IntroductionA functional antagonism between the hypothalamic decapeptide gonadotrophin-releasing hormone (GnRH) and the ovarian protein Gn-surge-inhibiting factor (GnSIF) on luteinizing hormone (LH) release has been demonstrated in the female gender of rat and human (Koppenaal, Messinis). It was hypothesized that this regulatory system keeps LH release low during the ovarian cycle, but also is responsible for the mid-cycle LH surge, preceding ovulation. In the latter process GnRH self-priming (i.e. GnRH induces an increased LH response to its own action) plays a role. Self-priming was found in response to relatively high exogenous GnRH pulses. However, this phenomenon was absent in response to endogenous, presumably low, GnRH pulses during the major part of the ovarian cycle. This was stated to be the result of the action of endogenous GnSIF. This GnSIF release is stimulated by follicle-stimulating hormone (FSH).The AIM of the present study was to establish whether there is a low dose pulsatile GnRH regime, that is in balance with basal or FSH-stimulated GnSIF release, in that no self-priming will take place. In addition it was studied whether this balance can be disturbed by increasing the pulse frequency of this dose of GnRH and/or by removing the source of endogenous GnSIF, in order to generate a mid-cycle LH surge.Experimental designEXP. 1: 4-day-cyclic rats were injected with saline or 10 IU FSH (Metrodin, Ares/Serono) on three occasions during the ovarian cycle. GnRH (Boehringer, Mannheim) pulses (250, 100, 25 or 10 pmol/kg) were given 1 h apart during 5 hours.EXP. 2: Rats from the 25 and 10 pmol/kg treated groups now received a regime of 3 pulses per hour during 5 hours. In addition, part of the animals were ovariectomized 4 h before these GnRH pulses started.In all cases, endogenous release of GnRH was blocked by fenobarbitol. Bloodsamples for LH estimation were taken just before and 20 min. after each GnRH pulseResultsEXP. 1: 250 and 100 pmol GnRH pulses showed self-priming. After FSH pretreatment GnRH self-priming was delayed (250 pmol) or almost absent (100 pmol). Pulses of 25 pmol GnRH still showed a moderate self priming but FSH pretreatment now caused a balance between GnRH and (stimulated) GnSIF on LH release. Ten pmol GnRH pulses were in balance with both endogenous GnSIF as well as with FSH-stimulated GnSIF on LH release.EXP. 2: Increasing the GnRH pulse frequency to 3 times an hour showed in the case of 10 pmol GnRH a moderate increase in LH blood levels, but in the case of 25 pmol almost a normal mid-cycle LH surge. Ovariectomy (i.e. elimination of GnSIF release) showed a similar immediate increase of LH blood levels.ConclusionThe physiological low LH levels as seen during most part of the ovarian cycle can be mimicked by administration of low GnRH pulses 1-h apart. Self-priming thus is antagonized by GnSIF. A moderate increased pulse frequency and/or discontinuation of GnSIF release leads to the mid-cycle LH surge. These results demonstrate the endogenous functional antagonistic action between GnRH and GnSIF.