Cyli Flutuations of the Alveolar Carbon Dioxide Tension during the Normal Menstrual Cyle Ruth L. Goodland, M.S., and W. T. Pommerenke, Ph.D., M.D. THE SHORT spa~ of funtional life of the unfertilized human egg makes it important, partiularly in those instanes of redued fertility when it is desirable to apitalize on the most propitious time for insemination, to know when ovulation ours. While the reovery of an egg from the tube or uterus or the appearane of a reently ruptured follile in the ovary offers proof of ovulation, from a pratial standpoint suh positive evidene of ovulation is of little value in alulating the exat time the ourrene will be repeated in the next menstrual yle. Thus, while onealed from view, the extrusion of the egg from the ovary is nevertheless assoiated with ertain biologi phenomena whih appear to bear suh a lose, if not ausal, relationship that these phenomena have ome to be regarded by many as true signs of ovulation. Among these ommonly employed riteria of ovulation may be mentioned ovulatory pain or mittelshmerz, hanges in the endometrial histology and vaginal ytology, and hanges in the quantity and appearane of the ervial muus. Most of these hanges appear to be under estrogeni and progesteronal ontrol. As early as 1904 Van de Velde orrelated basal body temperature hanges From the Department of Obstetris and Gyneology, The University of Rohester Shool of Mediine and Dentistry, Rohester, New York. Aided by a grant from the Ortho Researh Foundation, Raritan, New Jersey. The authors wish to express their appreiation to Dr. Hermann Rahn for his valued ounsel and for making available to us the speialized apparatus used in these experiments, and also to Mary Alie B. Brekenridge who onduted numerous preliminary experimental runs. 394
Vol. 3, No. 5, 1952] CARBON DIOXIDE TENSION 395 with different phases of the menstrual yle. Van de Velde's disovery was that the basal temperature of a woman flutuates over a low range after menstruation until the approximate time of mid-yle, when the temperature rises to a higher level, around whih it flutuates until the time of a subsequent menstrual period. Frequently the rise in temperature is immediately preeded by a short dip below the preeding level. Although a number of papers have regarded this biphasi temperature pattern as a riterion of ovulation, it seems impratial to designate with pinpoint auray the time of ovulation on the basis of temperature gradients, partiularly when the routine readings are of neessity taken under onditions of everyday living by the patient herself initially on awakening in the morning. Thus, Tompkins thought that the drop in temperature before the rise marks ovulation, while others believe that ovulation ours during the atual rise in temperature. 3 4 Buxton and Engle maintain that the mid-yle temperature rise may produe an error of as muh as four days in determining ovulation time. With the results presented herewith, we have eleted not to designate a speifi day for ovulation but rather an.. ovulatory phase" over whih days the basal body temperature shifts from a low to a higher level. This temperature elevation in the postovulatory phase is believed to be orrelated with progesterone, or with the ratio of progesterone to estrogen ativity. This is suggested by studies on men/ 2 post-menopausal women,11 women exhibiting seondary amenorrhea/ and normal, ovulating women. 7 Rubenstein has shown that a lose orrelation exists between temperature urves and the basal metaboli rates during different phases of the menstrual yle. Whatever the basi physiologi ausation, the inrease in. body temperature may orrelate with a hange in alveolar respiration. In 1929 Griffith et al. observed hanges in the alveolar C02 pressure in women and orrelated these hanges with phases of the monthly yle. The alveolar C02 was found to be lowest just preeding the onset of menstruation and then to rise, reahing a maximum in the seond or third week afterwards. Doring and Loeshke 5 in 1947 reported that alveolar pc02 is lowered during the luteal phase of the menstrual yle, and Loeshke10 further showed that a yli pattern evolved. The present study was undertaken to investigate in some detail the hanges in the C02 tensions of the alveolar air in women during the different phases of the menstrual yle, orrelating these with the hanges in basal body temperature as a riterion of ovulation.
