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.

Introduction

Anti-Müllerian hormone (AMH) is a homodimeric glycoprotein belonging to the transforming growth factor (TGF)-β family [1] and was initially identified for its role in regression of the Müllerian ducts in male embryos [2]. Prof. Jost [2] found that the Müllerian ducts of the rabbit would independently differentiate into the female reproductive system (i.e., the uterus, the fallopian tubes, and the upper two thirds of the vagina) in the absence of testicular secretions. Following gonadectomy of sexually undifferentiated rabbits, Jost [2] grafted either ovarian or testicular tissue in rabbits and witnessed the subsequent correct development of either female or male genitalia, respectively. The paradigm-shifting experiment came when, following gonadectomy, he implanted a testosterone proprionate crystal alone, noting that while the wolffian ducts were stimulated to develop, there was no regression of the Müllerian ducts - highlighting that a testicular factor other than testosterone was responsible for gonadal differentiation. Jost and Jost [3] called this factor “hormone inhibitrice” or “inhibiteur Müllerian,” and today it is better known as AMH or Müllerian-inhibiting substance (MIS).

The AMH gene was first sequenced and cloned in mammals in 1986 [1, 4]. It is located on human chromosome 19 and is extremely well conserved through evolution, being characterized in almost all mammals [5, 6, 7, 8], chickens [9], reptiles [10], marsupials [8], zebrafish [11], and amphibians [12]. It is comprised of 5 exons, with the highest degree of homogeneity being observed within exons 2–5.

AMH is a glycoprotein found in the blood, suggesting that it has a hormonal function. The primary sources of production, identified so far, are the Sertoli cells of the testes and the granulosa cells of the ovaries in postnatal animals. However, expression of AMH and its exclusive binding receptor AMH receptor 2 (AMHR2) has also been detected in the prostate, lungs [13, 14, 15], and several other organs, including the brain and the pituitary [16, 17, 18, 19, 20], suggesting that the biological effects of AMH are much broader than initially thought.

In the present review, we will briefly summarize previous studies describing the “canonical” functions of AMH in gonadal function and highlight our current understanding of emerging neuroendocrine actions of AMH in regulation of fertility in physiological and pathological conditions.

AMH: from Gene to Protein

The AMH gene encodes a pre-proprotein of 560 amino acids in humans. AMH is synthesized as a homodimeric glycoprotein precursor of 140 kDa (composed of 2 monomers of 70 kDa, stabilized by disulfide bridges), which undergoes proteolytic cleavage at monobasic sites to become biologically active [21, 22, 23]. AMH_N,C (a noncovalently associated 110-kDa N-terminal dimer with a 25-kDa C terminal dimer) represents thecleaved biologically active form, whereas uncleaved AMH (proAMH) is well described as biologically inactive [24, 25, 26]. Like many molecules of the TGF-β superfamily, AMH must therefore undergo proteolytic cleavage into 2 N and C terminal dimers to acquire its biological function. Cleavage of AMH gives rise to a 110-kDa N-terminal homodimer formed by two 57-kDa subunits and a 25-kDa active C homodimer composed of 2 identical 12.5-kDa subunits. The noncovalent complex and prohormone are the 2 forms predominantly found in the blood of humans [25, 27]. It has been shown that the N-terminal portion of the protein, despite having no intrinsic activity, has the role of amplifying the activity of the C-terminus, with only the biologically active C-terminus region required to cause regression of the Müllerian ducts [28].

As determined experimentally in vitro, recombinant AMH can be cleaved by plasmin [29]. However, in vivo, the enzymes capable of cleaving AMH remain largely unknown. Although the site of cleavage to form the bioactive AMH is currently unknown, subtilisin/kexin-like proprotein convertases are thought to be responsible for AMH cleavage and studies have shown that furin and proprotein convertase subtilisin/kexin type 5 (PCSK5), 2 such endoproteases, are coexpressed with AMH in embryonic rat testes [30]. Additionally, only PCSK5 is capable of cleaving this hormone after cotransfection into mammalian cells. It is also noteworthy that these convertases have been shown to be expressed by a high number of tissues and cells [31] and notably by neurons [32, 33, 34].

