Cesarean scar pregnancy is a precursor of morbidly adherent placenta.

OBJECTIVE: To provide further sonographic, clinical and histological evidence that Cesarean scar pregnancy (CSP) is a precursor to and an early form of second- and third-trimester morbidly adherent placenta (MAP). METHODS: This is a report of 10 cases of CSP identified early, in which the patients decided to continue the pregnancy, following counseling that emphasized the possibility of both significant pregnancy complications and a need for hysterectomy. Pregnancies were followed at 2-4-week intervals with ultrasound scans and customary monitoring. The aim was for patients to reach near term or term and then undergo elective Cesarean delivery and, if necessary, hysterectomy. Charts, ultrasound images, operative reports and histopathological examinations of the placentae were reviewed. RESULTS: The ultrasound diagnosis of CSP was made before 10 weeks. By the second trimester, all patients exhibited sonographic signs of MAP. Nine of the 10 patients delivered liveborn neonates between 32 and 37 weeks. In the tenth pregnancy, progressive shortening of the cervix and intractable vaginal bleeding prompted termination, with hysterectomy, at 20 weeks. Two other patients in the cohort had antepartum complications (bleeding at 33 weeks in one case and contractions at 32 weeks in the other). All patients underwent hysterectomy at the time of Cesarean delivery, with total blood loss ranging from 300 to 6000 mL. Placenta percreta was the histopathological diagnosis in all 10 cases. CONCLUSION: The cases in this series validate the hypothesis that CSP is a precursor of MAP, both sharing the same histopathology. Our findings provide evidence that can be used to counsel patients with CSP, to enable them to make an informed choice between first-trimester termination and continuation of the pregnancy, with its risk of premature delivery and loss of uterus and fertility.

Biomarkers of abnormally invasive placenta.

INTRODUCTION: Abnormally invasive placenta (AIP, aka placenta accreta spectrum; PAS) is an increasingly common pregnancy pathology, which, despite significant morbidity risk to the mother, is often undiagnosed prior to delivery. We tested several potential biomarkers in plasma from PAS mothers to determine whether any were sufficiently robust for a formal, diagnostic accuracy study. METHODS: We examined hyperglycosylated hCG (h-hCG), decorin and IL-8, based on biological plausibility and literature indications that they might be altered in PAS. These analytes were assayed by ELISA in maternal plasma from five groups, comprising (1) normal term controls, (2) placenta previa controls, and cases of (3) placenta increta/percreta without placenta previa, (4) placenta previa increta/percreta and (5) placenta previa accreta. RESULTS: There were no differences in h-hCG, ß-hCG or the h-hCG/ß-hCG ratio between the groups. Mean decorin levels were increased in previa controls (Group 2) compared to the other groups, but there was substantial overlap between the individual values. While an initial multiplex assay showed a greater value for IL-8 in the placenta previa increta/percreta group (Group 4) compared to placenta previa controls (Group 2), the subsequent validation ELISA for IL-8 showed no differences between the groups. DISCUSSION: We conclude that the absence of differences and the extent of overlap between cases and controls does not justify further assessment of these biomarkers.

Chronic hypoxia in vivo reduces placental oxidative stress.

Decreased placental oxygenation and increased oxidative stress are implicated in the development of preeclampsia. Oxidative stress arises from imbalance between pro-versus anti-oxidants and can lead to biological oxidation and apoptosis. Because pregnant women living at high altitude (3100 m, HA) have lowered arterial PO2 and an increased incidence of preeclampsia, we hypothesized that HA placentas would have decreased anti-oxidant enzyme activity, increased oxidative stress (lipid peroxidation, protein oxidation and nitration) and greater trophoblast apoptosis than low-altitude (LA) placentas. We measured enzymatic activities, lipid and protein oxidation and co-factor concentrations by spectrophotometric techniques and ELISA in 12 LA and 18 HA placentas. Immunohistochemistry (IHC) was used to evaluate nitrated proteins and specific markers of apoptosis (activated caspase 3 and M30). Superoxide dismutase activity was marginally lower (p=0.05), while glutathione peroxidase activity (p<0.05), thioredoxin concentrations (p<0.005) and thioredoxin reductase activity p<0.01 were all reduced in HA placentas. Decreased anti-oxidant activity was not associated with increased oxidative stress: lipid peroxide content and protein carbonyl formation were lower at HA (p<0.01). We found greater nitrotyrosine residues in the syncytiotrophoblast at 3100 m (p<0.05), but apoptosis did not differ between altitudes. Our data suggest that hypoxia does not increase placental oxidative stress in vivo. Nitrative stress may be a consequence of hypoxia but does not appear to contribute to increased apoptosis. Lowered placental concentrations of anti-oxidants may contribute to the susceptibility of women living at HA to the development of preeclampsia, but are unlikely to be etiological.

