Combined effects of female hormones and metabolic rate on ventilatory drives in women

Increased resting ventilation (VE) and hypoxic and hypercapnic ventilatory responses occur during pregnancy in association with elevations in female hormones and metabolic rate. To determine whether increases in progestin, estrogen, and metabolic rate produced a rise in VE and hypoxic ventilatory response (HVR) similar in magnitude to that observed at full-term pregnancy, we studied 12 postmenopausal women after 1 wk of treatment with placebo, progestin (20 mg tid medroxyprogesterone acetate), estrogen (1.25 mg bid conjugated equine estrogens), and combined progestin and estrogen. Progestin alone or with estrogen raised VE at rest and decreased end-tidal PCO2 (PETCO2) by 3.9 +/- 0.8 and 3.3 +/- 0.6 Torr, respectively (both P less than 0.05), accounting for approximately one-fourth of the rise in VE and three-fourths of the PETCO2 reduction seen at full-term pregnancy. The addition of mild exercise sufficient to raise metabolic rate by 33-36% produced the remaining three-fourths of the rise in VE but no further decline in PETCO2. Combined progestin and estrogen raised HVR and hypercapnic ventilatory response more consistently than progestin alone and could account for one-half of the increase in HVR seen at full-term pregnancy. Mild exercise alone did not raise HVR, but when exercise was combined with progestin and estrogen administration, HVR rose by amounts equal to that seen at full-term pregnancy. We concluded that female hormones together with mild elevation in metabolic rate were likely responsible for the pregnancy-associated increases in VE and HVR.     

The efficacy and safety of solifenacin in patients with overactive bladder syndrome

The aim of the randomised, double blind, placebo controlled study was to evaluate the efficacy, tolerability and safety of solifenacin, a once-daily M3 selective receptor antagonist, in patients with overactive bladder syndrome. Following a single blind 2-week placebo run in period, patients who complained from symptoms of OAB for at least 6 months, were randomized to 4 weeks of solifenacin in 5 mg once daily doses or placebo. 171 patients were enrolled in the study and 157 patients completed the study. Patients with solifenacin had significantly improved micturitions per 24 hours after first week of treatment (1.75 +/- 0.63 vs. 2.64 +/- 0.48, p < 0.001), and after four weeks (1.56 +/- 0.58 vs. 2.71 +/- 0.45, p < 0.001) compared to placebo group. The mean number of urgency episodes per 24 hours had significantly decreased in patients with solifenacin compared to placebo after first week (5.75 +/- 1.43 vs. 6.65 +/- 0.65, p < 0.001), and after four weeks of treatment (5.77 +/- 1.33 vs. 6.54 +/- 0.50, p < 0.001). Solifenacin was also significantly more effective than placebo in reducing the mean number of episodes of severe urgency from baseline to end point (5.83 +/- 1.16 vs. 6.48 +/- 0.50, p < 0.001). Compared with changes obtained with placebo, episodes of urinary frequency were significanlty reduced after first week (0.3 vs. -0.5, p < 0.001) and four weeks check up periods in patients treated with solifenacin (0.19 vs. -0.15, p < 0.001). Episodes of nocturia was significantly reduced in patients treated with solifenacin after first week (0.3 vs. -0.5, p < 0.001), and after four weeks treatment period (0.45 vs. -0.50, p < 0.001). The number of incontinence episodes was also significantly decreased in solifenacin group compared to placebo group after first week (1.06 +/- 0.57 vs. 2.74 +/- 0.47, p < 0.001) and four weeks check up (0.96 +/- 0.57 vs. 2.75 +/- 0.43, p < 0.001). The most common adverse effects with solifenacin were dry mouth and constipation. Adverse effects were mild or moderate severity. The discontinuation rate owing to adverse effects was 4.5%-6.7% with solifenacin and 3.8%-6.1% with placebo, respectively. According to subjective estimation, significant improvement was achieved in 71 (92.21%) of patients treated with solifenacin and in 68 (85%) patients treated with placebo there was no change in OAB symptoms compared to baseline values. UDI score was significantly improved after solifenacin (22.26 +/- 5.91 vs. 29.61 +/- 8.45, p < 0.001) compared to placebo. IIQ score was significantly decreased in patients with solifenacin (36.25 +/- 10.34 vs. 46.86 +/- 6.81, p < 0.001) compared to placebo. In conclusion, solifenacin is a safe and effective treatment alternative for patients with overactive bladder symptoms.     

