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Relationship of ovarian hormones to hypoxemia in women residents of 4,300 m. Am J Physiol Regulatory Integrative Comp Physiol 280: R488-R493, 2001.--Prevalence of excessive erythrocytosis, the main sign of chronic mountain sickness (CMS), is greater in postmenopausal Andean women than in premenopausal women. It is uncertain whether this greater prevalence is related to the decline in female hormones and ventilatory function after the occurrence of the menopause. To study this, we compared the physiological variables involved in the physiopathology of CMS [end-tidal [CO.sub.2] ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], Torr) and end-tidal [O.sub.2] ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], Torr), arterial oxygen saturation ([MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII], %), and Hb concentration (g/dl)] and progesterone and estradiol levels between postmenopausal and premenopausal women, both in the luteal and follicular phases. Women residing in Cerro de Pasco (n = 33; 4,300 m) aged 26-62 yr were studied. Postmenopausal women compared with premenopausal women in the luteal phase had lower [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (48 [+ or -] 4 vs. 53 [+ or -] 2 Torr, P = 0.005) and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] levels (82 [+ or -] 12 vs. 88 [+ or -] 12%, P [is less than] 0.005) and higher [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] (34 [+ or -] 2 vs. 29 [+ or -] 3 Torr, P = 0.005) and Hb concentration (19 [+ or -] 1 vs. 14 [+ or -] 2 g/dl, P [is less than] 0.005). In addition, plasma progesterone was negatively correlated with [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and positively correlated with [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII] and [MATHEMATICAL EXPRESSION NOT REPRODUCIBLE IN ASCII]. No clear relationship was found among the cycle phases between estradiol and the variables studied. In conclusion, our results reveal that, before menopause, there is better oxygenation and lower Hb levels in women long residing at altitude, and this is associated with higher levels of progesterone in the luteal phase of the cycle. menopause; chronic mountain sickness; end-tidal oxygen pressure; end-tidal carbon dioxide pressure; polycythemia; oxygen saturation

We used transgenic mice constitutively over-expressing erythropoietin ("tg6" mice) and wild-type (wt) mice to investigate whether the high hematocrit (hct), consequence of Epo over-expression affected: (1) the normoxic ventilation (V (E)) and the acute hypoxic ventilatory response (HVR) and decline (HVD), (2) the increase in ventilation observed after chronic exposure to hypobaric hypoxia (430mmHg for 21 days), (3) the respiratory "blunting", and (4) the erythrocythemic response induced by chronic hypoxia exposure. V (E) was found to be similar in tg6 and wt mice in normoxia (FIO2=0.21). Post-acclimation V (E) was significantly elevated in every time point in wt mice at FIO2=0.10 when compared to pre-acclimation values. In contrast, tg6 mice exhibited a non-significant increase in V (E) throughout acute hypoxia exposure. Changes in V (E) are associated with adjustments in tidal volume (V(T)). HVR and HVD were independent of EE in tg6 and wt mice before chornic hypoxia exposure. HVR was significantly greater in wt than in tg6 mice after chronic hypoxia. After acclimation, HVD decreased in tg6 mice. Chronic hypoxia exposure caused hct to increase significantly in wt mice, while only a marginal increase occurred in the tg6 group. Although pre-existent EE does not appear to have an effect on HVR, the observation of alterations on V(T) suggests that it may contribute to time-dependent changes in ventilation and in the acute HVR during exposure to chronic hypoxia. In addition, our results suggest that EE may lead to an early "blunting" of the ventilatory response.

