- Email: [email protected]
Regulation of the 24-hour rhythm of body temperature in menstrual cycles with spontaneous and gonadotropin-induced ovulation
FERTILITY AND STERILI~
Vol. 68, No. 3, September 1997
Copyright ’ 1997 American Society for Reproductive Medicine
Printed
on acid-free
paper
in U. S. A.
Published by Elsevier Science Inc.
Regulation of the 24hour rhythm of body temperature in menstrual cycles with spontaneous and gonadotropin-induced ovulation
Angelo Cagnacci, M.D.* Annibale Volpe, M.D.* Anna Maria Paoletti, M.D.* Gian Benedetto Melis, M.D.$ Institute of Pathophysiology and Pathophysiology
of Human Reproduction,
of Human Reproduction,
University of Modena, Modena, and Institute of Obstetrics,
Gynecology
University of Cagliari, Cagliari, Italy
Objective: To investigate the relation between gonadal steroids and the 24-hour body temperature rhythm.
Patient(s): Nineteen normally cycling women. Design: Controlled clinical study in volunteer women. Setting: Clinical hospital. Intervention(s): Eleven women were studied in the early follicular
and luteal menstrual phases of cycles with spontaneous ovulation, and 8 women were studied in the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development. Main Outcome Measure(s): Starting at 5:OO P.M., intravaginal body temperature was monitored continuously for 24 hours and its values were related to Ez and P levels. Result(s): Twenty-four-hour body temperature rhythm parameters were related to the P:E2 ratio. Very low P:Ez ratios in the preovulatory phase were associated with a reduced 24-hour mean and an elevated body temperature rhythm amplitude. The progressive increase in the P:E2 ratio in the early follicular and luteal phases was associated with an increase in the 24hour mean body temperature and a decrease in the rhythm amplitude. Body temperature differences between the luteal and early follicular phases were less pronounced in cycles with multiple follicular development. Conclusion(s): A woman’s body temperature is related to her P:E2 ratio. Even in the presence of elevated P values, alterations of this ratio may influence negatively the postovulatory rise in body temperature. (Fertil Sterilm 1997;68:421-5. 0 1997 by American Society for Reproductive Medicine.)
Key Words: Body temperature, circadian rhythms, estrogen, progesterone, strual cycle, multiple follicular development, reproduction
In young women, core body temperature shows a 24-hour rhythm, with a 0.8” to 1.0% oscillation between the maximum at day and the minimum at night (1). This 24-hour variation is believed to be the reflection of a central pacemaker localized in hypoReceived February 20, 1997; revised and accepted May 21, 1997. Supported by University of Modena grant 3.7.1, Modena, Italy. * Institute of Pathophysiology of Human Reproduction, University of Modena. t Reprint requests: Angelo Cagnacci, M.D., Istituto di Fisiopatologia della Riproduzione Umana, via de1 Pozzo 71, 41100, Modena, Italy (FAX: 39-59-424394). $ Institute of Obstetrics, Gynecology and Pathophysiology of Human Reproduction, University of Cagliari. 0015-0282/97/$17.00 PI1 s0015-0282(97)00242-2
ovulation,
men-
thalamic suprachiasmatic nuclei and is one of the most powerful indices of circadian rhythmicity (2-5). Besides circadian influences, women’s body temperature is modulated profoundly by menstrual cyclicity. Body temperature decreases in the preovulatory phase, along with elevation in the Ez level, and increases in the luteal phase, along with postovulatory elevation in the P level (6-13). How steroids may influence the expression of the circadian body temperature rhythm is not completely clear. Completely unknown is whether the preovulatory decline in body temperature is restricted to the morning hours or extended to the entire 24-hour period. Further, although several reports (14, 15) have defined 421
