COMBINED SUPPRESSION OF FOLLICLE ACTIVATION VIA INTRINSIC AND EXTRINSIC PATHWAYS COMPLETELY PROTECTS AGAINST CYCLOPHOSPHAMIDE-INDUCED OVARIAN RESERVE LOSS IN MICE

A better understanding of the mechanism of primordial follicle activation will help us better understand the causes of premature ovarian insufficiency (POI), and will help us identify new drugs that can be applied to the clinical treatment of infertility. In this study, single oocytes were isolated from primordial and primary follicles, and were used for gene profiling with TaqMan array cards. Bioinformatics analysis was performed on the gene expression data, and Ingenuity Pathway Analysis was used to analyze and predict drugs that affect follicle activation. An ovarian in vitro culture system was used to verify the function of the drug candidates, and we found that curcumin maintains the ovarian reserve. Long-term treatment with 100 mg/kg curcumin improved the ovarian reserve indicators of AMH, FSH, and estradiol in aging mice. Mechanistic studies show that curcumin can affect the translocation of FOXO3, thereby inhibiting the PTEN-AKT-FOXO3a pathway and protecting primordial follicles from overactivation. These results suggest that curcumin is a potential drug for the treatment of POI patients and for fertility preservation.

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441 Perinatal hypoxia leads to primordial follicle activation and premature depletion of ovarian reserve: rat model

American Journal of Obstetrics and Gynecology ◽

10.1016/j.ajog.2020.12.462 ◽

2021 ◽

Vol 224 (2) ◽

pp. S279-S280

Author(s):

Ola Gutzeit ◽

Roee Iluz ◽

Keren Nevenzahl ◽

Yuval Ginsberg ◽

Zeev Weiner ◽

...

Keyword(s):

Rat Model ◽

Ovarian Reserve ◽

Primordial Follicle ◽

Perinatal Hypoxia ◽

Primordial Follicle Activation ◽

Follicle Activation

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Perinatal hypoxia leads to primordial follicle activation and premature depletion of ovarian reserve

The Journal of Maternal-Fetal & Neonatal Medicine ◽

10.1080/14767058.2021.1937985 ◽

2021 ◽

pp. 1-5

Author(s):

Ola Gutzeit ◽

Roee Iluz ◽

Yuval Ginsberg ◽

Keren Nebenzahl ◽

Ron Beloosesky ◽

...

Keyword(s):

Ovarian Reserve ◽

Primordial Follicle ◽

Perinatal Hypoxia ◽

Primordial Follicle Activation ◽

Follicle Activation

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

Proceedings of the National Academy of Sciences ◽

10.1073/pnas.1620729114 ◽

2017 ◽

Vol 114 (9) ◽

pp. E1688-E1697 ◽

Cited By ~ 60

Author(s):

Motohiro Kano ◽

Amanda E. Sosulski ◽

LiHua Zhang ◽

Hatice D. Saatcioglu ◽

Dan Wang ◽

...

Keyword(s):

Ovarian Reserve ◽

Primordial Follicle ◽

Primary Ovarian Insufficiency ◽

Negative Regulator ◽

Ovarian Insufficiency ◽

Gene Therapy Vector ◽

Primordial Follicles ◽

Primordial Follicle Activation ◽

Virus Serotype ◽

Follicle Activation

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.

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Advances in human primordial follicle activation and premature ovarian insufficiency

Reproduction ◽

10.1530/rep-19-0201 ◽

2020 ◽

Vol 159 (1) ◽

pp. R15-R29 ◽

Cited By ~ 10

Author(s):

Emmalee A Ford ◽

Emma L Beckett ◽

Shaun D Roman ◽

Eileen A McLaughlin ◽

Jessie M Sutherland

Keyword(s):

Ovarian Reserve ◽

Mammalian Target Of Rapamycin ◽

Primordial Follicle ◽

Premature Ovarian Insufficiency ◽

Phosphatidylinositol 3 Kinase ◽

Ovarian Insufficiency ◽

Primordial Follicles ◽

Primordial Follicle Activation ◽

Future Fertility ◽

Follicle Activation

In women, the non-growing population of follicles that comprise the ovarian reserve is determined at birth and serves as the reservoir for future fertility. This reserve of dormant, primordial follicles and the mechanisms controlling their selective activation which constitute the committing step into folliculogenesis are essential for determining fertility outcomes in women. Much of the available data on the mechanisms responsible for primordial follicle activation focuses on a selection of key molecular pathways, studied primarily in animal models, with findings often not synonymous in humans. The excessive induction of primordial follicle activation may cause the development of premature ovarian insufficiency (POI), a condition characterised by menopause before age 40 years. POI affects 1–2% of all women and is accompanied by additional health risks. Therefore, it is critical to further our understanding of primordial follicle activation in order to diagnose, treat and prevent premature infertility. Research in primordial follicle activation has focused on connecting new molecules to already established key signalling pathways, such as phosphatidylinositol 3-Kinase (PI3K) and mammalian target of rapamycin (mTOR). Additionally, other aspects of the ovarian environment, such as the function of the extracellular matrix, in contributing to primordial follicle activation have gained traction. Clinical applications are examining replication of this extracellular environment through the construction of biological matrices mimicking the 3D ovary, to support follicular growth through to ovulation. This review outlines the importance of the events leading to the establishment of the ovarian reserve and highlights the fundamental factors known to influence primordial follicle activation in humans presenting new horizons for female infertility treatment.

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A putative role for anti-Müllerian hormone (AMH) in optimising ovarian reserve expenditure

Journal of Endocrinology ◽

10.1530/joe-16-0522 ◽

2017 ◽

Vol 233 (1) ◽

pp. R1-R13 ◽

Cited By ~ 22

Author(s):

Michael W Pankhurst

Keyword(s):

Ovarian Reserve ◽

Potential Role ◽

Expression Patterns ◽

Primordial Follicle ◽

Dependent Manner ◽

Primordial Follicles ◽

Simple Interpretation ◽

Primordial Follicle Activation ◽

Follicle Activation

The mammalian ovary has a finite supply of oocytes, which are contained within primordial follicles where they are arrested in a dormant state. The number of primordial follicles in the ovary at puberty is highly variable between females of the same species. Females that enter puberty with a small ovarian reserve are at risk of a shorter reproductive lifespan, as their ovarian reserve is expected to be depleted faster. One of the roles of anti-Müllerian hormone (AMH) is to inhibit primordial follicle activation, which slows the rate at which the ovarian reserve is depleted. A simple interpretation is that the function of AMH is to conserve ovarian reserve. However, the females with the lowest ovarian reserve and the greatest risk of early reserve depletion have the lowest levels of AMH. In contrast, AMH apparently strongly inhibits primordial follicle activation in females with ample ovarian reserve, for reasons that remain unexplained. The rate of primordial follicle activation determines the size of the developing follicle pool, which in turn, determines how many oocytes are available to be selected for ovulation. This review discusses the evidence that AMH regulates the size of the developing follicle pool by altering the rate of primordial follicle activation in a context-dependent manner. The expression patterns of AMH across life are also consistent with changing requirements for primordial follicle activation in the ageing ovary. A potential role of AMH in the fertility of ageing females is proposed herein.

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