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Role of Estrogen Receptor-ß in Regulation of Vasopressin and Oxytocin Release in Vitro

Department of Physiology and Biophysics, University of Colorado Health Sciences Center, Denver, Colorado 80262

Address all correspondence and requests for reprints to: Celia D. Sladek, Ph.D., Department of Physiology and Biophysics, University of Colorado Health Science Center, 4200 East Ninth Avenue, Denver, Colorado 80262. E-mail: . celia.sladek{at}uchsc.edu

	Abstract

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In rats, the magnocellular neurons that produce vasopressin (VP) and oxytocin (OT) express estrogen receptor-ß (ER-ß). Physiological concentrations of estrogen (E2) inhibit N-methyl-D-aspartate (NMDA)-stimulated VP and OT release from explants of the hypothalamo-neurohypophyseal system (HNS). To determine whether ER-ß mediates inhibition by E2, HNS explants were perifused with and without NMDA (50 µM) in the presence of E2 (50 pg/ml), E2 coupled to BSA (E2:BSA), genistein (100 nM, a phytoestrogen with affinity for ER-ß), or tetrahydrochrysene-R,R,-enantiomer (R,R-THC, a ligand that acts as an agonist on ER- but an antagonist on ER-ß). VP and OT released into the perifusate were measured by RIA. E2 and genistein inhibited NMDA-stimulated VP release, but E2:BSA and R,R,THC were not effective inhibitors. However, R,R,THC blocked E2 inhibition of NMDA-stimulated VP release. The inability of E2:BSA to mimic the effect of E2 indicates that E2 inhibition is not mediated by membrane receptors. The ability of genistein to mimic the effect of E2 suggests that the effect is mediated by ERß. This interpretation is supported by the ability of R,R,THC to block but not to mimic the effect of E2. Thus, E2 inhibition of NMDA-stimulated VP and OT release may be mediated by ER-ß.

	Introduction

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THE MAGNOCELLULAR NEURONS of the supraoptic and paraventricular nuclei in the hypothalamus produce the hormones, vasopressin (VP) and oxytocin (OT) that are released into the blood stream from the posterior pituitary. These hormones are recognized for their roles in fluid and electrolyte homeostasis, maintenance of blood pressure, and OT is important during parturition and lactation (1).

Gender differences in plasma VP (pVP), VP mRNA content, and stimuli-induced VP release suggested that gonadal steroids modulate VP neurons (2, 3, 4, 5, 6, 7). However, conflicting results as to the effect of estradiol (E2) and testosterone on pVP have been reported. In some studies, estrogen supplementation increased pVP in ovariectomized rats (2) and in postmenopausal women (8), but in other studies no effect of exogenous E2 on pVP was observed in intact female rats (9), ovariectomized rats (10), and in normally menstruating and anovulatory women (11). Similarly, in male rats castration resulted in a decline in pVP in one study (10) but increased pVP in another (2). Both studies reported reversal with testosterone administration. The discrepancies in the latter studies may reflect age differences at the time of gonadectomy. In addition, the numerous physiological effects of steroids may result in a wide range of responses to gonadal hormone manipulation in vivo including CNS actions as well as altered target tissue responses to VP (12, 13) that change feedback regulation of pVP.

Gonadal steroids have also been implicated in the regulation of the magnocellular OT neurons. Early studies reported that administration of E2 stimulated the peripheral release of OT (14). OT mRNA has been reported to vary in the supraoptic nucleus (SON) across the estrus cycle with the greatest expression observed during estrus when E2 level is at peak (15). Conversely, it also has been reported that neither ovariectomy in females nor castration in males alters the expression of OT mRNA (16, 17) nor OT pituitary content (17). Although numerous studies have reported an increase in OT mRNA in the magnocellular neurons during pregnancy and lactation associated with increased plasma E2, the increase in OT mRNA observed in these situations is also dependent upon a simultaneous increase in progesterone followed by a steep decline in progesterone (18). Thus, it reflects progesterone and E2 acting in concert rather than E2 alone.

