Changes in physiological, eeg and psychological parameters in women during the spontaneous menstrual cycle and following oral contraceptives

psychoneuroendocrinoloKv.Vo[.7, No. I, pp. 75 90, 1982

0306 4530/82/010075 16$03.00/0 • 1982PergamonPressLtd.

Printed in Great Britain.

C H A N G E S IN P H Y S I O L O G I C A L , E E G A N D P S Y C H O L O G I C A L P A R A M E T E R S IN W O M E N D U R I N G T H E S P O N T A N E O U S MENSTRUAL CYCLE AND FOLLOWING ORAL CONTRACEPTIVES D. BECKER,* O. D. CREUTZFELDT, M. SCHWIBBE* and W. WUTTKE Max-Planck-lnstitute for Biophysical Chemistry, Department of Neurobiology, 34 G0ttingen-Nikolausberg, Am FaBberg, F.R.G.; and *Psychological Institute, University of Gottingen, F.R.G.

(Received 18 September 1980; in final form 23 October 1981) SUMMARY In a controlled cross-over design study performed with 14 female subjects, serum hormone levels, the EEG and a number of performance tests were recorded during spontaneous and oral contraceptive-controlled menstrual cycles. The mean alpha-frequency showed cyclic changes, i.e. slower alpha-waves during the follicular phase and faster alpha-waves during the luteal phase. Smaller cycle stage-dependent differences in the power of the theta- and beta-bands also were noted. An increase in several performance task scores was noted during the periovulatory period, whereas lowest performance scores were recorded during the late luteal and early menstrual phases. No such effects were observed in the same subjects while they were taking oral contraceptives. These results demonstrate that the gross electrical activity of the brain changes in a parallel with changed hormone levels. The changes in performance tests coincide with increasing or decreasing alpha activities in the EEG. The c o m m o n underlying mechanism may be an activation of central nervous system monoaminergic pathways which are known to be involved in steroid feedback.

INTRODUCTION CERTAIN

psychological parameters, such as mood, appetite, aggressive and sexual

behavior, and locomotor activity, change significantly during the course of the normal estrous cycle in animals as well as during the menstrual cycle in women (Colvin & Sawyer, 1969; Tarttelin & Gorski, 1973; Little & Zahn, 1974; Beyer, 1979). Few attempts, however, have been made to quantify the psychic changes in women. This only is possible when tests are used which allow repetitive application and which give accurate measures. In 1976 we reported the results of such an attempt which employed the use of a testbattery measuring flicker-fusion frequency, reaction times to different sensory stimuli, visual orientation, and motor performance tasks (Wuttke et al., 1975; 1976). In this study we reported cycle-dependent changes in a number of variables which were observed only in women with spontaneous menstrual changes and not in subjects under oral contraceptives (o.c.). The spontaneous EEG also revealed cycle-dependent changes which were most prominent in the range of the alpha-waves and which consisted of a shift from lower to higher alpha-frequencies during the iuteal phase of the menstrual cycle (Lamb et al., 1953; Creutzfeldt et al., 1976). No such changes were observed in women taking o.c. The group taking o.c. did have significantly reduced mean alpha-frequencies, but this was 75

76

D. BECKER, O. D. CREUTZFELDT,M. SCHWIBBE and W. WUTTKE

difficult to interpret, because selection effects could not be excluded. Furthermore, at that time we had little information about and experience with the stability of the psychological test battery in long-term experiments. Finally, the EEG data were analyzed using the clinically practiced division into four bands. By factor analysis, however, seven frequency bands can be defined as independent dimensions (Elmgren & LOwenhard, 1969; Hermant, et al., 1978; Becker & Schwibbe, 1980). For these reasons we decided to repeat the experiments (Wuttke et al., 1975; 1976; Creutzfeldt et al., 1976) under more carefully defined conditions. MATERIAL AND METHODS Fourteen female subjects (SS), ages 18 - 28 yr, participated in this study. They all had regular menstrual cycles ( 2 6 - 30 days) and were on no medication for at least three m o n t h s prior to the beginning of the experiments. Seven of the SS were on an oral contraceptive preparation (o.c., containing 0.05 mg ethinyl-oestradiol and 0.5 mg D-norgestrel) for one m o n t h prior to experimentation, and the other seven had spontaneous menstural cycles. All SS were investigated over one cycle. Upon completion of this first experimental phase, the SS with spontaneous cycles received the o.c., and the others waited for the resumption of their spontaneous cycles. Four to six weeks later they were investigated over another cycle. Each subject thus served as her own control.

