AJP - Regu Fuel your research with LabChart
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
QUICK SEARCH:   [advanced]


     

Am J Physiol Regul Integr Comp Physiol 274: R187-R195, 1998;
0363-6119/98 $5.00
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stachenfeld, N. S.
Right arrow Articles by Nadel, E. R.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Stachenfeld, N. S.
Right arrow Articles by Nadel, E. R.
Vol. 274, Issue 1, R187-R195, January 1998

Estrogen influences osmotic secretion of AVP and body water balance in postmenopausal women

Nina S. Stachenfeld, Loretta Dipietro, Steven F. Palter, and Ethan R. Nadel

The John B. Pierce Laboratory and Departments of Epidemiology and Public Health, Cellular and Molecular Physiology, and Obstetrics and Gynecology, Division of Reproductive Endocrinology, Yale University School of Medicine, New Haven, Connecticut 06519

    ABSTRACT
Top
Abstract
Introduction
Methods
Results
Discussion
References

To determine if estrogen upregulates osmotic secretion of arginine vasopressin (AVP) and alters body water balance, we infused hypertonic (3% NaCl) saline in 6 women (68 ± 3 yr) after 14 days of 17beta -estradiol (transdermal patch, ~0.1 mg/day, E2) and placebo (control) administration. Hypertonic saline was infused at 0.1 ml · kg-1 · min-1 for 120 min, and after a 30-min equilibration period, the subjects drank water ad libitum for 180 min. E2 increased basal plasma estradiol concentration from <= 12 to 80 ± 12 pg/ml and plasma AVP concentration (P[AVP]) from 2.1 ± 0.7 to 3.1 ± 0.8 pg/ml (P < 0.05), but not plasma osmolality (Posm, 288 ± 1 and 287 ± 1, for control and E2, respectively). Hypertonic saline infusion increased Posm by 18 ± 1 and 17 ± 1 mosmol/kgH2O and P[AVP] by 5.2 ± 0.5 and 4.9 ± 0.4 pg/ml for control and E2 treatments, respectively. The P[AVP]-Posm relationship shifted upward after E2, with no change in sensitivity (slope, 0.36 ± 0.02 and 0.33 ± 0.03 pg · ml-1 · mosmol-1 for control and E2, respectively). Water intake was similar between control and E2 (24 vs. 22 ml/kg), but by 180 min of drinking, urine output and free water clearance (CH2O) were reduced by 5.6 ± 2.3 ml/kg and 2.6 ± 2.0 ml/min, respectively (P < 0.05) after E2. Plasma aldosterone concentration was unaffected by E2, but fractional sodium excretion was reduced from 2.7 ± 0.5 to 1.7 ± 0.4% (P < 0.05) at 180 min of drinking. Our data suggest that E2 augments osmotic AVP secretion, thereby implicating elevated AVP as a contributor to water retention in high E2 states; however, an increase in renal sodium reabsorption was a major component of the enhanced fluid retention.

renal osmoregulation; arginine vasopressin; hormonal regulation; 17beta -estradiol

    INTRODUCTION
Top
Abstract
Introduction
Methods
Results
Discussion
References

BODY WATER RETENTION is common in high estrogen states, such as that immediately preceding ovulation (30), during pregnancy (11), and while taking estrogen (E2) (1) or E2-dominant oral contraceptives (4). This body fluid retention could be due in part to enhanced osmotic stimulation of arginine vasopressin (AVP), the primary hormone involved in modulating renal water reabsorption. AVP is synthesized in the cell bodies of specific neurons (paraventricular and supraoptic nuclei) in the anterior hypothalamus, and axons from these areas project into the posterior pituitary, where it is stored and released because of stimulation of central osmoreceptors. These nerve endings lie in close proximity to capillary networks, so AVP release into the circulation occurs rapidly after elevations in plasma osmolality (Posm). There is evidence that E2 can modulate the osmotic regulation of AVP release in the brain (15, 21), although the precise mechanism for this effect is not known.

Investigations of the influence of estrogen on AVP regulation have yielded variable results. A number of studies have demonstrated that basal plasma AVP concentration (P[AVP]) is elevated in the presence of high plasma concentrations of unopposed estrogen (P[E2]), such as during the mid-follicular phase of the menstrual cycle in young women (12) and after exogenous E2 administration in postmenopausal women (13), whereas other studies have not found differences in basal P[AVP] across the menstrual cycle (31) or between men and women (33). High plasma concentrations of sex steroids (estrogen, progesterone) may increase the slope (22) or threshold (11, 31) of the P[AVP]-Posm relationship during hypertonic saline infusion, providing evidence that these hormones alter the osmotic regulation of AVP. During pregnancy, a period accompanied by elevated sex hormones and body water expansion, basal Posm is reduced by ~6 mosmol/kgH2O despite a constant P[AVP]. Furthermore, the P[AVP]-Posm relationship is shifted to a lower Posm, and the threshold for thirst sensation is reduced during hypertonic saline infusion, indicating enhanced osmotic AVP secretion and thirst perception in pregnancy (11).

Examining the specific effects of E2 on AVP and body fluid regulation is complex in young women because circulating sex hormone and gonadotropin levels are constantly changing. Pregnancy is associated with increased circulating progesterone and vasopressinase (an enzyme that rapidly clears AVP from plasma), as well as alterations in blood volume and mean arterial pressure, all of which may alter P[AVP] independent of E2. Postmenopausal women, however, are naturally low in both progesterone and estrogen, so they provide an appropriate model with which the modulatory effects of E2 on the osmotic regulation of AVP can be isolated. The purpose of the present study was to determine the effect of estrogen administration on the osmotic control of AVP and the consequent adjustments in body water. We hypothesized that increased P[E2] would enhance the P[AVP], thirst, and drinking responses to an osmotic stimulus (3.0% NaCl saline infusion) and result in greater body fluid expansion during the infusion and subsequent ad libitum drinking recovery period.