Evidence supporting direct actions of gonadal steroids on the VP/OT neurons comes from autoradiographic studies demonstrating both androgen and E2 binding sites on magnocellular neurons in the SON and paraventricular nucleus (19, 20), and the finding that SON neurons express estrogen receptor-ß (ER-ß) (21, 22, 23). Also, previous studies from this laboratory demonstrated that E2 and dihydrotestosterone (DHT) at concentrations that mimic physiological plasma concentrations, inhibited the release of VP from organotypic explants of the hypothalamo-neurohypophyseal system (HNS) in response to an increase in osmolality or the excitatory amino acid agonist, N-methyl-D-aspartate (NMDA) (24, 25). The current studies were performed to evaluate the role of membrane steroid receptors and/or ER-ß in mediating the E2 inhibition of NMDA-stimulated VP release. To evaluate the role of membrane receptors, E2 covalently conjugated to BSA (E2:BSA) was substituted for E2. Because BSA is a large, nonlipid soluble molecule, the bound hormone is unable to cross the cell membrane, thus limiting the action of E2:BSA to extracellular membrane receptors. To evaluate the role of ER-ß, two compounds were used: 1) genistein (4',5',7'-trihydroxyisoflavone), a soybean-derived isoflavone with preferential agonist activity at ER-ß over ER- (26, 27), was used to mimic the effect of E2 in inhibiting NMDA-stimulated release of VP; and 2) tetrahydrochrysene, R,R-enantiomer (R,R-THC), a nonsteroidal ligand that acts as an agonist on ER- but a complete antagonist on ER-ß (28). R,R-THC stimulated ER--mediated transcriptional activity while fully suppressing ER-ß-mediated transcriptional activity with a 10-fold excess giving 50% suppression (28). Thus, this compound was used to mimic effects of E2 that might be acting via ER- or to counteract effects of E2 that might be acting via ER-ß.

	Materials and Methods

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Explant preparation
Male Sprague Dawley rats (125–149 g) were obtained from Zivic-Miller (Portersville, PA). Following decapitation, the brain with pituitary attached was removed from the skull. Under a dissecting microscope, the anterior pituitary was removed, and a triangular block of tissue was dissected from the ventral hypothalamus by cutting rostral to the optic chiasm, lateral to either side of the median eminence, and under-cutting at a depth of 1–2 mm. The explants include the magnocellular neurons of the supraoptic nucleus with their axons projecting through the median eminence and terminating in the neurohypophysis. They also include the suprachiasmatic, arcuate, and ventral portions of the ventromedial, preoptic, and periventricular nuclei as well as the organum vasculosum of the lamina terminalis (29).

Perifusion conditions
Each explant was placed in a 500-µl perifusion chamber, maintained at 37 C in the multiple micro chamber unit (Endotronics, Inc., Minneapolis, MN), and perifused with F-12 nutrient mixture (Sigma, St. Louis, MO) fortified with 20% fetal calf serum, 1 mg/ml glucose, 50 µU/ml penicillin, 50 µg/ml streptomycin, and 1 x 10^-4 M bacitracin. The final osmolality of the culture medium was 295–300 milliosmoles/kg H₂O. The medium was maintained at 37 C and gassed (95% O₂ and 5% CO₂) immediately before entering the explant chamber. Six explants were perifused simultaneously at a rate of approximately 2.0 ml/h. The perifusate was collected at 4 C individually from each explant at 20-min intervals and subsequently assayed for VP and OT by RIA.

Experimental design
In all experiments, the experimental steroids were present in the medium from the time of dissection and throughout the entire perifusion period. The explants were perifused for 4 h to allow equilibration of hormone release before addition of NMDA (50 µM) or vehicle to the medium. NMDA reached the explants approximately 40 min after its addition to the perifusion medium. NMDA was dissolved in water and then diluted into perifusion medium. Explants were perifused with NMDA or vehicle for 3 h. At the end of this period, 25 mM KCl was added to the medium. Explants not responding to KCl with an increase in hormone release were excluded from the analysis. Experimental steroids were used as follows:

Experiment 1.
Explants were perifused in medium with or without E2:BSA (Steraloids, Wilton, NH). E2:BSA contained 30 mol E2:1 mol 3-carboxymethyloxime:BSA. The concentration of E2:BSA used was 0.462 ng/ml, which provided a concentration of E2 (50 pg/ml) corresponding to the peak concentration of E2 observed during rat proestrus (30). E2:BSA was dissolved in H₂O.

Experiment 2.
Genistein (100 nM; Sigma, St. Louis, MO) was present in the medium of some of the explants throughout the entire experiment. Because genistein is light sensitive, the experiment was conducted in a light-tight condition throughout. Genistein was dissolved in DMSO, and following dilution in the perifusion medium was maintained at 37 C.

Experiment 3.
E2 (50 pg/ml; Sigma) and/or R,R-THC (55.2 nM, a 300-fold excess relative to E2) were present in the medium of some of the explants throughout the entire experiment. R,R,-THC was kindly provided by J. A. Katzenellenbogen of the University of Illinois (Champaign, IL). Both E2 and R,R-THC were dissolved in ethanol. Control explants received comparable amounts of vehicle.