[Calls due to suicidal behaviour made to the prehospital, emergency department in Málaga: characteristics and associated factors]. / Las demandas por conducta suicida a los servicios de urgencias prehospitalarios de Málaga: características y factores asociados.

BACKGROUND: Suicidal behaviour (fatal and non-fatal) has become a serious public health problem in many countries. The aim of the study was to describe the differential characteristics of emergency calls due to suicidal behaviour made to the Emergency Coordinating Centre (CCUE) in the province of Málaga, in comparison with calls due to physical or psychiatric problems. METHODS: Retrospective observational study of the calls recorded in the database of the Public Company for Emergency Health during one year. Multivariate logistic regression analyses were carried out including age, gender and the following variables related with the demand: hours of the day, type of day (working days or bank holidays), months of the year and trimesters, number of resources mobilized and types of resolution. RESULTS: The analyses were carried out on 163,331 calls, of which 1,380 calls were due to suicidal behaviour (0.8%), 9,951 for psychiatric reasons (6.1%) and 152,000 for physical reasons (93%). The emergency calls for suicidal behaviour were mainly made by females, between 31-60 years, in the evening and at night, and required transfer to hospital and more than one mobilized resource. Calls due to completed suicide were more frequently made by older men. Calls due to suicidal tendencies predominated over those due to attempted or threatened suicide during the first trimester of the year, while the opposite was the case during the third trimester. CONCLUSIONS: The results indicated differential characteristics of suicide calls that are potentially relevant for prevention in spite of the limitations of the present study.

Effects of chronic hypoxia in vivo on the expression of human placental glucose transporters.

Birth weight is reduced and the risk of preeclampsia is increased in human high altitude pregnancies. There has been little work to determine whether hypoxia acts directly to reduce fetal growth (e.g. reduced blood flow and oxygen delivery), or via changes in functional capacities such as nutrient transport. We therefore investigated the expression of a primary nutrient transporter, the GLUT1 glucose transporter and two in vitro markers of hypoxia (erythropoietin receptor, EPO-R, and transferrin receptor, TfR) in the syncytial microvillous (MVM) and basal membrane fractions (BMF) of 13 high (3100 m) and 12 low (1600 m) altitude placentas from normal term pregnancies. Birth weight was lower at 3100 m than at 1600 m despite similar gestational age, but none of the infants were clinically designated as fetal growth restriction. EPO-R, TfR and GLUT1 were examined by immunoblotting and maternal circulating erythropoietin and transferrin by ELISA. EPO-R was greater on the MVM (+75%) and BMF (+25%) at 3100 m. TfR was 32% lower on the MVM at 3100 m. GLUT1 was 40% lower in the BMF at 3100 m. Circulating EPO was greater at high altitude, while transferrin was similar, and neither correlated with their membrane receptors. BMF GLUT1 was positively correlated with birth weight at high, but not low altitude. In this in vivo model of chronic placental hypoxia, syncytial EPO-R increased as expected, while nutrient transporters decreased, opposite to what has been observed in vitro. Therefore, hypoxia acts to reduce fetal growth not simply by reducing oxygen delivery, but also by decreasing the density of nutrient transporters.

Remodelling of uteroplacental arteries is decreased in high altitude placentae.

