Progesterone plays a role in early human sexual differentiation. Placental progesterone is the feedstock for the 5α-dihydrotestosterone (DHT) produced via the backdoor pathway found operating in multiple non-gonadal tissues of the fetus, whereas deficiencies in this pathway lead to undervirilization of the male fetus, resulting in incomplete development of the male genitalia. DHT is a potent androgen that is responsible for the development of male genitalia, including the penis and scrotum.
During early fetal development, the undifferentiated gonads can develop into either testes or ovaries. The presence of the Y chromosome leads to the development of testes. The testes then produce testosterone, which is converted to DHT via the enzyme 5α-reductase. DHT is a potent androgen that is responsible for the masculinization of the external genitalia and the development of the prostate gland. Progesterone, produced by the placenta during pregnancy, plays a role in fetal sexual differentiation by serving as a precursor molecule for the synthesis of DHT via the backdoor pathway. In the absence of adequate levels of steroidogenic enzymes during fetal development, the backdoor pathway for DHT synthesis can become deficient, leading to undermasculinization of the male fetus. This can result in the development of ambiguous genitalia or even female genitalia in some cases. Therefore, both DHT and progesterone play crucial roles in early fetal sexual differentiation, with progesterone acting as a precursor molecule for DHT synthesis and DHT promoting the development of male genitalia.