the 24-hour expression of the postovulatory rise in body temperature, it is not clear why this increase is not always detectable. It is known that in the luteal phase, the 24-hour mean body temperature is higher than in the early follicular phase, but that this difference is maximal at night and minimal during the day (14, 15). Accordingly, variations in the time of body temperature measurement may lead to inconsistent detection of the postovulatory rise in body temperature (16-21). On the other hand, the rise in body temperature always has been correlated with the rise in the P level, but its relation to the E2 level never has been considered, although Ez, by exerting a hypothermic effect, may have antagonized the body temperature rise of the luteal phase. To gain further insight into the influences exerted by gonadal steroids on body temperature regulation, we attempted to investigate in this study whether throughout the menstrual cycle any clear relation links P and Ez values to variations in the 24-hour body temperature rhythm. Given the marked modifications of the endocrine environment in cycles with multiple follicular development, body temperature modifications observed in these cycles were compared with those in cycles with spontaneous ovulation. MATERIALS AND lblF?lXODS
Nineteen healthy, young, normally cycling women, with a mean age of 28 to 35 years, gave their informed consent to participate in the study. The study, previously approved by the local ethics committee and the institutional review board, was conducted according to the guidelines of the Helsinki Declaration. Subjects were entrained normally to environmental photoperiod, were free from medications, and were within 15% of their ideal body weight. They were recruited from a population of normally cycling women with subfertile patterns. The presence of normal ovulatory cycles of 28 -C2 days (mean + SD) was documented by ultrasound (US) and by hormonal monitoring of previous cycles. Eleven women were studied during a cycle of spontaneous ovulation, both in the early follicular menstrual phase (days 4 to 6 after the onset of menses> and in the luteal menstrual phase (days 5 to 9 after the estimated ovulation). The other eight women were studied during a cycle of multiple follicular development performed for IUI (22). In this case, subjects were studied in the early follicular phase (days 4 to 6 after the onset of menses), in the preovulatory phase (when the Ez level was between 250 and 400 pg/mL; conversion factor to SI unit, 3.671), and in the luteal phase (days 5 to 422
Cagnacci
et al.
Ovarian
steroids
and body temperature
9 after the estimated ovulation). Multiple follicular development was induced with FSH injections (Metrodin; Serono, Rome, Italy). Four ampules of purified FSH (containing 75 IU of FSH in each ampule) were administered from day 8 onward. The plasma Ez level was assayed every day and pelvic US was performed every other day; the dosage of FSH was adjusted according to these parameters. The administration of FSH was curtailed when the Ez level reached 600 to 1,500 pg/mL and US showed at least two leading follicles of 18 mm (300 pg/mL for each follicle). The urinary LH level was assayed daily to rule out a spontaneous LH peak. Human chorionic gonadotropin (Profasi; Serono) was injected IM at a dose of 10,000 IU, 30 to 36 hours after the last FSH injection. After an accommodation night, on the day of investigation, each subject was admitted at the hospital at 1:00 P.M. A thermistor probe (YSI 44913; Yellow Springs Instrument Co., Inc., Yellow Springs, OH) was inserted deeply into the vagina, and the patient was restricted to bed rest. Body temperature was recorded every 5 minutes for 24 hours, from 5:00 P.M. the first day to 5:00 P.M. the next day, by a MiniLogger device (Mini-Metter Co., Inc. Sunriver, OR). During the study period, subjects were kept at bed rest with a constant ambient temperature of 20” to 21°C and a light intensity at the bed level of
In cycles with multiple follicular development, the P levels of the early follicular phase (745 ? 136 Fertility
and Sterility@
