Ventilation is greater in women than men, but the increase during acute altitude hypoxia is the same

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Abstract

We wished to determine whether the previously reported lower arterial or alveolar PCO2 in women than men, and in luteal (LUT) compared with follicular (FOL) menstrual cycle phase would persist during normal oral contraceptive use and during early altitude exposure. Ventilation and blood gases were measured at baseline (636 mmHg≈5400 ft, 1650 m) and during simulated altitude at 426 mmHg (≈16 000 ft, 4880 m), after 1 h (A1) and during the 12th h (A12), in 18 men (once) and in 19 women twice, during LUT and FOL and in 20 women twice while on placebo (PLA) or highest progestin dose (PIL) oral contraceptives. At baseline, PaCO2 was significantly higher in men than all women by 3.3 mmHg. When progesterone-progestin (PRO) was elevated in women, PaCO2 was significantly lower than in FOL and PLA, but the latter were still significantly lower than men. At altitude the PCO2 differences between men and women and PRO levels persisted, with PACO2 falling by 3.6 and 7.3 mmHg at A1 and A12 in all, indicating an equivalent increase in alveolar ventilation. The mean arterial-end tidal PCO2 difference was never >2 mmHg in the groups, indicating no V̇A/Q̇ mismatch related to gender, PRO levels or altitude. All women had higher breathing frequency than men, resulting in greater deadspace ventilation. At altitude, the mean PaO2 was ≈ 44 mmHg (SaO2≈79%) for all, indicating equivalent oxygenation, but alveolar-arterial PO2 differences were greater in women than men and higher when PRO was elevated. These results show that, relative to men, women have a compensated respiratory alkalosis, accentuated with elevated PRO. However, the ventilation response to acute altitude is the same in women and men.

Introduction

Nearly a century ago Fitzgerald and Haldane (1905) reported that the resting alveolar (end-tidal) PCO2 was 3 mmHg lower in women than men (average age: 24; range: 17–48 year), and that a smaller gender difference existed in young subjects (average age 12; range: 7–15 year). Fitzgerald (1913), went on to show that this difference remained essentially constant in permanent or seasonal adult residents (average age: 35 year) at altitudes up to 14 000 ft in mining camps in Colorado, implying that the ventilatory adjustment to altitude is the same for men and women. She attributed the difference to a compensation for the 11% lower hemoglobin in women. PCO2 differences between men and women have frequently been observed since then, but not incorporated into normal values for respiratory function. For example, Shock and Soley (1939) demonstrated lower PCO2 values in women in a large sample of adolescents and adults, ranging in age from 11 to 43 year, but failed to take note of them.

As well as the gender difference, the PCO2 is some 10% lower in the luteal than follicular phase of the menstrual cycle phase. This was first reported by Hasselbalch and Gammeltoft (1915) and later carefully confirmed (Griffith et al., 1929, Goodland and Pommerenke, 1952). The PCO2 also declines with advancing pregnancy, as initially observed by Hasselbalch (1912). These reports and numerous recent studies (reviewed by Tatsumi et al., 1995) have demonstrated the association between progesterone and estrogen levels and PCO2 differences between genders, within menstrual cycle and during advancing pregnancy. The present consensus is that elevated progesterone increases ventilation, resulting in a compensated respiratory alkalosis in women, relative to men, which is further accentuated in the luteal phase and during pregnancy. However, the contribution of primary metabolic acidosis has not been absolutely ruled out (England and Farhi, 1976). The ability of endogenous progesterone and its exogenous analog, progestin in oral contraceptives, to stimulate ventilation (Bonekat et al., 1987) has led to the question of how natural or induced hormonal fluctuations might alter the ability to respond appropriately to hypoxia resulting from pulmonary disease or high altitude.

Responses to short hypoxic ventilatory response (HVR) tests are usually greater when progesterone is elevated (Tatsumi et al., 1995) and responses to hypercapnic ventilatory response (HCVR) tests also tend to be higher (Lyons and Antonio, 1959). Comparisons of the acute ventilatory responses to acute altitude exposure between men and women and during varying progesterone and progestin levels in women have not been reported.

The acute consequences of a lower PCO2 are an elevated arterial PO2 if the respiratory exchange rate (R) and pulmonary gas exchange efficiency remain the same. If sustained, the CO2 content (HCO3) in blood and body fluids will be lower because renal HCO3 reabsorption and acid secretion are reduced. Also, the relationship of PaCO2 and PETCO2 to ventilation is usually assumed to be equivalent because these two measurements differ by <2 mmHg in healthy subjects and usually only one is measured. However, any perturbation of gas exchange resulting from edema, breathing pattern, pulmonary blood flow or V̇A/Q̇ redistribution during exposure to hypoxia could invalidate this assumption.

The objectives of this report were: (1) to describe arterial and end-tidal PCO2 and acid-base status under ambient conditions in men and in women during the luteal and follicular phases and in women taking progestin; (2) to describe PCO2 and associated changes during the second and 12th h at a simulated altitude of 16 000 ft and thereby determine whether the ventilation response to acute altitude varied with gender or endogenous or exogenous progesterone levels present in oral contraceptives; and (3) to determine whether changes in R, pulmonary gas exchange or acid-base status differed in these subjects in response to altitude.

Section snippets

Methods

The subjects and measurements were part of a larger study investigating differences in altitude sickness between men and women, menstrual cycle phase and oral contraceptives (OCPs) for the US army (Riboni et al., 1999).

Results

It was not always possible to obtain all measurements each time in the 33 women, for gender comparisons. Therefore, one average value was calculated for each woman, regardless of menstrual cycle phase or progestin level, by averaging all values for that subject so as not to bias the mean results toward any particular subject. These values are noted as ‘Wom’ in the tables. Similarly, PaCO2 values, reflecting ventilation, in high (LUT and PIL) and low (FOL and PLA) progesterone-progestin groups

Ventilation related to gender, menstrual cycle and OCPs

These findings confirm that PACO2 is about 3 mmHg lower in women than men, regardless of our acute altitude exposure. This difference is accentuated by about 1–1.5 mmHg in LUT and PIL and reduced by a similar amount in FOL and PLA, where it is still significantly lower. We cannot be sure that the women's cycle and OCP test dates corresponded to their highest and lowest plasma progesterone and ventilation levels. The smaller PACO2 differences between PLA and PIL may be related to the variable

Acknowledgements

We are indebted to the 51 subjects who gave many hours of their time and gave their full cooperation under frequently trying and uncomfortable circumstances. We also appreciate the dedication and extra effort given by the technical research team, Damon Maes, Katrina Riboni and Carole Conn for the many hours spent in collection of data and scheduling and management of the subjects and experimental logistics. We thank Tami McMahon for her special supervision of all endocrine and blood gas

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