RIA
VP and OT concentrations in the perifusate were determined by RIA using antisera (Arnel Products, Brooklyn, NY) at a final dilution of 1:100,000. The buffer used for both assays was 0.1 M PBS, pH 7.6, with 1 mg/ml BSA and 1 mg/ml sodium azide. Both standards and samples were incubated for 72 h at 4 C in the presence of 5000 cpm of ¹²⁵I-arginine VP or for 96 h at 4 C with 3500 cpm of ¹²⁵I-OT for (NEN Life Science Products, Boston, MA). Antibody-bound VP or OT was separated from free peptide with dextran-coated charcoal, and the amount of ¹²⁵I-VP or ¹²⁵I-OT in the pellet was determined with a -counter. The minimum sensitivity for VP assay was 1.0 pg/tube, whereas that of OT was 0.5 pg/tube.

Statistical analysis
Basal hormone release was determined for each explant as the mean hormone release at the end of the 4-h equilibration period. Hormone release is expressed as a percentage of this basal value. In each experiment, two-way ANOVA with repeated measures and post hoc test (Student-Newman-Keuls) was used to determine the specific group differences at individual time points. The value was set at P < 0.05. Results are expressed as the mean ± SE of mean (SEM).

	Results

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Effect of E2:BSA on response to NMDA
In prior experiments, E2:BSA mimicked the inhibition of osmotically stimulated VP release by E2 in HNS explants (24). Because NMDA receptor antagonists also blocked osmotically stimulated VP release, and E2 blocked the VP release induced by NMDA (25), it was suggested that the inhibitory effects of E2 might reflect direct actions on the NMDA receptors as has been reported in hippocampus (31). To test this hypothesis, the ability of E2:BSA to block NMDA-induced VP and OT release was evaluated. As shown in Fig. 1, A and B, E2:BSA used at a concentration to mimic the effective concentration of free E2 did not prevent VP or OT release in response to NMDA. VP release was stimulated by NMDA (F=7.82, P < 0.001), and the response was not statistically different in the presence or absence of E2:BSA (F=0.41). Similarly, OT release was significantly increased by NMDA (F=2.78, P = 0.009), but the response was not altered by E2:BSA (F=0.04). These results indicate that membrane-mediated mechanisms do not account for E2 inhibition of NMDA-induced VP and OT release in HNS explants, and therefore do not support the hypothesis that E2 directly modulates the NMDA receptors.

View larger version (23K): [in this window] [in a new window]   Figure 1. Effect of E2:BSA on VP (A) and OT (B) responses to NMDA. Both VP and OT increased in response to NMDA, but the peak response to NMDA was comparable in the presence and absence of E2:BSA. NMDA reached the explants at the time indicated by the arrow. Basal VP release (mean ± SEM, pg/ml) was 101.2 ± 22.0 for controls and 59.9 ± 14.0 for E2:BSA explants. Basal OT release (pg/ml) was 327.8 ± 89.0 for controls and 283.5 ± 99.9 for E2:BSA explants.

View larger version (21K): [in this window] [in a new window]   Figure 2. Effect of genistein (100 nM) on basal and NMDA-induced VP (A) and OT (B) release. Time control explants were maintained in unsupplemented basal medium throughout the experiment. Exposure to genistein did not alter basal VP nor OT release (time control vs. genistein control). NMDA was added to explants maintained in unsupplemented medium (control + NMDA) or medium supplemented with genistein following the 4-h equilibration period and reached the explants at the time indicated by the arrow. NMDA stimulated VP and OT release in the absence of genistein but was ineffective in the presence of genistein. *, P < 0.05, control + NMDA vs. all other groups. Basal VP release (mean ± SEM, pg/ml) was: genistein alone, 17.8 ± 6.3; genistein + NMDA, 18.1 ± 4.4; Time controls, 65.1 ± 38.1; NMDA alone, 41.3 ± 20.7. Basal OT release (pg/ml) was: genistein alone, 75.5 ± 24.2; genistein + NMDA, 172.5 ± 63.6; gime controls, 59.8 ± 4.2; NMDA alone, 146.3 ± 75.1.

