Oral Contraceptive Use and Acute Mountain ... - IngentaConnect

RESEARCH ARTICLE

Oral Contraceptive Use and Acute Mountain Sickness in South Pole Workers Michael F. Harrison, Paul Anderson, Andrew Miller, Kathy O’Malley, Maille Richert, Jacob Johnson, and Bruce D. Johnson HARRISON MF, ANDERSON P, MILLER A, O’MALLEY K, RICHERT M, JOHNSON J, JOHNSON BD. Oral contraceptive use and acute mountain sickness in South Pole workers. Aviat Space Environ Med 2013; 84:1166–71. Introduction: Progesterone has a number of properties that could influence the development of acute mountain sickness (AMS), including anti-inflammation, respiratory smooth muscle relaxation, ventilatory stimulation, and antidiuretic characteristics. Oral contraceptive (OC) use decreases levels of circulating progesterone by preventing ovulation. We hypothesized rates of AMS development would be significantly higher in OC users as compared to Non-OC users in a population traveling rapidly to the South Pole. Methods: There were 50 female subjects (OC N 5 13, no OC N 5 37) who traveled by airplane from Sea Level (SL) to Altitude (ALTD) (;3200 m) in , 4 h and were monitored for the development of AMS. SL and ALTD measurements of anthropometrics, vital signs, hematologic variables, blood chemistries, electrolytes, endocrine responses, and pulmonary function were assessed with t-test and Chi-square analyses, P , 0.05. Results: As compared to Non-OC users, OC users had lower progesterone levels (ng z ml21) at SL (0.7 6 0.5 vs. 3.2 6 4.6) and at ALTD (0.7 6 0.7 vs. 3.1 6 4.6). AMS was significantly more prevalent in OC users (85%) as compared to Non-OC users (51%). Acetazolamide prophylaxis was not protective, with a greater proportion of OC users (100%) developing AMS despite its use as compared to Non-OC users (50%). Blood pressure responses also differed significantly, with OC users displaying higher mean arterial pressures at ALTD vs. Non-OC users. Conclusion: OC use at ALTD is associated with an increased risk for the development of AMS. Acetazolamide prophylaxis with OC use was also associated with an increased rate of AMS development. Keywords: acute mountain sickness, oral contraceptive, progesterone, altitude, acetazolamide, Antarctica.

A

CUTE MOUNTAIN sickness (AMS) is the mildest and most common form of altitude illness and currently available research is conflicting with respect to predicting who is at risk of experiencing AMS with accuracy or identifying the specific pathophysiology that causes AMS (4,14,30). While not always indicative of progression along the spectrum of altitude-related illness, AMS can be a precursor to the more serious and life-threatening high-altitude cerebral edema (HACE) (14,26). The hypothesized mechanisms in the development of AMS include a relationship between hypoxia and inflammation (12), severe gag reflex or periodic sleep breathing (2,8,23), a depressed hypoxic respiratory drive in susceptible individuals (4), increased respiratory rate during initial exposure to altitude (19), abnormalities in body water (25), and increased levels of circulating catecholamines prior to or during altitude exposure (20). Progesterone is a well-known respiratory stimulant and the combined effects of estrogen and progesterone 1166

in response to hypoxia has been demonstrated to be synergistic (5,15). Specific to the reproductive cycle and the associated physiology, increased levels of progesterone in response to fertilization increases a woman’s respiratory rate, decreases her immune response to allow the pregnancy to proceed, and decreases smooth muscle contractility (13,28) while increased estrogen has been linked to fluid retention (34). Pregnancy has not been associated with an increased risk of developing AMS nor has it been identified as a protective condition (14). Menopause has been identified as a risk factor for the development of chronic mountain sickness among highaltitude residents (24). The use of oral contraceptive (OC) combination pills (i.e., estrogen and progestin in combination) is very common and the mechanism by which OC prevents ovulation, and subsequently pregnancy, is through negative feedback to the hypothalamus and pituitary glands (33,35). As a result, OC use suppresses ovulation, the formation of the corpus luteum, and the levels of circulating progesterone normally secreted by the corpus luteum (21,33). These effects are very similar to the effects of menopause but, to our knowledge, no study has addressed the influence of hormonal contraception on the rate of AMS development. Many sources hypothesize the pathophysiology of AMS to have direct CNS involvement (3,14,31) and another source summarizes in detail the cyclical relationships between hypoxia and inflammation – inflamed tissue becomes hypoxic while hypoxic tissue becomes inflamed (12). Progesterone has anti-inflammatory properties that can have specific effects on the central nervous system (CNS) (28). Our recent work supports previous hypotheses that an element of inflammation may play a role in the development of AMS, and helped generate our current hypothesis that decreased levels of progesterone From the Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN; and the Department of Emergency Medicine, Henry Ford Hospital, Detroit, MI. This manuscript was received for review in April 2013. It was accepted for publication in June 2013. Address correspondence and reprint requests to: Bruce D. Johnson, Ph.D., Division of Cardiovascular Diseases, Mayo Clinic, 200 1st St. SW, Rochester, MN 55905; [email protected]. Reprint & Copyright © by the Aerospace Medical Association, Alexandria, VA. DOI: 10.3357/ASEM.3717.2013

