Nina S. Stachenfeld

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

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 17β-estradiol (transdermal patch, ∼0.1 mg/day, E2) and placebo (control) administration. Hypertonic saline was infused at 0.1 ml ⋅ kg-1 ⋅ min-1for 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]-Posmrelationship shifted upward after E2, with no change in sensitivity (slope, 0.36 ± 0.02 and 0.33 ± 0.03 pg ⋅ ml-1 ⋅ mosmol-1for 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 ([Formula: see text]) 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 E2augments 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.

Moderate-intensity aerobic training improves glucose tolerance in aging independent of abdominal adiposity.

OBJECTIVE: To test the hypothesis that training‐related improvements in glucose and insulin responses to an oral glucose tolerance test (OGTT) are independent of changes in abdominal adiposity.

Blood pressure and water regulation: understanding sex hormone effects within and between men and women

Abstract  Cardiovascular disease remains the leading cause of death for both men and women. Hypertension is less prevalent in young women compared with young men, but menopausal women are at greater risk for hypertension compared with men of similar age. Despite these risks, women do not consistently receive first line treatment for the early stages of hypertension, and the greater morbidity in menopause reflects this neglect. This review focuses on ovarian hormone effects on the cardiovascular and water regulatory systems that are associated with blood pressure control in women. The study of ovarian hormones within young women is complex because these hormones fluctuate across the menstrual cycle, and these fluctuations can complicate conclusions regarding sex differences. To better isolate the effects of oestrogen and progesterone on the cardiovascular and water regulation systems, we developed a model to transiently suppress reproductive function followed by controlled hormone administration. Sex differences in autonomic regulation of blood pressure appear related to ovarian hormone exposure, and these hormonal differences contribute to sex differences in hypertension and orthostatic tolerance. Oestrogen and progesterone exposure are also associated with plasma volume expansion, and a leftward shift in the osmotic operating point for body fluid regulation. In young, healthy women, the shift in osmoregulation appears to have only a minor effect on overall body water balance. Our overarching conclusion is that ovarian hormone exposure is the important underlying factor contributing to differences in blood pressure and water regulation between women and men, and within women throughout the lifespan.

Acute effects of sodium ingestion on thirst and cardiovascular function.

Sweating during exercise, especially during exercise in the heat, leads to sodium and water losses, and the quantity of these losses depends upon the intensity and duration of the activity, genetic predisposition and conditioning of the individual, and environmental factors. In athletes, adequate sodium intake is necessary to maintain fluid balance during training and competition. To ensure the precise regulation of volume and osmolality of body fluids, a number of integrated neural and hormonal systems have evolved to control thirst and sodium appetite. These systems respond to stimuli that arise from a deficit of fluid arising in both the intracellular and extracellular fluid compartments or to systemic hypertonicity. Thirst is highly sensitive to increases in plasma sodium concentration and osmolality, requiring only a 2%-3% increase to induce feelings of thirst. A larger change in plasma volume (10%) is required to induce thirst if there is no concomitant change in plasma sodium concentration. If plain water is used to replenish body water, plasma volume is preferentially restored over the interstitial and intracellular fluid space, suppressing plasma sodium concentration and removing the dipsogenic drive long before total body fluid has been restored. During or after dehydrating exercise, sodium ingestion helps to maintain and restore plasma volume and osmolality by continuing thirst sensation (thus drinking) and also by increasing body fluid retention. A high sodium meal or intravascular hypertonic saline infusion may cause transient osmotically mediated blood pressure increases, but in healthy people, acute sodium ingestion does not cause sustained hypertension. The purpose of this review is to provide evidence that acute increases in sodium are an intrinsic part of the thirst response during and after exercise, and that blood pressure increases associated with hypertonicity appear to be short lived.

Regulation of blood volume during training in post-menopausal women

UNLABELLED In younger people the increase in aerobic capacity following training is related, in part, to blood volume (BV) expansion and the consequent improvements in maximal cardiac output. This training-induced hypervolemia is associated with a decrease in cardiopulmonary baroreflex (CPBR) control of peripheral vascular tone. PURPOSE To test the hypothesis that improvement in peak oxygen consumption (VO2peak) during training in older women is associated with specific central adaptations, such as BV expansion and a reduction in CPBR control of vascular tone. METHODS Seventeen healthy older women were randomized into training (N = 9, 71 +/- 2 yr) and control (N = 8, 73 +/- 3 yr) groups. The training group exercised three to four times per wk for 30 min at 60% peak heart rate for 12 wk and then 40-50 min at 75% peak heart rate for 12 wk. The control group participated in yoga exercises over the same time period. We measured resting BV (Evans blue dye), VO2peak, and the forearm vascular resistance response to unloading low pressure mechanoreceptors during low levels of lower body negative pressure (through -20 mm Hg) before and after aerobic training. The slope of the increase in forearm vascular resistance (response) per unit decrease in central venous pressure (stimulus) was used to assess CPBR responsiveness. RESULTS Aerobic training increased VO2peak 14.2% from 24.2 mL x kg(-1) x min(-1) to 27.7 mL x kg(-1) x min(-1) (P < 0.05), a smaller improvement than typically seen in younger subjects. Blood volume (59.9 +/- 1.9 and 60.9 +/- 1.9 mL x kg[-1]) and CPBR function (-3.98 +/- 0.92 and -3.46 +/- 0.94 units x mm(-1) Hg) were similar before and after training. CONCLUSIONS These data indicate that the inability to induce adaptations in CPBR function may limit BV expansion during training in older women. In addition, the absence of these specific adaptations may contribute to the relatively poor improvements in VO2peak in older women during short (10-12 wk) periods of training.

