The follicular ovarian reserve, constituted by primordial follicles (PMF), is established early in life, then keeps declining regularly along reproductive life. The maintenance of a normal female reproductive function implies the presence of a vast amount of dormant PMF. This process involves a continuous repression of PMF activation into early growing follicle through the balance between factors activating the initiation of follicular growth, mainly actors of the PI3K signaling pathway, and inhibiting factors such as anti-Müllerian hormone (AMH). Any disruption of this balance may induce follicle depletion and subsequent infertility. It has been recently proposed that cyclophosphamide (Cy), an alkylating agent commonly used for treating breast cancer, triggers PMF activation, further leading to premature ovarian insufficiency. Preventing chemotherapy-induced ovarian dysfunction might represent an interesting option for preserving optimal chances of natural or medically assisted conceptions after healing. The aim of the present study was to evaluate, in a model of Cy-treated pubertal mice, whether AMH administration might restrain PMF depletion. The counting of the total PMF number within mouse ovaries showed that recombinant AMH prevented Cy-induced PMF loss. Western blot analysis revealed activation of PI3K signaling pathway after Cy administration. After AMH injection, FOXO3A phosphorylation, a main actor of PMF activation, was significantly decreased. Taken together, these results support a protective role of AMH against Cy-induced follicular loss. We also provide evidence for a possible role of autophagy in the preservation of follicular pool reserve. Therefore, concomitant recombinant AMH administration during chemotherapy might offer a new option for preserving young patients' fertility.-Sonigo, C., Beau, I., Grynberg, M., Binart, N. AMH prevents primordial ovarian follicle loss and fertility alteration in cyclophosphamide-treated mice.

Hyperprolactinemia is the most common cause of hypogonadotropic anovulation and is one of the leading causes of infertility in women aged 25-34. Hyperprolactinemia has been proposed to block ovulation through inhibition of GnRH release. Kisspeptin neurons, which express prolactin receptors, were recently identified as major regulators of GnRH neurons. To mimic the human pathology of anovulation, we continuously infused female mice with prolactin. Our studies demonstrated that hyperprolactinemia in mice induced anovulation, reduced GnRH and gonadotropin secretion, and diminished kisspeptin expression. Kisspeptin administration restored gonadotropin secretion and ovarian cyclicity, suggesting that kisspeptin neurons play a major role in hyperprolactinemic anovulation. Our studies indicate that administration of kisspeptin may serve as an alternative therapeutic approach to restore the fertility of hyperprolactinemic women who are resistant or intolerant to dopamine agonists. IntroductionHyperprolactinemia is the most common cause of hypogonadotropic anovulation (WHO Group I) and represents a major etiology of infertility, with highest incidence in women aged 25-34 years (1). In men, hyperprolactinemia is also frequently associated with hypogonadotropic hypogonadism. This gonadotropic deficiency has been proposed to result from direct suppression of prolactin (PRL) on gonadotrophin-releasing hormone (GnRH) release, but evidence supporting this mechanism has never been provided. PRL is synthesized and secreted by the lactotrope cells of the pituitary, and high levels of circulating PRL are mainly caused by lactotroph adenomas, which account for approximately 40% of all pituitary tumors. Pulsatile GnRH replacement can reverse hypogonadotropic hypogonadism and infertility induced by hyperprolactinemia in women as well as men (2, 3), suggesting that PRL excess in humans affects hypothalamic release of GnRH rather than directly affecting pituitary or gonad function. However, very few GnRH neurons in mice express PRL receptors (PRLRs) (4), suggesting that PRL exerts its actions on upstream neurons regulating the GnRH neuron. Because GnRH neurons are stimulated by kisspeptin (Kp) neurons (5, 6), which unequivocally express PRLR (7), we hypothesized that GnRH deficiency resulting from hyperprolactinemia is caused by reduced Kp input, which is now considered to be a primary gatekeeper governing reproduction (8,9). Here, we show that hyperprolactinemia in mice induces hypogonadotropic anovulation and diminished Kp expression and that peripheral Kp administration restores GnRH and gonadotropin secretion and ovarian cyclicity. Therefore, we suggest that hyperprolactinemic women resistant or intolerant to dopamine agonists could take advantage of this therapeutic approach as a treatment for their infertility.

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ObjectivesOocyte and/or embryo vitrification after controlled ovarian stimulation (COS) represents the most established method of fertility preservation (FP) before cancer treatment. However, traditional COS regimens are associated with supraphysiologic serum estradiol and are therefore not recommended in estrogen-sensitive diseases such as breast cancer (BC). To protect the patients from the potential deleterious effects of elevated estrogen levels during COS for FP, protocols using aromatase inhibitors (letrozole) were developed. The present study aims at investigating whether COS with letrozole supplementation (COSTLES) modifies ovarian response in BC patients.Study designOne hundred and seventy-seven BC patients candidates for FP using oocyte and/or embryo vitrification following COS referred to our center between July 2013 and December 2016 were included in this retrospective case-control study. 94 patients underwent COSTLES while 83 had standard GnRH antagonist protocol. The number of oocytes retrieved, oocyte maturation rates, number of oocytes vitrified and follicle responsiveness to FSH assessed by the Follicular Output Rate (FORT) were assessed.ResultsWomen in both groups were comparable in terms of age and ovarian reserve tests leading to a similar number of oocyte recovered (13.1 ± 10.0 vs. 12.2 ± 8.0 oocytes, respectively, NS). However, oocyte maturation rates were significantly lower in COSTLES compared to standard protocol (64.9 ± 22.8 vs. 77.4 ± 19.3%, p < 0.001). As a result, the number of mature oocyte vitrified was lower in COSTLES group (7.8 ± 5.3 vs. 10.3 ± 8.5 oocytes, p < 0.001 respectively)ConclusionDespite similar response to exogenous FSH, BC patients having undergone COSTLES show reduced oocyte maturation rates in comparison with those having received standard stimulation regimen.

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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