The beneficial role of erythrocytosis for O2 transport has been questioned by evidence from bloodletting and hemodilution research as well as by studies suggesting the existence of an "optimal" hematocrit (Hct) or hemoglobin concentration ([Hb]) value. To assess to what extent erythrocytosis is beneficial in Andean men at high altitude, we examined and discussed optimal [Hb] using a mathematical approach by modeling the mixed (mean) venous Po2 (Pv(O2)) and arterial O2 content, considering for both the relation between [Hb] and arterial Po2. Relations of [Hb] to other physiological variables such as cardiac output and convective arterial O2 transport were also discussed, revealing the importance of Pv(O2) in this model. Our theoretical analysis suggests that increasing [Hb] allows increase and maintenance of Pv(O2) with only moderate declines in arterial Po2 as a consequence of moderate increases in altitude, reaching its maximum at the optimal [Hb] of 14.7 g/dl. Our analysis also shows that [Hb] corresponding to high arterial O2 content and O2 transport values is apparently not quite advantageous for improvement of oxygenation. Furthermore, chronic mountain sickness is discussed as an insightful example of the effects of excessive erythrocytosis at high altitude.

This study was designed to determine in subjects born at high altitude who move to sea level (HA-SL: born at 3500 m or above; n = 25) whether their cardiorespiratory responses to hypoxia and exercise are similar to those of sea level natives (SL,n = 25). The average age (39 +/- 7.3 yr), weight (72 +/- 7.3 kg), and height (1.71 +/- 0.01 m) did not differ between the SL and HA-SL subjects. All subjects were studied at rest or during exercise (60 W on cycle ergometer) while breathing room air (F(IO2) = 0.21 and P(B) = 760) or hypoxia (F(IO2) = 0.115 and PB = 760) in the following order: (1) normoxia at rest (NX-Rs), (2) hypoxia at rest (HX-Rs, 11.5% O(2)), hypoxia at exercise (HX-Ex), and normoxia at exercise (NX-Ex). Each period lasted 5 min. In absolute values, HA-SL showed significantly higher ventilation (V(E), L/min) during exercise in both normoxia and hypoxia and higher oxygen saturation (Sa(O2), %) during hypoxia both at rest and in exercise. They also had lower end-tidal CO(2) values (P(ETCO2), torr) at rest in both normoxia and hypoxia, but a higher P(ETCO2) in hypoxic exercise. Heart rate (HR, beats/min) was lower at rest in both normoxia and hypoxia, but higher in exercise. With acute hypoxia, Sa(O2) decreased less in the HA-SL than in the SL at rest (HA-SL, 9.2 +/- 0.8; SL, 12.0 +/- 0.82) and during exercise (HA-SL, 18.3 +/- 1.1; SL, 21.2 +/- 1.2). In conclusion, this study shows that HA-SL natives have increased ventilation and heart rate during exercise once their lifelong hypoxia is relieved.

There have been a number of reports describing the hematological indicators of Andean residents living at altitudes above 4,000 m, but several confounding factors have made the published results difficult to interpret. To clear up the effect of hypoxia on hemoglobin concentration (Hb, g/dL), hematocrit (Hct, %) and red blood cell concentration (RBC, cells/microL), this publication describes and analyzes these variables in children, men, and women from three large and homogeneous populations living at 4,355 m (n = 151), 4,660 m (n = 400), and 5,500 m (n = 273) in the Southern Peruvian Andes. Hb, Hct, and RBC increase with age in men (p < 0.001), as well as in women (p < 0.001) at the three altitudes of the study. In children (boys and girls) living at 5,500, Hb increases 11% when compared with children living at 4,355 m, and in adults, Hb increases 9.6% when comparing the same altitudes. The maximum percentage increase in Hb with age was 5.6% at 5,500 m, in men and 3.2% at 4,355 m, in women. The average percentage of difference for the Hb concentration between adult men and women is 6.6% at 4,355 m, 9.8% at 4,660 m, and 11.6% at 5,500 m. The differences in Hb concentration between men and women can only be seen after puberty. Finally, Hb is higher in older than younger women, which confirms the role of menopause in the development of erythremia. The result of this analysis reinforces the notion that Hb and Hct seem to be stable and useful parameters for acclimatization only at moderate altitudes; with aging or with increasing altitude, they may become excessive and lose their efficiency to protect the venous oxygen pressure.