Sleep, breathing, and menopause: the effect of fluctuating estrogen and progesterone on sleep and breathing in women.

BACKGROUND Sleep-disordered breathing (SDB), such as obstructive sleep apnea (OSA), is more common in men than in women. However, menopause increases the risk for development of OSA. Administration of estrogen and progesterone to postmenopausal women with OSA decreases apnea and hypopnea during sleep. OBJECTIVE Because beneficial changes can be observed soon after administration of a short course of hormones, we hypothesized that suppression of these hormones would rapidly result in the development of SDB. METHODS Production of sex hormones was suppressed with daily administration of leuprolide acetate (LA), a gonadotropin-releasing hormone analogue, for 5 weeks in women who were participating in a study on pharmacologically induced menopause and physiology. The subjects underwent polysomnographic evaluation at baseline and after 5 weeks of LA administration. RESULTS In the 12 healthy women aged 18 to 34 years who participated in the study, sleep architecture and respiration were normal at baseline. After LA administration, the subjects stopped their menses, and their plasma concentrations of l7beta-estradiol (preadministration, mean [SD] 33.9 [9.0] pg/mL; post administration, 10.2 [3.4] pg/mL) and progesterone (preadministration, 0.48 [0.05] ng/mL; post administration, 0.40 [0.06] ng/mL) reached menopausal levels. Sex hormone deficiency was associated with climacteric vasomotor symptoms such as hot flashes and sweating. Sleep latencies and architecture did not change significantly with LA administration. The participants subjectively noticed some increased snoring that was not confirmed by polysomnogram. Specifically, there was no change in arousal index and no evidence for sleep fragmentation to suggest the presence of increased upper-airway resistance during sleep. The apnea-hypopnea index, 0.07 (0.02) to 0.22 (0.11) events per hour of sleep, did not change with sex hormone deficiency. CONCLUSIONS In this study, sex hormone deficiency in young women resulted in climacteric symptoms and cessation of menses, and was not associated with sleep fragmentation or clinically significant SDB.

A Novel Approach Using Time–Frequency Analysis of Pulse-Oximeter Data to Detect Progressive Hypovolemia in Spontaneously Breathing Healthy Subjects

Accurate and early detection of blood volume loss would greatly improve intraoperative and trauma care. This study has attempted to determine early diagnostic and quantitative markers for blood volume loss by analyzing photoplethysmogram (PPG) data from ear, finger, and forehead sites with our high-resolution time-frequency spectral (TFS) technique in spontaneously breathing healthy subjects (n=11) subjected to lower body negative pressure (LBNP). The instantaneous amplitude modulations (AM) present in heart rate (AMHR) and breathing rate (AMBR) band frequencies of PPG signals were calculated from the high-resolution TFS. Results suggested that the changes (P <; 0.05) in AMBR and especially in AMHR values can be used to detect the blood volume loss at an early stage of 20% LBNP tolerance when compared to the baseline values. The mean percent decrease in AMHR values at 100% LBNP tolerance was 78.3%, 72.5%, and 33.9% for ear, finger, and forehead PPG signals, respectively. The mean percent increase in AMBR values at 100% LBNP tolerance was 99.4% and 19.6% for ear and finger sites, respectively; AMBR values were not attainable for forehead PPG signal. Even without baseline AMHR values, our results suggest that hypovolemia detection is possible with specificity and sensitivity greater than 90% for the ear and forehead locations when LBNP tolerance is 100%. Therefore, the TFS analysis of noninvasive PPG waveforms is promising for early diagnosis and quantification of hypovolemia at levels not identified by vital signs in spontaneously breathing subjects.

Androgens influence microvascular dilation in PCOS through ET-A and ET-B receptors