Aviation, Space, and Environmental Medicine x Vol. 84, No. 11 x November 2013

PROGESTERONE & AMS—HARRISON ET AL. will have implications related to the study of altitude exposure, specifically the development of AMS (17). Progesterone’s multiple influences within the body, coupled with the decreased levels of serum progesterone in women using OC, make it a variable of interest in a study related to the risk of AMS. We hypothesized that the use of OC would increase the rate of AMS development in female research subjects at the South Pole. METHODS Subjects IRB approval was obtained from Mayo Clinic, Rochester, MN, and all subjects provided written informed consent. All subjects underwent detailed medical screening prior to deployment to Antarctica, were available to the research team during the first 7 d of their deployment, and traveled from sea level (SL) at McMurdo Station to altitude (ALTD) at Amundsen-Scott South Pole Station (altitude of 2835 m; physiologic altitude of ;3200 m) via airplane in less than 4 h (thus a uniform exposure across subjects). Subjects (N 5 248) were included in the study if their duties at Amundsen-Scott South Pole Station exceeded 1 wk in duration. Of these, only female subjects (N 5 70) were eligible for inclusion in this data set. Of these 70 subjects, 17 did not provide information about their OC use and an additional three did not provide repeat blood samples at ALTD. As a result, 50 subjects were included in the final analysis. During 2006-2007, data were only collected from those who had not been a study subject in 2005-2006. Procedure The Antarctic Study of Altitude Physiology (ASAP) studied subjects in the United States Antarctic Program during the austral summer months from 2005 to 2007. This provided unique opportunities to observe a large and well-controlled subject population to assess which variables and factors might be used to predict those individuals who were susceptible to AMS. Following arrival at McMurdo Station, the majority of subjects “acclimatized” to the new timezone and ambient temperature for approximately two weeks prior to departure for Amundsen-Scott South Pole Station. During this time, subjects underwent baseline testing and education related to high altitude illness. Acetazolamide was made available to any subject who wished to employ AMS prophylaxis and its use was not a basis for exclusion from the analysis. Baseline questionnaire collection included Lake Louise Symptom Score questionnaires as well as an additional symptom questionnaire pertaining to the following: 1) dyspnea (at rest and on exertion); 2) general health limitations; 3) mental status changes; 4) cough; and 5) peripheral edema. Further questionnaire data included information related to past medical history and chronic medical conditions, current medication use, lifestyle assessment (i.e., tobacco and alcohol use; exercise habits), and previous experience with altitude and/or Antarctic expeditions. Baseline anthropometric and physiological measurements included height, weight, heart

