AMH and AMHR2 Involvement in Congenital Disorders of Sex Development

Abstract

Anti-müllerian hormone (AMH) is 1 of the 2 testicular hormones involved in male development of the genitalia during fetal life. When the testes differentiate, AMH is secreted by Sertoli cells and binds to its specific receptor type II (AMHR2) on the müllerian ducts, inducing their regression. In the female fetus, the lack of AMH allows the müllerian ducts to form the fallopian tubes, the uterus, and the upper part of the vagina. The human <i>AMH</i> gene maps to 19p13.3 and consists of 5 exons and 4 introns spanning 2,764 bp. The <i>AMHR2</i> gene maps to 12q13.13, consists of 11 exons, and is 7,817 bp long. Defects in the AMH pathway are the underlying etiology of a subgroup of disorders of sex development (DSD) in 46,XY patients. The condition is known as the persistent müllerian duct syndrome (PMDS), characterized by the existence of a uterus and fallopian tubes in a boy with normally virilized external genitalia. Approximately 200 cases of patients with PMDS have been reported to date with clinical, biochemical, and molecular genetic characterization. An updated review is provided in this paper. With highly sensitive techniques, AMH and AMHR2 expression has also been detected in other tissues, and massive sequencing technologies have unveiled variants in <i>AMH</i> and <i>AMHR2</i> genes in hitherto unsuspected conditions.

From Enrico Sertoli to freemartinism: the many phases of the master testis-determining cell

“…AMH, the first hormone, and putative freemartin factor produced by fetal Sertoli cells, was dispensable for normal testis morphogenesis at least in mice and humans [7]. Humans lacking AMH or its receptor, AMHR2 , exhibit a disorder of sex development almost identical to the knockout mouse models, in which the Mullerian ducts in the affected XY individuals fail to regress, eventually forming a uterus and fallopian tubes (reviewed in [57]). Sertoli cells of mouse fetal testes also produce another hormone activin B [8].…”

Anti-Müllerian Hormone Signal Transduction involved in Müllerian Duct Regression

“…In the testis, it is expressed from fetal life to puberty, whereas in the ovary, AMHR2 is expressed from fetal life to adulthood by granulosa cells of preantral and antral follicles ( 45 ). In humans, mutations in the genes coding for AMH or AMHR2 cause persistent Müllerian duct syndrome (PMDS), in which normal 46,XY males retain a uterus and fallopian tubes ( 46 , 47 ). Many of these mutations lead to unstable and/or truncated proteins.…”

Testicular Sertoli Cell Hormones in Differences in Sex Development

“…AMH is produced at high levels in early fetal life, but is not measurable in amniotic fluid ( 27 , 28 ). As the testes differentiate during the 7 th week of gestation, Sertoli cells start producing AMH, which binds to the specific AMH Receptor Type II (AMHR2) on the Müllerian ducts, resulting in their regression before week 10 ( 29 ). AMH levels rise progressively from this point and then decline in the second year of life ( Figure 1 ).…”