Experimental procedure In the week prior to the beginning of the experiments, the SS completed all tests three times in order to become acquainted with the experimental procedure. The SS then were tested every other day except on Sundays. Each individual always was tested at the same time of day. The experimental protocol included withdrawal of 5 - 10 ml of venous blood for later hormone analysis; recording of the occipito-central (OzCz), left and right temporocentral ( T r C z, T,-Cz), and temporo-ear (O2A2) EEG for a period of 10 min; psychological testing in a separate room; and lastly completion of a mood questionnaire. Hormone analysis Serum levels o f LH, FSH, prolactin and progesterone were measured by radioimmunoassays as described elsewhere (Albert et al., 1968; Hwang et aL, 1971; D0hler & Wuttke, 1974; 1975). EEG The EEG was recorded on paper and tape under conventional conditions for 10 rain. The recordings were digitalized and power spectra-analysis was performed as described previously (Becker & Schwibbe, 1980). Individual power spectra of the SS at comparable stages of the menstrual cycle were averaged and provided the basis for further analyses. During this recording period the pulse rate (beats/rain) also was monitored. Psychological tests Testing was done with an automatic test battery consisting of 11 tests. These tests gave 25 main- and several subvariables. The tests, their application, and the resulting main variables are described below. Upon completion of this study it was realized that only 11 out of the 25 main variables proved to be of relevance. These variables are given in the results section, and their codes are given in parentheses following the description of the test. 1. Test for flicker fusion frequency (FFF) was administered five times, and the mean was calculated. Two versions of this test were applied: FFF upwards (FFF/UP) and FFF downwards. 2. Reaction tests (Wiener Reaktionsger/at and EPS-73). (a) Reaction (pressing of a lever) to a tone (WT). The mean and shortest reaction times ( W T / M I N ) and the number of wrong reactions ( W T / F S U M ) to a total of 27 tone-exposures were determined. (b) Selective reaction (pressing of a lever) to a given colour-tone sequence, interposed into 'wrong' colourtone sequences. In this test 18 relevant signals were applied and the same variables as described above were determined. The code for the number of wrong reactions is W C T / F S U M . (c) Reaction (pressing of a lever) to the change from a continuously exposed red light to a flickering light. The mean ( C R D 4 C / T S U M ) and shortest reaction time and the number of incorrect reactions in response to 60 trials were determined. 3. Motoric performance was evaluated in three tests ( S c h o p p e - M o t o r i s c h e Leistungsserie). (a) Tapping. The preferred individual and maximally possible tapping frequencies ( S T / P T and S T / M X , respectively) were recorded over two periods of 16 sec each.

EEG, PERFORMANCE AND MENSTRUAL CYCLE

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FIG. 1. Learning curve in the Pauli 1 test (calculation of little arithmetic problems = P I / N R ) over two investigation periods. Note the rapid improvement during the first 10 days. (b) Line-tracing. Tracing o f a crooked line cut into a metal plate. The time required to complete two trials ( S L / T S U M ) and the n u m b e r and duration of contacts with the bordering walls were recorded. (c) Pursuit rotor. An illuminated circulating spot had to be followed with a light-sensitive pen for two periods of 16 sec. The number of contact losses (errors = S P / F S U M ) and the error times were recorded. 4. Cognitive performance was evaluated in three tests (Pauli - Leistungspr0fger~t and EPS-73). (a) Calculation of simple arithmetic problems. Over a period of five rain, two simultaneously displayed one-digit numbers had to be added. The total number and the number of correct (P1/MR) additions were recorded. (b) Calculation of simple arithmetic problems, which includes the short-term memory. In this test, two one-digit s u m m a n d s had to be added, but they were exposed successively. After the subject pressed the lever with the result, a new s u m m a n d appeared which had to be added to the s u m m a n d displayed for the previous calculation. This test also was applied for five min, and the total number and the number of correct calculations ( P 2 / N A and P 2 / N R respectively) were determined. (c) Calculation of simple arithmetic problems involving s p a t i a l - v i s u a l orientation. Two one-digit numbers had to be found as coordinates of an illuminated spot within a coordinate system. Simultaneously, a + or - sign was displayed, indicating whether addition or subtraction was demanded. The lever with the result had to be pressed. In this test the mean time needed to complete 35 calculations (CRD1/MT), the shortest time to complete a given calculation ( C R D I / T M I N ) , and the number o f incorrect calculations (CRD1/FSUM) were recorded. Upon completion o f this test battery the SS had to fill out a questionnaire which evaluated different aspects of rrtood (Hampel, SES).

