Paramesonephric duct

In the male-determined embryo, the testes produce two hormones responsible for masculinization – anti-Müllerian hormone (AMH), and testosterone. Sertoli cells secrete AMH, during weeks six and seven, which causes the paramesonephric ducts to regress. In week eight Leydig cells secrete testosterone which stimulates the formation of male genitals from the mesonephric ducts.

Each paramesonephric duct is situated just lateral to each mesonephric duct (Wolffian duct). The mesonephric ducts are not completely useless in the female case: they secrete protein Wnt-9b, which is necessary for the elongation of the paramesonephric ducts. Elongation also happens through the active migration of the paramesonephric epithelium, which happens through a phosphoinositide 3-kinase pathway.

Development

The female reproductive system develops from two embryological segments: the urogenital sinus and the paramesonephric ducts. The two are conjoined at the sinus tubercle. Paramesonephric ducts are present on the embryo of both sexes. Only in females do they develop into reproductive organs. They degenerate in males whereas the adjoining mesonephric ducts develop into male reproductive organs. The sex based differences in the contributions of the paramesonephric ducts to reproductive organs is based on the presence, and degree of presence, of anti-Müllerian hormone.

Initial formation

During the development of the reproductive system, the paramesonephric ducts are formed just lateral to the mesonephric ducts (formed earlier) in both female and male embryos 6 weeks after fertilization. A ribbon of thickened coelomic epithelium is selected by PAX2, and in turn the FGFs, and in turn LHX1, to become the Müllerian surface epithelium (MSE). During this time, primordial germ cells migrate from the yolk sac to the genital ridge, a region of mesenchyme running parallel with, and derived from, the mesonephros. The Müllerian duct mesenchyme (MDM) is formed from the MSE and possibly the mesonephros; WNT4 expression is required for this process. The MDM also secretes WNT4, which (together with other molecular factors) cause the craniocaudal invagination of the MSE. The invagination fuses into a duct, and the MSE becomes known as the Müllerian duct epithelium (MDE).

The early duct is short and needs to elongate to reach the urogenital sinus. This is caused by WNT9B produced by the neighboring mesonephric ducts.

By the time basic formation is complete, the duct's cross section consists of a central lumen, a layer of MDE, and a mass of MDM around it. The MDE produces WNT7A, which causes the MDM to produce AMHR2, allowing AMH to take effect. The caudal parts of the paramesonephric ducts fuse into a single tube, known as the uterovaginal primordium, before flowing into the dorsal aspect of the urogenital sinus at the sinus tubercle directly medial to the mesonephric ducts.

Anti-Müllerian hormone

The further development of the paramesonephric (Müllerian) ducts is controlled by anti-Müllerian hormone (AMH; also known as Müllerian-inhibiting substance, "MIF" for "Müllerian-inhibiting factor", "MIH" for "Müllerian-inhibiting hormone", or "APH" for anti-paramesonephric hormone).

AMH is a glycoprotein hormone that is secreted by Sertoli cells (a type of sustentacular cell) in males as they begin their morphologic differentiation in response to SRY expression. AMH begins to be secreted around week 8, which in turn causes the paramesonephric ducts to regress very rapidly between the 8th and 10th weeks. However, small paramesonephric ducts can still be identified, and the remnants can be detected in the adult male, located in the appendix testis, a small cap of tissue associated with the testis. Remnants of the paramesonephric ducts can also be found in the prostatic utricle, an expansion of the prostatic urethra at the center of the seminal colliculus.

When AMH is present, it first activates AMHR2 (AMH receptor-type II) expressed by the MDM (mesenchymal) cells surrounding the duct. The activation of AMHR2 causes the expression of "type 1" receptors, which include ACVR1 (ALK2), BMPR1A (ALK3), or BMPR1B (ALK6). Both types I and II are required for the correct development of the male reproductive system. Collectively they initiate Smad signaling and lead to the expression of apoptosis-encouraging metalloproteases.

• In the absence of the Wnt7a within the duct epithelium as the ducts regress, ductal AMHR-II expression is lost, and residual paramesonephric ducts would be retained in males, throwing off the urogenital system.
• Cryptorchidism (undescended testis) or ectopic testis with inguinal hernias have been identified in human males due to AMH and AMHR-II gene mutations.
• When the type I receptors are blocked or knocked out in mice within the paramesonephric duct mesenchyme, AMH-induced paramesonephric duct regression is lost. However, some of the type I receptors can be compensated by another: Alk2 knockouts are normal, while half of Alk3 knockouts show failed regression similar to Amh null mutants.

Non-AMH

When AMH is absent, regression does not occur. In this case, WNT7A from the MDE encourages the location-specific expression of HOXA10 and HOXA11, which specifies the development of the uterus and cervix, in the MDM. Two additional Hox genes, HoxA9 and HoxA13, specify the development of the Fallopian tube and the upper vagina. The expression of these Hox genes depend on WNT5A being expressed. WNT4 remains required for further uterine development.