pg/mL; conversion factor to SI unit, 3.180) were significantly lower (P < 0.01) than those of the preovulatory phase (1,091 k 323 pg/mL) and the luteal phase (42,910 t 7,845 pg/mL). Similarly, the Ez levels of the early follicular phase (42 + 17 pg/mL) were significantly lower (P < 0.01) than those of the preovulatory phase (677 + 159 pg/mL) and the luteal phase (790 2 195 pg/mL). The P:E2 ratio of the early follicular phase (17.7 2 5.9) was significantly higher (P < 0.01) than that of the preovulatory phase (1.5 + 0.3) and lower than that of the luteal phase (48.7 f 10.8). In comparison with early follicular phase, in the luteal phase of cycles with spontaneous ovulation, significantly higher levels of P (8,044 2 1,888 versus 448 + 87 pg/mL, respectively; P < O.Ol), E2 (139 + 18 versus 58 + 24 pg/mL, respectively) and P:Ez (60.9 2 12.8 versus 14.0 t 4.1) were observed. The E2 and P levels of cycles with spontaneous ovulation were similar to those of cycles with multiple follicular development in the early follicular phase, but significantly lower (P < 0.01) in the luteal phase. Stepwise regression analysis showed that only the P:Ez ratio, and not the P or Ez level alone, was related to body temperature values. The relation of the P:E2 ratio was direct with the 24-hour mean body temperature (y = -0.000057x2 + 0.01x + 36.99; r = 0.713, P < 0.0001) and inverse with the body temperature rhythm amplitude (y = 0.00003x2 -0.005x + 0.41; r = 0.532, P < 0.002) (Fig. 1). No significant relation was observed between P, E2, or P:E2 and the time of the 24-hour body temperature rhythm maximum. In cycles with multiple follicular development, the 24-hour mean body temperature of the early follicular phase (37.14” + O.OSV decreased significantly (P < 0.02) in the preovulatory phase (36.95” t 0.14’0 and increased significantly (P < 0.05) in the luteal phase (37.24” k O.OS°C>.The amplitude of the rhythm of the early follicular phase (0.37” -f O.OS’C>did not vary in the preovulatory phase (0.40” + 0.03”C) or in the luteal phase (0.318” 2 0.035”C). Similarly, the time of the maximum body temperature rhythm of the early follicular phase (3:52 P.M. + 26 minutes) was not modified significantly in the preovulatory phase (3:48 P.M. -+ 8 minutes) or the luteal phase (4:30 P.M. -+ 27 minutes) (Fig. 2). In comparison with the early follicular phase, in the luteal phase of cycles with spontaneous ovulation, the 24-hour mean body temperature increased (37.08” 2 0.05” versus 37.34” + O.O6”C,respectively; P < O.Ol), the body temperature rhythm amplitude decreased (0.360” + 0.03” versus 0.247” + O.O3”C, respectively; P < 0.02), and the time of the 24-hour body temperature rhythm maximum was delayed Vol. 68, No. 3, September 1997
=. r
369.
3
366.
0.
367" E E
366.
1 Regression analysis between the P:E2 ratio and the 24-hour mean body temperature (top) or the 24-hour body temperature rhythm amplitude (bottom) measured in 8 normally cycling women during the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development and in 11 women during the early follicular and luteal phases of cycles with spontaneous ovulation. Figure
significantly (3:28 P.M. + 18 minutes versus 4:44 P.M. + 29 minutes, respectively; P < 0.05) (Fig. 2). In comparison with cycles with spontaneous ovulation, in the luteal phase of cycles with multiple follicular development, the 24-hour mean body temperature was lower (P < 0.05) and the rhythm amplitude was higher (P < 0.05). Similarly, the increase in the 24-hour mean body temperature from the early follicular phase to the luteal phase was blunted in cycles with multiple follicular development (0.101’ + 0.03” versus 0.260” + O.O7”C,respectively; P < 0.05 by the Mann-Whitney U test). DISCUSSION The present study documents, in a great variety of endocrine situations, the capability of P to antagonize the effects of E2 on body temperature. Indeed, P increased 24-hour mean body temperature and blunted the rhythm amplitude. All these effects were dependent on the relative ratio of P:E2. For its short duration, the preovulatory decline in body temperature is difficult to detect and its circadian expression is difficult to document in cycles with spontaneous ovulation (17,18,20). Accordingly, we chose to evaluate the preovulatory 24-hour body temperature rhythm only in cycles with multiple folCagnacci
et al.