Hyperandrogenism and vascular dysfunction often coexist in women with polycystic ovary syndrome (PCOS). We hypothesized that testosterone compromises cutaneous microvascular dilation in women with PCOS via the endothelin-1 ET-B subtype receptor. To control and isolate testosterones effects on microvascular dilation, we administered a gonadotropin-releasing hormone antagonist (GnRHant) for 11 days in obese, otherwise healthy women [controls, 22.0 (4) yr, 36.0 (3.2) kg/m(2)] or women with PCOS [23 (4) yr, 35.4 (1.3) kg/m(2)], adding testosterone (T; 2.5 mg/day) on days 8-11. Using laser Doppler flowmetry and cutaneous microdialysis, we measured changes in skin microcirculatory responsiveness (ΔCVC) to local heating while perfusing ET-A (BQ-123) and ET-B (BQ-788) receptor antagonists under three experimental conditions: baseline (BL; prehormone intervention), GnRHant (day 4 of administration), and T administration. At BL, ET-A receptor inhibition enhanced heat-induced vasodilation in both groups [ΔCVC control 2.03 (0.65), PCOS 2.10 (0.25), AU/mmHg, P < 0.05]; ET-B receptor inhibition reduced vasodilation in controls only [ΔCVC 0.98 (0.39), 1.41 (0.45) AU/mmHg for controls, PCOS] compared with saline [ΔCVC controls 1.27 (0.48), PCOS 1.31 (0.13) AU/mmHg]. GnRHant enhanced vasodilation in PCOS [saline ΔCVC 1.69 (0.23) AU/mmHg vs. BL, P < 0.05] and abolished the ET-A effect in both groups, a response reasserted with T in controls. ET-B receptor inhibition reduced heat-induced vasodilation in both groups during GnRHant and T [ΔCVC, controls: 0.95 (0.21) vs. 0.51 (13); PCOS: 1.27 (0.23) vs. 0.84 (0.27); for GnRHant vs. T, P < 0.05]. These data demonstrate that androgen suppression improves microvascular dilation in PCOS via ET-A and ET-B receptors.

The myth of the female athlete triad

The female athlete triad is defined as a syndrome consisting of three necessary components: ( a ) disordered eating; ( b ) amenorrhoea; ( c ) osteoporosis.1 The American College of Sports Medicine (ACSM) published a Position Stand in 1997,1 and at that time indicated a strong need for more epidemiological, laboratory, and clinical data to support the importance of this syndrome. Currently, the prevalence of regular vigorous activity among adolescent girls remains out of reach of the Year 2010 objectives,2 and the problem of overweight among young people has achieved epidemic proportions in the United States and other industrialised countries.3 Our concern is that triad related data may be misinterpreted and used as justification for setting health and social policies that may ultimately counter the US Public Health Service efforts to promote the benefits of athletic participation and an active lifestyle among children and adolescents.4 Moreover, there are ample historical and medical examples of iatrogenic eating and psychosexual disorders ascribed to otherwise healthy, hard driving, and passionate women in their pursuit of social independence, political power, or athletic excellence.5–8 In fact, until 1972, women were banned from very challenging athletic events such as the marathon, because officials of the Amateur Athletic Union (AAU) believed that such competition would be harmful to female reproductive function.8 Therefore we maintain that, as girls and young women are currently striving to attain the same level of accessibility and achievement in organised sports as their male counterparts, the creation of yet another form of female specific pathology undermines this hard earned success and may have other serious implications for their health and wellbeing. Our purpose in writing this article is to describe the female athlete triad with regard to its epidemiology and physiology and to offer our comments and opinions which challenge …

Oestrogen effects on urine concentrating response in young women

Oestrogen lowers the plasma osmotic threshold for arginine vasopressin (AVP) release but without commensurate changes in renal concentrating response, suggesting oestrogen (OE2) may lower renal sensitivity to AVP. Ten women (23 ± 1 years) received a gonadotropin releasing hormone analogue (GnRHa), leuprolide acetate, to suppress OE2 for 35 days, and then added OE2 (two patches each delivering 0.1 mg day−1) on days 32–35. On days 28 and 35 we tested blood and renal water and sodium (Na+) regulation during stepwise 60 min AVP infusions (10, 35, 100, 150 and 200 μu (kg body weight)−1 Pitressin). Plasma OE2 concentration increased from 19 ± 4 to 152 ± 3 pg ml−1 and plasma progesterone concentration was unchanged (1.0 ± 0.4 and 0.7 ± 0.1 ng ml−1) for GnRHa and OE2 administration, respectively. Standard log plots of plasma AVP concentration ([AVP]P) vs. urine osmolality (OsmU) were fitted to a sigmoidal curve, and EC50 was determined by non‐linear regression curve fitting of concentration‐response data. OsmU rose exponentially during AVP infusions, but hormone treatments did not affect EC50 (3.3 ± 0.07 and 3.1 ± 0.6 pg ml−1, for GnRHa and OE2, respectively). However, the urine osmolality increase was greater within the physiological range (˜2.5−3.4 pg ml−1[AVP]P) during OE2 treatment. Throughout most of the AVP infusion, the rate of clearance of AVP from plasma (PCRAVP) was increased during OE2 (45.5 ml (kg body weight)−1 min−1) compared to GnRHa administration (33.1 ml (kg body weight)−1 min−1; mean for the 100–200 μu (kg body weight)−1 infusion rates). The rate of renal free water clearance (CH2O) was similar between hormone treatments. Sodium excretion fell during OE2 administration due to greater distal tubular sodium reabsorption. Despite more rapid PCRAVP, renal concentrating response to graded AVP infusions was unaffected by oestrogen treatment suggesting oestrogen does not affect overall renal sensitivity to AVP. However, OE2 may increase renal fluid retention within a physiological range of AVP.