Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

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

Hypothalamic-pituitary-ovarian Axis Reactivation by Kisspeptin-10 in Hyperprolactinemic Women with Chronic Amenorrhea

CONTEXT : Hyperprolactinemia-induced hypogonadotropic amenorrhea (hPRL-HA) is a major cause of hypothalamic gonadotrophin-releasing hormone (GnRH) deficiency in women. In hyperprolactinemic mice, we previously demonstrated that hypothalamic kisspeptin (Kp) expression was diminished and that Kp administration restored hypothalamic GnRH release, gonadotropin secretion, and ovarian cyclicity, suggesting that Kp neurons could also play a role in hPRL-HA. OBJECTIVE : To study the effect of Kp-10 on the gonadotropic-ovarian axis in women with hPRL-HA. PATIENTS : Two women (32 and 36 years old) with chronic hPRL-HA (prolactin: between 94 and 102 and 98 and 112 ng/mL, respectively) caused by cabergoline-resistant microprolactinomas. INTERVENTIONS : Cabergoline was discontinued 6 months before inclusion. Blood samples were taken every 10 minutes for 12 hours during 2 consecutive days to evaluate luteinizing hormone (LH) and follicle-stimulating hormone (FSH) secretion. Serum estradiol (E2), testosterone (T), and inhibin B (IB) levels were also measured. Vehicle or Kp-10 (1.5 mg/kg/h) was infused intravenously for 12 hours. RESULTS : Kp-10 induced a significant increase in LH and FSH levels and increased LH pulses. E2, T, and IB serum levels were also significantly increased. CONCLUSIONS : In this exploratory study, we demonstrated that administration of Kp-10 reactivated gonadotropin secretion in women with hPRL-HA and increased ovarian activity. Our data suggest that, as in rodents, GnRH deficiency in hPRL-HA is also mediated by an impairment of hypothalamic Kp secretion. Kp-10 or its analogues could have therapeutic application as an alternative approach to restore ovarian function and fertility in women with hPRL-HA resistant to dopamine agonists and in whom pituitary surgery is not possible.https://academic.oup.com/jesam2018ImmunologyPhysiolog

Hyperprolactinemia-induced ovarian acyclicity is reversed by kisspeptin administration

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.R. Millar is recipient of a grant from the Medical Research Council (South Africa) and the University of Pretoria.http://www.jci.or

Onco-Fertility : Impact of Factors affecting Ovarian Reserve after Chemotherapy

La chimiothérapie induit une baisse de la fertilité en exerçant une toxicité directe sur les ovaires entrainant une diminution du stock ovocytaire. Couramment utilisé dans le traitement du cancer du sein, le cyclophosphamide (Cy) est une des drogues reconnue comme la plus gonadotoxique. Récemment, il a été proposé que le Cy provoquait une déplétion folliculaire par une entrée en croissance massive des follicules au repos. L’Hormone Anti-Müllérienne (AMH) étant un des facteurs régulant la sortie des follicules primordiaux de la réserve ovarienne, nous avons émis l’hypothèse que cette hormone pourrait limiter la gonadotoxicité du Cy. Nous avons montré qu’un traitement par AMH recombinante chez des souris pubères traitées par Cy, permettait effectivement de limiter la déplétion folliculaire. Sur le plan fondamental, nous avons mis en évidence que l’autophagie pouvait être un des mécanismes impliqués dans l’inhibition du recrutement folliculaire exercée par l’AMH. Enfin, la méthode de référence consistant à évaluer la réserve ovarienne chez la souris étant particulièrement longue et fastidieuse, nous avons développé une technique de comptage folliculaire automatisé en utilisant des méthodes d’intelligence artificielle, et plus particulièrement une approche de « deep learning».Chemotherapy induces infertility by exerting a direct toxicity on the ovaries, resulting in a depletion of the follicular stockpile. Cyclophosphamide (Cy), widely used for breast cancer, is recognized as one of the most gonadotoxic agent. Recently, it has been proposed that Cy gives rise to follicular depletion by a massive growth of resting follicles which are then destroyed. Since Anti-Müllerian Hormone (AMH) is one of the factors regulating primordial follicles activation, we hypothesized that this hormone might limited Cy-induced gonadotoxicity. We have shown in pubertal mice that recombinant AMH injections are able to preserve primordial follicle loss Cy-induced and might improve fertility outcome after treatment. In addition, we provide evidence that autophagy could be one of the mechanisms involved in the inhibition of follicular recruitment by AMH. At least, nowadays, the “gold standard” method of evaluating ovarian reserve in mouse is a process particularly time-consuming and tedious. We developed a new methodology of automatic primordial follicles detection and counting within mouse ovaries, using modern artificial intelligence methods, especially deep learning approach

Onco-fertilité : Impact des facteurs influençant la réserve ovarienne après chimiothérapie