rate, blood pressure, arterial oxygen saturation (Sao2), and blood draw. Blood samples were analyzed for hemoglobin concentration and hematocrit; serum electrolyte and progesterone levels; and circulating catecholamine levels. The overall goal of the study was related to the general epidemiology of altitude illness; however, while OC use was hypothesized to play a potential role in modifying the risk of altitude illness, it was not discussed with the subjects and was simply part of the large set of data collected as a part of the study. Subjects completed questionnaires related to symptoms including the Lake Louise Symptom Score form on nine separate occasions. These were completed at SL, on the plane to ALTD, and daily for the first 7 d after arrival at ALTD. The first series of questionnaires at ALTD was completed prior to sleep on the first night and each of the subsequent series was completed upon waking. An individual was determined to have AMS if their Lake Louise Symptom Score was ⱖ 3 and included a headache. Changes in plasma volume were estimated using the equations derived by Dill and Costill (11). Statistical Analysis Data were compiled and analyzed with SPSS v20.0 (IBM Corporation, Armonk, NY). Comparisons of means were performed using Mann-Whitney U-test for between group differences (OC vs. Non-OC) for the continuous variables and Chi-square for categorical variables. Paired t-tests were performed to assess within group differences between measurements that were repeated at SL and at ALTD. Significance was determined as P , 0.05. RESULTS The final analysis was conducted with 50 subjects (OC N 5 13, Non-OC N 5 37) and their characteristics, vital signs, and basic pulmonary function test results are provided in Table I. Table II provides a summary of the electrolyte, chemistry, and hematologic results. Table III summarizes the endocrine and catecholamine responses. None of our subjects progressed along the AMS spectrum to the more severe conditions HAPE or HACE. The OC group had an increased rate of AMS development (85%) as compared to members of the Non-OC group (51%); additionally, the members of the OC group who opted to use acetazolamide had an increased rate of AMS development (100%) as compared to the members of the Non-OC group who also opted to use acetazolamide prophylactically (50%). As was expected, the levels of circulating progesterone at SL and at ALTD also differed between the OC group (0.7 6 0.5 and 0.7 6 0.7, respectively) and the Non-OC group (3.2 6 4.6 and 3.1 6 4.6, respectively). DISCUSSION The combination of OC use and travel to ALTD increased the risk of developing AMS. Furthermore, the prophylactic use of acetazolamide was not effective in subjects using OC. To our knowledge, this finding has


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PROGESTERONE & AMS—HARRISON ET AL. TABLE I. SUMMARY OF SUBJECT CHARACTERISTICS AND VITALS.

N AMS During Trip AMS Among Acetazolamide Users Age (yr) Ht (m) Wt (kg) • SL • ALTD Elevation of Residence for 3-mo Period Preceding Study Participation (m) Seated HR (bpm) • SL • ALTD Seated BP (mmHg) • SL Systolic Diastolic MAP • ALTD Systolic Diastolic MAP Seated O2Sat (%) • SL • ALTD FVC (L) • SL • ALTD FEV1 (L) • SL • ALTD FEV1 / FVC (%) • SL • ALTD

OC Group

Non-OC Group

P-Value Between Groups

Degrees of Freedom

13 11 (85%)* 7/7 (100%)* 34.2 6 9.2 1.7 6 0.1

37 19 (51%)* 8/16 (50%)* 36.2 6 10.1 1.7 6 0.1

0.03 ,0.01 0.62 0.53

49 49 22 49 49

67.0 6 8.1† 67.7 6 7.0† 615.2 6 694.7

73.8 6 18.9 73.4 6 19.7 912.0 6 876.6

0.14 0.19 0.35

49 49 49

70.9 6 11.1† 80.7 6 14.2†

70.8 6 12.0‡ 82.4 6 11.3‡

0.86 0.50

49 49

101.2 6 8.1* 63.2 6 6.2‡,* 75.9 6 5.8‡,*

108.3 6 13.2‡,* 70.3 6 12.0‡,* 83.0 6 11.7‡,*

0.04 0.04 0.04

49 49 49

106.6 6 11.0 73.5 6 6.3‡,* 84.5 6 7.3‡,*

99.7 6 16.0‡ 64.8 6 11.1‡,* 76.5 6 12.0‡,*

0.08 ,0.01 ,0.01

49 49 49

98.3 6 0.9† 88.8 6 6.0†

97.9 6 1.1‡ 90.4 6 2.9‡

0.22 0.78

49 49

4.1 6 0.4 4.2 6 0.5

4.1 6 0.6 4.1 6 0.5

0.81 0.83

49 48

3.3 6 0.3† 3.6 6 0.6†

3.3 6 0.4‡ 3.4 6 0.4‡

0.98 0.87

49 48

80.9 6 6.8† 84.9 6 6.9†

82.0 6 5.6‡ 84.2 6 5.5‡

0.67 0.91

49 48

* Difference between OC and Non-OC groups, P , 0.05. † Difference within OC group at SL and at ALTD, P , 0.05. ‡ Difference within Non-OC group at SL and at ALTD, P , 0.05.