Ovarian
steroids
and body temperature
423
1
Spontaneous
36.4 I t
1700
I
I
I
I
0500 CLOCK HOURS
t
1700
Figure 2 Mean (&SE) core body temperature values evaluated for 24 hours in 8 normally cycling women during the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development (top) and in 11 women during the early follicular and luteal phases of cycles with spontaneous ovulation (bottom). EFP, early follicular phase; POP, preovulatory phase; LP, luteal phase.
licular development, in which the period of Ez level elevation is artificially prolonged. The study was conducted when Ez levels were slightly higher than or in the range of spontaneous preovulatory surges (171, and although P levels probably were slightly higher than those of spontaneous preovulatory phases, the P:E2 ratio was very low. The results indicate for the first time that in an environment with elevated E2 values, body temperature is shifted downward uniformly for the entire 24-hour period and oscillates around this lower mean value with an unaltered amplitude. The results obtained in cycles with spontaneous ovulation confirm previous data (14, 15) showing that body temperature not only increases after ovulation, but its 24-hour rhythm is blunted, mainly as the consequence of a reduced nocturnal decline in body temperature. In addition, body temperature increased in the luteal phase of cycles with multiple follicular development, although less dramatically than in cycles with spontaneous ovulation. The 24-hour body temperature rhythm amplitude was not reduced significantly and the time of the 24hour body temperature maximum was not delayed, as in the subset of women with spontaneous ovula424
Cagnacci et al.
Ovarian
steroids
and body temperature
tion. Accordingly, in the luteal phase of cycles with multiple follicular development, the 24-hour body temperature rhythm cannot be generalized completely to that of cycles with spontaneous ovulation. A body temperature P:E2 ratio of approximately 60 to 80 seems to be optimal for full expression of the 24-hour body temperature rhythm modifications of the luteal phase. Because the P:Ez ratios of the luteal phase were closer in cycles with spontaneous ovulation than in cycles with multiple follicular development to optimality, less impressive body temperature modifications were expected. The emerging evidence is that cycles with multiple follicular development may present less favorable body temperature conditions for reproductive processes. Whether the reported inconsistency of the postovulatory rise in body temperature in spontaneous ovulatory cycles is associated with alterations in the P:E2 ratio, and with a greater incidence of unexplained infertility, presently is under investigation. REFERENCES
1. Cagnacci A, Elliott JA, Yen SSC. Melatonin: a major regulator of the circadian rhythm of core temperature in humans. J Clin Endocrinol Metab 1992;75:447-52. 2. Aschoff J, Wever R. The circadian system of man. In: Aschoff J, editor. Handbook of behavioral neurobiology and biological rhythms. New York: Plenum Press, 1981:311-31. 3. Moore-Ede MC, Czeisler CA, Richardson GS. Circadian timekeeping in health and disease. Basic properties of circadian pacemakers. N Engl J Med 1983;309:469-76. 4. Wever RA. Light effects on human circadian rhythms: a review of recent Andechs experiments. J Biol Rhythms 1989;4: 161-85. 5. Czeisler CA, Kronauer RE, Allan JS, Duffy JF, Jewett ME, Brown EN, et al. Bright light induction of strong (type 0) resetting of the human circadian pacemaker. Science 1989; 244:1328-33. Halbrecth I. Ovarian function and body temperature. Lancet 1945;2:668-9. Israel SL, Schneller 0. The thermogenic property of progesterone. Fertil Steril 1950; 1:53-65. Marshall J. Thermal changes in the normal menstrual cycle. Br Med J 1963; 1:102-5. de Mouzon J, Testart J, Lefevre B, Pouly JL, Frydman R. Time relationships between basal body temperature and ovulation or plasma progestins. Fertil Steril 1984;41:254-9. 10. Yen SSC, Veka P, Rankin J, Little AB. Hormonal relationships during the menstrual cycle. J Am Med Assoc 1970;211: 1512-7. 11. Newill RGD, Katz M. The basal body temperature chart in artificial insemination by donor pregnancy cycles. Fertil Steril 1982;38:431-8. 12. McCarthy JJ, Rockette HE. A comparison of methods to interpret the basal body temperature graph. Fertil Steril 1983; 39:640-6. 13. Pillet MC, Wu TF, Adamson GD, Subak LL, Lamb EJ. Improved prediction of postovulatory day using temperature recording, endometrial biopsy, and serum progesterone. Fertil Steril 1990;53:614-9. 14. Lee KA, Circadian temperature rhythms in relation to menstrual cycle phase. J Biol Rhythms 1988;3:255-63. Fertility