Uterine blood flow and birth weight are reduced and the risk of pre-eclampsia is increased in high-altitude pregnancies. Since IUGR and pre-eclampsia are associated with reduced invasion and remodelling of maternal spiral arteries we asked whether the terminal ends of uteroplacental arteries located at the maternal-foetal decidual interface evidenced less remodelling in 19 high (3100 m) compared with 13 moderate (1600 m) altitude placentae from normal pregnancies. Previous work has demonstrated marked villous angiogenesis in high altitude placentae. We asked whether such changes are compensatory for reduced modelling and/or whether they contribute to increased birth weight. Placentae were randomly sampled and examined with immunohistochemistry to evaluate vessel remodelling and foetal capillary density. The decidual ends of uteroplacental arteries were 8-fold more likely to be remodelled at 1600 vs. 3100 m (OR=8.1; CI 2.4, 27.0,P< 0.001). There were more than twice as many uteroplacental arteries observed in the high vs. moderate altitude placentae (OR=2.1; CI: 1.3, 3.5, P=0.006). Foetal capillary density was greater at 3100 vs. 1600 m (P< 0.001), but did not relate to remodelling nor to birth weight. In this in vivo model for chronic hypoxia, remodelling is reduced, and villous angiogenesis is not fully compensatory for reduced PO(2).

Increased risk of craniosynostosis with higher antenatal maternal altitude.

BACKGROUND: During the 1980s, the Colorado Department of Health received reports from several high-altitude communities of clusters of the malformation craniosynostosis. In a population-based, case-control study, we examined the association between overall and trimester-specific maternal antenatal altitude exposure and the occurrence of infant craniosynostosis. METHODS: We identified case children through a statewide registry and randomly sampled control children from birth records. By telephone interview, each mother provided data on the locations of all antenatal residences and places of employment as well as other factors. Staff mapped all locations and abstracted the corresponding altitudes. RESULTS: The odds ratio (OR) of any synostosis for a time-weighted mean antenatal altitude of > or = 2000 metres (high altitude) versus < 2000 metres (low altitude) was 1.4 (lower bound of the one-sided 95% test-based confidence interval (CI): 0.9). The OR was elevated in smokers but not in non-smokers. As compared to non-smokers, the OR of any synostosis for high-altitude smokers was 4.6 (lower bound of the 95% one-sided exact CI: 1.7). Particularly elevated were the corresponding OR of coronal (18.1, 4.4) and metopic synostosis (16.3, 2.8), and OR for high-altitude exposure during the second trimester (any synostosis: 6.4, 1.99; coronal: 28.6, 6.1; metopic: 26.7, 4.1). CONCLUSIONS: Antenatal maternal high-altitude exposure and smoking are associated with increased risk of infant craniosynostosis, perhaps through generation of intermittent hypoxaemia.

Sympathoadrenal responses to submaximal exercise in women after acclimatization to 4,300 meters.

The purpose of this investigation was to determine the sympathoadrenal response to exercise in women after acclimatization to high altitude. Sixteen eumenorrheic women (age, 23.6 +/- 1.2 years; weight, 56.2 +/- 4.3 kg) were studied at sea level and after 10 days of high-altitude exposure (4,300 m) in either the follicular (n = 11) or luteal (n = 5) phase. Subjects performed two 45-minute submaximal steady-state exercise tests (50% and 65% peak O2 consumption [VO2 peak]) at sea level on a bicycle ergometer. Exercise tests were also performed on day 10 of altitude exposure (50% VO2 peak at sea level). As compared with rest, plasma epinephrine levels increased 36% in response to exercise at 50% VO2 peak at sea level, with no differences found between cycle phases. This increase was significantly greater (increase 44%) during exercise at 65% VO2 peak. At altitude, the epinephrine response was identical to that found for 65% VO2 peak exercise at sea level (increase 44%), with no differences found between phase assignments. The plasma norepinephrine response differed from that for epinephrine such that the increase with exercise at altitude (increase 61%) was significantly greater compared with 65% Vo2 peak exercise at sea level (increase 49%). Again, no phase differences were observed. It is concluded that the sympathoadrenal response to exercise (1) did not differ between cycle phases across any condition and (2) was similar to that found previously in men, and (3) the relative exercise intensity is the primary factor responsible for the epinephrine response to exercise, whereas altitude had an additive effect on the norepinephrine response to exercise.