not been previously reported. A case study related to OC use at altitude highlighted the increased risk of hypercoagulable events and another presented the increased risk of high altitude decompression sickness (DCS), but AMS has not been studied (36,37). The development of AMS is linked to four factors: 1) rate of ascent; 2) peak altitude attained; 3) the sleeping altitude; and 4) individual susceptibility (3,4,31). In the present study, all subjects achieved the same altitude via the same rate of ascent and they did not descend to sleep. These strengths permitted the investigation of a specific difference between groups, i.e., the use of OC, and its role in the development of AMS. The rate of AMS development among Non-OC users was comparable to our previous findings (1). Our discussion will address the role of progesterone with respect to the increased rate of AMS. It is apparent that progesterone plays a role but serum estrogen was not measured. As such, we are left to speculate about its contribution to the development of AMS while encouraging future investigators to include serum estrogen concentrations in their study design. OC use was associated with a small but statistically significant effect on blood pressure. The OC group initially had lower blood pressures as compared to the Non-OC group, but the OC pressures increased at ALTD whereas 1168

the Non-OC pressures decreased. The lower initial blood pressures at sea level in the OC group were unexpected given the reports of increased systolic and diastolic blood pressure and, in some cases, clinical hypertension associated with the estrogen component of OC regardless of the OC’s progestogenic potency (34,38). Specific to progesterone, it is a higher-affinity human mineralocorticoid receptor binder but only a weak agonist as compared to aldosterone (29). Aldosterone levels have been reported to be higher prior to altitude exposure in individuals susceptible to AMS as compared to nonsusceptible individuals (25,30) and decreased levels of progesterone would leave more receptors available for aldosterone to bind and exert its full contributory effect to the development of AMS. In keeping with differences in the reninangiotensin-aldosterone system, higher levels of serum angiotensin II was found in the OC group at SL. Elevations in angiotensin II have been demonstrated to increase cerebrospinal fluid pressures in animal models (32). Further related to blood pressure, an exaggerated vasoconstrictive response from the chemoreceptors during hypoxic conditions may contribute to AMS (22). Epinephrine and norepinephrine increase during simulated altitude exposure with a concurrent elevation of heart rate (20). Our catecholamine findings were limited to significant


PROGESTERONE & AMS—HARRISON ET AL. TABLE II. ELECTROLYTE, BLOOD CHEMISTRY, AND HEMATOLOGY RESULTS.

21

Sodium (mEq z L ) Potassium (mEq z L21) Chloride (mEq z L21) Calcium (mEq z L21) Alkaline Phosphatase(U z L21) Transaminases (U z L21) • ALT • AST WBC (x109/L) RBC (x1012/L) Hemoglobin (g z dl21) Hematocrit (%) MCV (mg/cell) MCH (rg/cell) MCHC (%Hb/cell) RDW (%) D Plasma Volume (%) Platelets (x109/L) Iron Studies • Iron (mg z dl21) • Iron Sat (%) • TIBC (mg z dl21) • UIBC (mg z dl21)

OC Group

Non-OC Group


Degrees of Freedom

138.5 6 1.4 4.5 6 1.1 102.2 6 3.0 9.5 6 0.5 54.2 6 10.5

138.9 6 1.9 4.1 6 0.4 102.7 6 2.5 9.7 6 0.5 64.3 6 20.4

0.16 0.28 0.83 0.36 0.12

49 49 49 49 49

13.4 6 6.6 19.4 6 5.1 6.9 6 2.6 4.1 6 0.3* 13.6 6 0.9 40.6 6 3.1 95.3 6 4.6 31.9 6 1.2 33.4 6 0.9 13.8 6 1.2 -9.7 6 7.2 293.4 6 60.8

16.8 6 6.3 19.7 6 4.8 5.8 6 1.2 4.6 6 0.5* 14.1 6 1.0 42.3 6 3.1 94.1 6 5.7 31.3 6 1.7 33.3 6 1.0 14.2 6 1.7 -8.2 6 15.6 269.9 6 66.8

0.09 0.83 0.24 ,0.01 0.12 0.17 0.54 0.38 .0.99 0.56 0.76 0.20

49 49 49 49 49 49 49 49 49 49 49 49

120.6 6 58.6 34.1 6 15.2 361.0 6 60.3* 240.4 6 78.1

109.0 6 50.4 34.5 6 17.4 321.8 6 51.9* 214.8 6 76.2

0.57 .0.99 ,0.01 0.17

49 49 49 49

* Difference between OC and Non-OC groups, P , 0.05.