Chemotherapy induces infertility by exerting a direct toxicity on the ovaries, resulting in a depletion of the follicular stockpile. Cyclophosphamide (Cy), widely used for breast cancer, is recognized as one of the most gonadotoxic agent. Recently, it has been proposed that Cy gives rise to follicular depletion by a massive growth of resting follicles which are then destroyed. Since Anti-Müllerian Hormone (AMH) is one of the factors regulating primordial follicles activation, we hypothesized that this hormone might limited Cy-induced gonadotoxicity. We have shown in pubertal mice that recombinant AMH injections are able to preserve primordial follicle loss Cy-induced and might improve fertility outcome after treatment. In addition, we provide evidence that autophagy could be one of the mechanisms involved in the inhibition of follicular recruitment by AMH. At least, nowadays, the “gold standard” method of evaluating ovarian reserve in mouse is a process particularly time-consuming and tedious. We developed a new methodology of automatic primordial follicles detection and counting within mouse ovaries, using modern artificial intelligence methods, especially deep learning approach.La chimiothérapie induit une baisse de la fertilité en exerçant une toxicité directe sur les ovaires entrainant une diminution du stock ovocytaire. Couramment utilisé dans le traitement du cancer du sein, le cyclophosphamide (Cy) est une des drogues reconnue comme la plus gonadotoxique. Récemment, il a été proposé que le Cy provoquait une déplétion folliculaire par une entrée en croissance massive des follicules au repos. L’Hormone Anti-Müllérienne (AMH) étant un des facteurs régulant la sortie des follicules primordiaux de la réserve ovarienne, nous avons émis l’hypothèse que cette hormone pourrait limiter la gonadotoxicité du Cy. Nous avons montré qu’un traitement par AMH recombinante chez des souris pubères traitées par Cy, permettait effectivement de limiter la déplétion folliculaire. Sur le plan fondamental, nous avons mis en évidence que l’autophagie pouvait être un des mécanismes impliqués dans l’inhibition du recrutement folliculaire exercée par l’AMH. Enfin, la méthode de référence consistant à évaluer la réserve ovarienne chez la souris étant particulièrement longue et fastidieuse, nous avons développé une technique de comptage folliculaire automatisé en utilisant des méthodes d’intelligence artificielle, et plus particulièrement une approche de « deep learning»

Hormone anti-mullerienne (AMH) sérique chez les femmes en hyperprolactinémie

L hormone antimüllérienne (AMH) est considérée comme le marqueur biologique de la réserve ovarienne, puisque cette hormone est synthétisée et secrétée par les cellules de la granulosa des follicules en croissance, depuis le stade primaire jusqu au stade petit antral. Son dosage est utilisé en clinique dans le bilan de réserve ovarienne: du diagnostic de l insuffisance ovarienne primaire au syndrome des ovaires polykystiques. Or, dans les déficits en gonadotrophines et en particulier dans l hyperprolactinémie le dosage de l AMH n a pas été évalué. Nous avons étudié une série de 41 femmes en hyperprolactinémie âgées de 16 à 39 ans (la grande majorité en aménorrhée primaire ou secondaire et une minorité avec des cycles réguliers ou oligo-spanioménorrhée) qui a été comparée à une série de 36 femmes contrôles. L évaluation de la concentration d AMH dans cette étiologie variait de 4 à 99 pmol/L. Ces valeurs n étaient pas significativement différentes de celles retrouvées chez les contrôles (30,6 pmol/l +- 3,6 vs 33,3 pmol/l +- 2,7) alors que l inhibine B (48,5 pg/ml +- 6,2 pg/ml vs 79 +- 5,3) comme l œstradiol (25 pg/ml +- 3,3 vs 38,4 pg/ml +- 4,5) étaient significativement plus basses quand la prolactine était augmentée. Ces résultats sont en faveur d un maintien du pool des follicules en croissance mais d une altération de la croissance cyclique des follicules. Le dosage de l AMH n a pas de valeur discriminante dans l hyperprolacinémie, ce qui différencie cette cause d anovulation du syndrome des ovaires polykystiques ou de l insuffisance ovarienne primaire.PARIS6-Bibl.Pitié-Salpêtrie (751132101) / SudocSudocFranceF

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

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

Embryo transfer strategy and therapeutic options in infertile patients with thin endometrium: a systematic review

International audienceHuman endometrium has a key role in implantation process. The measurement of endometrial thickness is the most commonly used in clinical practice. Managing patients with thin endometrium still represents a major challenge for clinicians. The objective of this systematic review was to investigate all available interventions to improve endometrial thickness (EMT) in women with history of thin endometrium undergoing fresh or frozen-thawed embryo transfers (ET). We performed a comprehensive search of relevant studies from January 1978 to February 2018. The different strategies were categorized as hormonal, vascular, and growth factor approaches and specifically analyzed according to the type of ET. Thirty-one studies were included. Overall, quality of the evidence ranged from very low to moderate, with only few randomized controlled trials that support the use of either GnRH analogues in fresh ET or sildenafil in frozen ET for enhancing endometrial growth. Besides, intensified estradiol administration is a common approach that might improve EMT in frozen ET. The present review evidences the paucity of reliable data regarding the efficiency of different interventions aiming at increasing EMT before fresh or frozen-thawed ET. Robust and high-quality randomized controlled trials are still needed before guidelines can be established