396 GOODLAND & POMMERENKE [Fertility & Sterility EXPERIMENTAL PROCEDURES Subjets Nine young women ranging in age from 20 to 28 years served as subjets. They were employed as seretaries, tehniians, or nurses in the hospital adjaent to the laboratory. All of these women were healthy, had normal menstrual yles, and were believed to be ovulating. Eah subjet was hosen on the basis of biphasi oral basal temperature harts whih had been kept for 1 to 3 months. Eah ontinued to keep the basal temperature harts throughout the experimental period. One of the subjets ( L. B. ) ontinued taking 0.5 gr. of thyroid gland U.S.P. daily beause of a very mild hypothyroidism. None of the other subjets reeived hormone mediation. Method Alveolar air was olleted without interruption during normal breathing by means of a fae mask aording to the method of Rahn and Otis 14 and ontinuously analyzed using the Cambridge C02 Analyser. 13 The advantage of this method lies in the fat that it provides a ontinuous reord of the C02 onentration and enables one to determine when this value has attained a steady state. The mahine was alibrated before eah use with a gas mixture ontaining a known perentage of C02. Determinations were performed on the subjets, usually in the morning, two and one-quarter hours or more after their last food onsumption. Three or four preliminary runs were made on eah subjet to aquaint her with the proedure and to austom her to the fae mask before the test determinations. All subjets were enouraged to relax to allow them to ome to a steady, resting state before analyses were instituted. Readings were taken at one-minute intervals until five onseutive figures agreed to within 0.15 per ent C02. Per ent C02 was then onverted to C02 pressure [ «}'o C02 X (Barometri Pressure - 47) = pc02], orresponding to mm. Hg. Water vapor pressure is equivalent to 47mm. Hg. While the analyses were usually made on alternate days, oasionally daily determinations were performed. Determinations on eah subjet were made at the same time of day for at least one omplete yle, and 1 subjet was followed through four onseutive yles. In all, sixteen yles of 9 subjets were studied.
Vol. 3, No. 5, 1952] CARBON DIOXIDE TENSION 397 RESULTS Figures 1 to 4 present basal temperature and alveolar pc02 patterns exhibited by the 9 subjets. Single yles from 4 subjets are shown in Fig. 1. Two onseutive yles from 4 others may be seen in Figs. 2 and 3, while Fig. 4 presents four onseutive yles from 1 subjet. All of the subjets in eah of their yles exhibited a definite overall pattern. This pattern shows a postmenstrual rise in alveolar C02 whih is maintained until the ovulatory or luteal phase of the yle. The C02 level then :: ~SUBJECT P.E. ::.T H./vl 1"\ pc0 2 34 -..._... V ~ 32 40 38 36 pc02 34 32 INTERVALS- 5 DAYS Fig. I. Basal temperatures and alveolar C0 2 pressures from 4 subjets. Eah pattern inludes one omplete menstrual yle. The solid bar indiates days of menstruation, and the ~o~ indiates the ovulatory phase. Note that the pc0 2 level diminishes after the ovulatory phase. falls and reahes its lowest level before the onset of menstruation. Most individual yles do not exhibit this pattern as a smooth, unbroken urve, but show day-to-day flutuations. As has been stated, the determinations were performed with the subjets in a resting state whih was steady, but not basal. Were it possible to indue a true basal state, it is believed that these minor waves would have been largely eliminated. The average differene between the individual high levels and low levels of alveolar pc02 is 5.4 mm. Hg. A small inrease and subsequent derease in alveolar C02 seems to be present at about the beginning of the menstrual period. In some ases this
398 GOODLAND & POMMERENKE [Fertility & Sterility 41 39 37 pcoz 35 33 SUBJECT A.G. 41 39 37 pco 35 2 33 INTERVALS- 5 DAYS Fig. 2. Basal temperature and alveolar C0 2 pressures from 2 subjets. Eah pattern inludes two omplete and onseutive menstrual yles. The solid bar indiates days of menstruation and the ~o--+ indiates the ovulatory phase. Note that the overall pattern of yli hange in alveolar pc0 2 level is reprodued in all yles. 37 SUBJECT C.P. pc02 35 33 29 27 40 38 36 pc02 34 SUBJECT L.B. 32 INTERVALS- 5DAYS Fig. 3. Basal temperatures and alveolar C0 2 pressures during two onseutive menstrual yles of 2 subjets. The solid bar indiates menstruation and the ~o--+ denotes the ovulatory phase. In the seond yle of subjet C.P., two temperature points have been noted by an 0. These two points are depressed beause the subjet slept under old onditions. The alveolar pc0 2 patterns have again been reprodued, with a fall following the ovulatory phase.