Influence of gender on upper airway mechanics: upper airway resistance and Pcrit.

It has been proposed that the difference in sleep apnea prevalence is related to gender differences in upper airway anatomy and physiology. To explain the prevalence difference, we hypothesized that men would have an increased upper airway resistance and increased critical closing pressure (Pcrit) compared with women. In protocol 1, resistance at two points, fixed flow of 0.2 l/s (RL) and peak flow (Rpk), was measured in 33 men and 27 women without significant sleep-disordered breathing. We found no difference in either RL (-6.9 +/- 5.9 vs. -8.6 +/- 8.2 cmH2O) or Rpk (-9.3 +/- 6.8 vs. -10.0 +/- 11.9 cmH2O) between the men and women. A multiple linear regression to correct for the effects of age and body mass index confirmed that gender had no effect on resistance. In protocol 2, Pcrit was measured in eight men and eight women without sleep-disordered breathing. We found no difference in Pcrit (-10.4 +/- 3.1 vs. -8.8 +/- 2.7 cmH2O) between men and women. We conclude that there are no significant differences in collapsibility between men and women. We present an unifying hypothesis to explain the divergent findings of gender differences in upper airway physiology.     

Sleep-related obstructive disordered breathing in cleft palate patients after palatoplasty

Sleep-disordered breathing is frequently associated with children presenting congenital midface defects. Because of structural and functional anomalies in the upper airway, children with cleft palate, especially after surgery, may carry a higher risk of developing sleep-disordered breathing. However, the presence of such sleep-disordered breathing in older cleft palate children has not been emphasized. The aim of this comparative overnight cardiorespiratory sleep study was to evaluate cleft palate patients according to sleep-disordered breathing. A group of 43 cleft palate children (17 girls and 26 boys; mean age, 12.1 +/- 3.8 years) was compared with a control group of 20 randomly selected, noncleft children matched for age, sex, and body mass index. None of the patients suffered from manifest sleep-disordered breathing. Cleft palate patients had a statistically significantly higher respiratory disturbance index and snoring index, but no increased apnea index. The data suggest that cleft palate patients having undergone primary closure of the palate demonstrate microsymptoms of nocturnal upper airway obstruction.     

Changes in plasma volume during bed rest: effects of menstrual cycle and estrogen administration

Bed rest (BR) is associated with a decrease in plasma volume (PV), which may contribute to the impaired orthostatic and exercise tolerances seen immediately after BR. The purpose of this study was to determine whether increases in blood estrogen concentration, either during normal menstrual cycles or during exogenous estrogen administration, would attenuate this loss of PV. Nineteen healthy women (21-39 yr of age) completed the study. Twelve women underwent duplicate 11-day BR without estrogen supplementation. PV decreased significantly (P less than or equal to 0.01) during both BR's, from 2,531 +/- 113 to 2,027 +/- 102 ml during BR1 and from 2,445 +/- 115 to 2,244 +/- 96 ml during BR2. The women who began BR in the periovulatory stage of the menstrual cycle (n = 3), a time of elevated endogenous estrogens, had a transient delay in loss of PV during the first 5 days of BR. Women who began BR during other stages of the menstrual cycle (n = 17) showed the established trend to decrease PV primarily during the first few days of BR. Seven additional women underwent a single 12-day BR while taking estrogen supplementation (1.25 mg/day premarin). PV decreased during the first 4-5 days of BR, then returned toward the pre-BR level during the remainder of the BR (pre-BR PV, 2,525 +/- 149 ml; post-BR PV, 2,519 +/- 162 ml). Thus menstrual fluctuations in endogenous estrogens appear to have only small transient effects on the loss of PV during BR, whereas exogenous estrogen supplementation significantly attenuates PV loss.     

