Effects of chronic exposure to a high dose GnRH agonist (Deslorelin) Brian Edwards*, Arik Smith, Donal C. Skinner - Neurobiology Program and Department of Zoology and Physiology, University of Wyoming, USA Cheryl S. Asa – Research Department, Saint Louis Zoo, USA

Outline Overview of HPG axis Earlier work using deslorelin (DESL) Current work using DESL ICC of gonadotropes Hormone levels of FSH, LH, and T Effects on Testes

HPG-axis overview GnRH is secreted from the hypothalamus binds to GnRH-R on gonadotropes controls production/secretion of LH and FSH The axis is controlled by a negative feedback loop Testosterone, inhibin, FSH, LH, GnRH are key regulating factors

GnRH-R type 1 is a GPCR that lacks a c-terminal end GnRH agonist cause GnRH-receptor down regulation in rat gonadotrophs (conn et al., 1987). This causes suppression of LH and FSH Testosterone and sperm cell production **alternative to surgical castration!!

Earlier work using DESL Using 1.1 mg DESL implant in male rats (6 weeks) Significantly reduced FSHβ-immunoreactive cells 4, 7, & 11 weeks following implant removal FSHβ rebounded, but was still significantly reduced Plasma FSH levels rebounded to normal levels after 4 weeks Weeks following implant removal

Experimental hypothesis: Significantly increasing the dose of DESL will permanently suppress the reproductive axis in male rats.

Groups DESL DESL + 4 week recovery DESL + 12 week recovery DESL + Testosterone (T) (15mg/implant) Control Control + 12 week recovery -Male Sprague-Dawley rats (~185 days) treated sc (6 weeks) with slow-release DESL implants (14.1 mg) -pituitaries fixed by transcardial perfusion and sectioned (20μm). Blood collected via cardiac puncture

DESL FSHβ Control DESL + 4 week recovery DESL + T

DESL LHβ Control DESL + 4 week recovery DESL + T

*(P<0.05),**(<0.01), ***(P<0.001) control vs treated groups

EIA and RIA **Groups containing different letters in the individual graphs are significant from each other (P<0.05).

*GnRH agonists decrease lean muscle mass and increase fat mass in humans (Saylor P.J. and Smith M.R., 2010). Deslorelin implant removed

***(P<0.001) control vs treated groups DESL Control

Summary High dose DESL significantly reduced LHβ and FSHβ-immunoreactive gonadotropes FSH and T plasma concentrations were significantly reduced in DESL compared to control, while LH remained unaffected T replacement rescued plasma FSH concentrations in the presence of DESL even though FSHβ gonadotropes were reduced in DESL + T group Did not permanently suppress reproductive axis Currently trying same dose with a longer duration (6 months)