Trend analysis of performance data From previous experiments it was known that all the above-described variables are subject to learning effects. Since hormone or cycle effects were confounded with these effects, the learning trends had to be eliminated. Therefore, mean learning curves for eacla subject were determined over both experimental periods. For example, Fig. 1 shows that the mean learning curve for task 4a (solving of simple arithmetic problems) increased continuously during the first investigation month. It is of note that this learning curve continued during the second month, although these two periods were interrupted by four to six weeks. Similar calculations of trends were done for all variables and were used for correcting the original data.

Statistical treatment of data All data were lined up with the stage of the menstrual cycle. For this purpose, they were ordered around the two most prominent days of the cycle, i.e. the day of ovulation as determined by the L H peak ( = day 0) and the first day of menstruation ( = day 10). The data then were subjected to analysis of variance. Further analysis of all variables was done using a day-to-day comparison by the Wilcoxon test o f the EEG data and the psychological data. On the basis of the repeated measures design, hypotheses about cycledependent changes could be formulated and tested. Using the method o f linear contrasting, it was tested whether values of the dependent variables were significantly different between the follicular (days - 8 to 0) vs the luteal (days 2 to 10) phase, the follicular vs the menstrual (days 12, 14 and - 10) phase, and the luteal vs the menstrual phase. In addition, the same tests were applied for days of low (days - 10 to 0 and days 12 and 14) vs high (days

78

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FIG. 2. Serum LH, FSH and progesterone levels in SS with spontaneous menstrual cycles. Individual values were centered around the day of preovulatory LH release and around the first day of menstruation. Vertical lines in this and all subsequent figures indicate S.E.M. 2 to 10) levels of progesterone, LH (days - 10 to - 4 and days 2 to 14 vs days - 12 and 0), oestradiol (days - 10 to - 4 and 2, and 10 to 14 vs days - 2, 0 and 4 to 8) and basal body temperature (days - 10 to - 2 and 14 vs days 0 to 10). The resulting F-values were transformed to correlation coefficients (Keppel, 1973), which indicated the degree and direction of the differences. The following hypothesis was routinely tested: mean values of the dependent variables (i.e. EEG or psychological parameters) obtained during the first group of days were lower than mean values of second group of days. If this hypothesis were correct, the correlation coefficient would be positive, and vice versa.

RESULTS

Hormones and heart rate

Serum levels of LH, FSH and progesterone are shown in Fig. 2. The prominent midcycle LH and FSH surge was preceded by high oestradiol levels (not shown) and followed by elevated oestradiol and high progesterone values. In agreement with previous results (Wuttke et aL, 1976) serum prolactin levels (not shown) exhibited no cycle stagedependent fluctuations. The midcycle rise in LH and FSH and the high oestradiol and progesterone values were not detected in the SS ingesting the o.c. Following the LH peak, basal body temperature as measured sublingually was significantly increased compared to the preovulatory time (36.8 vs 36.4°C) a, d remained elevated until the immediate premenstrual period.

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PERFORMANCE AND MENSTRUAL CYCLE

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Mean heart rate in SS with spontaneous cycles and in the same SS under o.c. are shown in Fig. 3. Heart rate significantly increased prior to ovulation and reached maximal values on the day of preovulatory LH release (p < 0.01). Values remained high during the early luteal phase and decreased prior to menstruation. These changes were also statistically significant 07 < 0.01) and they were not observed under o.c. conditions. EEG Using the conventional division of the EEG into four bands, as done in our previous studies, analysis for changes of frequency shifts during the menstrual cycle revealed a drop in mean theta-frequencies (4 - 7.4 Hz band) during the luteal phase (Fig. 4). No such cycle-dependent changes were observed in the same SS under o.c. with the exception of one curiously high mean value on day 6. The mean theta-frequency under the two conditions, as calculated over the whole cycle length, did not differ significantly. A slight but significant rise from low values was noted in the alpha-frequency ( 7 . 8 - 1 4 . 1 Hz), prior to ovulation, and highest alpha-frequencies were recorded during the midluteal phase (Fig. 5). Again, such changes were not observed under o.c. conditions.