and Sterility@
15. Cagnacci A, Soldani R, Laughlin GA, Yen SSC. Modification of circadian body temperature rhythm during the luteal menstrual phase: role of melatonin. J Appl Physiol 1996;80:259. 16. Johansson EDB, Larsson-Cohn U, Gemzell C. Monophasic basal body temperature in ovulatory menstrual cycles. Am J Obstet Gynecol 1972; 113:933-7. 17. Moghissi KS. Accuracy of basal body temperature for ovulation detection. Fertil Steril 1976;27:1415-21. 18. Hilgers TW, Bailey AJ. Natural family planning. II. Basal body temperature and estimated time of ovulation. Obstet Gynecol 1980;55:333-9. 19. Leader A, Wiseman D, Taylor PJ. The prediction of ovulation: a comparison of the basal body temperature graph, cervical
Vol. 68, No. 3, September 1997
mucus score, and real-time pelvic ultrasonography. Fertil Steril 1985;43:385-8. 20. Luciano AA, Peluso J, Kock El, Maier D, Kuslis S, Davison E. Temporal relationship and reliability of the clinical, hormonal, and ultrasonographic indices of ovulation in infertile women. Obstet Gynecol 1990;75:412-6. 21. Jordan J, Craig K, Clifton DK, Soules MR. Luteal phase defect: the sensitivity and specificity of diagnostic methods in common clinical use. Fertil Steril 1994,62:54-62. 22. Melis GB, Paoletti AM, Strigini F, Menchini Fabris F, Canale D, Fioretti P. Pharmacologic induction of multiple follicular development improves the success rate of artificial insemination with husband’s semen in couples with male-related or unexplained infertility. Fertil Steril 1987;47:441-5.
Cagnacci
et al.
Ovarian steroids and body temperature
425
Vol. 68, No. 3, September 1997
Copyright ’ 1997 American Society for Reproductive Medicine
Printed
on acid-free
paper
in U. S. A.
Published by Elsevier Science Inc.
Regulation of the 24hour rhythm of body temperature in menstrual cycles with spontaneous and gonadotropin-induced ovulation
Angelo Cagnacci, M.D.* Annibale Volpe, M.D.* Anna Maria Paoletti, M.D.* Gian Benedetto Melis, M.D.$ Institute of Pathophysiology and Pathophysiology
of Human Reproduction,
of Human Reproduction,
University of Modena, Modena, and Institute of Obstetrics,
Gynecology
University of Cagliari, Cagliari, Italy
Objective: To investigate the relation between gonadal steroids and the 24-hour body temperature rhythm.
Patient(s): Nineteen normally cycling women. Design: Controlled clinical study in volunteer women. Setting: Clinical hospital. Intervention(s): Eleven women were studied in the early follicular
and luteal menstrual phases of cycles with spontaneous ovulation, and 8 women were studied in the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development. Main Outcome Measure(s): Starting at 5:OO P.M., intravaginal body temperature was monitored continuously for 24 hours and its values were related to Ez and P levels. Result(s): Twenty-four-hour body temperature rhythm parameters were related to the P:E2 ratio. Very low P:Ez ratios in the preovulatory phase were associated with a reduced 24-hour mean and an elevated body temperature rhythm amplitude. The progressive increase in the P:E2 ratio in the early follicular and luteal phases was associated with an increase in the 24hour mean body temperature and a decrease in the rhythm amplitude. Body temperature differences between the luteal and early follicular phases were less pronounced in cycles with multiple follicular development. Conclusion(s): A woman’s body temperature is related to her P:E2 ratio. Even in the presence of elevated P values, alterations of this ratio may influence negatively the postovulatory rise in body temperature. (Fertil Sterilm 1997;68:421-5. 0 1997 by American Society for Reproductive Medicine.)