    METHODS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Six (>55 yr) healthy, postmenopausal women, with no known cardiovascular, gynecological, or renal disease participated in this study. The subjects were cleared by their private physician and underwent physical and gynecological examinations before participation. All women reported that >10 yr had passed since their last menstrual period. The reproductive hormonal status of the subjects was confirmed by measuring plasma estrogen concentration. They gave written informed consent to participate in the study, which had prior approval by the Human Investigation Committee of Yale University School of Medicine.

Experimental procedures. Estrogen was administered through a percutaneous delivery system (Vivelle; Ciba Pharmaceuticals, Summit, NJ), designed to deliver 17beta -estradiol continuously (0.1 mg/day) on application to intact skin. Estrogen administration lasted for 14 days, and the patch was replaced twice weekly. The placebo patches were identical to the E2 patches but did not contain E2. Subjects were told to maintain their normal diet and exercise routines.

On day 14 of E2 administration the hypertonic saline infusion protocol was administered. This same protocol was also performed on day 14 of placebo control. The order of treatment was assigned alternately as each subject entered the study in a placebo-controlled crossover design.

Hypertonic saline infusion. The subjects refrained from heavy exercise for 24 h and from alcohol and caffeine for 12 h before the experiment. Subjects ate a light breakfast (~300 kcal) and drank 5 ml/kg of water at home ~1 h before arriving at the laboratory at 8 AM. After arrival they voided and were seated for 60 min (25°C, <40% relative humidity). Hydration status was immediately assessed from urine specific gravity and was <= 1.01 in all subjects. During the 60-min control period a 20-gauge Teflon catheter was placed in an antecubital or forearm vein. Baseline arterial blood pressure (Dinamap; Critikon, Tampa, FL) and heart rate (electrocardiogram) were recorded every 10 min for the last 30 min. At the end of the 60-min control period, a control blood sample (20 ml) was taken, thirst perception was assessed (see Thirst), and a total urine volume was collected. Hypertonic (3.0% NaCl) saline was then infused at a rate of 0.1 ml · kg body wt-1 · min-1 for 120 min. Blood was sampled (8 ml) at 30, 45, 60, 85, 90, and 120 min during the infusion, and a urine void was obtained at the end of infusion. A 30-min seated equilibration period followed the infusion, after which time the subject was allowed to drink ad libitum for 180 min. Blood samples (8-13 ml) were obtained at 0, 5, 15, 30, 60, 120, and 180 min during drinking. Urine was collected at 60, 120, and 180 min of drinking. Thirst perception was assessed at all blood sampling times.

Blood sampling. Free flowing venous blood was obtained for the measurement of hematocrit (Hct), hemoglobin (Hb), total protein (TP), Posm, P[AVP], plasma E2 concentration (P[E2]), plasma creatinine (P[Cr]), plasma aldosterone (P[Aldo]), urea, glucose, and serum electrolyte concentrations. An aliquot (1 ml) was removed for immediate assessment of Hct, Hb, and TP in triplicate by microhematocrit, cyanomethemoglobin, and refractometry, respectively. An aliquot for Posm, P[Cr], and P[Aldo] was transferred to a tube containing lithium heparin, and an aliquot for determination of P[AVP] and P[E2] was transferred into a tube containing EDTA. An aliquot for the determination of serum sodium (S[Na+]) and potassium (S[K+]) concentrations was placed into a tube without anticoagulant. Samples were centrifuged for 15 min at 4°C, after which plasma or serum was drawn off for the immediate analysis of Posm (freezing point depression, model 3D11 Advanced Instruments) and serum electrolytes (flame photometry, model 943, Instrumentation Laboratory, Lexington, MA). Whole blood used for serum electrolytes was allowed to clot before centrifugation. Plasma for analysis of P[Cr] was stored at -20°C. Plasma for the determination of P[AVP], P[E2], and P[Aldo] was stored at -70°C. Posm, Hct, Hb, TP, and P[AVP] were determined from all blood samples. P[Aldo] was determined at baseline, immediately after the infusion, and at 0, 60, and 180 min of ad libitum drinking. P[E2] was determined from baseline samples before each infusion. Serum solids concentration was determined from the regression equation relating TP and dried weight of serum (18). Serum electrolyte concentrations were represented as the concentrations in serum H2O (meq/kgH2O) after subtracting the solids fraction from the serum volume.

Plasma creatinine, urea, and glucose were assessed by colorimetric assay (Sigma kit, St. Louis, MO). P[AVP] was determined by radioimmunoassay (Nichols Institute Diagnostics, San Juan Capistrano, CA) after separation from binding proteins with ethanol extraction. Plasma concentration was corrected for recovery of AVP (average 70%) from plasma, determined by adding 125I-labeled vasopressin to plasma before extraction. This assay is highly specific for AVP, with cross-reactivity of lysine vasopressin and oxytocin <0.01%. The sensitivity of this assay is 1.2 pg/ml, with intra- and interassay coefficients of variation for P[AVP] (4.4 pg/ml) of 2.93 and 5.23%. P[Aldo] and P[E2] were also determined in duplicate by radioimmunoassay. Intra- and interassay coefficients of variation for P[Aldo] (131 pg/ml) were 2.19 and 2.74% (Coat-A-Count, Diagnostic Products). All samples from a given subject were determined within the same assay. For one subject, P[Aldo] was below the sensitivity of our assay (<16.0 pg/ml) for three of five blood samples during E2 and four of five blood samples during control, so all of her aldosterone data were excluded from further analysis. All samples for P[E2] were analyzed within one assay kit (Coat-A-Count, Diagnostic Products), with an intra-assay coefficient of variation for the mid-range standard (70.7 pg/ml) of 7.8%.

