Brainwork in the ovary: kisspeptin and BDNF signaling converge to ensure oocyte survival.

Abstract

Premature ovarian failure [now increasingly termed premature ovarian insufficiency (POI)] is the loss of ovarian function and consequently loss of fertility with estrogen deficiency before the age of 40 years and affects 1% of women. In some women, specific causes can be found,suchasevidenceofautoimmunefolliculardamage, chromosome abnormalities, premutations in the FMR1 gene or iatrogenic damage such as past exposure to chemotherapyorradiotherapy.Inamajorityofwomen,however,nospecificcauseisfound.Therehavebeenextensive searchesformutationsingenesknowntohavekeyrolesin physiological regulation of ovarian development and function, but these have been identified only rarely, with perhaps the exception of the transcription factor NOBOX oogeneis homeobox, which may account for a larger proportion of cases than other single-gene mutations (1). Genome-wide association studies have also provided some insight but have been of limited direct clinical relevancethusfarinunderstandingthisrelativelycommon condition. In the current issue of this journal, two new and converging pathways regulating ovarian follicle and oocyte survival are described, both causing POI phenotypes in mice. These two studies are the combined work of groups led by Sergio Ojeda and Manuel Tena-Sempere, thus bringing together expertise in neurotrophin and kisspeptin biology with intriguing results that shed new light on granulosa cell regulation of oocyte survival (4, 5). The identification that kisspeptin is a key regulator of reproductive function a decade ago (2) has led to a renaissance of interest in reproductive neuroendocrinology, elaborating the upstream pathways regulating GnRH secretion. The critical control of reproduction at the hypothalamiclevelbykisspeptinhasovershadowedandindeed complicates any attempts to explore the role of intraovarian kisspeptin. Previous studies have demonstrated that kisspeptin and the kisspeptin-1 receptor are expressed in severalcelltypesintheovaryofseveralrodentspeciesand in humans, with some evidence of intrafollicular involvement in the process of ovulation (3). In the present study, akisspeptinreceptorhaplo-insufficiencymodelrevealeda progressive loss of all classes of follicles within the ovary and of premature infertility, which was complete by 48 weeks of age (4). These animals were not gonadotropin deficient and indeed showed the expected late rise in FSH characteristic of ovarian failure. The ovaries of these animals appeared normal at a young age, but fewer ovulations were detected by 16 weeks with thereafter a progressivelossofantralandsubsequentlypreantralfollicles. In keeping with the reduced ovulatory function at 16 weeks, litter size was reduced in kisspeptin receptor hypomorphs at that age and animals older than 48 weeks were sterile. The necessity for kisspeptin signaling within the ovary was further explored in kisspeptin 1 receptor nullmice.Becauseoftheirprofoundhypogonadotropism, they were treated with a gonadotropin priming protocol, but despite this, these animals showed only atretic early antral follicles with no large antral follicles or corpora lutea.AprolongedGnRHplusgonadotropinprimingprotocol did support ovulation in the kisspeptin 1 receptor null animals, but they released significantly fewer oocytes than wild-type females. The potential mechanism involved in this phenotype is explored in the accompanying paper, which indicates a remarkablesynergybetweenkisspeptinandneurotrophin signaling necessary for oocyte survival in antral follicles