Key Words: Body temperature, circadian rhythms, estrogen, progesterone, strual cycle, multiple follicular development, reproduction
In young women, core body temperature shows a 24-hour rhythm, with a 0.8” to 1.0% oscillation between the maximum at day and the minimum at night (1). This 24-hour variation is believed to be the reflection of a central pacemaker localized in hypoReceived February 20, 1997; revised and accepted May 21, 1997. Supported by University of Modena grant 3.7.1, Modena, Italy. * Institute of Pathophysiology of Human Reproduction, University of Modena. t Reprint requests: Angelo Cagnacci, M.D., Istituto di Fisiopatologia della Riproduzione Umana, via de1 Pozzo 71, 41100, Modena, Italy (FAX: 39-59-424394). $ Institute of Obstetrics, Gynecology and Pathophysiology of Human Reproduction, University of Cagliari. 0015-0282/97/$17.00 PI1 s0015-0282(97)00242-2
ovulation,
men-
thalamic suprachiasmatic nuclei and is one of the most powerful indices of circadian rhythmicity (2-5). Besides circadian influences, women’s body temperature is modulated profoundly by menstrual cyclicity. Body temperature decreases in the preovulatory phase, along with elevation in the Ez level, and increases in the luteal phase, along with postovulatory elevation in the P level (6-13). How steroids may influence the expression of the circadian body temperature rhythm is not completely clear. Completely unknown is whether the preovulatory decline in body temperature is restricted to the morning hours or extended to the entire 24-hour period. Further, although several reports (14, 15) have defined 421
the 24-hour expression of the postovulatory rise in body temperature, it is not clear why this increase is not always detectable. It is known that in the luteal phase, the 24-hour mean body temperature is higher than in the early follicular phase, but that this difference is maximal at night and minimal during the day (14, 15). Accordingly, variations in the time of body temperature measurement may lead to inconsistent detection of the postovulatory rise in body temperature (16-21). On the other hand, the rise in body temperature always has been correlated with the rise in the P level, but its relation to the E2 level never has been considered, although Ez, by exerting a hypothermic effect, may have antagonized the body temperature rise of the luteal phase. To gain further insight into the influences exerted by gonadal steroids on body temperature regulation, we attempted to investigate in this study whether throughout the menstrual cycle any clear relation links P and Ez values to variations in the 24-hour body temperature rhythm. Given the marked modifications of the endocrine environment in cycles with multiple follicular development, body temperature modifications observed in these cycles were compared with those in cycles with spontaneous ovulation. MATERIALS AND lblF?lXODS
Nineteen healthy, young, normally cycling women, with a mean age of 28 to 35 years, gave their informed consent to participate in the study. The study, previously approved by the local ethics committee and the institutional review board, was conducted according to the guidelines of the Helsinki Declaration. Subjects were entrained normally to environmental photoperiod, were free from medications, and were within 15% of their ideal body weight. They were recruited from a population of normally cycling women with subfertile patterns. The presence of normal ovulatory cycles of 28 -C2 days (mean + SD) was documented by ultrasound (US) and by hormonal monitoring of previous cycles. Eleven women were studied during a cycle of spontaneous ovulation, both in the early follicular menstrual phase (days 4 to 6 after the onset of menses> and in the luteal menstrual phase (days 5 to 9 after the estimated ovulation). The other eight women were studied during a cycle of multiple follicular development performed for IUI (22). In this case, subjects were studied in the early follicular phase (days 4 to 6 after the onset of menses), in the preovulatory phase (when the Ez level was between 250 and 400 pg/mL; conversion factor to SI unit, 3.671), and in the luteal phase (days 5 to 422
Cagnacci
et al.