Mifepristone for the prevention of breakthrough bleeding in new starters of depo-medroxyprogesterone acetate

Depo-medroxyprogesterone acetate (DMPA) is an effective injectable contraceptive with worldwide availability. However, it is associated with a high incidence of breakthrough bleeding (BTB) during the first 6 months of use which often leads to discontinuation. Mifepristone is a progesterone receptor antagonist that has been demonstrated to decrease BTB caused by the levonorgestrel subdermal implant (Norplant). The purpose of this study was to determine if mifepristone would decrease BTB in new starters of DMPA. Twenty regularly cycling women who were new starters of DMPA were randomized to receive 50 mg of mifepristone or placebo every 2 weeks for 24 weeks. Percent days of BTB and number of cycles with bleeding intervals > or =8 and > or =14 days were evaluated using daily bleeding diaries. Ovulation was determined by measuring thrice-weekly urinary metabolites of estrogen and progesterone. Endometrial concentrations of ER and PR were determined by immunohistochemistry. Mifepristone significantly decreased the percent days of BTB and the number of cycles with prolonged bleeding intervals when compared to placebo. No subject ovulated in either group. ER immunostaining increased and PR immunostaining decreased after mifepristone treatment. In conclusion, a 50 mg dose of mifepristone taken every 2 weeks decreases the incidence of BTB in new starters of DMPA. This effect may be due to modulation of endometrial estrogen and progesterone receptors.     

Impact of long-term hormone replacement therapy on in vivo and in vitro markers of lipid oxidation

Postmenopausal hormone replacement therapy (HRT) with estrogen has been suggested to inhibit oxidation of low-density lipoprotein (LDL) in vitro, but progestins may oppose this effect. We studied whether estrogen HRT and combined HRT with estrogen and progestin differ in their ability to resist in vivo and in vitro oxidation of lipids. Study group included 15 women on oestradiol valerate (mean age 56 years, treatment duration 10.5 years) and 15 women on combined HRT with oestradiol valerate and levonorgestrel (mean age 58 years, treatment duration 11.3 years). In addition to lipid and apolipoprotein concentrations, the lagtime of LDL to oxidation, the rate of the propagation phase and the maximum concentration of conjugated dienes were recorded as indices of LDL susceptibility to copper-induced oxidation in vitro. As an in vivo marker of oxidative stress we measured 24-h excretion of urinary 8-iso-prostaglandin F2alpha (8-iso-PGF2alpha). All measurements were done after long-term HRT (baseline), after 4 weeks pause and again 3 weeks after reintroduction of HRT. High-density lipoprotein (HDL) cholesterol and apolipoprotein AI concentrations were significantly higher and LDL to HDL ratio significantly lower after long-term oestradiol valerate therapy than after combined therapy. Simultaneously, the triglyceride and lipoprotein (a) levels were higher in the estrogen group. Susceptibility of LDL to oxidation and the level of 8-iso-PGF2alpha were similar in both groups at all measurement points, and treatment group was not a statistically significant determinant of these markers at baseline. According to these results, estrogen and combined HRT do not differ in their abilities to oppose LDL oxidation in vitro or systemic oxidative stress in vivo, but have differential effects on blood lipids.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Effect of estrogens on renal responsiveness to parathyroid hormone in elderly female subjects

The effect of estrogens on the renal responsiveness to parathyroid hormone (PTH) was examined by PTH loading tests with synthetic human-PTH (1-34) in 8 normal elderly females (mean +/- SD age, 81.0 +/- 7.1 yr) before and after administration of estrogen (Premarin 1.25 mg/day for 4 weeks). Basal urinary adenosine cyclic 3', 5'-monophosphate (cAMP) excretion showed a tendency to increase after estrogen administration (5.47 +/- 1.68 vs 6.60 +/- 2.67 nmol/100 ml GFR) and the theoretical renal phosphorous threshold showed a tendency to decrease from 3.22 +/- 0.98 to 2.73 +/- 0.56 mg/dl. The blood ionized calcium concentration did not change after estrogen administration (4.44 +/- 0.16 vs 4.32 +/- 0.20 mg/dl) and serum phosphorous (P) decreased significantly (3.65 +/- 0.47 vs 3.01 +/- 0.42 mg/dl, p less than 0.05). There was no increase in mean serum immunoreactive PTH (0.34 +/- 0.10 vs 0.34 +/- 0.05 ngeq/ml). The urinary excretions of cAMP in response to PTH loading [100 U of human-PTH (1-34), intravenously] significantly (p less than 0.05) increased (94.8 +/- 57.0 vs 196.7 +/- 118.3 nmol/100 ml GFR/h) after estrogen administration. Moreover the changes in urinary excretion of cAMP (r = 0.698, p less than 0.01) and P (r = 0.555, p less than 0.05) induced by the PTH loading were positively correlated with serum estradiol in elderly females, assessed as groups before and after estrogen administration. These results suggest that estrogens may enhance the renal responsiveness to exogenous PTH administration.     