Red blood cell carbonic anhydrase (CA) activity has not been studied in high altitude natives. Because CA is an intraerythocytic enzyme and high altitude natives are polycythemic, it is important to know if the activity of CA per red cell volume is different from that of their sea level counterparts. Blood was collected from healthy subjects living in Lima (150m) and from twelve subjects from Cerro de Pasco (4330m), and hematocrit and carbonic anhydrase activity were measured. As expected, the high altitude natives had significantly higher hematocrits than the sea level controls (p = 0.0002). No difference in the CA activity per milliliter of red cells was found between the two populations. There was no correlation between the hematocrit and CA activity.

High-altitude (HA) natives have blunted ventilatory sensitivities to hypoxia, and it is uncertain whether this blunting is reversible on migration to sea level (SL). To study this, the ventilatory sensitivities to hypoxia of HA natives residing near SL were compared with those of SL natives. Two studies were performed. In study A, 24 HA subjects who had lived above 3,000 m for an average of 14 yr and had been resident at SL for an average of 23 yr were compared with 23 SL controls. In study B, 25 HA subjects who had lived above 3,500 m for at least 20 yr and had been resident at SL for no more than 5 yr were compared with 25 SL controls. Hypoxic sensitivities were assessed by breathing seven progressively more hypoxic gas mixtures that contained progressively more CO2 in an attempt to maintain isocapnia throughout. The ventilatory sensitivities to hypoxia (l . min-1 . %-1 . m-2) did not differ significantly (by analysis of variance) between HA and SL natives in either study A (-0.51 +/- 0.25, mean +/- SD) or study B (-0.34 +/- 0. 15), but the ventilatory sensitivities did differ significantly between the two studies for reasons which are not entirely clear. We conclude that HA natives residing at SL, even if previously at HA for >20 yr, do not maintain the severely blunted hypoxic responses that have been reported in such individuals.

This study was designed to determine whether subjects born at high altitude (HA; 2,000 m or above) who subsequently move to near sea level (SL) develop end-tidal PCO2 (PETCO2) and PO2 (PETO2) values that equal those of SL natives living near SL. A total of 108 male HA natives living near SL were identified by survey of a district in Lima, Peru, and a further 108 male SL natives from the same district were identified as control subjects. Of these subjects, satisfactory data for inclusion in the study were obtained from 93 HA and 82 SL subjects. Mean PETCO2 and PETO2 values were 37.7 +/- 2.5 (SD) and 104.7 +/- 3.2 Torr, respectively, in HA subjects and 37.7 +/- 2.2 and 104.8 +/- 3.0 Torr, respectively, in SL subjects. The average difference between SL natives and HA natives for PETCO2 was 0.07 Torr (-0.64 to 0.78; 95% confidence interval) and for PETO2 was 0.05 Torr (-0.89 to 0.99, 95% confidence interval). The average age and weight of the SL and HA subjects did not differ, but the HA subjects were shorter and tended to have larger vital capacities, consistent with their origin at HA. We conclude that the PETCO2 and PETO2 near SL of SL natives and HA natives do not differ.

We report the estimation of blood hemoglobin (Hb), arterial blood oxygen saturation (SaO2), and serum immunoreactive erythropoietin (siEPO) in a group of Peruvian workers residing in Cerro de Pasco at 4300 m showing "excessive erythrocytosis" (EE, Monge's disease, chronic mountain sickness). These estimates were compared with those of humans residing either in Cerro de Pasco and showing "normal erythrocytosis" (NE) or in Lima (sea level, SL) to determine whether Hb and SaO2 are related to siEPO in high altitude (HA) natives with NE or EE. The three parameters showed statistically significant differences between HA and SL groups--the values in SL being lower. Significant differences were also found between NE and EE groups in Hb and SaO2. There was no statistical difference in siEPo between the two groups. The results indicate, therefore, that HA residents who develop EE are not distinguishable from residents who develop NE on the basis of estimates of siEPO. As a result, siEPO and Hb do not show a dose-response relationship in HA residents, and variation in EPO does not explain the striking variation in Hb at high altitudes.

Chronic mountain sickness was first described in the Peruvian Andes. It consists of an excesive polycythemia for the altitude of residence. Its main symptoms are of cerebral congestion and occasionally of right heart insufficiency. The authors postulate that it is caused by a decay of the ventilatory rate with age with the corresponding increase in hematocrit.