Urinalysis. Urine samples were analyzed immediately for osmolality (freezing point depression, model 3D11 Advanced Instruments) and electrolytes (flame photometry, model 943, Instrumentation Laboratory). An aliquot for the determination of urine creatinine (colorimetric assay, Sigma Kit) was frozen at -20°C until analyzed.

Ad libitum fluid intake. During the drinking period bottled water (15°C) was provided for 180 min. To monitor the rate of water consumption, the container (~900 ml) was weighed during each blood sampling period. The subjects were instructed to drink if they felt thirsty and were told that fluid intake was being monitored to determine fluid balance.

Thirst. Perceptions of thirst, mouth dryness, and stomach distension were assessed by three visual analog rating scales (17, 20). The subjects responded to the question "how thirsty do you feel right now?" on a scale 180 mm in length with intersecting lines at 0 mm "not at all" and at 125 mm "extremely thirsty." Two analogous scales were used to assess perception of stomach distension, "not at all" to "extremely full," and mouth dryness "not at all" to "extremely dry." The subjects were instructed to mark anywhere on the line, including beyond the "extreme" mark, and they could extend the line if they wished. These rating scales have been used extensively for psychophysical assessments in older men and women and have been shown to correspond to physiological determinants of thirst, such as Posm (20).

Calculations. Net fluid gain during infusion and drinking was determined by subtracting urine output from the volume infused and water ingested. Relative changes in plasma volume were calculated based on changes in Hct and Hb during the experiment (seated upright position) using the equation (14)
&Dgr;PV (%) = 100
× [(Hb<SUB>pre</SUB>/Hb<SUB>post</SUB>) × (1 − Hct<SUB>post</SUB>/100)/(1 − Hct<SUB>pre</SUB>/100)] − 100
Fractional excretions of water (FEH2O) and Na+ (FENa+) were calculated from the equations
FE<SUB>H<SUB>2</SUB>O</SUB> = (U<SUB>v</SUB>/GFR)100
FE<SUB>Na<SUP>+</SUP></SUB> = (U<SUB>V</SUB> × [Na<SUP>+</SUP>]<SUB>u</SUB>/GFR × [Na<SUP>+</SUP>]<SUB>f</SUB>)100
[Na<SUP>+</SUP>]<SUB>f</SUB> = the Donnan factor for cations (0.95) × S<SUB>[Na<SUP>+</SUP>]</SUB>
where the subscripts f and u are glomerular filtrate and urine, respectively, Uv is urine flow rate, and S[Na+] is S[Na+] in protein-free solution (meq/kgH2O). Glomerular filtration rate (GFR) was estimated from creatinine clearance.

Statistics. Data are expressed as means ± SE. Repeated-measures analysis of variance models were performed to test differences in the dependent variables due to E2 administration. Bonferroni's t-test was used to correct for multiple comparisons when appropriate. We used paired t-tests to determine the effect of E2 administration on subject characteristics and baseline levels of P[AVP] and Posm. Pearson's product moment correlations were used to assess the relationships of P[AVP] and thirst as functions of Posm on individual data, excluding the baseline values. Paired t-tests were used to determine E2-related differences in the abscissal intercepts, which defined the "theoretical threshold" for AVP release (11). Analysis of covariance was applied to determine the E2-related differences in the P[AVP]-Posm slope during hypertonic saline infusion, with E2 status as the covariate (11). Based on an alpha level of 0.05 and a sample size of six our beta level (power) was >= 0.80 for detecting effect sizes of 35 mm, 2.0 pg/ml, and 0.67 ml/min for thirst, P[AVP], and renal CH2O, respectively (16, 23). Data were analyzed using BMDP statistical software (BMDP Statistical Software, Los Angeles, CA).

    RESULTS
Top
Abstract
Introduction
Methods
Results
Discussion
References

Subject characteristics. The mean age of the subjects was 68 ± 2 yr (range 57-70). The subjects weighed 72.3 ± 5.0 kg and were 166 ± 2 cm tall. P[E2] was <= 12 pg/ml in all subjects before participation and after placebo control, and was undetectable in three subjects. Fourteen days of E2 administration increased P[E2] in all subjects (79.7 ± 12.4 pg/ml, 50-124 pg/ml). Preinfusion body weight increased to 73.4 ± 4.9 (mean increase 1.0 ± 0.3 kg, P < 0.05) after 14 days of E2 administration but was unchanged after placebo control treatment [72.7 ± 5.0 kg, mean change 0.3 ± 0.4, not significant (NS)]. Compared with placebo control, E2 administration reduced Hct by 1.3 ± 0.1% and Hb by 0.6 ± 0.2 g/dl (Table 1), indicating a plasma volume expansion of 4.5 ± 1.9%. Baseline Posm was unchanged, but P[AVP] was increased from 2.1 ± 0.5 to 3.1 ± 0.7 pg/ml (P < 0.05) after E2 administration (Fig 1). Preinfusion S[Na+] was unchanged after E2 administration (Table 1) as were plasma concentrations of urea (18 ± 2 and 16 ± 1 g/dl for E2 and control patches, respectively) and glucose (116 ± 6 and 111 ± 7 mg/dl for E2 and control patches, respectively). Mean arterial blood pressure was unaffected by E2 administration (93 ± 3 vs. 93 ± 4 mmHg for E2 and control patches, respectively), as was baseline P[Aldo] (Table 1).