View larger version (23K): [in this window] [in a new window]   Figure 3. Effect of R,R-THC on basal, NMDA-induced, and E2 inhibition of NMDA-induced VP release. A, Explants were maintained in basal medium unsupplemented with R,R,-THC throughout the duration of the perifusion (time control) or were placed in medium supplemented with 55.2 nM R,R,-THC immediately after dissection and then perifused without NMDA (R,R,-THC) or exposed to NMDA after the equilibration period (R,R-THC + NMDA). NMDA reached these latter explants at the time indicated by the arrow. R,R-THC did not significantly alter basal release (time control vs. R,R,-THC) and it did not prevent stimulation of VP release by NMDA (R,R,-THC and time control vs. R,R-THC + NMDA). *, P < 0.05 R,R-THC + NMDA vs. both other groups; #, P < 0.05 R,R-THC + NMDA vs. time control. Basal VP release (mean ± SEM, pg/ml) was: time controls, 121.3 ± 37.5; R,R-THC, 73.6 ± 27.6; NMDA + R,R-THC, 148.4 ± 34.2. B. All three groups were exposed to NMDA at the time indicated by the arrow. NMDA stimulated VP release and this response was inhibited by E2. The NMDA response was not significantly different in explants exposed to NMDA alone or in the presence of both E2 and R,R-THC. *, P < 0.05 NMDA + R,R-THC + E2 vs. NMDA + E2; #, P < 0.05 NMDA alone vs. NMDA + E2. Basal VP release (pg/ml) was: NMDA, 120.9 ± 33.5; NMDA + 4R,R-THC + E2, 158.2 ± 31.8; E2 + NMDA, 217.9 ± 33.8.

	Discussion

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The present data support a role for ER-ß in mediating the inhibitory effect of E2 on VP and OT release from HNS explants. To our knowledge, this represents the first evidence for a function for this novel ER in the magnocellular neuroendocrine system.

The goal of this study was to evaluate the roles of membrane steroid receptors and the intracellular ERs in E2 inhibition of VP and OT release from HNS explants. Previous studies demonstrating inhibition of osmotically stimulated VP release by E2, DHT, and BSA conjugates of these steroids suggested a membrane-mediated mechanism (24). Reports that E2 acts as an allosteric antagonist of NMDA receptors in the hippocampus (31) combined with evidence that NMDA receptor activation is required for osmotic stimulation of VP release (25) supported this interpretation. However, the current finding that E2:BSA did not mimic the inhibitory effect of E2 on NMDA stimulation of VP and OT release suggests that E2 must enter the cell to be effective and, thus, reduces the likelihood that an allosteric effect of E2 on NMDA receptors is responsible for E2 inhibition of osmotically stimulated VP and OT release.

Potential roles for the ER- or its newer subtype ER-ß, in the E2 effect are suggested by their expression in the hypothalamo-neurohypophyseal system. Although ER- is not expressed in the magnocellular neurons, it is expressed in GABA neurons located in the perinuclear region of SON (32). These neurons are believed to project to the magnocellular neurons and function as interneurons for that nucleus (1, 33). Thus, E2 could indirectly modulate VP and/or OT release by acting on ER- receptors in these neurons. In contrast, ER-ß is expressed in the VP and OT neurons of the SON and paraventricular nucleus (21, 22, 23). To test the role of these ERs and differentiate between the - and -ß subtypes, steroid analogs with differential actions at ER- and ER-ß were employed. Genistein acts as an agonist on both receptor subtypes, but has a higher affinity for ER-ß (26, 27). Thus, the ability of genistein to mimic the effect of E2 on NMDA-stimulated VP and OT release suggests involvement of an ER-ß mechanism, because based on solubilized receptor binding assays (27), genistein selectively acts on ER-ß receptors at the concentration used. However, more convincing evidence for involvement of ER-ß was obtained in the studies with R,R-THC. Because this compound is an ER- agonist, but an ERß antagonist, opposite effects are expected if E2 is acting on only one of the ER subtypes. Thus, the observation that the inhibitory effect of E2 was reversed in the presence of R,R-THC also indicates that this event is due to activation of ER-ß. Also, because R,R-THC retains full agonist activity at ER- and it did not prevent NMDA-stimulated VP release, the inhibitory effect of E2 on NMDA-induced VP release is not solely mediated by ER-. Thus, we have demonstrated a functional role of ER-ß in the magnocellular supraoptic neurons in vitro.