Human urinary epidermal growth factor: effects of age, sex and female endocrine status

Urinary concentrations of immunoreactive epidermal growth factor (irEGF) were determined by specific homologous radioimmunoassay in 300 healthy women and 163 healthy men between 16 and 93 years of age. Both absolute (ng/ml) and relative (ng/mg creatinine) concentrations decreased with age in both sexes. The relative concentration was higher in women than in men at ages 20-70 years (P less than 0.001), the respective mean values (ng/mg creatinine) being 49.1 and 40.1 at 16-20 years, 58.9 and 41.8 at 20-30 years, 47.6 and 36.9 at 30-45 years, 42.8 and 29.0 at 45-55 years, 44.9 and 30.1 at 55-70 years, and 16.0 and 18.5 in those over 70 years. The values were unaffected by the menstrual cycle, pregnancy, oral contraceptives, or postmenopausal estrogen and/or progestin therapy.     

The effect of exogenous estradiol benzoate and altrenogest on uterine and ovarian blood flow during the estrous cycle in mares

In recent years, a positive relationship between genital perfusion and fertility has been established; in species other than horses, uterine and ovarian perfusion was improved by exogenous estrogen but impaired by exogenous progestin. The goal of the present study was to investigate the effect of exogenous estrogen and progestin on uterine and ovarian blood flow in cycling mares. Five Trotter mares were examined daily during three estrous cycles. Mares were given no treatment, altrenogest (0.044 mg/kg BW) orally from Day 0 (ovulation) to Day 14 and estradiol benzoate (5mg i.m.) on Days 0, 5, and 10, in three cycles, respectively. There was no difference ( P > 0.05 ) in the length of untreated versus estrogen-treated cycles ( 22.8 +/-1.3 days and 23.2 +/= 1.5 days, respectively), but cycle length was increased (P < 0.05) in progestin-treated cycles (26.0 +/- 1.2). To facilitate comparisons among cycles with different lengths, data from Days 0 to 15 (diestrus) and from Days -6 to -1 (estrus) were analyzed. Transrectal Doppler sonography was used to evaluate blood flow in both uterine arteries and in the ovarian artery ipsilateral to the preovulatory follicle during estrus and ipsilateral to the corpus luteum during diestrus. Blood flow was assessed semiquantitatively using the pulsatility index (PI); high PI values indicated high resistance and a low perfusion and vice versa. An immediate effect of treatments occurred only after the administration of estradiol benzoate on Day 0; uterine PI values decreased (P < 0.05) between Days 0 and 1 and estrogen-treated mares but increased (P < 0.05) at the corresponding time in untreated cycles. Mean PI values for the uterine and ovarian arteries during both diestrus and estrus were higher (P < 0.05) in estrogen-treated versus untreated mares. Furthermore, mean uterine PI values during diestrus and estrus were higher (P< 0.05) in altrenogest-treated versus untreated mares. Neither estrogen nor altrenogest treatments had a significant immediate effect on ovarian PI values. Compared to untreated cycles, mean ovarian PI values were elevated (P < 0.05) only in the estrus following altrenogest administration. In conclusion, exogenous estrogen and progestin both decreased genital perfusion in cycling mares.     

Estrogen modifies the temperature effects of progesterone.