                              
View this table:
[in this window]
[in a new window]
  		Table 1.   Responses of blood variables to hypertonic (3.0% NaCl) saline infusion and 180 min of ad libitum drinking during E2 administration and placebo control conditions


View larger version (22K):
[in this window]
[in a new window]
  		Fig. 1.   Plasma osmolality (Posm, top), plasma arginine vasopressin concentration (P[AVP], middle), and percent change plasma volume (PV, bottom) during hypertonic (3.0% NaCl) saline infusion and at 5, 15, 30, 60, 120, and 180 min of ad libitum fluid intake during estrogen and placebo control conditions. * Different from placebo control, P < 0.05. Data are expressed as means ± SE.

Hypertonic saline infusion produced similar graded increases in Posm from 287 ± 2 to 304 ± 1 mosmol/kgH2O during E2 administration and from 288 ± 1 to 306 ± 2 mosmol/kgH2O during placebo control (Fig. 1). The increase in Posm was accompanied by an increase in P[AVP] of 4.9 ± 0.4 pg/ml during E2 administration and 5.2 ± 0.5 pg/ml during placebo control treatment (Fig. 1, P < 0.05). As shown in Table 1, Hct and Hb were reduced similarly during E2 and placebo control treatments throughout hypertonic saline infusion and drinking, and therefore plasma volume expansion was also similar between the E2 and control patches (16.3 ± 2.8 and 16.9 ± 2.0%, respectively) after hypertonic saline infusion (Fig. 1). S[Na+], S[K+], and P[Aldo] also responded similarly to hypertonic saline infusion and drinking under both treatments (Table 1). After the hypertonic saline infusion, plasma concentrations of urea were unchanged (18 ± 2 and 14 ± 1 g/dl for E2 and control patches, respectively) and plasma glucose concentration fell slightly in both treatments to 109 ± 4 mg/dl during E2 administration and to 101 ± 9 mg/dl during control patches (NS).

Linear regression analysis of the individual data indicated significant correlations between Posm and P[AVP], with r values ranging from 0.88 to 0.98. The plots in Fig. 2 demonstrate that the P[AVP]-Posm relationship was shifted upward relative to placebo control in five of six subjects; the mean abscissal intercepts for the P[AVP]-Posm relationships were 280 ± 4 mosmol/kgH2O and 285 ± 4 mosmol/kgH2O for E2 and placebo control treatments, respectively (P < 0.05). The slopes of these relationships were unaffected by E2 administration (0.33 ± 0.02 and 0.36 ± 0.03 pg · ml-1 · mosmol-1 for E2 and placebo control, respectively).


View larger version (23K):
[in this window]
[in a new window]
  		Fig. 2.   Individual subjects' relationships between Posm and P[AVP] during hypertonic (3.0% NaCl) saline infusion during estrogen administration and placebo control. Mean linear regression equations were P[AVP] = 0.33 (Posm - 280) and P[AVP] = 0.36 (Posm - 285) for estrogen and placebo control treatments, respectively.

Hypertonic saline infusion led to an increase in the ratings of thirst to 70 ± 14 and 81 ± 11 mm on the line rating scale and resulted in water intake of 24 ± 3 and 22 ± 3 ml/kg by 180 min during ad libitum drinking for E2 and placebo control patches, respectively. Individual linear regression analyses of the thirst-Posm relationship revealed a mean slope of 6.85 ± 0.98 mm/mosmol and a threshold for the onset of thirst perception of 290 ± 1 mosmol/kgH2O during E2 administration, which were not different from placebo control treatment (6.65 ± 1.56 mm/mosmol and 292 ± 4 mosmol/kgH2O). Ratings of mouth dryness were increased during hypertonic saline infusion, but the responses were unaffected by E2 treatment. Individual linear regression analysis of the mouth dryness-thirst relationship during saline infusion and the early part of drinking yielded correlation coefficients exceeding 0.90 (P < 0.05) for all subjects. Stomach fullness ratings were unaffected by saline infusion or by E2 treatment. Hypertonic saline infusion led to significant increases in mean arterial pressure (12 ± 3 mmHg, P < 0.05) during placebo control but not during E2 treatment (7 ± 6 mmHg, NS).

Fluid balance. Figure 3 shows the cumulative fluid balance over the infusion and ad libitum drinking periods, with zero time denoting the beginning of drinking. There were no E2-related differences in fluid intake, but urine output was lower after E2 (9.1 ± 1.7 vs. 13.2 ± 2.3 ml/kg, P < 0.05), resulting in a net fluid gain during the drinking period (18.2 ± 3.3 vs. 12.5 ± 2.7 ml/kg, P = 0.05, for E2 and control conditions, respectively).


View larger version (17K):
[in this window]
[in a new window]
  		Fig. 3.   Fluid balance during estrogen administration (A) and placebo control (B) after hypertonic (3.0% NaCl) saline infusion. * Different from placebo control, P < 0.05. Data are expressed as means ± SE.

Renal water and electrolyte regulation. Hypertonic saline infusion reduced Uv, FEH2O, CH2O, and increased urine osmolality (Uosm), FENa+, and renal osmolar clearance in a similar fashion during E2 administration and placebo control (Table 2). However, E2 administration reduced CH2O, Uv, FEH2O, and FENa+ by 180 min of drinking (P < 0.05), indicating greater renal water and sodium retention. Urine potassium excretion was greater during the last 60 min of infusion and through the first 60 min of drinking during E2 administration (Table 2, P < 0.05).