Quantitative estimation of human uterine artery blood flow and pelvic blood flow redistribution in pregnancy.

OBJECTIVE: To determine the contributions of uterine artery diameter and mean flow velocity to the increase in volumetric flow during human pregnancy. METHODS: Volunteers (18 pregnant and six not pregnant) were studied using both a commercially available Doppler instrument with imaging ultrasound and an improved Doppler instrument with software that can determine instantaneous true mean blood flow velocity. Diameter and mean flow velocity measurements were combined to yield volumetric flows in the common iliac, external iliac, and uterine arteries during and after pregnancy. RESULTS: Compared with the nonpregnant state, uterine artery diameter doubled by week 21 (from 1.4 +/- 0.1 to 2.8 +/- 0.2 mm; P < .05), did not change between weeks 21 and 30 (2.9 +/- 0.1 mm), and increased between weeks 30 and 36 (to 3.4 +/- 0.2 mm). Uterine artery mean flow velocity rose progressively from nonpregnant values to attain at week 36 a velocity nearly eight times faster (8.4 +/- 2.2 versus 61.4 +/- 3.0 cm/second; P < .05). Unilateral uterine artery blood flow at week 36 was 312 +/- 22 mL/minute. CONCLUSIONS: Compared with nonpregnant values, common iliac artery flow increased and external iliac artery flow decreased during pregnancy, suggesting that redistribution of pelvic flow to favor the uterus contributed to the pregnancy-associated rise in uterus artery flow. Early in pregnancy, the increase in uterine artery blood flow was due in equal parts to changes in uterine artery diameter and mean flow velocity, whereas late in pregnancy, the rise was due mainly to faster mean flow velocity.

Effect of altitude on uterine artery blood flow during normal pregnancy.

To determine whether uterine blood flow was reduced and indexes of pelvic blood flow distribution altered in normotensive pregnancy at high (3,100 m) compared with low altitude (1,600 m), we measured uterine, common iliac, and external iliac artery blood flow velocities and diameters in women during pregnancy and again postpartum. Pregnancy increased uterine artery diameter, blood flow velocity, and volumetric flow at both altitudes. Uterine artery blood flow velocity was greater (69.0 +/- 2.2 vs. 59.4 +/- 3.0 cm/s; P < 0.005) but diameter was smaller at 3,100 m than at 1,600 m (2.5 +/- 0.3 mm vs. 3.4 +/- 0.2 mm; P < 0.005), resulting in volumetric flow that was one-third lower at week 36 of pregnancy (203 +/- 48 vs. 312 +/- 22 ml/min, respectively; P < 0.01). Pregnancy increased common iliac blood flow velocity and decreased external iliac artery blood flow velocity at both altitudes. The uterine artery received a smaller percent of common iliac flow at 3,100 than at 1,600 m (46 +/- 7 vs. 74 +/- 6%; P < 0.005). Gestational age was similar but birth weight was lower at 3,100 m than at 1,600 m. Among subjects at 1,600 m, variation in uterine blood flow velocity correlated positively with infant birth weight. We concluded that reduced uterine blood flow and altered pelvic blood flow distribution during pregnancy at high altitude likely contributed to the altitude-associated reduction in infant birth weight.

Catecholamine response during 12 days of high-altitude exposure (4, 300 m) in women.