increases in NE in the Non-OC group and heart rate increased significantly at ALTD within both groups. An interesting and unexpected finding was the lack of benefit provided by the use of prophylactic acetazolamide in the OC group. Acetazolamide is a diuretic but other loop diuretics and thiazides are ineffective in the prevention of AMS (23). Only spironolactone, a competitive inhibitor of aldosterone that has antagonistic properties at the mineralocorticoid receptor, is of benefit in the prevention of AMS (25). Given the relationship previously discussed between progesterone and aldosterone receptors, perhaps the mechanism of action of acetazolamide was not specific enough to this sample population and future work may wish to employ spironolactone instead of acetazolamide in OC users traveling to altitude. Hypoxic tissue becomes inflamed and inflamed tissue becomes hypoxic (12). As a result, altitude exposure and the associated hypoxia are linked to increased presence of circulating proinflammatory cytokines and “vascular leakage” (6,12). The relationship between a hypoxia-related inflammatory response and AMS is supported by the use of steroids, e.g., dexamethasone, as a more effective form of treatment after the onset of AMS as compared to acetazolamide (26). Intraperitoneal progesterone, a steroid itself, decreases the expression of inflammationrelated factors in animal models following traumatic brain injury and limits the severity of the brain damage, the lesion’s water content, and the lesion’s volume (27). Progesterone has further downstream effects on the inflammatory pathways, including antagonism of cyclooxygenase-2 (COX-2), one of the key players in oxidative stress secondary to hypoxia (6,16). While AMS is more of a “nuisance,” the requirement of a headache in the Lake Louise Scoring System diagnosis and multiple sources suggest an important CNS component in the pathophysiology

of AMS (3,4,31). AMS can have a profound impact on lifetstyle and its potential to progress to HACE and HAPE are of concern (10,18). Progesterone has a multifactorial influence on the respiratory system but its use as a respiratory stimulant has not demonstrated a benefit to AMS prevention (13,39). Progesterone’s effect on upper airway musculature is associated with decreases in asthmatic symptoms in females during their cycle’s peak progesterone levels (7,28). At altitude, this relaxation of smooth muscle would decrease the resistance to flow during breathing and permit larger tidal volumes. Jafarian et al. report significantly higher respiratory rates during the first hour at altitude among individuals who developed AMS as compared to their counterparts who did not (19). Despite this, no significant differences were detected between the OC and Non-OC subjects with respect to the pulmonary function tests in our study. With respect to hematologic results, the OC group had lower RBC mass but was still within the normal range. These lower values may be explained by a dilutional effect caused by the retention of fluid or due to an increased rate of folate metabolism and subsequent depletion of folate stores often seen with OC use (34,35). The increased total iron binding capacity (TIBC) is consistent with OC use (35). Erythropoietin levels differed initially at SL but the difference was not present at ALTD. At ALTD leptin was significantly lower in the OC group. One of the symptoms of AMS is anorexia and leptin levels have been demonstrated to decrease in short-term underfeeding and do not normalize until the negative energy balance caused by underfeeding is addressed (9). This finding may be an objective indication of the severity of the symptoms of a subjective condition experienced by the subjects using OC.


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PROGESTERONE & AMS—HARRISON ET AL. TABLE III. ENDOCRINE AND CATECHOLAMINE RESULTS. OC Group