To test the hypothesis that progestin-mediated increases in resting core temperature and the core temperature threshold for sweating onset are counteracted by estrogen, we studied eight women (24 +/- 2 yr) at 27 degrees C rest, during 20 min of passive heating (35 degrees C), and during 40 min of exercise at 35 degrees C. Subjects were tested four times, during the early follicular and midluteal menstrual phases, after 4 wk of combined estradiol-norethindrone (progestin) oral contraceptive administration (OC E+P), and after 4 wk of progestin-only oral contraceptive administration (OC P). The order of the OC P and OC E+P were randomized. Baseline esophageal temperature (T(es)) at 27 degrees C was higher (P < 0.05) in the luteal phase (37.08 +/- 0.21 degrees C) and in OC P (37.60 +/- 0.31 degrees C) but not during OC E+P (37.04 +/- 0.23 degrees C) compared with the follicular phase (36.66 +/- 0.21 degrees C). T(es) remained above follicular phase levels throughout passive heating and exercise during OC P, whereas T(es) in the luteal phase was greater than in the follicular phase throughout exercise (P < 0.05). The T(es) threshold for sweating was also greater in the luteal phase (38.02 +/- 0.28 degrees C) and OC P (38.07 +/- 0.17 degrees C) compared with the follicular phase (37.32 +/- 0.11 degrees C) and OC E+P (37.46 +/- 0.18 degrees C). Progestin administration raised the T(es) threshold for sweating during OC P, but this effect was not present when estrogen was administered with progestin, suggesting that estrogen modifies progestin-related changes in temperature regulation. These data are also consistent with previous findings that estrogen lowers the thermoregulatory operating point.     

Alternative hormone replacement regimens: is there a need for further clinical trials?

PURPOSE OF REVIEW: To review the randomized trials of hormone replacement therapy. RECENT FINDINGS: Studies have shown that conjugated equine estrogen 0.625 mg a day plus medroxyprogesterone acetate 2.5 mg a day increased the risk of cardiovascular events during the first year of treatment in women both with and without coronary heart disease. Conjugated equine estrogen plus medroxyprogesterone acetate also increased the overall risk of myocardial infarction and stroke in women without coronary heart disease, and myocardial infarction or death in women with coronary heart disease, and also increased the risk of breast cancer, cognitive decline and dementia. Unopposed, oral 17B-estradiol increased the risk of stroke during the first 6 months of treatment in women with a previous stroke. Oral 17B-estradiol with or without cyclic progestin had no effect on the progression of atherosclerosis or reinfarction. Transdermal 17B-estradiol plus cyclic progestin was associated with a non-significant increase in coronary heart disease events in women with coronary heart disease. Compared with placebo, cardiovascular events increased in the ongoing estrogen-only arm of the Women's Health Initiative, indicating that unopposed conjugated equine estrogen is unlikely to be cardioprotective. However, oral 17B-estradiol retarded the progression of subclinical atherosclerosis in younger women without coronary heart disease. SUMMARY: Hormone replacement therapy should not be initiated for the primary or secondary prevention of coronary heart disease in women. A trial of 17B-estradiol started at menopause in women without coronary heart disease should be considered.     

Effects of estrogen replacement therapy on abdominal fat compartments as related to glucose and lipid metabolism in early postmenopausal women.

The effects of estrogen replacement therapy on lipid and glucose metabolism as related to abdominal fat distribution were investigated in fifty-one healthy postmenopausal women aged 52-53 years. They were randomized to treatment with either estradiol 2 mg or placebo daily for three months in a double-blind design. Forty-six women continued with estradiol for another nine months in an open design with the addition of medroxyprogesterone for ten days every three months. Intra-abdominal and subcutaneous abdominal fat, and intrapelvic and subcutaneous pelvic fat was estimated by computed tomography before and after one year of estrogen treatment. Euglycemic hyperinsulinemic clamp, oral glucose tolerance test and analyses of blood lipids were performed after 3 and 12 months of treatment. Estrogen replacement therapy decreased body fat mass as well as intra-abdominal and intrapelvic fat, but not the subcutaneous fat compartments. LDL cholesterol decreased and HDL cholesterol increased, whereas triglycerides were not changed by one year of estrogen treatment. Insulin sensitivity and glucose tolerance were not affected by estrogen treatment. In postmenopausal women estrogen treatment for one year decreased intra-abdominal and intrapelvic fat compartments, but this was not related to changes in plasma lipid levels. Insulin sensitivity and plasma triglycerides were not affected by estrogen treatment.     