As a member of the TGF-β family, AMH signals through a heterodimeric complex of transmembrane serine-threonine kinase receptors. AMH has been shown to bind exclusively to one type II receptor, i.e., AMHR2, while no other ligand has been shown to have effective binding to it [35]. AMHR2 has been shown to interact with the type 1 receptor serine/threonine kinases ACVR1 (activin A receptor type 1), BMPR1A (bone morphogenetic protein receptor type 1A), and BMPR1B (bone morphogenetic protein receptor type 1B) [36, 37]. Finally, the complex canonically recruits SMAD1/5/8 proteins that are translocated to the nucleus and involved in regulation of gene expression [38, 39].

Roles of AMH in Postnatal Gonads

Role of AMH in Ovarian Function

In women, circulating AMH levels correlate well with ovarian reserve [40, 41], with the predictive power of AMH levels for ovarian reserve recently being widely adopted as the gold standard in primary health care systems [42] and as a useful co-predictor of stimulated ovarian response [41, 43].

AMH is produced by granulosa cells and, in women, a strong correlation exists between serum AMH levels and the number of small antral follicles between 2 and 9 mm as detected by ultrasound [43, 44, 45]. AMH is also a regulator of folliculogenesis as it inhibits the initial follicular recruitment from primordial follicles to primary follicles in mice [46, 47]. This role has been confirmed by experiments in Amh knockout mice, which have statistically increased levels of primary and secondary follicles at 25 days and 4 months of age versus heterozygous and wild-type littermates. However, at 4 and 13 months, decreased numbers of primordial follicles were observed in Amh-knockout mice, suggesting a premature exhaustion of ovarian reserve [48]. The authors concluded that, although the number of initial primordial follicles available immediately following birth was independent of the presence of AMH, it was an important factor in inhibiting follicular recruitment and thus AMH presence was essential for prolonging fecundity. AMH is already expressed in infantile ovaries in mammals [46, 49, 50, 51, 52, 53, 54], and the findings of Garrel et al. [20] in 2016 raised the intriguing hypothesis that AMH could play a critical role in the female pituitary gonadotropic activity during the infantile period. This issue will be further discussed in “Emerging” Roles of AMH in Neuroendocrine Control of Reproduction.

In both rodent and human studies, it has been agreed that AMH secreted by primary and growing small antral follicles acts as a “brake” inhibiting further follicular recruitment and development. Further, FSH-dependent follicular maturation is inhibited in vitro by the addition of AMH, indicating that AMH is important in attenuating follicular sensitivity to cyclical FSH action [55]. This is supported by a recent study that indicated that AMH levels parallel fluctuations in antral follicle count through the menstrual cycle [56].

In vitro experiments of cultured granulosa cells have indicated that exogenous AMH also decreases aromatase activity and the luteinizing hormone/choriogonadotropin receptor (LHCGR) number [57, 58]. Consistent with this, a negative correlation has been shown between AMH and estradiol levels in the follicular fluid of small antral follicles in humans [59, 60].

Role of AMH in Testicular Function

In boys, AMH is synthetized by Sertoli cells, and it is the first hormone secreted by differentiated Sertoli cells of the fetal testis triggering regression of the Müllerian ducts [61]. It has been demonstrated in humans that testicular AMH expression begins at 44 days postconception and that AMH levels in fetal testes were positively correlated with age [62].

