GONADOTROPIN AND GONADAL-STEROID RELEASE IN RESPONSE TO A GONADOTROPIN-RELEASING-HORMONE AGONIST IN G(Q)ALPHA AND G(11)ALPHA KNOCKOUT MICE

In this study, we used mice lacking the G(11)alpha [G(11) knockout (KO )] or G(q) alpha gene (G(q) KO) to examine LH release in response to a metabolically stable GnRH agonist (Buserelin). Mice homozygous for th e absence of G(11)alpha and G(q) alpha appear to breed normally. Treat ment of (5 wk old) female KO mice with the GnRH agonist Buserelin (2 m u g/100 mu l, SC) resulted in a rapid increase of serum LH levels (rea ching 328 +/- 58 pg/25 mu l for G(11) KO; 739 +/- 95 pg/25 mu l for G( q) KO) at 75 min. Similar treatment of the control strain, 129SvEvTacf Br for G(11) KO or the heterozygous mice for G(q) KO, resulted in an i ncrease in serum LH levels (428 +/- 57 pg/25 mu l for G(11) KO; 884 +/ - 31 pg/25 mu l for G(q) KO) at 75 min. Both G(11) KO and G(q) KO male mice released LH in response to Buserelin (2 mu g/100 mu l of vehicle ; 363 +/- 53 pg/25 mu l and 749 +/- 50 pg/25 mu l 1 h after treatment, respectively). These values were not significantly different from the control strain. In a long-term experiment, Buserelin was administered every 12 h, and LH release was assayed 1 h later. In female G(11) KO mice and control strain, serum LH levels reached approximately 500 pg/ 25 mu l within the first hour, then subsided to a steady level (simila r to 100 pg/25 mu l) for 109 h. In male G(11) KO mice and in control s train, elevated LH release lasted for 13 h; however, LH levels in the G(11) KO male mice did not reach control levels for approximately 49 h . In a similar experimental protocol, the G(q) KO male mice released l ess LH (531 +/- 95 pg/25 mu l) after 13 h from the start of treatment than the heterozygous male mice (865 +/- 57 pg/25 mu l), but the femal e KO mice released more LPI (634 +/- 56 pg/25 mu l) after 1 h from the start of treatment than the heterozygous female mice (346 +/- 63 pg/2 5 mu l). However, after the initial LII flare, the LH levels in the he terozygous mice never reached the basal levels achieved by the KO mice . G(11) KO mice were less sensitive to low doses (5 ng/per animal) of Buserelin than the respective control mice. Male G(11) KO mice produce d more testosterone than the control mice after 1 h of stimulation by 2 mu g of Buserelin, whereas there was no significant difference in Bu serelin stimulated testosterone levels between G(q)KO and heterozygous control mice. There was no significant difference in Buserelin stimul ated estradiol production in the female G(q) KO mice compared with con trol groups of mice. However, female G(11) KO mice produced less estra diol in response to Buserelin (2 mu g) compared with control strain. A lthough there were differences in the dynamics of LH release and stero id production in response to Buserelin treatment compared with control groups of mice, the lack of complete abolition of these processes, su ch as stimulated LH release, and steroid production, suggests that the se G proteins are either not absolutely required or are able to functi onally compensate for each other.