Effect of postmenopausal hormone replacement therapy on lipoprotein and homocysteine levels in Chinese women.

Epidemiological studies have revealed that postmenopausal estrogen replacement therapy results in a marked reduction in the risk for cardiovascular diseases. In the present study, we evaluated plasma lipoprotein profile as well as homocysteine levels in 145 postmenopausal and premenopausal Chinese women living in Hong Kong. We also investigated the effect of hormone-replacement therapy (HRT) with estrogen or estrogen combined with progestin on plasma lipoprotein profile and homocysteine concentrations in those individuals. Postmenopausal women displayed significantly higher plasma levels of total cholesterol, LDL-cholesterol and apoB as well as higher plasma homocysteine levels than that of premenopausal women. HRT with either estrogen (17beta-estradiol or conjugated equine estrogen) alone or estrogen combined with progestin for 3.5-4.5 years significantly improved the lipoprotein profile in postmenopausal women by decreasing the levels of total cholesterol (12-20% reduction), LDL-cholesterol (26-29% reduction) and apoB (21-25% reduction). In women treated with 17beta-estradiol or conjugated equine estrogens their plasma levels of apoAl were significantly elevated (18% elevation) as compared to non-users. HRT also reduced plasma concentrations of homocysteine (13-15% reduction). In conclusion, we found that long-term HRT was associated with improvement in plasma lipoprotein profile and a reduction in homocysteine concentration in postmenopausal women. These results support the notion that the improvement of lipoprotein profile and a reduction in homocysteine concentration may contribute to the beneficial effect of HRT on cardiovascular risk.     

Androgen, estrogen and progestin binding in cytosols of benign gynecologic tumors and tumor-like lesions

Specific androgen (Kd 0.27 +/- 0.06 nM), estrogen (Kd 0.19 +/- 0.04 nM) and progestin (Kd 0.22 +/- 0.07 nM) binding were investigated in benign gynecologic tumors and tumor-like lesions. The simultaneous presence of androgen and progestin receptors was a common finding. In one endometrioma, specific androgen, estrogen and progestin binding was observed simultaneously.     

Increased memory load-related frontal activation after estradiol treatment in postmenopausal women

Prior research shows that menopause is associated with changes in cognition in some older women. However, how estrogen loss and subsequent estrogen treatment affects cognition and particularly the underlying brain processes responsible for any cognitive changes is less well understood. We examined the ability of estradiol to modulate the manipulation of information in working memory and related brain activation in postmenopausal women. Twenty healthy postmenopausal women (mean age (SD) = 59.13 (5.5)) were randomly assigned to three months of 1 mg oral 17-β estradiol or placebo. At baseline and three months later each woman completed a visual verbal N-back sequential letter test of working memory during functional magnetic resonance imaging (fMRI). The fMRI data showed that women who were treated with estradiol for three months had increased frontal activation during the more difficult working memory load conditions compared to women treated with placebo. Performance on the verbal working memory task showed no difference between estradiol and placebo treated subjects. These data are consistent with prior work showing increases in frontal activation on memory tasks after estrogen treatment. However, this is the first study to show that estrogen-induced increases in brain activity were tied to cognitive load during a verbal working memory task. These data suggest that estradiol treatment effects on cognition may be in part produced through modulation of frontal lobe functioning under difficult task conditions.     

Hormone replacement therapy increases renal kallikrein excretion in healthy postmenopausal women

