Blockage of Ovarian Compensatory Hypertrophy in Hemicastrated Rats With a Dithiocarbamoylhydrazine Derivative

Abstract

\g=a\-Methylallylthiocarbamoyl-2-methyl-thiocarbamoylhydrazine (ICI 33828) is a non-steroidal inhibitor of gonadotrophin production, acting presumably on the pituitary or hypothalamus (Paget, Walpole & Richardson, 1961; Parkes 1963). We have recently examined ICI 33828 in an assay for gonadotrophin blockade based upon prevention ofthe compensatory hypertrophy that follows unilateral ovariectomy in rats (Peterson, Edgren & Jones, 1962, 1964.Following methods described previously, female Charles River rats (160\p=n-\180g.) were hemicastrated on the first day of the assay; administration of the compound was begun immediately and continued daily for 14 days. At autopsy on day 15 the ovaries were removed, cleaned and weighed on a torsion balance. Selected ovaries were prepared for histological examination. Groups of oil-treated intact and operated rats controlled each experiment, and the difference in left ovary weight between these groups was employed as a criterion for evaluation of the effect of the compound. The compound was administered as a corn oil suspension. ICI 33828 prevented the compensatory hypertrophy that followed hemicastration in controls. The percentage changes in ovarian weights were fitted to linear regressions using the method of least squares (Table 1); and the ED 100 values, the doses that completely prevented the postoperative hypertrophy of the ovary, were calculated. Given subcutaneously, ICI 33828 appeared to be about 2\ times more potent than Table 1. Regression formulae, and ED 100 values for prevention of ovarian hypertrophy with ICI 33828 Standard error 95 % confidence Regression formula N* Dose range of slope ED 100 limits Subcutaneous administration: ml3-^S)j/t = 246-4-120-9 log dose 7(2) 0-1-10 11-3 733 701-6-764-4Gavage tr\ = 243-4-106-4 log dose 5(2) 0-3-3 8-7 1690 1662-3-1717-7 * Number of groups of 5-8 rats employed in the calculation of the dose-response curve ; the figures in parentheses indicate the number of separate tests in which these were examined. f y = percentage change in ovarian weight.

Effect of the Pituitary Inhibitor, Methallibure, on the Secretion of Gonadotrophic Hormones in Parabiotic Rats

“…Methalli¬ bure, although non-steroidal, resembles the steroids in its antigonadotrophic effects. It has been shown that this compound produces a blockage of ovarian compensatory hypertrophy in hemicastrated rats (Edgren & Peterson, 1964). The present investiga¬ tion further establishes its antigonadotrophic property.…”

Effects of methallibure on the external morphology, behaviour and chromatic physiology of the teleost, Tilapia Mossambica (Peters).

“…33,828) can selectively block the pituitary gonadotropic activity in several vertebrates is now well established (Paget et al, 1961;Schmidt-Elmendorff et al, 962;Brown, I963;Sykes, 1963, 964;Edgren & Peterson, 1964;Loraine et al, 965;Hoar et al, 1967;Wiebe, I968;Pandey, 1970;Pandey & Leatherland, 1970). Very recently, the present authors (1975) have also experimentally substantiated this action of methallibure in T. mossambica.…”

The Influence of the Route of Administration of 1-Alpha-Methylallylthiocarbamoyl-2-Methylthiocarbamoylhydrazine on Reproduction in Rats and Mice

“…Brown (1963) concluded that it specifically inhibited formation of the gonadotrophins by the anterior pituitary gland. Edgren & Peterson (1964) found that it would prevent com¬ pensatory hypertrophy in hemicastrated rats when treatment was initiated on the day of castration and continued for 15 days. However, they were unable to determine whether it specifically blocked fsh or lh.…”