                              
View this table:
[in this window]
[in a new window]
  		Table 2.   Renal function, fluid, and osmoregulatory responses to hypertonic (3% NaCl) saline infusion and 180 min of ad libitum drinking during E2 administration and placebo control conditions

    DISCUSSION
Top
Abstract
Introduction
Methods
Results
Discussion
References

In postmenopausal women, 14 days of E2 administration increased basal P[AVP], thus shifting the P[AVP]-Posm relationship upward during hypertonic saline infusion, suggesting that E2 modulates AVP release by the hypothalamus. During ad libitum drinking, water and sodium reabsorption rates were enhanced by E2 treatment, whereas thirst and water intake were unaffected, leading to greater water retention. The greater water retention was due in part to an AVP-mediated fall in CH2O, but primarily to increased renal sodium reabsorption. An increase in sodium retention occurred in the presence of a constant P[Aldo], suggesting that E2 may directly influence electrolyte handling in the kidney.

Osmotic AVP regulation. Earlier studies have demonstrated increased basal P[AVP] (5, 13) and plasma volume expansion (32) in women after E2 administration. Our data confirm and extend these findings, demonstrating an upward shift of the P[AVP]-Posm relationship during osmotic stimulation. Although P[AVP] increased concomitantly with Posm with both E2 and placebo control patches, P[AVP] was greater through the physiological range of Posm (i.e., ~287-297 pg/ml) during E2 administration, with no difference between E2 and control in the slope (sensitivity) of the P[AVP]-Posm relationship.

Whether P[AVP] is elevated in the presence of high endogenous estrogen, such as during pregnancy (11) and the mid-follicular and mid-luteal phases of the menstrual cycle (12, 31), is still controversial. Vokes et al. (31) did not find differences in basal P[AVP] over the course of the menstrual cycle. However, basal Posm was lowest (~4 mosmol/kgH2O) in the mid-luteal phase, when estrogen and progesterone peak, indicating an earlier osmotic threshold for AVP secretion. These findings are similar to those reported in pregnant women (11) but are in contrast to those in young, cycling women (12), in whom Posm was unaffected by the menstrual cycle, but P[AVP] was increased in the mid-luteal phase. The findings in our present study in which unopposed E2 was administered, are consistent with earlier studies of exogenous E2 administration (13), in which basal P[AVP] was elevated, whereas Posm was unaffected. The cause of the discrepant findings between endogenous and exogenous E2 cannot be determined from our data but may be related to differences in bioavailability or binding characteristics between the synthetic and natural forms of this hormone.

Although the mechanism for the E2-associated change in P[AVP] response cannot be determined from our data, it is likely that E2 influences the central regulation of AVP synthesis and release. Estrogen readily crosses the blood-brain barrier and thereby gains access to sites in the brain that control AVP release. In lower animals, E2 acts directly on the central nervous system through neurons that bind E2 and increase hypothalamic AVP synthesis and/or release (2, 3, 9, 10, 21). Sar and Stumpf (21) identified estradiol receptors in the nuclei of neurophysin- and AVP-producing cells in the mouse supraoptic nucleus. Furthermore, the threshold for osmotic stimulation of vasopressinergic neuronal activation is lower in the supraoptic nucleus of brain slices of ovariectomized rats given E2, compared with untreated rats (2). It is likely that sex steroids play a modulating role in AVP gene expression in the paraventricular and supraoptic nuclei because osmotically stimulated hypothalamic AVP mRNA concentration is reduced after gonadectomy in the rat (9).

Estrogen could modify AVP release directly through E2 receptors in the hypothalamus or indirectly by acting on catecholaminergic (15) and/or angiotensinergic (26) neurons, which bind estrogen and project to the paraventricular and supraoptic nuclei. Using [3H]estradiol, Heritage et al. (15) identified estradiol binding sites in the nuclei of catecholamine cell bodies, as well as the presence of catecholaminic nerve terminals near estradiol target sites in the paraventricular and supraoptic nuclei. Crowley et al. (10) noted parallel changes in brain norepinephrine and AVP in normally cycling rats and that ovarian steroids modulated norepinephrine turnover in the paraventricular nucleus, indicating that E2 may act on the osmoregulatory system through catecholamines. There also is evidence for cholinergic and angiotensinergic innervation of vasopressinergic cells in the paraventricular and supraoptic nuclei, both of which are modulated by sex steroids (26). Alternatively, the effect of E2 on osmoregulation could be due to an indirect effect through luteinizing or follicle-stimulating hormones, which may indirectly elevate AVP through an adenylate cyclase mechanism. We did not measure these substances, but gonadotropins are slightly reduced after E2 administration in postmenopausal women (27), making this mechanism unlikely.

Although a central mechanism for the increase in AVP secretion with E2 seems the most plausible, peripheral effects cannot be ruled out. To provide several examples, a reduction in the metabolic clearance rate of AVP, a decrease in blood pressure, or an alteration in plasma concentration of atrial natriuretic peptide could elevate P[AVP]. The first explanation seems unlikely because E2 would more likely increase, rather than decrease metabolic clearance of AVP, as plasma volume expansion would be expected to increase blood flow to the liver and kidneys, where most AVP breakdown occurs. Thus expanded blood volume should have diminished the AVP response, making the rise in AVP even more remarkable. Estrogen administration attenuated the rise in blood pressure during hypertonic saline infusion amd therefore may have contributed to the elevation in P[AVP]. However, this small difference in blood pressure (~5 mmHg) was probably insufficient to affect P[AVP] (19). Finally, it is unlikely that changes in circulating levels of atrial natriuretic peptide played a role in the enhanced AVP response. In young women, the follicular phase of the menstrual cycle (when P[E2] is high) is associated with increased plasma levels of atrial natriuretic peptide at baseline and during hypertonic saline infusion (29). Furthermore, atrial natriuretic peptide has been shown to suppress the osmotically induced rise in AVP (8). Preliminary data on two of our six subjects showed E2 administration increased plasma atrial natriuretic peptide concentration both at baseline (76.7 and 59.4 pg/ml) and after hypertonic saline infusion (163.7 and 92.0 pg/ml, for E2 and placebo control administration, respectively).

