Anti-Müllerian hormone initiates growth of human primordial follicles in vitro

Schmidt, K.L.T.; Kryger-Baggesen, Niels; Byskov, Anne Grete; Andersen, Claus Yding

doi:10.1016/j.mce.2004.12.010

Cited by 104 publications

(69 citation statements)

References 23 publications

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“…Observations support the inhibitory actions of AMH on primordial follicles, as previously reported (Durlinger et al 1999, 2002b, Ikeda et al 2002, Gigli et al 2005, Carlsson et al 2006. In contrast, one study with cultured human ovarian cortex demonstrated that AMH stimulated primordial follicle transition (Schmidt et al 2005). This study is distinct from others due to conflict with the findings of Carlsson et al (2006), who found that primordial follicle transition was inhibited in human ovarian cortex treated with AMH.…”

Section: Discussionmentioning

confidence: 93%

Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Nilsson¹,

Rogers²,

Skinner³

2007

Reproduction

171

102

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The oocytes found within the primordial follicles of mammalian ovaries remain quiescent for months to years until they receive the appropriate signals to undergo the primordial to primary follicle transition and initiate folliculogenesis. The molecular mechanisms and extracellular signaling factors that regulate this process remain to be fully elucidated. The current study investigates the mechanisms utilized by anti-Mü llerian hormone (AMH; i.e. Mü llerian inhibitory substance) to inhibit the primordial to primary follicle transition. Ovaries from 4-day-old rats were placed into organ culture and incubated in the absence or presence of AMH, either alone or in combination with known stimulators of follicle transition, including basic fibroblast growth factor (bFGF), kit ligand (KITL), or keratinocyte growth factor (KGF). Following 10 days of culture, the ovaries were sectioned, stained, and morphologically evaluated to determine the percentage of primordial versus developing follicles. As previously demonstrated, AMH treatment decreased primordial to primary follicle transition. Interestingly, AMH inhibited the stimulatory actions of KITL, bFGF, and KGF. Therefore, AMH can inhibit the basal and stimulated development of primordial follicles. To investigate the mechanism of AMH actions, the influence AMH has on the ovarian transcriptome was analyzed. AMH treatment when compared with controls was found to alter the expression of 707 genes. The overall effect of AMH exposure is to decrease the expression of stimulatory factors, increase the expression of inhibitory factors, and regulate cellular pathways (e.g. transforming growth factor b signaling pathway) that result in the inhibition of primordial follicle development. Analysis of the regulatory factors and cellular pathways altered by AMH provides a better understanding of the molecular control of primordial follicle development.

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Section: Discussionmentioning

confidence: 93%

Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Nilsson¹,

Rogers²,

Skinner³

2007

Reproduction

171

102

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“…S2A). Reports of the effect of MIS on follicles have been mixed, with some studies suggesting an activating effect (45,46) and others implying a direct inhibitory effect (18,47), indirect inhibition via gonadotropins (48,49), or even regulation of meiosis (50). In past studies, the magnitude of inhibition of primordial follicle recruitment in vivo and in vitro has been perceived as relatively modest because of difficulties in achieving high concentrations of the protein.…”