Both Leydig and Sertoli cells of the testes express AMHR2, indicating a potential paracrine role in regulating male gonadal function [63]. Indeed, high doses of AMH result in decreased expression of some steroidogenic enzymes, mostly P450 17α-hydroxylase/C17–20 lyase (P450c17), and hence in reduced testosterone secretion in vitro [64] and in vivo[65]. Concomitantly, AMH also causes a decrease in LHR expression, which should further act to decrease testosterone secretion [64]. In line with these findings, in boys with nonpalpable testes, circulating AMH level determination can help to distinguish between cryptorchidism and anorchism, as well as in differentiating the dysgenetic causes of disorders of sexual development from those due to defective androgen synthesis or action [66]. Physiologically, AMH levels fall in boys at puberty with the increase in testosterone and the initiation of spermatogenesis [67]; however, it should be noted that this androgen-mediated decrease in AMH levels is restricted to postnatal life, as immature Sertoli cells lack expression of the androgen receptor [68, 69]. Interestingly, AMH-deficient mice have circulating levels of testosterone within the normal range, suggesting that compensatory mechanisms may act to replace the interconnected feedback between the 2 hormones. Meanwhile, male mice with targeted mutations of AMHR2 develop Leydig cell hyperplasia, suggesting an inhibitory role of AMH on Leydig cell proliferation [70]. While secreting AMH into the peripheral blood circulation, Sertoli cells also secrete AMH into the seminiferous tubules, where it is present at a much higher concentration compared to the plasma [71, 72]; however, the role of AMH in semen is currently unclear.

“Emerging” Roles of AMH in Neuroendocrine Control of Reproduction

Role of AMH in the Hypothalamus

In the adult brain, it has been shown that mature neurons express high levels of AMH receptors in both sexes [16, 17, 18].

In recent years, novel neuroendocrine actions of AMH have started to be elucidated. In 2016, Cimino et al. [19] uncovered that AMHR2 is expressed in a significant subset of hypothalamic gonadotropin-releasing hormone (GnRH) neurons both in mice (Fig. 1) and in humans. Interestingly, AMHR2 is also broadly expressed in different brain areas and cell types involved in the central control of reproduction, including the organum vasculosum laminae terminalis (OVLT) of the hypothalamus and the median eminence [19]. Unpublished data from the same group have shown that neurons expressing nitric oxide synthase (nNOS) located in the OVLT also express AMHR2 (Fig. 1e). nNOS neurons distributed in the preoptic region at the median preoptic nucleus (MEPO) and in the OVLT, where neurons expressing nNOS and GnRH are located [73, 74, 75] and interact functionally [76, 77], are known to participate in the control of reproductive functions in mammals [78]. Future studies will be aimed at addressing the exact role of AMH on hypothalamic nNOS neurons and whether it could be involved in the nNOS-mediated effects required for the onset of the LH surge induced by gonadal steroids in mice [75]. At the level of the median eminence, AMHR2 has been shown to be expressed by endothelial cells, by tanycytes, and by the majority of arcuate nucleus neurons (Fig. 1f–h). Interestingly, fenestrated endothelial cells and tanycytes are known to regulate GnRH secretion by interacting closely with GnRH terminals in the ME [79]. However, the role of AMH on these non-neuronal cell types is yet to be determined. The first functional study assessing the role of AMH on GnRH neuronal activity was published in 2016 and reported that approximately half of the GnRH neuronal population located in the hypothalamic preoptic area expresses AMHR2 and responds to exogenous AMH by increasing its neuronal activity and GnRH secretion, resulting in an increase in LH secretion equivalent to levels required to produce an ovulatory surge [19].

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].

Electrophysiological experiments performed on slice cultures of preoptic areas from GnRH<GFP> animals revealed that the action of exogenous AMH on neuronal activity is direct [19]; however, based on the wide expression of AMHR2 in hypothalamic regions, synergistic actions from other neuronal and non-neuronal cell types, ultimately resulting in increased GnRH secretion, cannot be ruled out.

