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ESTRADIOL-17{BETA} INHIBITS GNRH-INDUCED CA2+ IN GONADOTROPES TO REGULATE NEGATIVE FEEDBACK ON LH RELEASE.

6) Endocrinology. 2009 May 28

Iqbal J, Latchoumanin O, Sari IP, Lang RJ, Coleman HA, Parkington HC, Clarke IJ.

In pituitary gonadotropes, estrogens have biphasic actions to cause an initial negative feedback followed by a positive feedback on LH secretion, but the mechanisms involved are not clearly understood. To investigate the feedback effects of estrogen, we used mixed ovine pituitary cell cultures (48-72h) which were treated with 10(-9)M estradiol-17beta (E2) or vehicle followed by a pulse of 10(-9)M GnRH. Medium was collected for LH assay and cells extracted to determine activation of mitogen-activated protein kinase (MAPK) (phosphorylated ERK-1/2). E2 treatment for 5 min reduced GnRH-induced LH release and caused phosphorylation of ERK-1/2. E2 alone also caused phosphorylation of ERK-1/2, similar to the response evoked by GnRH alone. GnRH increased cytoplasmic [Ca(2+)]i and this was abolished by 2 min pretreatment with E2 or E-bovine serum albumen conjugate. Blockade of Ca(2+) channels with nifedipine had no effect on the initial peak of GnRH-induced increase in [Ca(2+)]i, but reduced its duration by 27 +/- 6%. Depletion of intracellular Ca(2+) stores with thapsigargin prevented GnRH-induced increase in [Ca(2+)]i. Thapsigargin (10(-7)M) or nifedipine (10(-5)M) pretreatment (15 min) of cells lowered GnRH-induced LH secretion by 30 +/- 6% and 50% +/- 4%, respectively. We conclude that inhibition of the GnRH-induced increase in [Ca(2+)]i in gonadotropes by E2 is a likely mechanism for the negative feedback effect of E2 on LH secretion involving a rapid non-genomic effect of E2. Activation of the MAPK pathway by E2 may be the mechanism for the time-delayed positive feedback effect on LH secretion at the level of the gonadotrope.

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