Renal water and electrolyte handling. Our subjects were in positive fluid balance during hypertonic saline infusion in both E2 administration and placebo control conditions. Despite the greater elevation of P[AVP] during E2 treatment during the early part of hypertonic saline infusion, renal excretion of free water and renal concentrating capacity (Uosm/Posm) were similar in both conditions, perhaps indicating that antidiuretic action of AVP in the collecting duct was already at maximal level. Although little is known about the influence of E2 in the human kidney, some evidence suggests that E2 attenuates the antidiuretic action of AVP in the rat (7), and that E2 modulates AVP action in the collecting duct at the level of the receptors (28). However, the supposition that E2 downregulated renal AVP action in our subjects is complicated by our observation of an increased renal concentrating response (greater Uosm/Posm) during ad libitum drinking, despite similar P[AVP]. This would suggest that E2 enhances, rather than attenuates renal free water retention. Perhaps this relationship is affected by plasma volume status, which was elevated at the end of drinking, or reflects a sluggish renal response to the recovery of P[AVP]. In addition, because the subjects drank ad libitum, drinking patterns may have transiently affected individual P[AVP] measurements (23). Clearly, more studies are needed to elucidate the impact of E2 on AVP modulation of renal water regulation. Nonetheless, estrogen administration increased overall body water retention over placebo control (18.6 vs. 12.5 ml/kg) during the ad libitum drinking period, and this fluid retention was due in part to increased free water reabsorption (negative CH2O).

Although CH2O was reduced during drinking with E2 administration, the primary cause of the greater water retention was a reduction in sodium and total osmol excretion. Our observation that sodium retention during ad libitum drinking was enhanced after E2 administration is consistent with earlier findings in postmenopausal women during long-term estrogen therapy (1), as well as in young women during estrogen-dominant oral contraceptive administration (4). Although there is evidence to suggest that E2-related sodium retention is mediated through aldosterone (7), E2 administration did not alter P[Aldo] at baseline or in response to hypertonic saline infusion. Furthermore, an increase in potassium excretion did not accompany the sodium retention during most of the ad libitum drinking period, which also argues against an aldosterone-dependent mechanism. We speculate that the alteration in electrolyte handling with E2 is due to an effect of E2 on aldosterone distal tubule binding sites (7) or a direct effect of E2 on the proximal tubule (24, 28). There are no data that directly address this question, but Stock et al. (25) have demonstrated altered renal mineral metabolism in postmenopausal women after E2 treatment.

In summary, we found that E2 administration augmented P[AVP] at baseline and in response to hypertonic saline infusion in postmenopausal women. The elevated plasma AVP levels may be due to a direct action of E2 on structures in the anterior hypothalamus that secrete AVP or through catecholaminergic or angiotensinergic neuronal action on these same structures. Although thirst, drinking, and P[Aldo] responses were unaffected, total body water and sodium retention were increased after E2 administration. The AVP-mediated reduction in renal CH2O during E2 only partially explains the greater body water retention, suggesting that E2 may have directly affected water and electrolyte handling in the renal tubule.

Perspectives

Body water retention is common following estrogen replacement therapy and administration of oral conceptive pills, as well as during pregnancy and the periods of the menstrual cycle when endogenous estrogens are at their peaks in the blood. However, it is difficult to isolate estrogen as the cause of the water retention in young women because the levels of the sex hormones (estrogen, progesterone) and gonadotropins (luteinizing or follicle-stimulating hormones) are constantly fluctuating. This study uses postmenopausal women as a low estrogen model to isolate the effects of estrogen on an important fluid regulating hormone, AVP. AVP is primarily responsible for the retention of free water by the kidney and is highly sensitive to changes in Posm. We found that AVP was increased at baseline and throughout infusion of hypertonic saline, despite similar osmolality throughout the protocol. However, we also found that the primary mechanism for the enhanced body fluid expansion was not due to free water retention, i.e., to the effects of AVP. The body water retention was primarily the result of increased salt retention, suggesting a role for estrogen in renal electrolyte handling.

    ACKNOWLEDGEMENTS

We gratefully acknowledge the technical support of Cheryl Weseman-Kokoszka and the cooperation of the volunteer subjects.

    FOOTNOTES

This work was supported in part by the National Institute on Aging Grants AG-09872 and AG-10469-04.

Address for reprint requests: N. S. Stachenfeld, The John B. Pierce Laboratory, 290 Congress Ave., New Haven, CT 06519.

Received 17 March 1997; accepted in final form 23 September 1997.

    REFERENCES
Top
Abstract
Introduction
Methods
Results
Discussion
References

1.   Aitken, J. M., R. Lindsay, and D. M. Hart. The redistribution of body sodium in women on long-term oestrogen therapy. Clin. Sci. Mol. Med. 47: 179-187, 1974[Medline].

2.   Akaishi, T., and Y. Sakuma. Estrogen-induced modulation of hypothalamic osmoregulation in female rats. Am. J. Physiol. 258 (Regulatory Integrative Comp. Physiol. 27): R924-R929, 1990[Abstract/Free Full Text].

3.   Barron, W. M., J. Schreiber, and M. D. Lindheimer. Effect of ovarian sex steroids on osmoregulation and vasopressin secretion in the rat. Am. J. Physiol. 250 (Endocrinol. Metab. 13): E352-E361, 1986[Abstract/Free Full Text].

