GNRH SECRETION INTO CSF IN RAMS TREATED WITH A GNRH ANTAGONIST

The equilibrium of the brain-pituitary-testicular axis is controlled b y negative feedback exerted primarily through changes in the circulati ng concentrations of gonadal steroids. This is usually studied in gona dectomised animals treated with single large doses or constant low lev els of exogenous steroid. However, the feedback system probably also c ontains dynamic components, perhaps expressed as delays to changes in GnRH secretion following a change in steroid concentration. These dela ys must be measured without interference from surgical procedures, inc luding anaesthesia, bias associated with changes in pituitary responsi veness (which affect the efficiency of pulse detection), and chronic s ide-effects of gonadectomy. We used a GnRH antagonist ['Antarelix': Ac -D-Nal, D-Cpa, D-Pal, Ser, Tyr, D-Hci, Leu, Lys-(iPr), Pro, D-Ala-NH2] to transiently block LH and steroid secretion (in effect, inducing an d reversing castration) in mature male sheep, and measured GnRH secret ion into cerebrospinal fluid (CSF) in the third cerebral ventricle. Th e CSF was withdrawn with a peristaltic pump at a rate of 2 ml/h and po oled every 20 min. Jugular plasma was sampled every 20 min and analyse d for testosterone and LH pulses. The antagonist (500 mu g i.v.) was i njected after 6 h of baseline sampling and the study continued for a f urther 24 h. The pulses of LH and testosterone disappeared shortly aft er antagonist injection, with delays of 20 +/- 12 min for LH and 80 +/ - 29 min for testosterone. This led to an increase in GnRH pulse frequ ency, starting 300 +/- 54 min after antagonist injection. Secretion of LH and testosterone pulses resumed at 553 +/- 38 and 530 +/- 30 min ( after antagonist injection), and GnRH pulse frequency returned to base line values after 170 +/- 42 min (relative to LH) and 117 +/- 35 min ( relative to testosterone). The consistent nature of these responses ac ross the group of animals suggests that this can be used to test the e ffects of exteroceptive factors on the dynamics of negative feedback.