Non-OC Group


Degrees of Freedom

0.7 6 0.5* 0.7 6 0.7*

3.2 6 4.6* 3.1 6 4.6*

0.02 0.04

49 49

16.0 6 8.3‡,* 25.0 6 10.2†

10.8 6 4.1‡,* 26.2 6 14.0‡

0.06 0.99

49 49

12.3 6 18.7 6.6 6 3.2*

13.4 6 9.9 11.6 6 7.4*

0.07 0.02

49 49

45.5 6 36.8* 22.5 6 24.7

5.5 6 2.9‡,* 15.3 6 22.3‡

,0.01 0.35

49 49

1.5 6 0.8 1.7 6 0.7

1.3 6 0.7 1.4 6 0.6

0.68 0.30

49 49

44.4 6 14.5 75.6 6 47.9

43.3 6 22.5‡ 71.9 6 65.0‡

0.86 0.58

49 49

565.5 6 281.0 759.7 6 659.1

611.2 6 323.0 582.4 6 298.2

0.93 .0.99

49 49

2.0 6 1.4† 2.6 6 2.1†

1.6 6 1.0‡ 2.0 6 1.3‡

0.29 0.33

49 49

413.8 6 207.4† 715.3 6 378.4†

373.0 6 116.9‡ 600.9 6 279.9‡

.0.99 0.63

49 49

21.5 6 11.3 28.7 6 31.8

24.5 6 21.9 26.8 6 20.3

0.91 0.61

49 49

15.4 6 6.6 26.6 6 22.4

16.2 6 13.8 20.8 6 19.1

0.66 0.42

49 49

21

Progesterone (ng z ml ) • SL • ALTD Erythropoietin (mIU z ml21) • SL • ALTD Leptin (ng z ml21) • SL • ALTD Angiotensin II (pg z ml21) • SL • ALTD Tumor Necrosis Factor-a (pg z ml21) • SL • ALTD Vascular Endothelial Growth Factor (pg z ml21) • SL • ALTD Atrial Natriuretic Peptide (pg z ml21) • SL • ALTD Thyroid Stimulating Hormone (mIU z ml21) • SL • ALTD Norepinephrine (pg z ml21) • SL • ALTD Epinephrine (pg z ml21) • SL • ALTD Dopamine (pg z ml21) • SL • ALTD

* Difference between OC and Non-OC groups, P , 0.05. † Difference within OC group at SL and at ALTD, P , 0.05. ‡ Difference within Non-OC group at SL and at ALTD, P , 0.05.

As in our previous publication, many variables differed significantly between those who did and those who did not develop AMS but none differed to the point that they were outside normal ranges (17). This suggests that the “nuisance” of AMS is a result of minor or subtle variants of normal rather than overtly pathological disturbances. The present study illustrates a relationship between progesterone and AMS but does not yet provide the full explanation, particularly with respect to acetazolamide use. Future research should be mindful of OC use among their subjects as it appears their full effects in extreme environments are not completely understood. In conclusion, study subjects using OC and traveling to altitude at the South Pole were at a greater risk of developing AMS as compared to their counterparts who were not taking OC. The exact pathophysiology related to the development of AMS is not presently understood but perhaps this finding and subsequent discussion will guide future work related to AMS as well as future work related to the use of OC in extreme environments. ACKNOWLEDGMENTS We would like to thank the employees of the U.S. Antarctic Program. This includes general science support, station management and cargo crew at South Pole, Crary Lab, medical team and transportation/shipping at both McMurdo and South Pole. We would also like to thank

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Dr. Kenneth Beck, Jay O’Brien, Kent Bailey, and Josh Mueller for assistance with the many aspects of data collection and analysis. This study was supported by a grant from the National Science Foundation, B-179-M, as well as funding through the Mayo Clinic Center for Translational Science Activity (CTSA), Clinical Research Unit, Grant Number 1 UL1 RR024150 from the National Center for Research Resources. Authors and afﬁliations: Michael F. Harrison, M.D., Ph.D., Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN and Department of Emergency Medicine, Henry Ford Hospital, Detroit MI; Paul Anderson, M.D., Andrew Miller, M.Sc., Kathy O’Malley, Maille Richert, Ph.D., Jacob Johnson, M.Sc., and Bruce D. Johnson, Ph.D., Division of Cardiovascular Diseases, Mayo Clinic, Rochester MN. REFERENCES 1. Anderson PJ, Miller AD, O’Malley KA, Ceridon ML, Beck KC, et al. Incidence and symptoms of high altitude illness in south pole workers: Antarctic Study of Altitude Physiology (ASAP). Clin Med Insights Circ Respir Pulm Med 2011; 5:27–35. 2. Austin D, Sleigh J. Prediction of acute mountain sickness. BMJ 1995; 311:989–90. 3. Barry PW, Pollard AJ. Altitude illness. BMJ 2003; 326:915–9. 4. Basnyat B, Murdoch DR. High-altitude illness. Lancet 2003; 361:1967–74. 5. Bayliss DA, Millhorn DE. Central neural mechanisms of progesterone action: application to the respiratory system. J Appl Physiol 1992; 73:393–404. 6. Behn C, Araneda OF, Llanos AJ, Celedon G, Gonzalez G. Hypoxia-related lipid peroxidation: evidences, implications and approaches. Respir Physiol Neurobiol 2007; 158:143–50. 7. Brenner BE, Holmes TM, Mazai B, Camargo CA. Relation between phase of the menstrual cycle and asthma presentations in the emergency department. Thorax 2005; 60:806–9.


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