Mullerian Inhibiting Substance: An Instructive Developmental Hormone with Diagnostic and Possible Therapeutic Applications

Abstract

Dr. Alfred Jost pioneered the field of reproductive endocrinology with his seminal observation that two hormones produced by the testes are required for the male embryo to develop a normal internal reproductive tract. T induces the Wolffian ducts to differentiate into epididymides, vasa deferens, and seminal vesicles. Müllerian inhibiting substance (MIS) causes regression of the Müllerian ducts, which in its absence would normally develop into the Fallopian tubes, uterus, and upper vagina as is observed in female embryos. This review will summarize our current understanding of molecular mechanisms underlying the function of MIS both as a fetal gonadal hormone that causes Müllerian duct regression and as an adult hormone, the roles for which are currently being investigated, i.e., inhibition of steroidogenesis, germ cell development, and cancer. We will also address the regulation of MIS expression as one of the first genes expressed after the commitment of the bipotential gonads to differentiate into testes under the influence of SRY, the gene on the sex-determining region of the Y chromosome. We will discuss what is known regarding MIS signal transduction, which as with other members of the TGFbeta family of growth and differentiation factors, occurs through a heteromeric complex of single transmembrane serine/threonine kinase receptors to effect downstream signaling events, including Smad, nuclear factor-kappaB, beta-catenin, and p16 activation. Finally, we will assess the clinical relevance of studying MIS in patients with persistent Müllerian duct syndrome and our efforts to determine the therapeutic value of MIS for patients with ovarian and other MIS receptor-expressing cancers.

Testis Function in Prepubertal Boys and Young Men Born Small for Gestational Age

“…One study reported that serum AMH levels in boys reach peak levels between 3 and 6 months after birth. These levels are maintained throughout infancy and childhood but decline just before puberty [27]. …”

Germ cell development in the descended and cryptorchid testis and the effects of hormonal manipulation

“…Leydig cells are prominent in early life, peaking at 3-4 months and thereafter degenerating to minimal numbers by the age of 2 years [5]. Subsequently at puberty, another population of Leydig cells differentiate to adult Leydig cells [6].…”

“…Serum levels of MIS and testosterone in childhood have an inverse relationship after infancy, with MIS levels falling at puberty coinciding with the rise in serum testosterone levels [6]. Hence, during childhood when testosterone levels are too low to test reliably, MIS serves as a useful marker of testicular tissue, such as in the differential diagnosis of complex intersex disorders [69].…”

GnRH Transactivates Human AMH Receptor Gene via Egr1 and FOXO1 in Gonadotrope Cells

“…AMH is secreted by Sertoli cells of the fetal testis and plays a crucial role during early male sex differentiation by inducing the regression of Müllerian ducts [17]. The expression of AMH is however not restricted to embryonic development as AMH can be found in the Sertoli and granulosa cells of postnatal gonads and AMH produced by ovarian granulosa cells is now recognized as an important regulator of folliculogenesis [18, 19]. In addition, AMH expression was reported in adult mouse brain [20-22] and in pituitaries of immature male and female rats [16].…”

“…AMH exerts its function by binding to a specific type 2 receptor, AMHR2, that heterodimerizes with a type 1 receptor [23]. Both receptors are transmembrane serine/threonine receptors that recruit and phosphorylate SMAD proteins that will then translocate into the nucleus to regulate the transcription of several target genes [18, 24]. Amhr2 expression was initially found in mesenchymal cells surrounding the Müllerian epithelium in the bipotential urogenital ridge [17].…”