Cyclophosphamide Triggers Follicle Activation and “Burnout”; AS101 Prevents Follicle Loss and Preserves Fertility

Kalich-Philosoph, Lital; Roness, Hadassa; Carmely, A.; Bartal, Michal Fishel; Ligumsky, Hagai; Paglin, Shoshana; Wolf, Ido; Kanety, Hannah; Sredni, Benjamin; Meirow, Dror

doi:10.1126/scitranslmed.3005402

Cited by 417 publications

(375 citation statements)

References 80 publications

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“…This may represent a persistent process of follicle activation and loss resulting in overall decrease in follicular reserve triggered by the disease. This Bburn-out^effect on follicle reservoir was previously shown as a major mechanism leading to chemotherapy-induced ovarian reserve loss and may also be a common pathway of follicle loss post toxic injury [42,43].…”

Section: Reduced Ovarian Reserve In Patients Affected By Endometriosismentioning

confidence: 82%

The role of fertility preservation in patients with endometriosis

Carrillo

Seidman

Cittadini

et al. 2016

J Assist Reprod Genet

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Patients affected with severe endometriosis are at significant risk for ovarian tissue damage, which may lead to infertility, reduced response to ovarian stimulation, and occasionally, premature ovarian failure. The risk for a compromised ovarian reserve in young patients is especially high following repeated surgical intervention and in the presence of bilateral endometriomas. In many cases, enhanced loss of ovarian reserve may also result from the damaging effect of the pathologic process on follicle reservoir even without surgical interventions. Women diagnosed with severe endometriosis and those designated for extensive ovarian surgical intervention are frequently not planning to conceive. In light of recent advances in fertility preservation techniques (FPT), such as oocytes and ovarian tissue freezing, as well as their increasing success rates, we critically evaluate the options for FPT in patients suffering from endometriosis. Personalized counseling should be offered to all patients with endometriosis taking into account age, extent of ovarian involvement, current ovarian reserve, previous and impending surgeries for endometriosis, along with current success rates and possible risks associated with FPT.

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Section: Reduced Ovarian Reserve In Patients Affected By Endometriosismentioning

confidence: 82%

The role of fertility preservation in patients with endometriosis

Carrillo

Seidman

Cittadini

et al. 2016

J Assist Reprod Genet

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“…To test these hypotheses, we used gene therapy with MIS, or rhMIS parenteral protein administration, to create a complete arrest in primordial follicle activation concurrently with chemotherapy cycles. As a proof of concept we chose three commonly used chemotherapeutic classes with well-described gonadotoxicities: platinums (54), anthracyclins (55), and alkylating agents (56). Both platinums (such as CBP) and anthracyclins (DOX) interfere with DNA replication and as such are particularly toxic to dividing granulosa cells of secondary and antral follicles, albeit with distinct toxicity profiles (55), and thus represent ideal targets for an MIS oncofertility intervention.…”

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.

164

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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“…Hyperphosphorylation of FOXO3a results in its nuclear export, culminating with the global activation of primordial follicles and premature ovarian failure (Kalich-Philosoph et al 2013). In addition, the mammalian target of rapamycin (mTOR) activation accelerates primordial follicle activation in a synergistic way with the Pi3k/Akt1 pathway (Adhikari et al 2010;Caron et al 2010).…”

Section: Introductionmentioning

confidence: 99%

Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries

Schneider

Zhi

Bartke

et al. 2014

AGE

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The activation of the Pi3k-Akt1-FOXO pathway seems to be involved in the extended longevity observed in growth hormone receptor/growth hormone binding protein knockout (GHRKO) mice and is related to the growth of primordial ovarian follicles. The aim of this work was to measure the expression of genes in the ovaries of GHRKO and normal (N) mice treated with phorbol 12-myristate 13-acetate (PMA), an inhibitor of GH and IRS1 signaling. For this study, a group of N (n= 10) and GHRKO (n=10) mice, N mice treated (n=10) or not (n=10) with PMA, and GHRKO mice treated (n= 10) or not (n=10) with PMA were used. All were 6-month-old female mice. After the last PMA injection, the ovaries were collected for gene expression analysis. Expression of Amh, Gdf9, and Bmp15 was higher in GHRKO than N mice (P<0.05), but was not different between PMA-treated N mice (P>0.10). Expression of Amh and Gdf9 was higher (P<0.05) for GHRKO PMAtreated mice. In addition, we observed a higher expression of Socs3 (P<0.001) in GHRKO than N mice and a tendency for increased expression of Foxo3a (P=0.07). For GHRKO PMA-treated mice, Foxo3a mRNA expression was higher (P=0.02) and a tendency for higher expression of Mtor (P=0.06) and Socs3 (P=0.10) in GHRKO PMA-treated mice was observed. To summarize, the present data further confirm the previous histological observations that GHRKO mice have an ovarian phenotype characteristic of younger mice indicated by higher expression of Amh, Gdf9, and Bmp15 mRNA. In addition, we have shown a higher expression of Socs3 in GHRKO mice and higher Foxo3a expression in PMAtreated GHRKO mice, suggesting a role for these mediators in the process of ovarian aging.

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Cyclophosphamide Triggers Follicle Activation and “Burnout”; AS101 Prevents Follicle Loss and Preserves Fertility

Cited by 417 publications

References 80 publications

The role of fertility preservation in patients with endometriosis

The role of fertility preservation in patients with endometriosis

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

Effect of growth hormone receptor gene disruption and PMA treatment on the expression of genes involved in primordial follicle activation in mice ovaries

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