Ovarian
steroids
and body temperature
9 after the estimated ovulation). Multiple follicular development was induced with FSH injections (Metrodin; Serono, Rome, Italy). Four ampules of purified FSH (containing 75 IU of FSH in each ampule) were administered from day 8 onward. The plasma Ez level was assayed every day and pelvic US was performed every other day; the dosage of FSH was adjusted according to these parameters. The administration of FSH was curtailed when the Ez level reached 600 to 1,500 pg/mL and US showed at least two leading follicles of 18 mm (300 pg/mL for each follicle). The urinary LH level was assayed daily to rule out a spontaneous LH peak. Human chorionic gonadotropin (Profasi; Serono) was injected IM at a dose of 10,000 IU, 30 to 36 hours after the last FSH injection. After an accommodation night, on the day of investigation, each subject was admitted at the hospital at 1:00 P.M. A thermistor probe (YSI 44913; Yellow Springs Instrument Co., Inc., Yellow Springs, OH) was inserted deeply into the vagina, and the patient was restricted to bed rest. Body temperature was recorded every 5 minutes for 24 hours, from 5:00 P.M. the first day to 5:00 P.M. the next day, by a MiniLogger device (Mini-Metter Co., Inc. Sunriver, OR). During the study period, subjects were kept at bed rest with a constant ambient temperature of 20” to 21°C and a light intensity at the bed level of
In cycles with multiple follicular development, the P levels of the early follicular phase (745 ? 136 Fertility
and Sterility@
pg/mL; conversion factor to SI unit, 3.180) were significantly lower (P < 0.01) than those of the preovulatory phase (1,091 k 323 pg/mL) and the luteal phase (42,910 t 7,845 pg/mL). Similarly, the Ez levels of the early follicular phase (42 + 17 pg/mL) were significantly lower (P < 0.01) than those of the preovulatory phase (677 + 159 pg/mL) and the luteal phase (790 2 195 pg/mL). The P:E2 ratio of the early follicular phase (17.7 2 5.9) was significantly higher (P < 0.01) than that of the preovulatory phase (1.5 + 0.3) and lower than that of the luteal phase (48.7 f 10.8). In comparison with early follicular phase, in the luteal phase of cycles with spontaneous ovulation, significantly higher levels of P (8,044 2 1,888 versus 448 + 87 pg/mL, respectively; P < O.Ol), E2 (139 + 18 versus 58 + 24 pg/mL, respectively) and P:Ez (60.9 2 12.8 versus 14.0 t 4.1) were observed. The E2 and P levels of cycles with spontaneous ovulation were similar to those of cycles with multiple follicular development in the early follicular phase, but significantly lower (P < 0.01) in the luteal phase. Stepwise regression analysis showed that only the P:Ez ratio, and not the P or Ez level alone, was related to body temperature values. The relation of the P:E2 ratio was direct with the 24-hour mean body temperature (y = -0.000057x2 + 0.01x + 36.99; r = 0.713, P < 0.0001) and inverse with the body temperature rhythm amplitude (y = 0.00003x2 -0.005x + 0.41; r = 0.532, P < 0.002) (Fig. 1). No significant relation was observed between P, E2, or P:E2 and the time of the 24-hour body temperature rhythm maximum. In cycles with multiple follicular development, the 24-hour mean body temperature of the early follicular phase (37.14” + O.OSV decreased significantly (P < 0.02) in the preovulatory phase (36.95” t 0.14’0 and increased significantly (P < 0.05) in the luteal phase (37.24” k O.OS°C>.The amplitude of the rhythm of the early follicular phase (0.37” -f O.OS’C>did not vary in the preovulatory phase (0.40” + 0.03”C) or in the luteal phase (0.318” 2 0.035”C). Similarly, the time of the maximum body temperature rhythm of the early follicular phase (3:52 P.M. + 26 minutes) was not modified significantly in the preovulatory phase (3:48 P.M. -+ 8 minutes) or the luteal phase (4:30 P.M. -+ 27 minutes) (Fig. 2). In comparison with the early follicular phase, in the luteal phase of cycles with spontaneous ovulation, the 24-hour mean body temperature increased (37.08” 2 0.05” versus 37.34” + O.O6”C,respectively; P < O.Ol), the body temperature rhythm amplitude decreased (0.360” + 0.03” versus 0.247” + O.O3”C, respectively; P < 0.02), and the time of the 24-hour body temperature rhythm maximum was delayed Vol. 68, No. 3, September 1997
=. r
369.