80

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FIG. 4. Mean theta-frequencies during spontaneous (sp. c.) and during o.c. (or.c.) cycles. Note the shift of higher to lower theta-frequencies during the periovulatory period and the reversed shift during the perimenstrual period. Means of both cycles are indicated by horizontal lines.

Interestingly, an extremely low mean value was found on day 6. The overall mean alphafrequencies under the two conditions were identical. No statistically significant or obvious cycle-dependent changes were observed in the beta-bands, and the overall means of the beta-frequencies under the two conditions did not differ. Upon completion of this analysis we became aware of several attempts to characterize the EEG on the basis of factor analysis (Elmgren & LOwenhard, 1969; Herrmann et al., 1978). At this time we had a total of 406 power spectra from each derivation of the EEG records of our previous and of this experimental series, and we decided to subject them to factor analysis. Principally, factor analysis resulted in similar solutions for each derivation. Figure 6 shows the factor loadings of the OzC z derivation, which is the relevant recording site for the data discussed in this report. Figure 6 also shows the borderlines of the frequency dimension of the OzC z record which were further analyzed. The loadings of the different EEG frequencies (0 - 30 Hz, A = 0.5 Hz) indicate that the EEG indeed can be separated into seven independently varying dimensions: the delta-factor ( 0 . 5 - 2.0 Hz), the theta-factor ( 2 . 5 - 6 Hz), three alpha-factors: alpha 0 ( 6 . 5 - 9 Hz), alpha 1 ( 9 . 5 - 10.5 Hz) and alpha 2 (11 - 13 Hz), and two beta-factors: beta 1 ( 1 3 . 5 - 22 Hz) and beta 2 ( 2 2 . 5 - 30 Hz). For each of these new frequency areas, mean power and frequency were calculated using EEG data which derived from the experiment during the spontaneous menstrual cycle. Table I details the magnitude and direction of the correlation of the dependent

EEG, PERFORMANCEAND MENSTRUAl CYCLE

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FIe;. 5. Mean alpha-frequencies during spontaneous (sp.c.) and during o.c. (or.c.) cycles. Note the shift from lower to higher frequencies during the late follicular and early luteal phases and a reverse shift during the

perimenstrual period. The mean frequency over the whole spontaneous cycle was identical to the mean frequencyunder o.c. and is indicatedby the horizontalline. variables (which resulted from the method of linear contrasting) with the different cycle stages and hormones, and the basal body temperature. The correlation coefficients in this table indicate that the theta-frequency is significantly higher during the menstrual phase (day 12, 14 and -10) than during the luteal phase (days 2-10). Also, an inverse correlation of the theta-frequency with progesterone levels and temperature was evident. The frequency of the alpha-0-factor was significantly higher during the follicular phase compared to the lower values during the perimenstrual phase, and the power of this alphafactor was higher during the follicular phase, at times of low progesterone levels, in comparison to the luteal phase with high progesterone levels. No statistically significant cycle stage, hormone or temperature-dependent frequency shifts were demonstrable in the other bands (alpha 1 and 2 and beta 1 and 2). The relatively good correlation of the alpha1-frequency with serum progesterone levels and temperature just failed to be statistically significant. Also, the drop of alpha-I power during the periovulatory phase (i.e. at the time of preovulatory LH release) is worth mentioning. Interestingly, the absolute power of the beta 1 and 2 bands was significantly higher during the follicular phase than during the luteal phase. Accordingly, the power of the beta bands was also significantly higher at times of low progesterone and low temperature levels, An attempt to demonstrate changes of any of the EEG parameters during the o.c. cycle failed to show differences between o.c. and o.c.-free conditions.

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EEG, PERFORMANCEAND MENSTRUAl CYCLE

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TABLE I. CORRELATION COEFFICIENTS OF FREQUENCIES ( F ) AND POWER ( P ) WITHIN THE DIFFERENT E E G BANDS WITH STAGES OF THE MENSTRUAL CYCLE, SERUM HORMONE LEVELS AND BODY TEMPERATURE

Independent variable EEG parameter

Foil. vs Lut. Foil. vs Mens. Lut. vs Mens.