Another point worth considering relates to the central effects of peripheral AMH and whether it could access the brain or not. In a recent study [80] it was shown that peripherally administered bioactive AMH_C reaches the brain at the level of the ME and acts centrally by inducing GnRH neuronal activation, as shown by the increase in the number of GnRH neurons expressing c-fos. It has been previously shown that human blood contains proAMH and AMH_N,C [25, 81]. In light of these considerations, at least 2 possible scenarios exist regarding how the peripheral AMH may result in the central activation of GnRH neurons: circulating AMH_N,C could (1) bind to endothelial cells of the ME, which express AMHR2, to induce the release of NO, which is known to powerfully control GnRH secretion and structural plasticity at the neurohemal junction [78], or (2) act directly on GnRH dendrites and terminals that extend outside the blood-brain barrier at the OVLT [82] and in the ME, respectively, and/or modulate cytoskeletal remodeling in specialized ependymal glial cells called tanycytes to increase GnRH delivery to the pituitary [79] (Fig. 2). Indeed, the ME and the OVLT contain highly permeable, fenestrated endothelial cells that allow the free passage of molecules below 35 kDa [83, 84], such as bioactive AMH. However, whether prohormone convertases and furin, responsible for the cleavage to form the bioactive AMH, are expressed by fenestrated vessels of circumventricular organs and whether circulating AMH_N,C undergoes further cleavage at these sites remain to be investigated.

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.

Role of AMH in the Pituitary

Both AMHR2 transcripts and protein were found in immortalized mouse pituitary gonadotrope-derived cell lines (LβT2) and in rat pituitaries [20, 85]. Bédécarrats et al. [85] demonstrated that AMH stimulation of LβT2 cells induces transcriptional activation of Lhb but not Fshbgene promoters. Interestingly, costimulation of LβT2 cells with AMH and a GnRH agonist increased both the Fshb and the Lhb gonadotropin gene promoter-driven luciferase activity [85]. This suggests that AMH enhances the effect of GnRH on the Fshbgene promoter and synergizes with the GnRH agonist to stimulate Lhb gene promoter activity. The group of Cohen-Tannoudji has further explored this issue in a set of subsequent studies [20, 86]. Using a combination of in vitro and in vivo approaches, these authors reported a sexually dimorphic expression of Amhr2 transcripts in the postnatal rat pituitary, with higher steady-state transcript levels in immature female rats than in males [20]. In addition, they provided compelling evidence that AMH increases the secretion of FSH in immature females. AMH was reported to upregulate FSH secretion and pituitary Fshb transcripts without affecting LH levels [20]. The same group also recently demonstrated that gene expression of both human and murine Amhr2 in gonadotrope cells is regulated by GnRH [86]. Indeed, using LβT2 cells in a perifusion system, those authors showed that GnRH at a high pulse frequency increases Amhr2 expression whereas lower frequencies are ineffective [86]. However, the physiological implication of Amhr2 upregulation by a high pulse frequency of GnRH remains to be understood.

In mammals, the infantile period is characterized by a transient elevation of the levels of the 2 gonadotropins shortly after birth [52, 87, 88, 89, 90]. This phenomenon, known as minipuberty in humans, is the first of 3 activational periods that primes the HPG axis for puberty and adult fertility, setting in motion the growth of the first wave of ovarian follicles that will ovulate at puberty in females and the development of the testes in males [91]. Intriguingly, the amplitude of minipuberty (attested by FSH levels) varies tremendously depending on the gestational age at birth in both boys and girls, increasing up to 300-fold in preterm female infants [92]. In rodents, a similar transient FSH peak has been reported at ∼12–14 days of postnatal life [93, 94]. Remarkably at the same time (PN14), AMH is downregulated in preantral/early antral follicles of the first waves [54]. Using cultures of infantile mice ovaries, those authors demonstrated the existence of a repressive action of FSH on AMH expression in preantral/early antral follicles of the first follicular waves. Since treatment of infantile ovaries in organotypic cultures with AMH decreases FSH-mediated expression of Cyp19a1 aromatase, the authors hypothesized that the negative action of FSH on AMH expression is necessary to alleviate the inhibitory action of AMH on FSH-dependent E2 biosynthesis in these growing follicles [54].

