Recovery of Gonadal Functions in the Adult Male Rat Following Cessation of Five‐month Daily Treatment with an LHRH Agonist
Authors: LEFEBVRE F. A. , BÉLANGER A. , PELLETIER G. , LABRIE F. 
Published: December 2015

This study describes the recovery of various parameters of the pituitary‐gonadal axis following five months of daily treatment of adult male rats with a potent LHRH (luteinizing hormone‐releasing hormone) agonist. Two‐month‐old male rats were treated daily with either 250 ng or 1?g of [D‐Ser(TBU)6, des‐Gly‐NH210]LHRH ethylamide (LHRH‐A) s.c. for five months. At the end of treatment, prostate weights were within normal limits and seminal vesicle weights were only slightly decreased. While normal values were found three months following cessation of treatment, it was observed, somewhat unexpectedly, that ventral prostate and seminal vesicle weights were increased by 66 and 54%, respectively, five months after cessation of treatment with the 1?g daily dose of LHRH‐A. Immediately following the five‐month treatment period with either dose of the LHRH agonist, basal testicular levels of pregnenolone, progesterone (P), 17‐OH‐progesterone (17‐OH‐P), androstenedione, testosterone, androstane‐3?,17? ‐diol and androst‐5‐ene‐3?,17? ‐diol were decreased, while the concentrations of dihydrotestos‐terone (DHT), androstane‐3?,17? ‐diol (3? ‐diol) and 17? ‐estradiol were increased. Three months following cessation of treatment, all basal testicular steroid levels had returned to normal except pregnenolone, P, 17‐OH‐P and androstenedione, which were still reduced by 40 to 60%. Five months following cessation of treatment, on the other hand, basal levels of all testicular steroids were 40 to 200% increased in the animals having received either dose of the LHRH agonist. The testicular steroidogenic responsiveness was measured 2 hours following the subcutaneous administration of 10?g oLH. Following five months of daily treatment with the LHRH agonist, the main findings are a decreased response of pregnenolone, P, 17‐OH‐P and androst‐5‐ene‐3?,17? ‐diol, and an increased DHT, 3? diol and androstane‐3?,17? ‐diol responsiveness. Three months post‐treatment, on the other hand, particularly at the higher dose of LHRH agonist, there was an increased responsiveness of androstenedione, T, DHT and 3a‐diol, a finding which was maintained after two additional months of recovery. Degenerative changes were observed in most tubules following five months of LHRH‐A treatment. While most tubules returned to normal five months later, some tubules still showed degenerative changes. Plasma LH measured by radioimmunoassay (RIA) was elevated after five months of treatment with the daily 1?g dose, but all other values were within normal limits. Plasma FSH was increased following treatment as well as during recovery in all groups treated with the LHRH agonist.

The present data show that long‐term treatment with an LHRH agonist in the rat induced compensatory changes in the testicular steroidogenic pathway (especially increased 5?‐reductase activity) which probably compensated for the marked reduction in testosterone formation. Moreover, following discontinuation of treatment, there was evidence of increased 5?‐reductase and 17, 20‐desmolase activities which led to increased weight of the accessory sex organs. The overall increase in basal concentrations of testicular steroids also suggests increased gonadotropin secretion and/or increased Leydig cell responsiveness to LH during the recovery period, which is coupled with a decreased sensitivity of the hypothalamo‐pituitary set‐point of an‐drogen feedback. Although species differences exist, such data should be taken into consideration when using these peptides in the promising clinical applications presently under investigation.