F p F alpha 0 p F alpha 1 p F alpha 2 p F beta 1 p F beta 2 p

Theta

- 0.50* - 0.28 0.29 -0.59* + 0.44" -0.18 -0.27 + 0.22 - 0.29 -0.56* +0.08 -0.53*

+ 0.06 + 0.38 -0.56* +0.37 +0.38 -0.05 -0.25 + 0.39 - 0.43 ÷ +0.26 -0.13 -0.18

+ 0.54* + 0.32 +0.03 +0.49* -0.25 +0.27 +0.00 + 0.24 - 0.25 +0.70* -0.27 +0.51"

Prog. - 0.49* - 0.27 -0.12 -0.34 +0.42* -0.21 -0.15 + 0.02 - 0.17 -0.61" +0.18 -0.57*

Low vs high LH Oestr. - 0.23 + 0.09 -0.28 -0.09 +0.14 -0.49* -0.13 - 0.01 - 0.25 -0.11 -0.05 +0.09

- 0.37 - 0.27 +0.09 -0.25 +0.14 -0.37 -0.02 - 0.19 + 0.03 -0.34 +0.32 +0.02

Temp. - 0.54" 0.30 -0.42 ÷ -0.59* + 0.46" -0.33 -0.35 + 0.07 - 0.33 -0.66* +0.08 -0.59*

Foil. = follicular phase (day - 8 to 0); Lut. luteal phase (day 2 to 10); Mens = menstrual phase (day 12, 14 and - 10); Prog. = progesterone; LH = luteinizing hormone; Oestr. = oestradiol; Temp. = temperature. The table should be read as follows: upper left value ( - 0.50) indicates that the theta-frequency is higher during the follicular phase when compared to the luteal phase. Upper line, third value (+ 0.54) indicates the theta-frequency is higher during the menstrual phase when compared to the luteal phase. Upper line right value ( 0.54) indicates that body temperature is negatively correlated with theta-frequency; *indicates significant correlation (*p < 0.05; +p > 0.05 but < 0.10).

As indicated earlier, factor analysis of EEG-frequencies of the other three derivations (i.e. O2A_,, T , - C z, T4-Cz) g a v e s o l u t i o n s i d e n t i c a l t o t h e o n e f o r t h e O z C z r e c o r d . Furthermore, analysis of variance of the data obtained from these derivations revealed results similar to those described above. In summarizing the results from these two d i f f e r e n t E E G a n a l y s e s , it c a n b e s t a t e d t h a t t h e s h i f t f r o m l o w t o h i g h e r f r e q u e n c i e s in t h e a l p h a r a n g e (Fig. 5) w a s p r i m a r i l y d u e t o a n i n c r e a s e in t h e a l p h a 1 m e a n f r e q u e n c y concomitant

w i t h a r e d u c t i o n in t h e a l p h a 0 p o w e r .

Psychological tests Figures 7 and 8 show variations of seven test variables during the spontaneous and the o.c. cycles. T h e d o w n w a r d s d e f l e c t i o n a t d a y 0, i.e. t h e d a y o f p r e o v u l a t o r y L H r e l e a s e , i n d i c a t e s t h a t all f u n c t i o n s w e r e i m p r o v e d o n t h a t d a y . L e s s o b v i o u s b u t a l s o c o n s i s t e n t are the changes in the opposite direction prior to menstruation. No such changes could be o b s e r v e d d u r i n g t h e o . c . c o n t r o l l e d cycle. O f t h e m a i n t e s t v a r i a b l e s , 11 p r o v e d t o b e s i g n i f i c a n t l y c o r r e l a t e d w i t h t h e s t a g e o f t h e m e n s t r u a l cycle, w i t h h o r m o n e levels, o r w i t h t h e b o d y t e m p e r a t u r e . C o r r e l a t i o n c o e f f i c i e n t s r e s u l t i n g f r o m t h e a n a l y s i s o f v a r i a n c e a r e d e t a i l e d i n T a b l e II. T h e f l i c k e r f u s i o n f r e q u e n c y ( F F F / U P , see a l s o Fig. 7) w a s h i g h d u r i n g t h e t i m e o f p r e o v u l a t o r y L H r e l e a s e , as well as d u r i n g t h e m e n s t r u a l t i m e , a n d w a s l o w e s t , t h o u g h n o t s i g n i f i c a n t l y so, during the luteal phase. The number of errors made in reaction to a tone (WT/FSUM) was increased during the menstrual period, whereas the total time needed to trace a line

