1. 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

2. 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

3. 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

4. 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!!

5. 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

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

7. 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

8. DESL
FSHβ
Control
DESL + 4 week recovery
DESL + T

9. DESL
LHβ
Control
DESL + 4 week recovery
DESL + T

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

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

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

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

14. 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)