We have previously demonstrated that acclimatization to high altitude elicits increased sympathetic nerve activity in men. The purpose of this investigation was to determine 1) whether women respond in a similar manner as found previously in men and 2) the extent to which menstrual cycle phase influences this response. Sixteen eumenorrheic women (age, 23.6 +/- 1.2 yr; weight, 56.2 +/- 4. 3 kg) were studied at sea level and during 12 days of high-altitude exposure (4,300 m) in either their follicular (F; n = 11) or luteal (L; n = 5) phase. Twenty-four-hour urine samples were collected at sea level and during each day at altitude. Catecholamines were determined by high-performance liquid chromatography with electrochemical detection. Compared with sea-level values, urinary norepinephrine excretion increased significantly during altitude exposure, peaking on days 4-6. Thereafter, levels remained constant throughout the duration of altitude exposure. The magnitude of this increase was similar between the F (138%) and L (93%) phase. Urinary epinephrine levels were elevated on day 2 of altitude exposure compared with sea-level values for both F and L subjects (93%). Thereafter, urinary epinephrine excretion returned to sea-level values, and no differences were found between F and L subjects. Plasma catecholamine content was consistent with urinary values and supports the concept of an elevation in sympathetic activity over time at altitude. Mean and diastolic blood pressure as well as heart rate adjustments to high altitude correlated significantly with urinary norepinephrine excretion rates. It was concluded that 1) urinary and plasma catecholamine responses to 12 days of high-altitude exposure in women are similar to those previously documented to occur for men; 2) whereas no differences in catecholamine levels were observed between F- and L-phase assignments, for a given urinary norepinephrine excretion rate, blood pressure and heart rates were lower for F vs. L subjects; and 3) several cardiovascular adaptations associated with high-altitude exposure correlated with 24-h urinary norepinephrine excretion rates and thus sympathetic nerve activity.

Blood volume expansion, preeclampsia, and infant birth weight at high altitude.

Low blood volume (BV) during pregnancy is associated with intrauterine growth retardation and preeclampsia, which are more common at high altitude (HA) than at low altitude. We hypothesized that reduced BV expansion during pregnancy predisposed some women to develop preeclampsia and/or have lower-birth-weight infants at HA. BV was lower in 34 HA residents (3,100 m) than in 22 moderate-altitude residents (1,600 m) while nonpregnant (58.3 +/- 1.2 vs. 72.3 +/- 1.3 ml/kg; P < 0.001) and 36 wk pregnant (69.9 +/- 1.9 vs. 83.3 +/- 3.6 ml/kg; P < 0.01). BV fell between weeks 24 and 36 of pregnancy, and total BV increment with pregnancy was less in women who developed preeclampsia or transient hypertension at HA (n = 12). At HA, total blood and plasma volume expansion and arterial O2 saturation correlated negatively with the highest mean arterial pressure recorded during pregnancy (r = -0.73, P < 0.01 and r = -0.58, P < 0.01, respectively). Total BV and late pregnancy change in BV correlated positively with infant birth weight. We concluded that BV expansion in normotensive pregnancy at HA vs. moderate altitude was similar but that nonpregnant BV was less among HA women, accounting for the low BV in pregnancy. HA women who developed preeclampsia or transient hypertension had less BV expansion, particularly during the third trimester, which was associated with smaller infants.

Alterations in uteroplacental blood flow precede hypertension in preeclampsia at high altitude.

High-altitude residence during pregnancy is associated with an increased incidence of preeclampsia. To determine whether uteroplacental blood flow was reduced and pelvic blood flow distribution altered before the onset of hypertension, we measured common iliac (CI), uterine (UA), and external iliac (EI) artery flow velocities (FV), indexes of flow distribution, and blood volume (BV) at week 12, 24, and 36 of pregnancy and 6 mo postpartum in 23 normotensive, 7 preeclamptic, 5 transiently hypertensive, and 3 chronically hypertensive residents of 3,100 m. Normotensive women had a progressive increase in CIFV and UAFV, decrease in EIFV, redistribution of CIFV from the EI to the UA, and increase in BV with advancing pregnancy. Preeclamptic women attained maximal UAFV and redistribution of CIFV from the EI to the UA well before the onset of hypertension and, unlike normotensive women, showed no further increases near term. Plasma volume increment with pregnancy related to the fall in the EIFV/CIFV ratio. Transiently hypertensive women resembled normotensive subjects in the parameters measured, whereas chronically hypertensive subjects resembled preeclamptic subjects. We concluded that preeclamptic vs. normotensive pregnant residents of high altitude had less redistribution of CI flow to the UA and no increase in UA blood flow near term. That these differences were present before the onset of hypertension supports the concept that preeclampsia is characterized by an incomplete vascular adjustment to pregnancy.

Women at altitude: changes in carbohydrate metabolism at 4,300-m elevation and across the menstrual cycle.