3
366.
0.
367" E E
366.
1 Regression analysis between the P:E2 ratio and the 24-hour mean body temperature (top) or the 24-hour body temperature rhythm amplitude (bottom) measured in 8 normally cycling women during the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development and in 11 women during the early follicular and luteal phases of cycles with spontaneous ovulation. Figure
significantly (3:28 P.M. + 18 minutes versus 4:44 P.M. + 29 minutes, respectively; P < 0.05) (Fig. 2). In comparison with cycles with spontaneous ovulation, in the luteal phase of cycles with multiple follicular development, the 24-hour mean body temperature was lower (P < 0.05) and the rhythm amplitude was higher (P < 0.05). Similarly, the increase in the 24-hour mean body temperature from the early follicular phase to the luteal phase was blunted in cycles with multiple follicular development (0.101’ + 0.03” versus 0.260” + O.O7”C,respectively; P < 0.05 by the Mann-Whitney U test). DISCUSSION The present study documents, in a great variety of endocrine situations, the capability of P to antagonize the effects of E2 on body temperature. Indeed, P increased 24-hour mean body temperature and blunted the rhythm amplitude. All these effects were dependent on the relative ratio of P:E2. For its short duration, the preovulatory decline in body temperature is difficult to detect and its circadian expression is difficult to document in cycles with spontaneous ovulation (17,18,20). Accordingly, we chose to evaluate the preovulatory 24-hour body temperature rhythm only in cycles with multiple folCagnacci
et al.
Ovarian
steroids
and body temperature
423
1
Spontaneous
36.4 I t
1700
I
I
I
I
0500 CLOCK HOURS
t
1700
Figure 2 Mean (&SE) core body temperature values evaluated for 24 hours in 8 normally cycling women during the early follicular, preovulatory, and luteal phases of cycles with multiple follicular development (top) and in 11 women during the early follicular and luteal phases of cycles with spontaneous ovulation (bottom). EFP, early follicular phase; POP, preovulatory phase; LP, luteal phase.
licular development, in which the period of Ez level elevation is artificially prolonged. The study was conducted when Ez levels were slightly higher than or in the range of spontaneous preovulatory surges (171, and although P levels probably were slightly higher than those of spontaneous preovulatory phases, the P:E2 ratio was very low. The results indicate for the first time that in an environment with elevated E2 values, body temperature is shifted downward uniformly for the entire 24-hour period and oscillates around this lower mean value with an unaltered amplitude. The results obtained in cycles with spontaneous ovulation confirm previous data (14, 15) showing that body temperature not only increases after ovulation, but its 24-hour rhythm is blunted, mainly as the consequence of a reduced nocturnal decline in body temperature. In addition, body temperature increased in the luteal phase of cycles with multiple follicular development, although less dramatically than in cycles with spontaneous ovulation. The 24-hour body temperature rhythm amplitude was not reduced significantly and the time of the 24hour body temperature maximum was not delayed, as in the subset of women with spontaneous ovula424
Cagnacci et al.
Ovarian
steroids
and body temperature
tion. Accordingly, in the luteal phase of cycles with multiple follicular development, the 24-hour body temperature rhythm cannot be generalized completely to that of cycles with spontaneous ovulation. A body temperature P:E2 ratio of approximately 60 to 80 seems to be optimal for full expression of the 24-hour body temperature rhythm modifications of the luteal phase. Because the P:Ez ratios of the luteal phase were closer in cycles with spontaneous ovulation than in cycles with multiple follicular development to optimality, less impressive body temperature modifications were expected. The emerging evidence is that cycles with multiple follicular development may present less favorable body temperature conditions for reproductive processes. Whether the reported inconsistency of the postovulatory rise in body temperature in spontaneous ovulatory cycles is associated with alterations in the P:E2 ratio, and with a greater incidence of unexplained infertility, presently is under investigation. REFERENCES
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