Vol. 3, No. 5, 1952] CARBON DIOXIDE TENSION 399 appears to be a premenstrual rise, while in others the rise ours during early menstruation.. To test the validity of the postovulatory derease and the flutuation' around the menstrual period, an average urve was drawn from all the patterns presented. The values used orrespond to the time of the basal temperature shift through the end of menstruation. All patterns were adjusted to 19 days, the average length of time involved, and the alveolar C02 pres- 39 37 35 pc02 33 37.0 36.5 36.0 SUBJECT G.T. -----~ -MAY JUNE JULY 39 37 pco 35 2 33 INTERVALS- 5 DAYS Fig. 4. Basal temperatures and alveolar C0 2 pressures from 1 subjet for four onseutive menstrual yles. The solid bar indiates menstruation and the... 0-+ indiates the ovulatory phase. The dotted line in the alveolar pc0 2 pattern toward the end of the first menstrual yle indiates a span during whih determinations were not performed. This figure shows the onstant reproduibility of the pattern in an ovulating subjet. sures were then averaged. Figure 5 shows this day-to-day average urve. The postovulatory derease has proved to be statistially signifiant, with a probability of less than 0.002. Further studies will have to be undertaken to determine the signifiane of seondary flutuations. DISCUSSION As is illustrated in Figs. 1 to 4, the alveolar pc02 patterns are yli in harater and are reproduible from month to month and from subjet to subjet in normal, ovulating women. The variations in the general pattern,
400 GOODLAND & POMMERENKE [fertility & Sterility i.e., small waves whih may be seen at times, are believed to be due to individual variations relating to the quality of the resting state of the subjet. Some of the temperature harts are not ideally adapted for hoosing the exat ovulatory phase. The authors, however, believe that ovulation ourred in all ases and have attempted to selet the phase on the basis of yle length and previously determined ovulatory periods as well as on the basis of the temperature shift. The degree of the postovulatory suppression of alveolar pc02 varies. It is postulated that this derease is aused by the elaboration of progesterone from the orpus luteum,5 6 9 10 and it seems probable that the extent of the 37 36 35 pc02 34 33 32 Fig. 5. Average alveolar C0 2 pressures from sixteen yles of 9 subjets taken from the time of the basal temperature shift through the end of the next menstrual period. Eah span of time has been saled to an average length of 19 days. The solid bar indiates the average menstrual period and the ~o~ denotes the ovulatory phase. The vertial lines show ± one standard error. The major deline in alveolar pc02 is regarded as being statistially signifiant. derease, at least in part, may be ontrolled by the quantities of progesterone metabolized. Loeshke, from his experiments, onluded that there were three alveolar pc02 flutuations determinable during the menstrual yle. Our laboratory was unable to identify three distint and onstant flutuations in eah subjet. The assumptions may be made that the alveolar pc02 is equivalent to the arterial pc02, and also that hanges in the alveolar C02 tension may reflet a primary respiratory alkalosis or ompensation for a metaboli aidosis. If the reprodutive hormones at diretly on the respiratory system to ause hyperventilation as Doring et al. suggest, 6 a dereased pc02 ould lead to an inrease in blood ph with a subsequent derease in alkali reserve. The above workers atually found these hanges but regarded them as being too slight for statistial signifiane. This laboratory hose
Vol. 3, No. 5, 1952] CARBON DIOXIDE TENSION 401 another method of studying the problem, that of diret measurement of Na+, K+, Cl-, and Ca++ in the blood during the menstrual yle. Results of this study onstitute the body of another ommuniation. SUMMARY The respiration of 9 young women with normal menstrual yles was analyzed for alveolar pc02 ontent throughout a total of sixteen yles. It was found that the alveolar pc02 varies within a definite yli pattern. At the beginning of and after menstruation, the C02 inreases until the ovulatory phase of the yle. This is followed by a derease whih is sustained until the next menstrual period. It is suggested that these hanges in alveolar pc02 reflet the end results of rhythmi estrogen and progesterone ativity. REFERENCES 1. BuXTON, C. L., and ATKINSON, W. B. ]. Clin. Endorinol. 8:544, 1948. 2. BuxTON, C. L., and ENGLE, E. T. Am. ]. Obst. & Gyne. 60:539, 1950. 3; DAVIS, M. E. ].A.M.A. 130:929, 1946. 4. DAvis, M. E., and FuGo, N. W. /. Clin. Endorinol. 8:550, 1948. 5. DoRING, G. K., and LoESCHCKE, H. H. Arh. ges. Physiol. 249:437, 1947. 6. DORING, G. K., LoESCHCKE, H. H., and 0CHWADT, B. Arh. ges. Physiol. 252:216, 1950. 7. FoRBES, T. R. Am.]. Obst. & Gyne. 60:180, 1950. 8. GRIFFITH, F. R., JR., PuHER, G. W., BROWNELL, K. A., KLEIN, J. D., and CARMER, M. E. Am. ]. Physiol. 89:449, 1929. 9. HEERHABER, I. Arh. ges. Physiol. 250:42, 1948. 10. LoESCHCKE, H. H. Arh. ges. Physiol. 252:301, 1950. 11. MAGALLON, D. T., and MASTERS, W. H. /. Clin. Endorinol. 10:511, 1950. 12. PERLMAN, R. M. ]. Gerontal. 5:26, 1950. 13. RAHN, H., MoHNEY, J., OTis, A. B., and FENN, W. 0. ]. Aviation Med. 17:173, 1946. 14. RAHN, H., and OTis, A. B. /. Appl. Physiol. 1:717, 1949. 15. RuBENSTEIN, B. B. Endorinology 22:41, 1938. 16. ToMPKINs, P. /.A.M.A. 124:698, 1944. 17. VAN DE VELDE, T. H. Uber den Zusammenhang zwishen Ovarialfunktion, Wellenbewegung und Menstrualblutung. Haarlem, F. Bohn, 1904. 18. VAN DE VELDE, T. H. Ideal Marriage. London, Heinemann, 1929.