25.13: How does an embryo become male or female?

During the first few weeks after fertilization, surprisingly little distinguishes males from females. Then, about four weeks into embryonic development in mammals, a gene carried on the Y chromosome, called SRY (for sex-determining region on the Y chromosome), can initiate development as a male (FIGURE 25-27). The gene is expressed in the tissue that will form the gonads, and usually, when SRY is expressed, the gonads develop as testes. (There is a gene on the X chromosome that also influences sex determination and, in rare cases, can alter typical sex development.) If SRY is not present, ovaries develop instead.

Once the fetal gonads develop, they start producing steroid hormones. If testes, they produce testosterone. If ovaries, they produce estrogen. The presence of high levels of testosterone causes ducts that connect the gonads and the outside of the body to develop into the male internal reproductive organs, including the vas deferens (on each side), ejaculatory duct, and prostate. In the absence of testosterone, adjoining ducts become the female reproductive organs, including the uterus, cervix, and Fallopian tubes.

Following development of the internal reproductive organs, undifferentiated external genitals develop. If testosterone is present and is modified slightly (by an enzyme called 5-alpha-reductase) into dihydrotestosterone (DHT), it causes the external genitals to become the penis and scrotum. In the absence of DHT, female external genitals develop, including the clitoris, labia, and vagina. Sex differentiation is generally complete by about the 12th week of development in humans.

At several points, the development of an embryo as male or female can be disrupted. Disruptions of this type occur in several genetic disorders.

1. Recombination leading to XX individuals with the SRY gene or XY individuals lacking SRY. It is possible, during the production of sperm, for crossing over to occur between the X and Y chromosomes. If this crossover causes the SRY gene to be moved to the X chromosome, and if the sperm cell carrying the X with SRY or the Y without SRY fertilizes an egg, irregular development occurs. In XX individuals with the SRY gene, the individual appears to develop as a male. Although testes develop, they are smaller than average. These individuals are infertile and also tend to be shorter than XY males. In XY individuals without the SRY gene, the gonads develop incompletely. These individuals appear to develop as female. At puberty, however, they are taller than average, do not develop secondary sex characteristics, and do not menstruate.

2. Androgen insensitivity syndrome. Some XY individuals (approximately 1 in 20,000) carry a nonfunctioning copy of the androgen receptor. Although the SRY gene triggers the development of testes, this X-linked recessive trait causes the tissues of the body to be unresponsive to testosterone’s effects. Consequently, individuals with androgen insensitivity syndrome develop what appears to be a female body. The condition is usually not detected until the girl fails to menstruate, because, internally, this individual has neither uterus nor ovaries but, rather, internal testes.

3. 5-Alpha-reductase deficiency. Some XY individuals (the worldwide incidence is unknown, but is thought to be very rare) carry a non-functioning version of the gene for the enzyme that converts testosterone into DHT. Without DHT to direct the development of external male genitals, these individuals possess testes, but the external genitals develop as they would in a female. Consequently, individuals with 5-alpha-reductase deficiency are generally identified as female at birth. At puberty, however, in response to increased testosterone production, they develop male secondary sex characteristics, including a deeper voice, facial hair, and increased muscle mass. The external genitals grow and often come to resemble a penis and scrotum more than a clitoris and labia.