Brain Health Research Institute (BHRI) and Department of Biological Sciences at Kent State University


Defining the GnRH pulse generator controlling fertility.

Reproductive capacity in mammals is controlled by a small group of cells in the brain known as gonadotrophin-releasing hormone (GnRH) neurons. These neurons release GnRH into the pituitary gland, which then stimulates the production and release of gonadotrophins, luteinizing hormone (LH) and follicle-stimulating hormone (FSH). LH and FSH travel through the circulatory system to control ovarian or teste function.

The release of GnRH occurs in a pulsatile pattern, which is essential for the continued release of gonadotropins. While the precise mechanism behind pulse generation remains unknown, it has been established that it involves upstream cell populations. 

KNDy (kisspeptin/neurokinin B/dynorphin) cells of the arcuate nucleus are hypothesized to form a crucial component of the neural mechanism controlling GnRH pulse generation. Our goal is to determine the mechanism by which KNDy cells and associated cell populations generate and regulate GnRH pulses. To achieve this, we use preclinical models and a range of cutting-edge anatomical and fucntional tools, including immunolabellng, in situ hybridization, viral tract-tracing, chemogenetics, optogenetics, in vivo calcium imaging, and different types of imaging techniques such as confocal and light-sheet microscopy.

Investigating the neuroendocrine etiology of PCOS

Approximately 10-17% of people worldwide are affected by disorders that lead to infertility.  One of the most prevalent forms of infertility is polycystic ovary syndrome, or PCOS, which is diagnosed by oligo-or-anovulation, high testosterone secretion and cystic ovaries in patients assigned female at birth.  PCOS is further associated with various co-morbidities, including obesity, insulin resistance, cardiovascular disease, and gynecological cancers. There is no known cure for PCOS. Treatments are limited to managing symptoms with chronic oral contraceptives or anti-androgen drugs and switching to assisted fertility treatments when pregnancy is desired. However, many PCOS patients fail to respond to ovulatory induction protocols and are at higher risk of dangerous complications such as ovarian hyperstimulation syndrome. As of 2020, the cost of diagnosing and treating PCOS in the US alone is approximately $8 billion a year, adding a chronic financial burden to patients with infertility and to healthcare systems. A major challenge in producing treatments for PCOS is that the mechanisms mediating the syndrome's pathophysiology are largely unclear. Traditionally, PCOS has been viewed as an ovarian or metabolic disorder. However, clinical and basic research indicate symptoms of PCOS are caused by defects in central networks mediating fertility.

PCOS patients demonstrate an increase in the frequency of GnRH/LH pulsatile secretion. The increase in GnRH/LH pulsatile secretion then leads to the diagnostic features of PCOS, including anovulation, elevated testosterone and ovarian cysts. Therefore, it is hypothesized that PCOS arises due to changes in brain circuits controlling fertility. Using preclinical models and the tools described above, our laboratory is investigating whether the etiology of neuroendocrine dysfunction in PCOS originates at KNDy cells, the hypothesized GnRH pulse generator. Overall, our research aims to guide the development of novel treatments and therapeutics targeting central dysfunction in the syndrome.


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