We hypothesized that, in women, the blood glucose response to a meal (BGR) would be lower after exposure to 4,300 m compared with sea level (SL) and that BGR would be reduced in the presence of estrogen plus progesterone (E+P) relative to estrogen alone (E). Sixteen women were studied in both the E and E+P conditions at SL and in either the E or E+P condition at 4,300 m. On day 9 in each condition, blood was sampled before, and every 30 min for 2 h after, the subjects ate a high-carbohydrate meal. At 4,300 m, BGR peaked at a lower value (5.73 +/- 0.94 mM) than at SL (6.44 +/- 1.45 mM) and returned to baseline more slowly (P < 0.05). Plasma insulin values were the same but C peptide was slightly higher at 4,300 m (P < 0. 05). At SL, BGR returned to baseline more slowly in E+P condition (5. 13 +/- 0.89 and 5.21 +/- 0.91 mM at 60 and 90 min, respectively) relative to E condition (4.51 +/- 0.52 and 4.69 +/- 0.88 mM, respectively) (P < 0.05). Insulin and C peptide were not different between E and E+P conditions. The data indicate that BGR is lower in women at high altitude compared with the SL, possibly due to greater suppression of hepatic glucose production or stimulation of peripheral glucose uptake by insulin. BGR was lower in E condition relative to E+P condition at SL and possibly at 4,300 m, but the relative concentrations of ovarian hormones do not appear to alter the magnitude of the change in BGR when women are exposed to high altitude.

Catecholamine responses to alpha-adrenergic blockade during exercise in women acutely exposed to altitude.

We have previously documented the importance of the sympathetic nervous system in acclimatizing to high altitude in men. The purpose of this investigation was to determine the extent to which alpha-adrenergic blockade affects the sympathoadrenal responses to exercise during acute high-altitude exposure in women. Twelve eumenorrheic women (24.7 +/- 1.3 yr, 70.6 +/- 2.6 kg) were studied at sea level and on day 2 of high-altitude exposure (4,300-m hypobaric chamber) in either their follicular or luteal phase. Subjects performed two graded-exercise tests at sea level (on separate days) on a bicycle ergometer after 3 days of taking either a placebo or an alpha-blocker (3 mg/day prazosin). Subjects also performed two similar exercise tests while at altitude. Effectiveness of blockade was determined by phenylephrine challenge. At sea level, plasma norepinephrine levels during exercise were 48% greater when subjects were alpha-blocked compared with their placebo trial. This difference was only 25% when subjects were studied at altitude. Plasma norepinephrine values were significantly elevated at altitude compared with sea level but to a greater extent for the placebo ( upward arrow 59%) vs. blocked ( upward arrow 35%) trial. A more dramatic effect of both altitude ( upward arrow 104% placebo vs. 95% blocked) and blockade ( upward arrow 50% sea level vs. 44% altitude) was observed for plasma epinephrine levels during exercise. No phase differences were observed across any condition studied. It was concluded that alpha-adrenergic blockade 1) resulted in a compensatory sympathoadrenal response during exercise at sea level and altitude, and 2) this effect was more pronounced for plasma epinephrine.

Women at altitude: ventilatory acclimatization at 4,300 m.

Women living at low altitudes or acclimatized to high altitudes have greater effective ventilation in the luteal (L) compared with follicular (F) menstrual cycle phase and compared with men. We hypothesized that ventilatory acclimatization to high altitude would occur more quickly and to a greater degree in 1) women in their L compared with women in their F menstrual cycle phase, and 2) in women compared with men. Studies were conducted on 22 eumenorrheic, unacclimatized, sea-level (SL) residents. Indexes of ventilatory acclimatization [resting ventilatory parameters, hypoxic ventilatory response, hypercapnic ventilatory response (HCVR)] were measured in 14 women in the F phase and in 8 other women in the L phase of their menstrual cycle, both at SL and again during a 12-day residence at 4,300 m. At SL only, ventilatory studies were also completed in both menstrual cycle phases in 12 subjects (i.e., within-subject comparison). In these subjects, SL alveolar ventilation (expressed as end-tidal PCO(2)) was greater in the L vs. F phase. Yet the comparison between L- and F-phase groups found similar levels of resting end-tidal PCO(2), hypoxic ventilatory response parameter A, HCVR slope, and HCVR parameter B, both at SL and 4,300 m. Moreover, these indexes of ventilatory acclimatization were not significantly different from those previously measured in men. Thus female lowlanders rapidly ascending to 4,300 m in either the L or F menstrual cycle phase have similar levels of alveolar ventilation and a time course for ventilatory acclimatization that is nearly identical to that reported in male lowlanders.

