During embryonic development there is a sexually indifferent stage in which the embryo has the potential to develop either male or female structures. Internally, adjacent to each developing gonad, are two primitive ducts that can give rise to either the male or the female reproductive tracts. The Wolffian (mesonephric) ducts are more medial. The Müllerian (paramesonephric) ducts are more lateral, but then fuse in the midline more caudally.
Sexual differentiation begins with sexual determination,
which depends upon the sex chromosomes, X and Y. Sexual
determination involves the specification of the gonads as either
testes or ovaries. If the embryo is XY, the SRY
gene (for sex-determining region of the Y
chromosome) will be present. The protein produced by SRY
activates a gene network that directs the gonads to develop as
testes. In the absence of a Y chromosome and SRY, the gonads
develop as ovaries.
Once the gonad begins to develop as a testis, the two support cells in the testis differentiate and begin to generate important regulatory molecules that direct sexual differentiation. The Leydig cells produce testosterone, which promotes development of the Wolffian ducts. The Wolffian ducts then differentiate to form the epididymis, vas deferens, seminal vesicles, and ejaculatory ducts. The Sertoli cells produce anti-Müllerian hormone (AMH; also known as Müllerian Inhibiting Substance, MIS), a peptide hormone that causes the Müllerian ducts to regress.
Female development proceeds when there is an absence of the SRY gene. No testosterone or AMH is made. The Wolffian ducts regress, and the Müllerian ducts persist, developing into the fallopian tubes, the uterus and the upper part of the vagina.
Anti-Müllerian hormone (AMH) is actually produced by granulosa
cells in the ovary (after it differentiates). AMH is expressed
mainly by small growing follicles. The level of AMH is thus a
good indicator of the size of the ovarian reserve (ability to
produce eggs capable of being fertilized). A test for AMH
level may be used in the context of in vitro fertilization
treatment, as a means to predict how the woman will respond to
controlled ovarian stimulation.
Ovarian development occurs in the absence of SRY activity, but
it does not occur by "default". Several genes (RSPO1,
WNT4, FOXL2) have been shown to be necessary to initiate ovarian
development, and to actively repress the gene network that
promotes testis development.
Our understanding of the important signals required for sexual differentiation derives in part from the study of rare individuals who have disorders of sex development. Two disorders that affect genetically XY individuals are particularly instructive: androgen insensitivity syndrome and 5-α-reductase deficiency.
In androgen insensitivity syndrome, there is a mutation in the androgen receptor such that the tissues do not respond to testosterone or other androgens. (Note that the following description is that of complete androgen insensitivity, in which the androgen receptor is completely defective with no response to androgens. However, partial androgen insensitivity can also occur.)
The gonads that develop in androgen insensitivity syndrome are testes.
An individual with complete androgen insensitivity syndrome will
develop externally as a female, because the development of the
external genitalia (penis with penile urethra and scrotum with
descended testes) depends upon androgen signaling. Furthermore, at
puberty, breast development occurs because the testosterone
produced is converted to estrogen by other tissues, and this
estrogen stimulates breast development. The syndrome may be
initially recognized because the individual has amenorrhea
(a lack of menstruation). Amenorrhea is due to the fact that a
uterus never developed because AMH caused regression of the
Müllerian ducts. Another aspect of the phenotype is little
growth of armpit or pubic hair, which also depends upon androgen
Once it has been discovered that amenorrhea is due to complete androgen insensitivity syndrome, treatment involves removal of the abdominal testes (gonadectomy). Cryptorchidism (failure of the testes to descend into the scrotum) and low androgen action are both associated with an increased risk for the development of testicular cancer. The best approach is to wait until early adulthood to perform the gonadectomy, allowing the patient to progress through puberty at a natural pace. Following gonadectomy, the patient would be maintained on hormone replacement therapy.
We know that the proper development of the penis and the prostate gland depends upon the more potent androgen dihydrotestosterone (DHT). This is illustrated in the disorder of sex development that occurs when there is a mutation in the gene coding for the enzyme 5-α-reductase type 2. Individuals with this mutation are born with female-appearing external genitalia. Because of the lack of DHT, the penis does not enlarge, the testes do not descend, and folds of tissue do not fuse to form a scrotum. The outlet of the urethra is not at the tip of the phallus (a term that denotes the developing erectile tissue), but in the perineum (floor of the pelvic cavity), a condition referred to as hypospadias. At puberty, however, large levels of circulating testosterone stimulate development of male structures. The erectile tissues enlarge and there is development of male secondary sexual characteristics. Often these individuals, although initially raised as girls, will decide to adopt a male gender identity after puberty.