Section: Discussionmentioning

confidence: 99%

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Kano

Sosulski

Zhang

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

166

171

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The ovarian reserve represents the stock of quiescent primordial follicles in the ovary which is gradually depleted during a woman's reproductive lifespan, resulting in menopause. Müllerian inhibiting substance (MIS) (or anti-Müllerian hormone/AMH), which is produced by granulosa cells of growing follicles, has been proposed as a negative regulator of primordial follicle activation. Here we show that long-term parenteral administration of superphysiological doses of MIS, using either an adeno-associated virus serotype 9 (AAV9) gene therapy vector or recombinant protein, resulted in a complete arrest of folliculogenesis in mice. The ovaries of MIS-treated mice were smaller than those in controls and did not contain growing follicles but retained a normal ovarian reserve. When mice treated with AAV9/MIS were paired with male breeders, they exhibited complete and permanent contraception for their entire reproductive lifespan, disrupted vaginal cycling, and hypergonadotropic hypogonadism. However, when ovaries from AAV9-MIS-treated mice were transplanted orthotopically into normal recipient mice, or when treatment with the protein was discontinued, folliculogenesis resumed, suggesting reversibility. One of the important causes of primary ovarian insufficiency is chemotherapy-induced primordial follicle depletion, which has been proposed to be mediated in part by increased activation. To test the hypothesis that MIS could prevent chemotherapy-induced overactivation, mice were given carboplatin, doxorubicin, or cyclophosphamide and were cotreated with AAV9-MIS, recombinant MIS protein, or vehicle controls. We found significantly more primordial follicles in MIS-treated animals than in controls. Thus treatment with MIS may provide a method of contraception with the unique characteristic of blocking primordial follicle activation that could be exploited to prevent the primary ovarian insufficiency often associated with chemotherapy.M üllerian inhibiting substance (MIS), also known as antiMüllerian hormone (AMH), has long been appreciated for its role in sex differentiation and reproduction, and sensitive ELISAs measuring blood levels are used in fertility clinics around the world as a measure of ovarian reserve (1-6). MIS plays important roles in the development of the gonad and the differentiation of the urogenital ridge. In the male fetus, MIS produced by the developing testes causes regression of the Müllerian duct (7). In the female fetus, MIS may play a role in early follicle assembly in the gonad by primordial germ cells (not to be confused with primordial follicles), since mice overexpressing MIS are devoid of germ cells shortly after birth (8), and, similarly, ex vivo incubation of fetal ovaries with MIS results in the inhibition of follicle assembly (9). These data highlight a role of MIS during fetal development that is distinct from its regulatory role of folliculogenesis postnatally.In the adult, MIS is produced predominantly by the cumulus (less so by the mural) granulosa cells of secondary and early antral...

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“…This inhibitory factor is produced by early secondary, preantral and antral follicles in several species (Weenen et al 2004). However, it remains to be confirmed whether AMH also has an inhibitory effect in humans, since Schmidt et al (2005) reported that AMH initiates growth of human primordial follicles in vitro. The absence of antral follicles and the lack of secondary and preantral follicles in grafted cortical fragments and isolated follicle preparations in the present study may have disrupted the balance between stimulatory and inhibitory factors, thereby inducing follicular activation.…”

Section: Discussionmentioning

confidence: 99%

Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice

Dolmans¹,

Martínez-Madrid²,

Gadisseux³

et al. 2007

Reproduction

188

125

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This study was designed to evaluate follicular survival and growth after short-term transplantation of fresh isolated human follicles and ovarian cortical tissue to nude mice. Ovarian biopsies were obtained from nine women undergoing laparoscopy. Twelve nude mice were xenografted with an ovarian cortical fragment in the right ovarian bursa, and a clot containing isolated follicles in the left, for a period of 7 days. One ungrafted fragment was used as a control. Histological sections were analyzed to determine follicle number and stage. The proliferative status of follicular cells was assessed by Ki-67 immunostaining. A total of 659 follicles was analyzed by histology and 545 follicles by immunohistochemistry. The percentage of primordial follicles was found to be markedly reduced 1 week post-grafting when compared with ungrafted tissue, while the percentage of primary follicles had significantly increased. Only 8% of follicles showed Ki-67-positive granulosa cells before grafting, whereas 1 week after grafting, 71% of follicles in fragments and 67% of isolated follicles were Ki-67-positive (P!0.001). Moreover, the histological aspect of isolated follicle grafts was similar to that of grafted fragments: follicles were surrounded by vimentin-positive stroma-like tissue of human origin, as confirmed by fluorescent in situ hybridization with human-specific probes. Our results demonstrate, for the first time, that isolated human follicles are able to survive and grow after xenografting. This study also shows massive in vivo follicular activation after transplantation of grafted fragments and isolated follicles. One week after grafting, well-structured stroma-like tissue of human origin was observed around the isolated follicles. The potential origin of this stroma is discussed. Reproduction (2007) 134 253-262

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Anti-Müllerian hormone initiates growth of human primordial follicles in vitro

Cited by 104 publications

References 23 publications

Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

Actions of anti-Müllerian hormone on the ovarian transcriptome to inhibit primordial to primary follicle transition

AMH/MIS as a contraceptive that protects the ovarian reserve during chemotherapy

Short-term transplantation of isolated human ovarian follicles and cortical tissue into nude mice

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