Hormonal Regulation During Gonadal Development

Although the karyotype of the embryo is decided during fertilization, many other crucial intrauterine events must take place to engender a normal male or female phenotype at birth. These events are classified as phases of sex determination and sex differentiation. Complex interactions of multiple genes, transcription factors, proteins, and hormones are responsible for these intricate changes. The phase of sex differentiation is chiefly brought about by peptide and steroid hormones produced by the developing gonad. Different developing cell types in the fetal testis express different hormones in a pre-programmed manner resulting in the male phenotype. Broadly, Antimullerian Hormone (AMH) causes regression of Mullerian structures, Testosterone stabilizes the Wolffian duct and Dihydrotestosterone (DHT) brings about masculinization of external genitalia. Descent of the testes into the scrotum occurs as a two-stage process influenced by Insulin-like peptide 3 (INSL3), testosterone, and calcitonin gene-related peptide (CGRP). Female sex differentiation occurs in the absence of AMH and testosterone. Ovarian estrogen does not have significant effects on intrauterine sex development. An appreciation of the genetic and hormonal mechanisms of sex development provides insights regarding the causes of differences in sex development (DSDs) and guides investigations and management of this perplexing group of disorders.