84

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(SL/TSUM) was significantly longer during this period compared to the follicular phase. Interestingly, the maximal tapping frequency (ST/MX) was highest, and the number of errors made while following the bright spot in the pursuit rotor test (SP/FSUM) was lowest, during the periovulatory time compared to times of low LH levels. The personally preferred tapping frequency (ST/PT) was lower during the menstrual phase compared to the follicular phase. The total number and the number of correctly calculated arithmetic tasks within a given time period (P2/NA and P2/NR) were increased during the time of preovulatory LH release. The number of correct calculations in the simple calculation test (PI/NR) varied in the same direction, but the best correlation coefficients were obtained under condition of elevated body temperature. In the calculation test, which involved a component of spatial-visual orientation, the total time needed to complete a given number of calculations (CRDI/MT) was shorter during the menstrual phase compared to the follicular phase. During the former period as well as during the luteal phase the SS calculated most accurately (CRD1/FSUM). It is notable that the most dramatic improvement in five out of I 1 main performance tasks was observed during preovulatory LH release• Similarly prominent changes, but with the opposite sign of the correlation coefficient, could be demonstrated during the menstrual phase•

EEG, PERI.ORMAN( I: AND MENSTRLA[

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-8

day from LH-peak FIG. 8. I r r e g u l a r c h a n g e s o f the s a m e seven v a r i a b l e s s h o w n in Fig. 7 d u r i n g the o . c . c o n t r o l l e d cycle.

In the Hampel questionnaire, three of the seven scales proved to be significantly related to hormone changes. During the time of high oestradiol levels the SS felt more tired but less depressed. High serum progesterone levels correlated significantly with elevated mood. Comparison of performance on the psychological test battery during the spontaneous cycle and during the o.c.-cycle resulted in some notable differences. In the calculation test, which involves a components of s p a t i a l - v i s u a l orientation (CRD1/MT), mean scores were lower, and the time needed to follow a crooked line (SL/TSUM) was shorter, during the spontaneous cycle in comparison to the o.c. cycle. The fact that the oral contraceptives contained 21 hormone and seven placebo pills made it possible to compare the variables under these two conditions. Withdrawal of the o.c., at the beginning of the o.c.-free interval, resulted in few significant changes (as tested by the method of linear contrasting) compared to the values obtained under o.c. The SS tapped with a significantly lower personally preferred frequency (ST/PT) while ingesting the o.c. The number of correctly solved arithmetic problems (P1/NR) was lower under o.c., whereas the sum of incorrectly calculated problems in the test which employed a v i s u a l - spatial component ( C R D I / F S U M ) was lower under o.c. compared to the o.c.-free interval. All other variables, even those which were significantly influenced by changes occurring during the spontaneous menstrual cycle, were not affected by the o.c.

86

D. BE(KbR, 0 . D. CR[UTZFEI DT, M. S(HW'IBBE and W. WLITTK[;

TABLE U. CORRELATION OF SOME VARIABLES OBTAINED IN THE PSYCHOLOGICAL TEST BATTERY WITH STAGES OF THE

MENSTRUAL CYCLE, SERUM HORMONE LEVELSAND BODYTEMPERATURE Independent variables Test variable

Foil. vs Lut. Foil. vs Mens. Lut. vs Mens.

FFFUP WTFSUM STPT STMX SLTSUM SPFSUM P 1NR P2NA P2NR CRDIMT CRDIFSUM

- 0.40" -0.11 -0.39 +0.12 +0.43 ÷ -0.07 + 0.24 -0.18 -0.08 -0.34 -0.54*

+0.15 +0.55* -0.54* -0.08 +0.53* +0.45 + - 0.22 -0.52* -0.39 -0.52* -0.48"

+0.57* +0.41 -0.07 +0.05 -0.26 +0.45 + - 0.43* -0.26 -0.17 -0.13 +0.43"

Prog. -0.46 + -0.33 -0.18 +0.06 +0.38 -0.19 + 0.39 -0.04 + 0.00 -0.23 -0.54*

Low vs high LH Oestr. +0.56* +0.22 +0.38 +0.68* -0.36 -0.52* + 0.26 +0.63* +0.53* +0.11 +0.27

+0.04 -0.21 +0.27 -0.11 -0.29 -0.42" + 0.24 +0.31 +0.29 +0.16 +0.02

Temp. -0.31 +0.04 -0.10 +0.43" +0.42" -0.27 + 0.54" +0.29 +0.31 -0.38 -0.26

flicker fusion frequency as measured from low to high frequencies sum of errors in reaction to a tone personally preferred tapping frequency maximal tapping frequency time needed to follow a crooked line sum of errors made while following a bright circulating spot number of correctly calculated little arithmetic problems total number (NA) of and number of correctly calculated (NR) problems. The results of the previous calculation had to be memorized = Total time (MT) needed to complete a given number of little arithmetic problems. The result had to be found in a coordinate system. FSUM is the number of incorrect = calculations *and *indicate significance (*p < 0.05; *p > 0.05 bnt < 0.10).