4.   Blahd, W. H., M. A. Lederer, and E. T. Tyler. Effects of oral contraceptives on body water and electrolytes. J. Reprod. Med. 13: 223-225, 1974[Medline].

5.   Bossmar, T., M. Forsling, and M. Akerlund. Circulating oxytocin and vasopressin is influenced by ovarian steroid replacement in women. Acta Obstet. Gynecol. Scand. 74: 544-548, 1995[Medline].

7.   Christie, N. P., and J. C. Shaver. Estrogens and the kidney. Kidney Int. 6: 366-376, 1974[Medline].

8.   Clark, B. A., D. Elahi, L. Fish, M. McAloon-Dyke, K. Davis, K. L. Minaker, and F. H. Epstein. Atrial natriuretic peptide suppresses osmostimulated vasopressin release in young and elderly humans. Am. J. Physiol. 261 (Endocrinol. Metab. 24): E252-E256, 1991[Abstract/Free Full Text].

9.   Crowley, R. S., and J. A. Amico. Gonadal steroid modulation of oxytocin and vasopressin gene expression in the hypothalamus of the osmotically stimulated rat. Endocrinology 133: 2711-2718, 1993[Abstract].

10.   Crowley, W. R., T. L. O'Donohue, J. M. George, and D. M. Jacobowitz. Changes in pituitary oxytocin and vasopressin during the estrous cycle and after ovarian hormones: evidence for mediation by norepinephrine. Life Sci. 23: 2579-2586, 1978[Medline].

11.   Davison, J. M., E. A. Gilmore, J. Durr, G. L. Robertson, and M. D. Lindheimer. Altered osmotic thresholds for vasopressin secretion and thirst in human pregnancy. Am. J. Physiol. 246 (Renal Fluid Electrolyte Physiol. 15): F105-F109, 1984.

12.   Forsling, M. L., M. Akerlund, and P. Stromberg. Variations in plasma concentrations of vasopressin during the menstrual cycle. J. Endocrinol. 89: 263-266, 1981[Abstract].

13.   Forsling, M. L., P. Stromberg, and M. Akerlund. Effect of ovarian steroids on vasopressin secretion. J. Endocrinol. 95: 147-151, 1982[Abstract].

14.   Greenleaf, J. E., V. A. Convertino, and G. R. Mangseth. Plasma volume during stress in man: osmolality and red cell volume. J. Appl. Physiol. 47: 1031-1038, 1979[Abstract/Free Full Text].

15.   Heritage, A. S., W. E. Stumpf, M. Sar, and L. D. Grant. Brainstem catecholamine neurons are target sites for sex steroid hormones. Science 207: 1377-1379, 1980.

16.   Kelsey, J. L., W. D. Thompson, and A. S. Evans. Methods in Observational Epidemiology. New York: Oxford University Press, 1986.

17.   Marks, L. E., J. C. Stevens, L. M. Bartoshuk, J. F. Geny, B. Rifkin, and V. K. Stone. Magnitude-matching: the measurement of taste and smell. Chem. Senses 13: 66-87, 1988.

18.   Nose, H., G. W. Mack, X. Shi, and E. R. Nadel. Shift in body fluid compartments after dehydration in humans. J. Appl. Physiol. 65: 318-324, 1988[Abstract/Free Full Text].

19.   Robertson, G. L., and S. Athar. The interaction of blood osmolality and blood volume in regulating plasma vasopressin in man. J. Clin. Endocrinol. Metab. 42: 613-620, 1976[Abstract].

20.   Rolls, B. J., and P. A. Phillips. Aging and disturbances of thirst and fluid balance. Nutr. Rev. 48: 137-144, 1990[Medline].

21.   Sar, M., and W. E. Stumpf. Simultaneous localization of [3H]estradiol and neurophysin I or arginine vasopressin in hypothalamic neurons demonstrated by a combined technique of dry-mount autoradiography and immunohistochemistry. Neurosci. Lett. 17: 179-184, 1980[Medline].

22.   Spruce, B. A., P. H. Baylis, J. Burd, and M. J. Watson. Variation in osmoregulation of arginine vasopressin during the human menstrual cycle. Clin. Endocrinol. (Oxf.) 22: 37-42, 1985[Medline].

23.   Stachenfeld, N. S., G. W. Mack, A. Takamata, L. DiPietro, and E. R. Nadel. Thirst and fluid regulatory responses to hypertonicity in older adults. Am. J. Physiol. 271 (Regulatory Integrative Comp. Physiol. 40): R757-R765, 1996[Abstract/Free Full Text].

24.   Stock, J. L., J. A. Coderre, E. M. Burke, D. B. Danner, S. D. Chipman, and J. R. Shapiro. Identification of estrogen receptor mRNA and estrogen modulation of parathyroid hormone-stimulated cyclic AMP accumulation on opossum kidney cells. J. Cell. Physiol. 150: 517-525, 1992[Medline].

25.   Stock, J. L., J. A. Coderre, and J. T. Posillico. Effects of estrogen on mineral metabolism in post menopausal women as evaluated by multiple assays measuring parathyrin bioactivity. Clin. Chem. 35: 18-22, 1989[Abstract/Free Full Text].

26.   Stone, J. D., J. T. Crofton, and L. Share. Sex differences in central cholinergic and angiotensinergic control of vasopressin release. Am. J. Physiol. 263 (Regulatory Integrative Comp. Physiol. 32): R1030-R1034, 1992[Abstract/Free Full Text].

27.   Studd, J., and A. Magos. Hormone pellet implantation for the menopause and premenstrual syndrome. In: Obstetrics and Gynecology Clinics of North America: The Menopause, edited by R. D. Gambrell. Philadelphia, PA: Saunders, 1987, p. 229-249.

