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The endocrine activity of compounds of the rhizome of CIMICIFUGA RACEMOSA can be demonstrated in the IN VIVO model of the ovariectomized rat as well as in the IN VITRO system of the estrogen receptor assay. A reduction of the serum levels of luteinizing hormone in ovariectomized rats takes place upon application of a methanol-extract. This extract contains substances, which are able to bind to estrogen receptors of rat uteri. Using the estrogen receptor assay as a pharmacological testsystem to determine the activity of different fractions, the chromatographic separation of the methanol-extract resulted in at least three different endocrine active compounds. One of these could be identified as the isoflavon Formononetine. The endocrine activity of this isoflavon was characterized in both described testsystems. It can be shown that Formononetine is a competitor in the estrogen receptor assay, but failed to reduce the serum levels of luteinizing hormone in overiectomized rats.

In static cultures of dispersed rat pituitary cells and in the reverse hemolytic plaque assay PACAP inhibits prolactin (Prl) secretion, while in vivo application of PACAP stimulates Prl release in rats. To elucidate the mechanism of this contradictory action, we compared the in vitro effects of PACAP on Prl secretion in cultures of dispersed or reaggregated cells and in pituitary fragments. While in monolayer cultures Prl release was inhibited by PACAP, in cultures of aggregated cells and in pituitary fragments Prl release was stimulated. Dopamine (DA) inhibited Prl release in either type of culture. PACAP also stimulated interleukin 6 (IL6) release under each of the experimental conditions. We conclude that PACAP has a direct inhibitory action on lactotropes. In addition, PACAP may induce the release of a paracrine acting factor within the pituitary which stimulates Prl release and which may be IL6. In the intact pituitary tissue and in reaggregated cells this paracrine factor stimulates Prl release more potently than PACAP directly inhibits Prl secretion resulting in a net effect of enhanced hormone release. In monolayer cultures, however, the direct inhibition is dominant, because the stimulatory paracrine factor is diluted in the culture medium. Therefore we suggest that paracrine cell to cell communication is crucial for the action of PACAP on Prl release.

The GnRH antagonist cetrorelix inhibits the pituitary-gonadal axis in peripubertal male rats and may be effective in treating central precocious puberty in males.

Endocrine activity can be demonstrated for components of the rhizome of CIMICIFUGA RACEMOSA using ovariectomized rats as experimental model. A selective reduction of the serum concentration of the pituitary luteinizing hormone (LH) takes place upon application of an extract. The active principle can be concentrated by extraction with dichloromethane. Enzymatic hydrolysis of glucosides leads to a significant loss of endocrine activity in the experimental model system of the ovariectomized rat.

The hypothalamic peptide "pituitary adenylate cyclase activating polypeptide (PACAP)" stimulates cAMP production in cultured rat pituitary cells and enhances LH release. It has been suggested that the stimulation of LH release by PACAP comprises two distinct mechanisms: a direct stimulatory action on LH secretion and a potentiation of the response of the gonadotrophes to LHRH. Thus the possibility exists that PACAP may enhance LH secretion not only by increased cAMP production but also by increasing cytosolic Ca2+ concentrations ([Ca2+]). In the present study we examined whether PACAP affects cytosolic [Ca2+] in identified rat gonadotrophes (as determined by the fura-method) and whether the suggested potentiating effect of PACAP on LHRH induced LH release is dependent on Ca2+. PACAP (1 nM) and 0.1 nM LHRH significantly increased LH concentrations in the culture medium after 5 hrs of incubation. Coincubation of cells with both peptides resulted in an additive increase of LH release. While the stimulatory effect LHRH was blunted in Ca(2+)-free medium, PACAP remained stimulatory to LH release. PACAP stimulated cAMP formation regardless whether the culture medium contained Ca2+ or not. Gonadotrophes were selected by their response to LHRH (1 microM) and were subsequently challenged with PACAP (1 microM). About 75% of gonadotrophes responded also to PACAP with an increase of cytosolic [Ca2+] which was blunted by removal of extracellular Ca2+. We suggest that in the rat pituitary the majority of the gonadotrophes are PACAP responsive as determined by an increase of cytosolic [Ca2+].(ABSTRACT TRUNCATED AT 250 WORDS)