FFFUP WTFSUM STPT STMX SLTSUM SPFSUM P1NR P2NA P2NR } CRD1MT CRDIFSUM }

= = = = = = =

DISCUSSION

The present results confirm parts of our earlier studies (Wuttke et al., 1975; 1976; Creutzfeldt et al., 1976) and allow a deeper insight into some of the common psychoneuroendocrine interactions. The hormone data are consistent with many other reports; they only were determined to provide data for later statistical correlation with changes in the EEG and performances on the different psychological tests. Some well-known facts, as derived from animal experiments, concerning the neural part of the C N S - p i t u i t a r y - g o n a d a l axis should be mentioned. The so-called positive feedback action of oestradiol, which is responsible for preovulatory LH-release, is believed to involve activation of the noradrenergic system (Sawyer et al., 1947; Wuttke, 1976; Weiner & Ganong, 1978; Krulich, 1979; Honma & Wuttke, 1980). The perikarya of noradrenaline producing neurones are located primarily in the brain stem. The majority of estrogen receptive neurons, are located in the preoptic - septal complex of the hypothalamus and in the amygdala (Pfaff & Keiner, 1973; Stumpf & Grant, 1975). Much less is known about the distribution of progestin binding neurons. They are clearly present in the hypothalamus (Stumpf & Grant, 1975). Some midbrain structures also may be progesterone receptive (Morin & Feder, 1974). The preoptic, hypothalamic and limbic

EEG,

pERIORMAN('E AND MENNIRUAI C ' ~ ( I E

87

estrogen and progestin binding neurons are clearly associated with the negative and positive feedback functions of the gonadal steroids and with sexual behavior (Stumpf & Grant, 1975). The estrogen receptive noradrenergic neurons (Sar & Stumpf, 1980), however, appear to innervate large parts of the CNS; hence, they may be at least in part responsible for the observed changes in the EEG and psychological performance. Recording of the pulse rate and the basal body temperature provided physiological variables which are known to change during the menstrual cycle (Engel & Hildebrandt, 1969; Little & Zahn, 1974). Increased body temperature is known to be a function of elevated progesterone levels (Little et al., 1974). The heart rate appears to be influenced primarily by estrogens (Little & Zahn, 1974). In these previous reports, and in the present experiments, heart rate increased prior to ovulation, when estradiol levels were increasing but progesterone was still low. Little et al. (1974) came to similar conclusions when they demonstrated that progesterone administration to male SS had no effect on heart rate. The division of the EEG spectrum in one theta, three alpha and two beta bands, as revealed by factor analysis, agrees with earlier reports (Elmgren & LOwnhard, 1969; Herrmann et al., 1978; Becket & Schwibbe, 1980). The same EEG structure is found in both male and female subjects. While this new EEG classification does not facilitate interpretations of hormonal effects on the EEG, such effects become clearly demonstrable. The most obvious statistically significant changes were observed in the theta, alpha 0, and both beta bands. As shown in Fig. 5, the increase from lower to higher alpha-frequencies occurred during the luteal phase. This is also the time of lowest power values in the alpha 0 and and alpha 1 factors; in other words, less slow alpha waves a n d / o r slow alpha waves with lower amplitudes occur during the luteal phase at times of high progesterone levels. It therefore is not surprising that the power of the alpha 0 band also correlates significantly negatively with the body temperature. It therefore is possible that progesterone is not the causative factor for these phenomena, but rather that the increased body temperature results in the speeding-up of the alpha 1 range. Experiments currently are being performed to elucidate this. Neither frequency nor power of the alpha 2 band showed significant cycle-dependent changes, which indicates that the overall effect within the whole alpha band reported previously (Creutzfeldt et al., 1976) and now (Fig. 5) are primarily due to cycle stagedependent changes in the low frequency ranges of the alpha band. The two beta bands revealed by factor analysis are also strongly influenced by hormonal changes. Although significant frequency shifts within the two bands were not observed, the power of both bands correlated negatively with serum progesterone levels and with the body temperature. Hence, the power was low during the luteal phase, higher during the follicular phase, and highest during the menstrual period. It also is interesting that the biphasic pattern of serum oestradiol, with high values prior to ovulation and at the midluteal phase, did not correlate with shifts in frequencies or power of any of the bands. This suggests that circulating estrogen levels have no or minor changes on the appearance of the EEG. Similar conclusions can be drawn from male SS treated either with an estrogen or a progesterone, i.e. only the progestational compound induced changes similar to those observed in spontaneously cycling women (Becker et al., 1981). Furthermore, at the preovulatory time, characterized by high L H levels, relatively few

