Determining the role of RFRP-3 in stress-related female infertility

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DESCRIPTION (provided by applicant): The proposed project is an investigation into a potential mechanistic link between stress and infertility in women. The female reproductive system may be more prone to stress-induced dysregulation since female cycling requires precise and balanced hormone signals along the hypothalamic-pituitary-gonadal (HPG) axis. Despite this, the mechanistic link between the stress response system and the reproductive system has yet to be defined. This research aims to characterize how stress interacts with the HPG axis via RFRP-3, the mammalian ortholog for gonadotropin inhibitory hormone, a hormone that has been shown to directly suppress GnRH and LH release. In the proposed project, we will first characterize the interplay between the female system and stress-related effects on RFRP-3. To this end, the first aim of this proposal will define specific effects of acute stress on RFRP3 at each stage of the estrous cycle while also determining which components of the stress response system directly affect RFRP-3 expression. Within this aim, the candidate will learn and utilize laser capture microscopy and real-time RT-PCR to isolate and precisely analyze relative glucocorticoid and corticotropin releasing hormone receptors (GR and CRH-R1, respectively) on RFRP-3 neurons. In addition, the candidate will learn to utilize viral vectors to express a type of GR that disrupts the stress-induced signal from corticosterone (the main stress hormone in rodents) thus precisely analyzing the role of this hormone at the level of RFRP-3 neurons. The second aim will investigate chronic stress effects on the system and the researchers will investigate how changes in sensitivity at the level of the hypothalamus may lead to altered gonadotropin release by measuring the change in sensitivity of RFRP neurons to stress hormones and the change in sensitivity of GnRH neurons to RFRP-3. While this project mainly focuses on the female system overall sex differences will be analyzed when information on male subjects is incomplete. The overall prediction is that RFRP-3 plays an important role in the link between the stress response system and the reproductive system and that, at the acute stress level, this link is rapid and temporary. However, during and following exposure to chronic stress, the regulation of RFRP-3 release and sensitivity to the hormone is predicted to be disrupted such that this signal between the stress system and the reproductive system results in a dysregulated HPG axis and downstream effects that can lead to decreased fertility. Ultimately, the goal of this research is to help define a mode of dysregulation underlying stress-induced infertility in women. PUBLIC HEALTH RELEVANCE: Stress as a potential cause of infertility or decreased fertility in women is well known, but the mechanistic link between stress and the reproductive system is still somewhat of a mystery. The proposed project will investigate an inhibitory hormone that acts on the hypothalamic-pituitary-gonadal axis and determine its relative role in disrupting reproductive hormone release and, therefore, disturbing the balance of appropriate cycle signals in the female brain. Understanding how the stress response system interacts with the reproductive system at the most basic, mechanistic level is a fundamental step towards truly understanding the stress-fertility connection.