Studies in diabetic rats haye found abnormalities at the hypothalamic, pituitary, and/or ovarian level but have not controlled for changes in estrogen levels induced by diabetes. The purpose of this investigation was to study the effect of diabetes on the hypothalamic-pituitary axis in ovariectomized rats treated with estradiol (E2). Ovariectomized 60 day old female rats were assigned to control (C, n = 42), diabetic (D, n = 47) or insulin-treated diabetic (DI, n = 16) groups. Diabetes was induced with an injection of streptozotocin in the D and DI groups. In the C, D, and DI groups, estrogen was replaced by implanting blank, 5 µg or 20 µg E2 pellets sc. Pituitary LH responsiveness to GnRH was assessed in C and D animals. Anterior hypothalamic and midhypothalamic concentrations of proGnRH and GnRH, pituitary LH and FSH and serum levels of LH, and E2 were measured by RIA. Anterior hypothalamic proGnRH concentrations were decreased in diabetic rats treated with 5 µg E2 compared to 5 µg E2 control animals (P < 0.05). Midhypothalamic GnRH concentrations were also reduced in D vs. C animals despite comparable estrogen therapy (P < 0.004). GnRH-stim-ulated LH levels were greater in E2-treated diabetic females than in similarly treated control rats (P < 0.001). D and DI animals were more sensitive than controls to the inhibitory effect of estrogen on basal LH levels. Pituitary LH and FSH content was lower in 20 µg E2-replaced animals but was not influenced by the diabetic state. These data demonstrate a diabetes-induced decrease in hypothalamic proGnRH and GnRH concentration which is not corrected with E2 replacement. The hyper-respon-siveness of the diabetic rat pituitary to GnRH also suggests a chronic lack of GnRH stimulation from the hypothalamus but a continued ability of the pituitary to respond to GnRH.
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