88

D. B[!{ker, O. D. CRtiU-tZFEIK)r, M. ScHWml3ti and W. Wt.rt rl,,t

EEG parameters appeared to be altered, in contrast to the alteration of a number of variables on the psychological test battery. From the 25 main variables of the psychological test battery, 11 were significantly influenced by the hormonal changes during the spontaneous menstrual cycle. Five variables were changed during the time of preovulatory LH release. Apparently, a number of brain functions are changed during that time, such that they appear 'improved'. It is interesting that this improvement includes 'basal functions' such as the FFF but also motoric and higher cognitive functions such as calculations with short-term memory. Surprisingly, the two calculation tests which did not involve the short-term memory did not improve, which may indicate that it is the short-term memory or simply attention, rather than the calculation ability, which is improved during the preovulatory period. Another interesting time during the menstrual cycle is the pre- and perimenstrual period. A large number of women suffer from more or less prominent symptoms during this time. Estimates about the frequency of such premenstrual symptoms, taken from other reports, vary between 20 and 80°70 (Cullberg, 1972). In the present study, care was taken to exclude SS suffering from any premenstrual complaints. Nevertheless, nine out of 25 main variables measured with the test battery were affected during the pre- and perimenstrual period in comparison to the luteal or follicular phase. These results allow the conclusion that performance is generally decreased during the perimenstrual period. The present experiments also were designed to study possible effects of an oral contraceptive on the various physiological and EEG parameters and on psychological functions. Relatively few effects could be observed under the o.c. Comparison of EEG parameters and performance tasks during the o.c. ingestion with those during the pill-free interval (i.e. the placebo period) was expected to result in effects similar to those observed during the perimenstrual period in the SS under spontaneous menstrual cycle conditions. Neither heart rate nor any of the EEG variables were significantly affected. Furthermore, few of the psychological variables showed significant differences between the o.c. and the o.c.-free intervals. The relatively weak effects of o.c. withdrawal on physiological, EEG and psychological measures is in contrast to reports by Kutner & Brown (1972) and Sommer (1972). The former authors, however, used patients with a history of depression. The subjective feelings of the SS during the two periods of prominent changes in performance were not different from those during any other stage of the menstrual cycle. Significant correlations of tiredness and less suppressed mood with serum oestradiol levels, and a correlation of elevated mood with serum progesterone levels, contrasts with the lack of a correlation between the performance parameters and serum estradiol levels. A global explanation for the sum of our findings is impossible. The increased heart rate and changes in other autonomic parameters during the time of increased oestradiol levels reach a maximum at the time of the preovulatory L H surge. As mentioned above, animal experiments suggest the involvement of the noradrenergic system in the positive feedback effect of oestradiol on gonadotropin secretion. Hence, these changes and the repeatedly observed increase of alpha-frequencies in the EEG may be attributed to an activation of the noradrenergic sysiem. Midcycle changes in blood catecholamines have been reported (Zuspan & Zuspan, 1973). Hence, these changes may signify a general arousal phenomenon.

EEG, PERIORMAN{'E AND MENSFRU&I CY(I l

89

During the periovulatory and the perimenstrual periods, the most conspicuous changes in performance and the EEG were observed, whereas at the time of relatively stable hormone levels, no such changes could be demonstrated. It thus appears as if objectively measurable psychic effects occur primarily at times of changing hormone levels. In the present experiment, the shifts of EEG frequencies were related to both increasing and decreasing hormone levels. The question whether the improved performance during the midcycle time and the decreased performance during the premenstrual period were due to direct hormonal effects which also occurred without concomitant shifts in EEG frequencies remains to be examined. Radioimmunoassay kits for LH, FSH and prolactin were kindly provided by the NIAMDD and Dr. H. Friesen (Winnipeg, Canada). This research was partially funded by the German Research Society (Grant Nos. Be 721/'2 and Wu 60/3). The supply of the oral contraceptive by the Schering Company (Berlin) is also acknowledged.

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