Analysis of the Effect of Progesteronein Vivoon Estrogen Receptor Distribution in the Rat Anterior Pituitary and Hypothalamus^*

Abstract

An acute injection of estradiol is known to cause a rapid redistribution of estrogen receptors in responsive cells, measurable as depletion of the cytosol receptor content with accompanying accumulation in the nucleus. We have examined the effects of progesterone on this process in the anterior pituitary and hypothalamus using an animal model in which sensitivity to steroidal feedback control of gonadotropin secretion has been defined. Ovariectomized immature rats were administered low dose estrogen replacement for 4 days. On the morning of the fifth day, groups of animals were injected according to one of the following protocols: 1) vehicle alone; 2) 5 or 10 micrograms estradiol; and 3) 0.8 or 3.2 mg progesterone, followed 1 h later by vehicle or 5 or 10 micrograms estradiol. All animals were killed 1 h after estradiol (or vehicle) injection, and levels of cytosol and nuclear estrogen receptors were measured. The only change occasioned by progesterone treatment was a decrease in anterior pituitary nuclear estrogen receptor levels. At the 5-microgram dose of estradiol, 0.8 and 3.2 mg progesterone were equally effective in diminishing nuclear estrogen receptor binding. When 10 micrograms estradiol were used to cause receptor redistribution, only the higher 3.2-mg dose of progesterone significantly depressed nuclear receptor binding. If ovariectomized animals were maintained in the absence of estrogen replacement, progesterone at either the 0.8- or 3.2-mg dosage was completely ineffective in altering the patterns of estradiol-induced cytosol or nuclear estrogen receptor levels. The results demonstrate a tissue-specific inhibitory action of progesterone on estrogen-induced enhancement of nuclear estrogen receptor binding. This inhibition can be partially overcome by increasing the level of estrogen used to effect receptor redistribution. The requirement for maintenance of a background level of estrogen suggests that the inhibitory action of progesterone is mediated through progesterone receptor interactions.

Inhibitory Effect of 5-Alpha-Dihydroprogesterone on Nuclear Estrogen Receptor Binding of the Anterior Pituitary and Uterus in the Rat

“…Formation o f 5 u -D H P by the hy pothalamus and pituitary in vitro has also been demonstrated [10]. Among the many actions o f progesterone on the hypothal amus and anterior pituitary in the regulation o f gonadotropin secretion is the depletion of occupied nuclear E 2R binding in the anterior pituitary [17,18,20], The decrease in occupied nu clear E :R binding was found to have biological relevance be cause, during the period o f a decrease in occupied nuclear E2R levels induced by progesterone, estrogen-induced progesterone receptor synthesis [18] and prolactin release were inhibited [21 ]. Furthermore, progesterone was found to have a dose-related effect on the decrease in occupied E2Rs o f the anterior pituitary, the 0.8-and 4.0-mg/kg BW doses being much more effective than the 2.0-mg/kg BW dose [20].…”

“…In our previous experiments with progesterone, the observed decrease in E 2Rs also required estrogen priming in order to induce progesterone receptors that mediated the pro gesterone action [17,20]. 5 a -D H P probably acts by a similar receptor-mediated mechanism, but it is unclear at this moment if this action is mediated by its own receptor or by the progester one receptor system.…”

“…They include a rapid release of hypothalamic LH-releasing hor mone (LH R H ) [14,15], suppression o f enzymes that degrade L H R H [16] and a decrease in occupied nuclear estrogen recep tor (E2R) binding in the anterior pituitary [17,18]. In addition, progesterone has been shown to exert dose-dependent multiphasic effects on gonodotropin secretion [ 19], to reduce occu pied nuclear E2R binding o f the anterior pituitary [20] and to inhibit estrogen-induced prolactin release [21].…”

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

“…Αν και η απάντηση της Ε2 στην FSH ήταν παρόµοια και στις δύο πειραµατικές οµάδες των γυναικών µε PCOS (Exp-1 PCOS και Exp-2 PCOS), στην πρώτη οµάδα (Exp-1 PCOS) φαίνεται ότι η µακροχρόνια, ευοδοτική, µη αντιστρεπτή από προγεστερόνη, δράση της Ε2 στην υπόφυση µπορούσε να ξεπεράσει αυτή την ανασταλτική δράση των ωοθηκικών ουσιών, ενώ στη δεύτερη πειραµατική οµάδα (Exp-2 PCOS), που είχε προηγηθεί η χορήγηση της προγεστερόνης, φαίνεται ότι δεν µπορούσε. Ο µηχανισµός αυτής της διαφοράς δεν είναι σαφής, αν και η προγεστερόνη θα µπορούσε να τροποποιήσει τη δράση της Ε2 κεντρικά, ελαττώνοντας τον αριθµό των υποδοχέων της Ε2 (Smanik et al, 1983;Blaustein and Brawn, 1984). Σύµφωνα µε αυτή την άποψη, είναι πιθανόν η αυξηµένη ευασθησία της υπόφυσης στη GnRH, η αυξηµένη δηλαδή έκκριση της LH κατά τη διάρκεια της ανωοθυλακιορρηξίας στις γυναίκες µε PCOS, να µην οφείλεται σε ελαττωµένη παραγωγή ουσιών από τις ωοθήκες, αλλά σε ελαττωµατική δράση αυτών των ωοθηκικών ουσιών στο υποθαλαµοϋποφυσιακό σύστηµα.…”

“…∆ηλαδή, η µακροχρόνια έκθεση της υπόφυσης σε µια µη αντιστρεπτή από προγεστερόνη δράση της Ε2, µπορεί να υπερκεράσει την ανταγωνιστική δράση του GnSAF στην υπόφυση πριν, αλλά όχι µετά τη χορήγηση προγεστερόνης. Είναι πιθανόν η προγεστερόνη να τροποποιεί τη δράση της Ε2 στην υπόφυση ελαττώνοντας των αριθµό των Ε2 υποδοχέων που υπάρχουν σ΄αυτή (Smanik et al, 1983;Blaustein and Brawn, 1984 Αποτελέσµατα: Οι τιµές της ∆LH, της απάντησης της υπόφυσης δηλαδή στη GnRΗ, ήταν στατιστικά σηµαντικά αυξηµένες στην οµάδα 1 των γυναικών µε PCOS από ότι στην οµάδα 2 των γυναικών µε PCOS και στην οµάδα ελέγχου των υγιών γυναικών.…”