Hypertension and its related increase in cardiovascular morbidity in postmenopausal women is a major public health problem. The hypotensive property of urinary kallikrein has been described since 1909. Despite the controversy surrounding the effects of hormone replacement therapy on blood pressure regulation, its mechanisms remain incompletely understood, and no evidence has yet been provided for its effects on renal kallikrein excretion in postmenopausal women. In a double-blind, randomized study we examined the effects of hormone replacement therapy in the form of 2 mg 17-beta estradiol (ERT) or 2 mg 17-beta estradiol combined with continuous 5 mg medroxyprogesterone acetate (HRT) on urinary kallikrein excretion in postmenopausal women. Thirty-nine postmenopausal women collected their urine for 24 hours on two separate occasions 3 months apart. During the 3 month period women were randomized to placebo, ERT, or HRT. Urine samples were assayed for kallikrein activity, normalized to urine creatinine and expressed as mU/gm creatinine. Urinary kallikrein excretion increased significantly after 3 months in the ERT (p < 0.001) and HRT (p < 0.01) groups, and decreased non-significantly in the placebo group (p > 0.06). There were no significant blood pressure changes after 3 months of therapy. The findings demonstrate that hormone replacement therapy in the form of estrogen or estrogen combined with continuous medroxyprogesterone is effective in increasing urinary kallikrein excretion. Given that a decrease in kallikrein excretion may mark risk for development of hypertension, the findings of this study are of value in demonstrating a novel mechanism underlying cardioprotective properties of postmenopausal hormone replacement therapy in women without pre-existing coronary disease.     

A beneficial effect of estrogen on working memory in postmenopausal women taking hormone replacement therapy

Recent neurophysiological data suggest that the prefrontal cortex (PFC) may be susceptible to modulation by estrogen. In humans, the PFC mediates a number of cognitive processes that contribute to memory function, particularly working memory. The present study examined whether memory tasks that recruit PFC-dependent information processing might exhibit estrogen sensitivity in women. Performance on several memory tasks, including measures of working memory, was evaluated in three groups of postmenopausal women: (1) women who were tested when taking estrogen only (n = 38, M(age) = 55.1 years), (2) women who were tested when taking estrogen and a progestin concurrently (n = 23, M(age) = 55.9 years), and (3) women who were not taking hormone replacement therapy (n = 35, M(age) = 56.0 years). Estrogen users exhibited significantly better performance on a verbal task and on a spatial task, each with a prominent working memory component, but did not differ from nonusers on control tasks involving simple passive recall. These findings are consistent with the hypothesis that estrogen is active within PFC and is capable of influencing functions dependent on this region. The results of this study raise the possibility that estrogen may play a role in maintaining certain frontal lobe functions in women.     

Effects of oral contraceptives on body fluid regulation.

To test the hypothesis that estrogen reduces the operating point for osmoregulation of arginine vasopressin (AVP), thirst, and body water balance, we studied nine women (25 +/- 1 yr) during 150 min of dehydrating exercise followed by 180 min of ad libitum rehydration. Subjects were tested six different times, during the early-follicular (twice) and midluteal (twice) menstrual phases and after 4 wk of combined [estradiol-norethindrone (progestin), OC E + P] and 4 wk of norethindrone (progestin only, OC P) oral contraceptive administration, in a randomized crossover design. Basal plasma osmolality (P(osm)) was lower in the luteal phase (281 +/- 1 mosmol/kgH(2)O, combined means, P < 0.05), OC E + P (281 +/- 1 mosmol/kgH(2)O, P < 0.05), and OC P (282 +/- 1 mosmol/kgH(2)O, P < 0. 05) than in the follicular phase (286 +/- 1 mosmol/kgH(2)O, combined means). High plasma estradiol concentration lowered the P(osm) threshold for AVP release during the luteal phase and during OC E + P [x-intercepts, 282 +/- 2, 278 +/- 2, 276 +/- 2, and 280 +/- 2 mosmol/kgH(2)O, for follicular, luteal (combined means), OC E + P, and OC P, respectively; P < 0.05, luteal phase and OC E + P vs. follicular phase] during exercise dehydration, and 17beta-estradiol administration lowered the P(osm) threshold for thirst stimulation [x-intercepts, 280 +/- 2, 279 +/- 2, 276 +/- 2, and 280 +/- 2 mosmol/kgH(2)O for follicular, luteal, OC E + P, and OC P, respectively; P < 0.05, OC E + P vs. follicular phase], without affecting body fluid balance. When plasma 17beta-estradiol concentration was high, P(osm) was low throughout rest, exercise, and rehydration, but plasma arginine vasopressin concentration, thirst, and body fluid retention were unchanged, indicating a lowering of the osmotic operating point for body fluid regulation.