Women at altitude: short-term exposure to hypoxia and/or alpha(1)-adrenergic blockade reduces insulin sensitivity.

After short-term exposure to high altitude (HA), men appear to be less sensitive to insulin than at sea level (SL). We hypothesized that the same would be true in women, that reduced insulin sensitivity would be directly related to the rise in plasma epinephrine concentrations at altitude, and that the addition of alpha-adrenergic blockade would potentiate the reduction. To test the hypotheses, 12 women consumed a high-carbohydrate meal at SL and after 16 h at simulated 4,300-m elevation (HA). Subjects were studied twice at each elevation: once with prazosin (Prz), an alpha(1)-adrenergic antagonist, and once with placebo (Pla). Mathematical models were used to assess insulin resistance based on fasting [homeostasis model assessment of insulin resistance (HOMA-IR)] and postprandial [composite model insulin sensitivity index (C-ISI)] glucose and insulin concentrations. Relative to SL-Pla (HOMA-IR: 1.86 +/- 0.35), insulin resistance was greater in HA-Pla (3.00 +/- 0.45; P < 0.05), SL-Prz (3.46 +/- 0.51; P < 0.01), and HA-Prz (2.82 +/- 0.43; P < 0.05). Insulin sensitivity was reduced in HA-Pla (C-ISI: 4.41 +/- 1.03; P < 0.01), SL-Prz (5.73 +/- 1.01; P < 0.05), and HA-Prz (4.18 +/- 0.99; P < 0.01) relative to SL-Pla (8.02 +/- 0.92). Plasma epinephrine was significantly elevated in HA-Pla (0.57 +/- 0.08 ng/ml; P < 0.01), SL-Prz (0.42 +/- 0.07; P < 0.05), and HA-Prz (0.82 +/- 0.07; P < 0.01) relative to SL-Pla (0.28 +/- 0.04), but correlations with HOMA-IR, HOMA-beta-cell function, and C-ISI were weak. In women, short-term exposure to simulated HA reduced insulin sensitivity compared with SL. The change does not appear to be directly mediated by a concurrent rise in plasma epinephrine concentrations.

Interleukin-6 response to exercise and high-altitude exposure: influence of alpha-adrenergic blockade.

Interleukin-6 (IL-6), an important cytokine involved in a number of biological processes, is consistently elevated during periods of stress. The mechanisms responsible for the induction of IL-6 under these conditions remain uncertain. This study examined the effect of alpha-adrenergic blockade on the IL-6 response to acute and chronic high-altitude exposure in women both at rest and during exercise. Sixteen healthy, eumenorrheic women (aged 23.2 +/- 1.4 yr) participated in the study. Subjects received either alpha-adrenergic blockade (prazosin, 3 mg/day) or a placebo in a double-blinded, randomized fashion. Subjects participated in submaximal exercise tests at sea level and on days 1 and 12 at altitude (4,300 m). Resting plasma and 24-h urine samples were collected throughout the duration of the study. At sea level, no differences were found at rest for plasma IL-6 between groups (1.5 +/- 0.2 and 1.2 +/- 0.3 pg/ml for placebo and blocked groups, respectively). On acute ascent to altitude, IL-6 levels increased significantly in both groups compared with sea-level values (57 and 84% for placebo and blocked groups, respectively). After 12 days of acclimatization, IL-6 levels remained elevated for placebo subjects; however, they returned to sea-level values in the blocked group. alpha-Adrenergic blockade significantly lowered the IL-6 response to exercise both at sea level (46%) and at altitude (42%) compared with placebo. A significant correlation (P = 0.004) between resting IL-6 and urinary norepinephrine excretion rates was found over the course of time while at altitude. In conclusion, the results indicate a role for alpha-adrenergic regulation of the IL-6 response to the stress of both short-term moderate-intensity exercise and hypoxia.

