Estradiol Regulates Neuropeptidase Activity in Hypothalamic Regions Involved in Regulating Gonadotropin‐Releasing Hormone

Abstract

Thimet oligopeptidase (TOP) and prolyl endopeptidase (PEP) are neuropeptidases involved in the degradation of gonadotropin‐releasing hormone (GnRH), an important regulator of the ovarian steroid hormone estradiol (E) via the hypothalamic‐pituitary‐gonadal axis. PEP's action to remove the N‐terminal glycinamide of GnRH occurs prior to hydrolysis of the Try5‐Gly6 bond, the rate‐determining step catalyzed by TOP. E levels in turn regulate GnRH by exertion of positive and negative feedback control. TOP and PEP may potentiate GnRH effects and therefore may be regulated by E. We have previously shown that TOP and the estrogen receptor co‐localize within individual hypothalamic cells, and that levels of TOP in specific regions are down‐regulated by E. In order to determine whether E regulates TOP or PEP enzymatic activity in brain regions associated with reproduction, homogenized hypothalamic brain samples of the medial preoptic area (MPA), periaqueductal gray (PAG), and ventral medial nucleus of the hypothalamus (VMN) were collected from ovariectomized mice treated with E or oil control. Fluorometric kinetic assays were conducted to analyze differences in levels of enzymatic activity between treatments. Kinetic assay data showed that E alters TOP and PEP activity in both the VMN and mPOA, but not in the PAG. These results suggests that, in female mice, TOP and PEP are regulated by E in the hypothalamic regions involved in reproductive physiology.