Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects

Roness, Hadassa; Spector, Itay; Leichtmann‐Bardoogo, Yael; Savino, Angela Maria; DerehHaim, Sanaz; Meirow, Dror

doi:10.1007/s10815-019-01507-9

Cited by 38 publications

(43 citation statements)

References 49 publications

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“…5,[10][11][12][13][14][15][16][17][18] This observation was supported by the injection of AMH into mice with the combination of chemotherapy (cyclophosphamide, carboplatin, or doxorubicin), proposing that AMH could be a fertoprotective agent against alkylating agent-inducible primordial follicle activation. [19][20][21][22] The other pathway for follicle loss predicates that oocytes of primordial follicles undergo atresia via the apoptotic pathway induced by chemotherapy. Our previous works, as well as the work of others, show that oocytes within primordial follicles are highly sensitive to DNA damage.…”

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confidence: 99%

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

Eldani

Luan

et al. 2020

FASEB j.

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Chemotherapy directly or indirectly affects organs in a short‐term or continuous manner. Endocrine organs are especially sensitive to cancer treatment, leading to concerns among patients regarding their quality of life afterward. Side effects to the ovary include damage to the ovarian reserve, resulting in follicle loss, endocrine hormone deficiency, and infertility. It has been previously demonstrated that continuous treatment with 2 mg/kg cisplatin for 15 days can activate primordial follicles, suggesting that the response in the oocytes of primordial follicles was dependent on cisplatin concentration and administration frequency. However, our results demonstrate that continuous treatment with 2 mg/kg cisplatin for 15 days leads to the same consequence as with the continuous treatment of 5 mg/kg cisplatin: the death of oocytes in primordial follicles without indication of activation. Moreover, animals co‐injected with melatonin and cisplatin did not display any significant differences from those treated with cisplatin only contrary to the known results. 6‐hydroxymelatonin, a metabolite of melatonin, could not prevent follicle destruction, implying that melatonin does not confer the protection of ovarian follicles, either directly or indirectly. Altogether, our data support that fertoprotectants against cisplatin must target molecules that control cell death pathways in the oocytes of primordial follicles.

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confidence: 99%

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

Eldani

Luan

et al. 2020

FASEB j.

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“…Not just in mice, the role of AMH in the suppression of follicle activation was also verified in bovines (Yang et al, 2017) and humans (Carlsson et al, 2006). Administration of a recombinant human AMH reduced the follicle activation induced by cyclophosphamide in a mouse model, thereby protecting the primordial follicle reserve and improving long-term fertility and reproductive outcomes (Roness et al, 2019).…”

Section: Anti-mullerian Hormonementioning

confidence: 94%

The Factors and Pathways Regulating the Activation of Mammalian Primordial Follicles in vivo

Yao

Yang

Shi

et al. 2020

Front. Cell Dev. Biol.

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Mammalian ovaries consist of follicles as basic functional units. Each follicle comprised an innermost oocyte and several surrounding flattened granulosa cells. Unlike males, according to the initial size of the primordial follicle pool and the rate of its activation and depletion, a female's reproductive life has been determined early in life. Primordial follicles, once activated, will get into an irreversible process of development. Most follicles undergo atretic degeneration, and only a few of them could mature and ovulate. Although there are a lot of researches contributing to exploring the activation of primordial follicles, little is known about its underlying mechanisms. Thus, in this review, we collected the latest papers and summarized the signaling pathways as well as some factors involved in the activation of primordial follicles, hoping to lead to a more profound understanding of the cellular and molecular mechanisms of primordial follicle activation.

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“…Further, Roness et al confirmed the fertoprotective role of recombinant AMH in the same mouse model as pharmacological administration of AMH during chemotherapy treatment reduced follicle activation and primordial follicle loss and significantly improved reproductive outcomes [63]. Interestingly, they also showed that AMH does not interfere with the therapeutic actions of chemotherapy.…”

Section: Follicular Activationmentioning

confidence: 94%

“…It is produced by follicles from the primary stage of development until selection for dominance, and plays a key role during folliculogenesis. As it has been shown to limit the activation of primordial follicles in in vivo or in vitro mouse models [59,60,61], it was suggested in three recent studies that this hormone could be an effective treatment option to limit chemotherapy-induced gonadotoxicity [48,62,63].…”

Section: Follicular Activationmentioning

confidence: 99%

The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage

Sonigo

Beau

Binart

et al. 2019

IJMS

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Cancer treatment, such as chemotherapy, induces early ovarian follicular depletion and subsequent infertility. In order to protect gametes from the gonadotoxic effects of chemotherapy, several fertility preservation techniques—such as oocyte or embryo cryopreservation with or without ovarian stimulation, or cryopreservation of the ovarian cortex—should be considered. However, these methods may be difficult to perform, and the future use of cryopreserved germ cells remains uncertain. Therefore, improving the methods currently available and developing new strategies to preserve fertility represent major challenges in the area of oncofertility. Animal and ovarian culture models have been used to decipher the effects of different cytotoxic agents on ovarian function and several theories regarding chemotherapy gonadotoxicity have been raised. For example, cytotoxic agents might (i) have a direct detrimental effect on the DNA of primordial follicles constituting the ovarian reserve and induce apoptosis; (ii) induce a massive growth of dormant follicles, which are then destroyed; or (ii) induce vascular ovarian damage. Thanks to improvements in the understanding of the mechanisms involved, a large number of studies have been carried out to develop molecules limiting the negative impact of chemotherapy on the ovaries.

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Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects

Cited by 38 publications

References 49 publications

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

Continuous treatment with cisplatin induces the oocyte death of primordial follicles without activation

The Factors and Pathways Regulating the Activation of Mammalian Primordial Follicles in vivo

The Impact of Chemotherapy on the Ovaries: Molecular Aspects and the Prevention of Ovarian Damage

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