28.   Stumpf, W. E., M. Sar, R. Narbaitz, F. A. Reid, H. F. DeLuca, and Y. Tanaka. Cellular and subcellular localization of 1,25-(OH)2-vitamin D3 in rat kidney: comparison with localization of parathyriod hormone and estradiol. Proc. Natl. Acad. Sci. USA 77: 1149-1153, 1980[Abstract/Free Full Text].

29.   Trigoso, W. F., J. M. Wesly, D. L. Meranda, and Y. Shenker. Vasopressin and atrial natriuretic peptide hormone responses to hypertonic saline infusion during the follicular and luteal phases of the menstrual cycle. Hum. Reprod. 11: 2392-2395, 1996[Abstract/Free Full Text].

30.   Veille, J. C., M. J. Morton, K. Burry, M. Nemeth, and L. Speroff. Estradiol and hemodynamics during ovulation induction. J. Clin. Endocrinol. Metab. 63: 721-724, 1986[Abstract].

31.   Vokes, T. J., N. M. Weiss, J. Schreiber, M. B. Gaskill, and G. L. Robertson. Osmoregulation of thirst and vasopressin during normal menstrual cycle. Am. J. Physiol. 254 (Regulatory Integrative Comp. Physiol. 23): R641-R647, 1988[Abstract/Free Full Text].

32.   Whitten, C. L., and J. T. Bradbury. Hemodilution as a result of estrogen therapy. Estrogenic effects in the human female. Proc. Soc. Exp. Biol. Med. 78: 626-629, 1951.

33.   Zerbe, R. L., J. Z. Miller, and G. L. Robertson. The reproducibility and heritability of individual differences in osmoregulatory function in normal human subjects. J. Lab. Clin. Med. 117: 51-59, 1991[Medline].

AJP Regul Integr Compar Physiol 274(1):R187-R195
0363-6119/98 $5.00 Copyright © 1998 the American Physiological Society


This article has been cited by other articles:


Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
H. Ji, W. Zheng, C. Falconetti, D. M. Roesch, S. E. Mulroney, and K. Sandberg
17beta-Estradiol deficiency reduces potassium excretion in an angiotensin type 1 receptor-dependent manner
Am J Physiol Heart Circ Physiol, July 1, 2007; 293(1): H17 - H22.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
M. J. Toth, C. K. Sites, D. E. Matthews, and P. R. Casson
Ovarian suppression with gonadotropin-releasing hormone agonist reduces whole body protein turnover in women
Am J Physiol Endocrinol Metab, September 1, 2006; 291(3): E483 - E490.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
M. Desai, D. Gayle, N. Kallichanda, and M. G. Ross
Gender Specificity of Programmed Plasma Hypertonicity and Hemoconcentration in Adult Offspring of Water-Restricted Rat Dams
Reproductive Sciences, September 1, 2005; 12(6): 409 - 415.
[Abstract] [PDF]

Home page
 J. Appl. Physiol.Home page
N. S. Stachenfeld and H. S. Taylor
Effects of estrogen and progesterone administration on extracellular fluid
J Appl Physiol, March 1, 2004; 96(3): 1011 - 1018.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
N. S. Stachenfeld and D. L. Keefe
Estrogen effects on osmotic regulation of AVP and fluid balance
Am J Physiol Endocrinol Metab, October 1, 2002; 283(4): E711 - E721.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
W. L. Calzone, C. Silva, D. L. Keefe, and N. S. Stachenfeld
Progesterone does not alter osmotic regulation of AVP
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2011 - R2020.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. S. Stachenfeld, A. E. Splenser, W. L. Calzone, M. P. Taylor, and D. L. Keefe
Genome and Hormones: Gender Differences in Physiology: Selected Contribution: Sex differences in osmotic regulation of AVP and renal sodium handling
J Appl Physiol, October 1, 2001; 91(4): 1893 - 1901.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
N. S. Stachenfeld, D. L. Keefe, and S. F. Palter
Estrogen and progesterone effects on transcapillary fluid dynamics
Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2001; 281(4): R1319 - R1329.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
E. M. Evans, R. E. Van Pelt, E. F. Binder, D. B. Williams, A. A. Ehsani, and W. M. Kohrt
Effects of HRT and exercise training on insulin action, glucose tolerance, and body composition in older women
J Appl Physiol, June 1, 2001; 90(6): 2033 - 2040.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
E. M. Brooks-Asplund, J. G. Cannon, and W. L. Kenney
Influence of hormone replacement therapy and aspirin on temperature regulation in postmenopausal women
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R839 - R848.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
J. R. Claybaugh, A. K. Sato, L. K. Crosswhite, and L. H. Hassell
Effects of time of day, gender, and menstrual cycle phase on the human response to a water load
Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2000; 279(3): R966 - R973.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Heart Circ. Physiol.Home page
A. A. Nekooeian and C. C. Y. Pang
Effects of estrogen on venous function in rats with chronic heart failure
Am J Physiol Heart Circ Physiol, June 1, 2000; 278(6): H1941 - H1947.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. S. Stachenfeld, C. Silva, and D. L. Keefe
Estrogen modifies the temperature effects of progesterone
J Appl Physiol, May 1, 2000; 88(5): 1643 - 1649.
[Abstract] [Full Text] [PDF]

Home page
 J. Appl. Physiol.Home page
N. S. Stachenfeld, C. Silva, D. L. Keefe, C. A. Kokoszka, and E. R. Nadel
Effects of oral contraceptives on body fluid regulation
J Appl Physiol, September 1, 1999; 87(3): 1016 - 1025.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Stachenfeld, N. S.
Right arrow Articles by Nadel, E. R.