic sex
Egg (23,X) + Sperm (23,X) = 46,XX genetic girl
OR
Egg (23,X) + Sperm (23, Y) = 46, XY genetic boy

Step 2: Formation of Organs Common to Both Sexes

The fertilized egg multiplies to form a large number of cells, all of which are similar to each other. However, at specific times during the growth of an embryo, the cells differentiate to form the various organs of the body. Included in this development is the differentiation of the sex organs. At that stage, both 46,XX and 46,XY fetuses have similar sex organs, specifically:

  1. the gonadal ridges
  2. the internal ducts
  3. the external genitalia

a. The gonadal ridges can be easily recognized by 4-5 weeks of gestation. At that time, they already include the undifferentiated germ cells which will later develop into either eggs or sperm. The formation of gonadal ridges similar in both sexes is a prerequisite step to the development of differentiated gonads. This organization of cells into a ridge requires the effects of several genes, such as SF-1, DAX-1, SOX-9, etc. If any one of these genes is non-functional, then there is no formation of a gonadal ridge and therefore no formation of either testes or ovaries.

b. By 6-7 weeks of fetal life, fetuses of both sexes have two sets of internal ducts, the Mullerian (female) ducts and the Wolffian (male) ducts.

c. The external genitalia at 6-7 weeks gestation appear female and include a genital tubercle, the genital folds, urethral folds and a urogenital opening. (see Figure 2)

Step 3: Gonadal Differentiation

The important event in gonadal differentiation is the commitment of the gonadal ridge to become either an ovary or a testis.

a. In males, the gonadal ridge develops into testes as a result of a product from a gene located on the Y chromosome. This product has been termed the "testis determining factor" or "sex determining region of the Y chromosome" (SRY).

b. In females, the absence of SRY, due to the absence of a Y chromosome, permits the expression of other genes which will trigger the gonadal ridge to develop into ovaries.

Step 3 in Sex Differentiation:
Determination of Gonadal Sex
XX fetus = ovary
(with no SRY)
OR
XY fetus = testes
(with SRY located on the Y chromosome)

Step 4: Differentiation of the Internal Ducts and External Genitalia

The next step in sex differentiation depends upon the formation of two important hormones: the secretion of Mullerian (female) Inhibiting Substance (MIS) and the secretion of androgens.

If testes are developing normally, then Sertoli cells of the developing testes produce MIS which inhibits the growth of the female Mullerian ducts (the uterus and fallopian tubes) which are present in all fetuses early in development. Additionally, the Leydig cells of the testes start secreting androgens. Androgens are hormones that produce growth effects on the male Wolffian ducts (the epididymis, vas deferens, seminal vesicles) which are also present in all fetuses early in development.

Unlike the testes, the ovaries do not produce androgens. As a result, the Wolffian ducts fail to grow and consequently disappear in fetuses with ovarian development. In addition, the ovaries do not produce MIS at the appropriate time, and as a consequence, the Mullerian (female) ducts can develop.

In other words, two products of the developing testes are needed for normal male development. First, MIS must be secreted to inhibit female duct growth and androgens must be secreted to enhance male duct growth. In contrast, a female fetus with no developing testes will produce neither MIS nor androgens, and hence female ducts will develop and male ducts will disappear.

Step 4 in Sex Differentiation: Determination of Internal Ducts
Males
Testes produce MIS = inhibit female development
Testes produce androgens = enhance male development
OR
Females
Ovaries do not produce MIS = enhance female development
Ovaries do not produce androgens = inhibit male development

External Genitalia

In the female, absence of androgens permits the external genitalia to remain feminine: the genital tubercle becomes the clitoris, the genital swellings become the labia majora and the genital folds become the labia minora.

In the male, fetal androgens from the testes masculinize the external genitalia. The genital tubercle grows to become the penis and the genital swellings fuse to form the scrotum. The following diagrams illustrate each of these processes.


Figures (click to view detailed images)
FIG. 1 FIG. 2 FIG. 3
Fig. 1 Fig. 2: Female (no androgen effect) Fig. 3: Male (androgen effect)

Summary of Normal Sex Differentiation

  • genetic sex is determined
  • testes develop in XY fetus, ovaries develop in XX fetus
  • XY fetus produces MIS and androgens and XX fetus does not
  • XY fetus develops Wolffian ducts and XX fetus develops Mullerian ducts
  • XY fetus masculinizes the female genitalia to make it male and the XX fetus retains female genitalia

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