Direct Actions of Estradiol on the Anterior Pituitary Gland Are Required for Hypothalamus-Dependent Lactotrope Proliferation and Secretory Surges of Luteinizing Hormone but Not of Prolactin in Female Rats

Abstract

Estradiol induces surges of prolactin (PRL) and luteinizing hormone (LH) secretion as well as lactotrope proliferation in female rats. We examined whether these hypothalamus-dependent events require the direct action of estradiol on the anterior pituitary gland by selective blockade of its peripheral actions, using ICI182,780 (ICI), an antiestrogen that cannot cross the blood-brain barrier. Injection of ICI into ovariectomized rats, at a dose of 250 µg/day for 4 days, almost completely inhibited estradiol-induced growth of the uterus, proliferation of lactotropes as determined by bromodeoxyuridine incorporation, and afternoon surges of LH secretion. However, ICI only partially inhibited estradiol-induced surges of PRL secretion and had no effect on estradiol-induced tonic inhibition of LH secretion even at the highest dose of 1,000 µg/day. The inhibitory effects of ICI found at 250 µg/day were attributable to its selective peripheral, but not central actions since ICI did not alter hypothalamic expression of progesterone receptors, an estradiol-dependent brain process. Estradiol-induced increases in the number of progesterone receptor-immunoreactive cells in the hypothalamic ventromedial nucleus and the medial preoptic area were not inhibited by this dose of ICI but were inhibited by 500 µg/day tamoxifen, an antiestrogen that can cross the blood-brain barrier. Treatment of cycling female rats with 250 µg/day ICI beginning from diestrus day 2 was also effective in blocking estrous lactotrope proliferation and preovulatory surges of LH secretion but not PRL secretion. Finally, in ovariectomized estradiol-treated pup-deprived lactating rats, ICI did not affect suckling-induced PRL secretion but completely blocked lactotrope proliferation. These results suggest that a direct estradiol action on the anterior pituitary gland is required for lactotrope proliferation and the positive feedback action on LH secretion but not for the secretory surges of PRL or for negative feedback.

Estrogens sensitize anterior pituitary gland to apoptosis

“…This effect of estradiol could be mediated by modifying cell phenotypic features that increase the responsiveness of the anterior pituitary cells to proapoptotic signals. Also, it has been suggested that the sensitizing action of estradiol is required for lactotrope proliferation at estrus (32). Therefore, estradiol may participate in anterior pituitary cell renewal sensitizing the cells to both mitogenic and apoptotic signals.…”

Peripheral estrogen receptor-α selectively modulates the waveform of GH secretory bursts in healthy women

“…Accordingly, discerning whether estrogen amplifies GH secretion via actions on the hypothalamus compared with the pituitary gland remains difficult. Based upon preliminary evidence that E 2 may prolong GH secretory bursts (13), we hypothesized that the estrogen effect is secretagogue selective and depends upon ER␣ pathways outside the brain.To begin to address the question where E 2 acts in vivo, we implemented a tripartite experimental paradigm comprising 1) escalating transdermal E 2 delivery on a schedule known to double GH secretion in postmenopausal women (13); 2) concomitant administration of placebo or a selective ER␣ antagonist [fulvestrant (FUL)] that does not cross the blood-brain barrier (33,46,50); 3) maximally effective stimulation with combined secretagogues that drive GH secretion via GHRP and/or GHRH receptors (12,42,43). The rationale was based on three considerations.…”

“…To begin to address the question where E 2 acts in vivo, we implemented a tripartite experimental paradigm comprising 1) escalating transdermal E 2 delivery on a schedule known to double GH secretion in postmenopausal women (13); 2) concomitant administration of placebo or a selective ER␣ antagonist [fulvestrant (FUL)] that does not cross the blood-brain barrier (33,46,50); 3) maximally effective stimulation with combined secretagogues that drive GH secretion via GHRP and/or GHRH receptors (12,42,43). The rationale was based on three considerations.…”

“…Under maximal stimulation, any estrogenic effects on GH secretory-burst waveform cannot then be attributed to increased GH secretion per se. Second, the drug intervention was designed to block peripheral ER␣ pathways selectively with a pure antiestrogen that does not gain access to hypothalamic ER (33,46,50). The anterior pituitary gland lies outside the blood-brain barrier and hence is construed to be peripheral (17,45).…”

Ο ωοθηκικός έλεγχος της υποφυσιακής ευαισθησίας στη GnRH στις γυναίκες με PCOS

“…Μία πρόσφατη µελέτη σε επίµεις έδειξε, ότι η απευθείας δράση της Ε2 στον πρόσθιο λοβό της υπόφυσης είναι υποχρεωτική για τη δράση της θετικής παλλίνδροµης ρύθµισης (positive feedback) στην έκκριση της LH (Yin et al, 2002). Η προγεστερόνη φαίνεται επίσης να ασκεί θετική παλλίνδροµη ρύθµιση (positive feedback) µέσω του υποθαλάµου (Terasawa et al, 1982).…”