The effects of oral contraceptives on respiration*

Vol. 39, No.4, April 1983 Printed in U.8A.

FERTILITY AND STERILITY Copyright < 1983 The American Fertility Society

The effects of oral contraceptives on respiration*

Ana Montes, B.A. t David Lally, Ph.D.t Ralph W. Hale, M.D. t§ University of Hawaii School of Medicine, Honolulu, Hawaii

The effect synthetic progestins found in current oral contraceptives may exert on respiratory function has not been thoroughly investigated. This study monitored potential changes in respiratory parameters 3 and 6 months subsequent to beginning administration. Static and timed spirometric maneuvers showed significant increases in only tidal volume (P = 0.01). Ventilatory response to treadmill exercise monitored the oxygen uptake, CO2 elimination (Yco2 ), minute ventilation (VFJ, and respiratory exchange ratio at each offour workloads. An analysis of the covariance (ANCOVA) for the slopes revealed no significant variation between test periods. The ANCOVA for the means showed increases in VE and VC02 ' These results suggest a stimulatory role for synthetic progestins, although ventilatory performance in response to moderate exercise does not appear compromised. Fertil Steril 39:515, 1983

Received September 20,1982; revised and accepted December 23, 1982. *Supported by a grant from the Leahi Foundation, Honolulu, Hawaii. tDepartment of Obstetrics and Gynecology. :j:Department of Physiology. §Reprint requests: Ralph W. Hale, M.D., Professor and Chairman, Department of Obstetrics and Gynecology, University of Hawaii School of Medicine, 1319 Punahou Street, Honolulu, Hawaii 96826.

P eo2 and hyperventilation. 5, 6 This or other effects that synthetic progestins found in OCs may exert on respiratory parameters at rest and during exercise have not been reported. In addition, pulmonary function during OC administration has only been assessed by utilizing static and dynamic spirometry studies that compare users with nonusers. 7. 8 Medroxyprogesterone acetate, a 17-0H P, has been shown to cause a significant decrease in arterial P eo2 within 48 hours after drug administration, although at significantly higher doses than those found in current OCs. 9 The lack of information on ventilatory response changes in relation to OC administration becomes more significant in view of the fact that no data exist assessing the potential effects of progestins at current pharmacologic doses and under common physiologic stresses such as exercise. The purpose of this study was to assess pulmonary function in 12 nulliparous patients before and after OC administration. Potential changes in respiratory parameters were monitored at rest and during programmed exercise for a period of 6 months.

Vol. 39, No.4, April 1983

Montes et aI.

While many laboratory and clinical studies have been performed on patients using oral contraceptives (OCs), there have been only a few studies of pulmonary function. It is known that lowered levels of alveolar pulmonary carbon dioxide elimination (Peo) occur both in the luteal phase of the menstrual cycle and during pregnancy; this effect is presumably due to elevated levels of progesterone (p).1-4 Further evidence for this effect has been provided by studies showing that parenteral administration of P to normal subjects and obese patients with the hypoventilation syndrome results in lowered arterial and alveolar

Synthetic progestins and respiration

515

MATERIALS AND METHODS

Twelve nulliparous subjects, with an age range of 21 to 30 years (mean, 23), volunteered for this study. The subjects were not obese and denied any previous history of cardiovascular disease. Two women had a history of allergic asthma but had experienced no attacks within the previous 4 months. One patient was found to have a history of multiple episodes of bronchitis. Each patient was asked to volunteer after she had been screened at the University Family Planning Clinic and had elected to use an ~C. The patients were placed on medication after completion of the control evaluations. Ten patients were placed on 1 mg norethindrone with 0.035 mg mestranol (Ortho Pharmaceutical Corporation, Raritan, NJ), and two patients were started on 1 mg ethynodiol diacetate with 0.050 mg ethinyl estradiol (Searle and Company, San Juan, PR). The first testing session occurred immediately prior to beginning OC administration. No volunteer was admitted to the study if she had been taking OCs within the past 6 months. The second testing session was scheduled 3 months after beginning OCs, and the last testing session was scheduled 6 months after starting medication. Before each testing session, the patient was instructed as to the purpose of each test and allowed to become familiar with the equipment. This permitted the subjects to become comfortable with the test conditions. There were two phases to the investigation, a spirometry evaluation and an exercise stress study. The vital capacity (VC), tidal volume (VT ) . . ' resting JI}inute ventilation (VE), resting oxygen uptake (V0), forced expiratory volume (FEV 1.0), and midmaximal expiratory flow (MMEF) were measured with the use of a 9- or 13.5-liter Collins spirometer. Static spirometric measurements were performed a minimum of three times in the sitting position, and the highest value was recorded. The volume of air forcibly expired in 1 second (FEV 1.0) and the MMEF were obtained with the use of room air in a 13.5-liter Collins spirometer. Resting VE and Vo ) were measured with medical oxygen (99.5% pu:e). To assess pulmonary function during exercise, the patients were placed on a Quinton treadmill (Quinton Instruments, model #18-60, Seattle, WA) and exercised at a constant velocity of 3.5 mph while the workload was increased successively by varying the percentage of grade. The 516