Breathing and brain blood flow during sleep in patients with chronic mountain sickness.

Chronic mountain sickness (CMS) patients have lower arterial O2 saturation (SaO2) during sleep compared with healthy high-altitude residents, but whether nocturnal arterial O2 content (CaO2) and brain O2 delivery are reduced is unknown. We measured SaO2, CaO2, sleep-disordered breathing (SDB), and internal carotid artery flow velocity in 8 CMS patients, 8 age-matched healthy CMS controls, 11 healthy younger-aged Han, and 11 healthy younger-aged Tibetan male residents of Lhasa, Tibet (3,658 m). CMS patients spent a greater portion of the night in SDB (total no. of episodes of apnea, hypopnea, and hypoventilation) than did the CMS controls, young Han, or young Tibetans (15% vs. 5, 1, and 1%, respectively; P < 0.05) because of more frequent apnea and hypoventilation episodes and longer duration of all types of episodes. SDB and unexplained arterial O2 desaturation caused nocturnal SaO2 to be lower and more variable in CMS patients than in CMS controls or in younger-aged Han or Tibetan men. Average CaO2 was similar, but the CMS patients spent 29%, whereas the other groups spent < 4%, of the night at values < 18 ml O2/100 ml whole blood. Internal carotid artery flow velocity during wakefulness was similar in CMS patients and CMS controls despite higher end-tidal PcO2 values in the CMS patients. When contiguous sleep stages are compared, flow velocity rose from stage 2 to rapid-eye-movement sleep in both groups. Whereas flow velocity remained elevated from awake to rapid-eye-movement sleep in the CMS controls, it fell in the CMS patients. During episodes of SDB, internal carotid flow velocity increased in CMS controls but did not change in the CMS patients such that values were lower in the CMS patients than in CMS controls at the end and after SDB episodes. We concluded that SDB and episodes of unexplained desaturation lowered nocturnal SaO2 and CaO2, which, together with a lack of compensatory increase in internal carotid artery flow velocity, likely decreased brain O2 delivery in CMS patients during a considerable portion of the night.

Erythropoiesis in women during 11 days at 4,300 m is not affected by menstrual cycle phase.

Because the ovarian steroid hormones, progesterone and estrogen, have higher blood levels in the luteal (L) than in the follicular (F) phase of the menstrual cycle, and because of their known effects on ventilation and hematopoiesis, we hypothesized that less hypoxemia and less erythropoiesis would occur in the L than the F phase of the cycle after arrival at altitude. We examined erythropoiesis with menstrual cycle phase in 16 women (age 22.6 +/- 0.6 yr). At sea level, 11 of 16 women were studied during both menstrual cycle phases, and, where comparison within women was available, cycle phase did not alter erythropoietin (n = 5), reticulocyte count (n = 10), and red cell volume (n = 9). When all 16 women were taken for 11 days to 4,300-m altitude (barometric pressure = 462 mmHg), paired comparisons within women showed no differences in ovarian hormone concentrations at sea level vs. altitude on menstrual cycle day 3 or 10 for either the F (n = 11) or the L (n = 5) phase groups. Arterial oxygen saturation did not differ between the F and L groups at altitude. There were no differences by cycle phase on day 11 at 4,300 m for erythropoietin [22.9 +/- 4.7 (L) vs. 18.8 +/- 3.4 mU/ml (F)], percent reticulocytes [1.9 +/- 0.1 (L) vs. 2.1 +/- 0.3% (F)], hemoglobin [13.5 +/- 0.3 (L) vs. 13.7 +/- 0.3 g/100 ml (F)], percent hematocrit [40.6 +/- 1.4 (L) vs. 40.7 +/- 1.0% (F)], red cell volume [31.1 +/- 3.6 (L) vs. 33.0 +/- 1.6 ml/kg (F)], and blood ferritin [8.9 +/- 1.7 (L) vs. 10.2 +/- 0.9 microg/l (F)]. Blood level of erythropoietin was related (r = 0.77) to arterial oxygen saturation but not to the levels of progesterone or estradiol. We conclude that erythropoiesis was not altered by menstrual cycle phase during the first days at 4,300-m altitude.