Emerging Roles of Anti-Müllerian Hormone in Hypothalamic-Pituitary Function

Abstract

Since its initial discovery in the 1940s, research into the physiological actions of anti-Müllerian hormone (AMH), from its eponymous role in male developmental biology to its routine clinical use in female reproductive health, has undergone a paradigm shifting change. With several exciting studies recently reporting hitherto unforeseen AMH actions at all levels in the hypogonadal-pituitary-gonadal axis, the importance of this hormone for both hypothalamic and pituitary reproductive control is finding increasing support and significance. In this review, we will briefly summarize what is known about the traditional roles and biology of AMH and how this could be integrated with new findings of AMH actions at the level of the hypothalamic-pituitary axis. We also synthesize the important findings from these new studies and discuss their potential impact and significance to our understanding of one of the most common reproductive disorders currently affecting women, polycystic ovary syndrome.

Keywords: Anti-Müllerian hormone; Hypothalamic-pituitary function; Polycystic ovary syndrome.

Fig. 1

AMHR2 expression in adult female mouse hypothalamic cell populations controlling fertility. a–h Representative coronal sections immunolabeled using antibodies against GnRH, Tomato, GFP and nNOS. a GnRH immunoreactivity at the level of the OVLT. The arrows indicate GnRH cell bodies. b–d AMHR2 expression in Amhr2::Cre^+/−;tdTomato^loxP/+ OVLT sections. Amhr2 is widely expressed in this region. A subpopulation of GnRH neurons (nearly 50%) expresses Tomato (arrows). The arrowheads point to GnRH cell bodies, which are Amhr2 negative. e nNOS immunoreactivity at the level of the OVLT. Several nNOS-expressing neurons in this region express Amhr2 (arrows). f–hAmhr2 expression was also analyzed in a Amhr2::Cre^+/−;LacZ/EGFP reporter mouse line. Amhr2 was found in the arcuate nucleus (ARN) and in the median eminence (ME; arrows in g), where GnRH terminals project (red staining). Amhr2-expressing cells were found in hypothalamic tanycytes (tan; arrowheads in h) lining the third ventricle (3V) and endothelial cells (ec; arrows in h) [see also 19].

Fig. 2

Expression and function of AMH along the female hypothalamic-pituitary-gonadal axis in rodents. AMH is expressed in the ovaries from the infantile period until adulthood [see 46, 49, 50, 51, 52, 53]. AMHR2 is broadly expressed in different brain areas and cell types involved in the central control of reproduction, including the OVLT of the hypothalamus and the median eminence (ME) [19], although the AMH role in those cell populations has yet to be determined. GnRH neurons also express AMHR2 and respond to AMH by increasing their neuronal activity and GnRH secretion. Amhr2 transcripts and AMHR2 protein were found in rodent pituitaries [20, 85]. AMH has been reported to upregulate FSH secretion and pituitary Fshb transcripts [20]. GnRH transactivates the human AMHR2 promoter in LβT2 cells and Amhr2expression has been shown to be differentially regulated by GnRH pulse frequency with an induction under high GnRH pulsatility [86]. Increasing frequencies of GnRH are also known to result in preferential secretion of LH. Finally, high levels of gonadotropin hormones during the infantile period have been recently proposed to prematurely sensitize the first follicular waves to the action of FSH [54], which lowers the Amh expression in these follicles, favoring Cyp19a1aromatase expression and E2 production.

Fig. 3

AMH prenatal reprogramming of PCOS: potential prenatal and postnatal mechanisms. Pregnant women with PCOS have a 2-fold increase in circulating AMH levels compared to pregnant women with normal fertility during the second trimester of gestation as well as at term [80, 121]. In mice, prenatal exposure to elevated AMH levels leads to increased GnRH/LH pulsatility in dams, driving gestational steroidogenesis and hyperandrogenism. The maternal LH excess (driven by AMH action in the maternal hypothalamus), alone or in combination with AMH, engages placental deficits by inhibition of aromatase expression. This leads to an increase in testosterone bioavailability. The elevated levels of testosterone trigger a cascade of events in the offspring, which converge into altered hypothalamic wiring. In adult female PCOS offspring, the increase in excitatory input to GnRH drives a persistent rise in the GnRH neuronal firing activity. Finally, the constitutive hyperactivity of GnRH neurons stimulates ovarian androgen production, which appears to inhibit the negative feedback effects of estrogens and progesterone on pulsatile LH release, impairing folliculogenesis and ovulation and thus contributing to the vicious circle of PCOS [see also 80].