Montes et al. Synthetic progestins and respiration

patients used standard headgear, and all breathing was through the mouth. A one-way valve attached to the mouthpiece allowed selective collection of expired air. Gas samples were obtained at each of four workloads: 0% grade, 5% grade, 10% grade, and 15% grade. Samples were collected in 200-liter rubberized canvas bags (Warren E. Collins, Braintree, MA). The collections were timed and performed only after steady-state conditions were achieved. Steady state was defined as a constant heart rate at each workload and was continually monitored by a Burdick EK/5A electrocardiograph (Burdick Company, Milton, WI). Gas collections were made after at least 4 minutes at each workload, and the collection time was 2 minutes. Determination of 02 and CO 2 content was made with the use of a Beckman 02 analyzer, model E2, and a Beckman CO 2 medical gas analyzer, model LB-1 (Beckman Instruments, Shiller Park, IL). The total volume of the gas sample was measured with the use of a Parkinson Cowan CD meter (Parkinson Cowan, England) and pump.

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Figure 1 Carbon dioxide elimination as a function of increasing levels of exercise. Plot represents mean values at each workload. Open circles represent control test period; squares, 3 months on OCs; and closed circles, 6 months on OCs. ANCOV A for the slopes: P > 0.5.

Fertility and Sterility

Table 1. Results of ANCOVA for Means-P Values

Test period comparison

YE

Yeo.

Yo.

R

1_2a 2-3 b 1-3c

0.03 0.07 0.07

0.06 0.84 0.09

0.30 0.50 0.54

0.45 0.56 0.18

aComparison between control test period and 3 months after beginning treatment. bComparison between 3 months and 6 months. cComparison between control and 6 months.

Gas volumes were corrected for barometric pressure, water vapor, and ambient temperature. In the analysis of the spirometric values, a oneway analysis of variance (ANOVA) was employed after the individual values were corrected for water vapor saturation, temperature, and pressure. Corrections for body surface area, age, and height were also done where indicated. We used an analysis of the covariance (ANCOVA) to analyze our exercise stress study. A separate ANCOV A was done for the slopes and means after plotting each respiratory parameter as a function of workload. The carbon dioxide elimination (V co 2 ) data, shown in Figure 1, also reveals no significant differences in slope. The means analysis does show increased values of Vco 2 for test sessions subsequent to beginning contraceptive administration, although these increases are not statistically significant. Table 1 summarizes these results. An assessment of VE (Fig. 2) indicates no significant changes in slope. The ANCOVA shows a significant increase in VE after 3 months of contraceptive exposure and a less increased level 6 months later (Table 1). Vco 2 divided by V02 defines the respiratory exchange ratio (R) and serves as an indicator of the type of fuel metabolized by the body. The ANCOVA indicates no significant changes occur in the slope nor in the means for R (Fig. 3).

RESULTS Table 2 summarizes the results for the spirometry study. An ANOVA was done on all the parameters to determine the existence of significant variations in respiratory parameters between testing periods. The VC values exemplify the results of the static spirometry portion of the study. They are expressed as the percentage of the predicted value and are standardized for age and height. Neither VC nor V T , as measured from static spirometric maneuvers, was significant (P = 0.36). Vol. 39, No.4, April 1983

FEV 1.0 and MMEF clinically are indicative of airway resistance, and our test results indicate no changes in these parameters after treatment with oqs (P = 0.9 and P = 0.5, respectively). VE shows an increase between the before and after treatment sessions, although the difference is not significant (P = 0.07). Because VE is equal to breathing frequency multiplied by V T, these parameters were determined. Breathing frequency was found not to vary between test sessions (P = 0.9). The VT was measured over the period of quiet breathing on the spirometer and was observed to increase significantly subsequent to contraceptive treatment (P = 0.01). In assessing pulmonary function under the stress of exercise, four parameters were determined at each workload: VO 2 , Vco 2 , VE, and R. An ANCOVA was done for comparison of the slopes of the three test sessions after plotting the variables as a function of workload. Since the slopes might remain constant while the position of the

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Figure 2 Minute ventilation as a function of increasing levels of exercise. Designations as in Figure 1. ANCOVA for the slopes: P > 0.7.

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517

Table 2. Spirometry Values Test period

Vital capacity (% predicted) "Minute ventilation (l/min) Tidal volume (l) Frequency (breaths/min) FEYl.o (l) MMEF (l/sec) Vo /m 2 BSA (mllm2 ) STPD

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± ± ± ± ± ±

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16.6 1.17 16.0 2.5 3.4 118.3

± ± ± ± ± ±

1.6 0.06 1.4 0.2 0.2 7.9

14.7 1.18 15.0 2.7 3.6 121.2

± ± ± ± ± ±

0.36

1.6 0.11 1.0 0.4 0.2 8.0

0.07 0.01 0.79 0.58 0.46 0.20

aYalues are mean ± standard error. bp values are obtained by ANOYA. Unless otherwise indicated, the values are expressed in BTPS (body condition saturated with water vapor at body temperature and ambient pressure). V02 is corrected for body surface area (BSA) at standard temperature pressure dry (STPD).

lines is shifted, another ANCOVA was undertaken for comparison of the means. When Vo 2 is plotted as a function of workload (Fig. 4), the ANCOV A reveals no significant change between test sessions.