Altogether, these studies shed new light on the role of AMH in the control of the hypothalamic-pituitary function and regulation of fertility in physiological conditions during the infantile period and in adulthood (Fig. 2).

AMH Relevance for Polycystic Ovary Syndrome

Functional Variation of AMH Pathway in Polycystic Ovary Syndrome

Polycystic ovary syndrome (PCOS) is a complex reproductive endocrine disorder, affecting more than 10% of women worldwide and representing the primary cause of anovulatory infertility [95]. Furthermore, PCOS associates comorbidities including metabolic dysfunction and an increased risk of type 2 diabetes mellitus and cardiovascular disease [96, 97].

A recent international guideline for the assessment and management of PCOS announced in 2018 [98] promotes the use of the Rotterdam diagnostic criteria [99]. These criteria require the presence of at least 2 of the following 3 features of PCOS: oligo-anovulation, hyperandrogenism, and polycystic ovary morphology at ultrasound.

PCOS has long been considered mainly a gonadal pathology, but more recently accumulating evidence has started to shed light on the neuroendocrine impairments associated with the pathophysiology of this syndrome [100]. In women with PCOS, AMH serum levels are frequently found to be 2- to 3-fold higher than in women with healthy ovaries [101, 102]. Moreover, the severity of the PCOS phenotype correlates with AMH production, which is higher in anovulatory than in ovulatory PCOS patients [103, 104, 105]. Interestingly, circulating AMH levels have been found to be significantly higher also in naturally hyperandrogenic female rhesus monkeys, which exhibit traits typical of women with PCOS [106].

Clinically observed correlations between enhanced basal levels of AMH and PCOS have led to a well-developed physiological role for AMH in follicular development [107].

In women with PCOS, a positive correlation between LH and AMH serum levels has been shown [108] independently of androgen and FSH levels [109]. In addition, several authors have shown that LH could stimulate AMH secretion and expression [103, 110]. LH hypertonia is found in about 50% of women with PCOS, with a prevalence of up to 95% in metabolically healthy women with PCOS [111]. The high circulating LH levels reported in women with PCOS further exacerbate hyperandrogenism by stimulating thecal cell androgen production. The increase in LH frequency in these women could be attributed to a lack of negative feedback from progesterone as a result of hypothalamic prenatal androgenization [100, 112]. The elevated LH pulse frequency is also suggestive of an acceleration of the GnRH pulse frequency [113, 114]. Nevertheless, the origin of GnRH hypersecretion in women with PCOS is unknown, as is whether this alone could be sufficient to trigger the cascade of events leading to PCOS. As detailed above, a recent study showed that in rodent AMH induces LH secretion by stimulating GnRH neuronal activation and subsequent neuropeptide secretion [19]. These results raise the innovative hypothesis that AMH, the circulating levels of which are abnormally elevated in PCOS patients with severe oligo-anovulation, might contribute significantly to the hormonal and gonadal alterations that are observed in women with PCOS and have an impact on fertility by centrally affecting GnRH neuronal excitability prenatally and/or postnatally.

AMH and Neuroendocrine Origins of PCOS

Familial clustering and twin studies have shown that PCOS has a strong heritable component [115]. Polymorphisms in both AMH and AMHR2 have been identified in women with PCOS [116, 117, 118]. However, the polymorphisms identified in the AMH signaling pathway and in other genes do not explain the frequency of the disease [119], suggesting that environmental and epigenetic mechanisms may play far greater roles in the onset of PCOS.