Direct regulation of VP and OT gene expression by E2 has been demonstrated using reporter gene assays in cells expressing ER- (34, 35, 36, 37). Although early studies identified a sequence similar to an estrogen response element in the proximal regulatory element of the OT gene (34), the importance of this element to E2 regulation of OT expression in the magnocellular neurons has been questioned due to the lack of expression of ER- by these neurons and the low affinity of this element for either ER- or ER-ß. Other members of the steroid hormone receptor family such as the orphan receptors, steroidogenic factor-1, and chicken ovalbamin upstream promoter-transcription factor 1 (COUP-TF1), may use this element for regulation of the OT gene (38). Gene reporter assays using a 5.5-kb fragment of the VP gene promoter have found evidence for components mediating both ER- and ER-ß activation as well as ER-ß-mediated inhibition (39). Although the latter is clearly a candidate mechanism for the ER-ß-mediated inhibitory effect reported here, the E2 inhibition of NMDA-stimulated VP and OT release need not be limited to direct effects on VP and OT gene expression. Numerous proteins are required for NMDA-stimulated hormone release. For example, the NMDA receptor itself as well as proteins (e.g. kinases and/or phosphatases) involved in regulation of NMDA-receptor desensitization and trafficking might be candidates for regulation by ER-ß. Other possible candidates that would be less specific to NMDA-stimulated release include those involved in secretion. However, earlier studies demonstrated that E2 did not inhibit hormone release induced by direct depolarization of the nerve terminals (25).

Another important issue is the physiological significance of an inhibitory role for E2 and ER-ß on VP and OT release from the posterior pituitary in male rats. E2 was used as the agonist in these studies due to the focus of these studies on ER-ß. Although testosterone is the primary gonadal steroid in males, it can be aromatized to estradiol in the brain by the enzyme aromatase cytochrome P450. Immunoreactivity and activity of this enzyme have been reported in SON of rat (40, 41). Therefore, since plasma testosterone is normally around 3 ng/ml in male rats, it is conceivable that the ER-ß receptors in SON might be exposed to 50 pg/ml of E2 in male rats as a result of aromatization. However, it has also been reported that certain androgenic metabolites have affinity for ER-ß. Specifically, 5-androstane-3ß, 17ß-diol displaced ER-ß binding of 17ß-estradiol and stimulated reporter gene activity (42). Therefore, these observations with E2 may reflect effects that are normally mediated by androgenic metabolites in males. The previous findings that both E2 and DHT inhibited osmotic and NMDA stimulated VP and OT release from HNS explants (24, 25) is consistent with the possibility that ER-ß is a common locus for both estrogenic and androgenic steroid effects in SON.

It is clear that healthy adults whether rat or human, male or female, are able to regulate fluid and electrolyte homeostasis (e.g. release VP in response to changes in osmolality) in the presence of normal circulating levels of gonadal steroids. Thus, the importance of the observed inhibitory effects of gonadal steroids on VP release from HNS explants remains to be determined. One possible explanation is that the HNS explant represents only a subcomponent of a complex system for regulating VP release. In vivo there are multiple pathways providing osmoregulatory information to the VP and OT neurons as well as numerous pathways providing additional information about blood pressure and volume (1). The HNS explant only includes the osmoreceptive elements in the OVLT and SON neurons themselves, and thus, may allow evaluation of effects on these components in isolation from other input. A complex role for steroid hormones in the whole animal is supported by the divergent results obtained in studies of the effects of manipulating gonadal steroids in vivo in animals as well as studies in humans with natural fluctuations in gonadal hormones. Nevertheless, the observed inhibitory effects of E2 acting via ER-ß may be important for subtle modulation of responses. This suggestion is supported by observations that the expression of ER-ß in SON can be regulated. Specifically, in situ hybridization studies demonstrated a 2.5-fold increase in ER-ß mRNA following adrenalectomy and a 60% decrease in ER-ß mRNA in SON following 3 d of 2% sodium chloride ingestion in male rats (43, 44). Combining the latter observation with the current data suggests that reduction of an ER-ß-mediated inhibitory effect of E2 on VP release by decreased production of the receptor could contribute to increased VP release during chronic hypernatremia. It is likely that this type of subtle regulatory modulation would not be detected in studies looking for changes in baseline plasma VP levels following gonadectomy, hormone replacement, or during female reproductive cycle. However, it might participate in achieving the precise homeostatic regulation of water and electrolyte balance in response to physiological perturbations that characterizes mammals.

	Acknowledgments

 
We thank J. A. Katzenellenbogen for generously providing the R,R-THC compound used in these studies.

	Footnotes

 
This work was supported by NIH Grant RO1NS27975 (to C.D.S.) and American Heart Association Fellowship 0120582Z (to S.S.).

Abbreviations: DTH, Dihydrotestosterone; E2, estradiol; ER- or -ß, estrogen receptor- or -ß; HNS, hypothalamo-neurohypophyseal system; NMDA, N-methyl-D-aspartate; OT, oxytocin; pVP, plasma VP; R,R-THC, tetrahydrochrysene-R,R,-enantiomer; SON, supraoptic nucleus; VP, vasopressin.

Received January 22, 2002.

Accepted for publication April 10, 2002.

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