The increase in VE was significant during exercise but not in the resting state, where only VT rose to significant levels. The increased enhancement of ventilation during exercise has been observed by other investigators9 and may reflect cellular potentiation to other chronic stimuli such

DISCUSSION

Orally administered norethindrone in doses found in current OCs (1 mg) was found to be a moderate ventilation stimulator in normal patients. Studies implicating progestins as the source of the ventilatory response are numerOUS. I -6 , 9-11 A similar role for norethindrone is implicated by our study. Our results also indicate increases in V T at rest, VCO 2 , and VE during exercise, and are based on an experimental design that allows the subject to serve as her own control. The question of short-term effects on ventilation has been investigated by others, 9 who noted a decrease in alveolar Peo2 7 days following the administration of medroxyprogesterone acetate. Our results indicate that this effect with synthetic progestins is sustained on a long-term basis. Our data also suggest a greater effect at 3 months than at 6 months. Whether a "peak" actually occurs at about 3 months was not determined, and the mechanism responsible for the diminished response by 6 months is unknown. None of the four parameters measured during exercise was observed to have any significant changes in slope for the three test sessions. We could find no evidence that synthetic progestins, in pharmacologic doses, decrease exercise performance in untrained individuals during exercise of short duration. The effect on trained individuals over long periods of time is yet to be determined. 518

Montes et al.

Synthetic progestins and respiration

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There is no evidence in our data to indicate changes in airway resistance or in lung compliance. Those patients having previous respiratory ailments developed no particular problems, nor did these patients deviate from the general pattern. We found no evidence of an asthmogenic effect brought on by the contraceptives, as has been implicated by certain studies. 14 We also did not observe an increase in V02 at rest lO or during exercise in this study.

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Figure 4 Oxygen uptake as a function of increasing levels of exercise. Plot represents mean values at each workload. Prior to ANCOV A, individual values were corrected for current body weight and body surface area. Open circles represent control test period; squares, 3 months on OCs; and closed circles, 6 months on OCs. ANCOVA for the slopes: P > 0.5.

as chronic hypoxia and temperature. Whether increasing VT or breathing frequency is the cause of the observed increase in VE during exercise could not be determined because simultaneous spirometric measurements were not made during the exercise session. It has been established that steroids easily traverse the blood-brain barrier,12, 13 and the cellular site of action of progestins is, in the view of several investigators,g, 11 located in the central nervous system, rather than in peripheral receptors. It is conceivable that progestins increase VE via a pathway that effects VT without significant alterations of breathing frequency.

Vol. 39, No.4, April 1983

1. England SJ, Farhi LE: Fluctuations in alveolar CO 2 and in base excess during the menstrual cycle. Respir Physiol 26:157, 1976 2. Prowse CM, Gaensler EA: Respiration and acid base changes during pregnancy. Anesthesiology 26:381, 1965 3. Hellegers A, Metcalfe J, Huckabee WE, Prystowsky H, Meschia G, Barron DH: Alveolar P eo2 and P 02 in pregnant and nonpregnant women at high altitude. Am J Obstet Gynecol 82:241, 1961 4. Lim VS, Katz AI, Lindheimer M: Acid-base regulation in pregnancy. Am J Physiol 231:1764, 1976 5. Lyons HA, Huang CT: Therapeutic use of progesterone in alveolar hypoventilation associated with obesity. Am J Med 44:881, 1968 6. Goodland RL, Reynolds JG, McCoord AB, Pommerenke WT: Respiratory and electrolyte effects induced by estrogen and progesterone. Fertil Steril 4:300, 1953 7. Freedman SH, Anderson NE: Spirometry and oral contraceptives. Am J Obstet Gynecol 116:682, 1973 8. EI Heneidy AR, Gemei Y, Abdel-Latif AE, Toppozada HK: Effect of an oral contraceptive on the pulmonary functions. Contraception 14:137, 1976 9. Skatrud JB, Dempsey JA, Kaiser DG: Ventilatory response to medroxy-progesterone acetate in normal subjects: time course and mechanism. J Appl Physiol 44:939, 1978 10. Milne JA, Pack AI, Coutts JRT: Gas exchange and acid base status during the normal human menstrual cycle and in subjects taking oral contraceptives. J Endocrinol (Abstr) 75:17,1977 11. Mei S, Gort D, Kao F: The investigation of respiratory effects of progesterone in cross-circulating dogs. Fed Proc (Abstr) 36:488, 1977 12. Lurie AO, Weiss JB: Progesterone in cerebrospinal fluid during pregnancy. Nature 215:1178, 1967 13. Backstrom T, Caistensenand H, Sodergard A: Concentration of estradiol, testosterone, and progesterone in cerebrospinal fluid compared to plasma unbound and total concentration. J Steroid Biochem 7:469, 1976 14. Horan JD, Lederman JJ: Possible asthmogenic effect of oral contraceptives (Letter). Can Med Assoc J 99:55, 1968

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