In women with PCOS, endocrine alterations, such as hormonal imbalances, during gestation may contribute to an increased risk of their offspring developing PCOS [120]. Prenatal exposure to androgens, testosterone (T) or dihydrotestosterone, have been reported to generate the closest PCOS-like phenotype in a variety of animal models [100]. This points to prenatal hyperandrogenism as one of the main triggers of the developmental programming of PCOS. Notably, 2 recent studies [80, 121] showed that pregnant women with PCOS have significantly higher circulating AMH levels (during the second trimester of gestation as well as at term) than pregnant women with normal fertility. This 2-fold greater AMH level compared to controls adds AMH to the list of potential candidates in the prenatal programming of PCOS. Piltonen et al. [121] also reported novel data on the correlation between gestational AMH and androgen levels in humans in late pregnancy in a time window sensitive to the trigger PCOS-like phenotype in offspring in animal models. Moreover, recent data also suggest a possible role for AMH in transgenerational PCOS pathogenesis, as high gestational AMH levels in mice result in a hyperandrogenic PCOS-like phenotype in adult female offspring [80] (Fig. 3).

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].

Interestingly, prenatal AMH treatment leads to a significant 3-fold T increase in the dams, which is likely responsible for rewiring of the fetal hypothalamic circuits (Fig. 3) to excessive excitatory inputs onto GnRH neurons and finally leads to neuroendocrine and reproductive defects in the offspring. However, whether T levels are also elevated in the amniotic liquid of the fetus remains to be assessed. AMH-dependent maternal androgenization is most likely the result of a dual action of AMH on the dams' physiology: (1) a central action exacerbating GnRH- and LH-driven ovarian steroidogenesis and (2) AMH-driven inhibition of aromatase expression in the placenta, which leads to an increase in T bioavailability [80]. In humans, AMH has been shown to modify the enzymatic activity of steroid hormone synthesis [122], and women with PCOS have been reported to have reduced placental aromatase activity and increased steroidogenic activity [101], giving support to the findings of the group of Giacobini also in humans. Most women with PCOS are hyperandrogenic during pregnancy [120, 123], yet the cause of this remains enigmatic. The work of Tata et al. [80] raises the intriguing hypothesis as to whether the origin of the gestational hyperandrogenism of women with PCOS lies in elevated AMH levels during pregnancy and inhibition of aromatase expression/activity, although it is not yet known whether a causal relationship between AMH and T exists during gestation in humans. Another important finding of this study relates to the fact that the AMH-dependent prenatal hyperandrogenism leads to a persistent GnRH neuronal hyperactivity in the adult offspring (Fig. 3). The novel proposal guiding this study is that PCOS could involve brain deregulation and that exacerbation of GnRH neuronal activity/secretion could be the basis for neuroendocrine anomalies that accompany the gonadal disturbances in the syndrome. Indeed, prenatal co-treatment of AMH with a GnRH antagonist prevented the appearance of PCOS-like neuroendocrine traits in the offspring, suggesting a critical role for GnRH in prenatal programming of the disease [80]. Even more strikingly, the same authors provided compelling evidence that intermittent delivery of a GnRH antagonist to adult prenatal AMH-treated mice corrected their neuroendocrine and reproductive alterations. Given the fact that GnRH antagonists are frequently used in the clinic, pharmacological antagonism aimed at tempering GnRH-LH secretion is an attractive therapeutic strategy to restore ovulation and fertility in individuals with PCOS characterized by high LH levels.

Conclusion

Since its discovery, great strides have been made that have allowed us to develop an appreciation of the role of AMH in both male and female gonadal function and how dysregulated AMH signaling is involved in infertility syndromes. While we now have a much broader understanding of and insight into disorders such as PCOS thanks to this enormous amount of work, we are still far from comprehending the true etiology of this syndrome, with genetic traits only partially able to sustain a fraction of the clinical cases. The recent work building on the discovery of AMH receptors outside of the gonads and their ability to regulate both gonadotropic cells of the anterior pituitary and the hypothalamus strongly suggests that AMH is a neuroendocrine regulator of fertility. Much work still needs to be done to elucidate the mode of action in the hypothalamus and the significance of its role in the pituitary, but these novel sites of action provide new insights into the pathophysiology of reproductive dysfunction and open further routes of investigations.

Disclosure Statement

The authors have nothing to disclose.