- Email: [email protected]
Influence of the menstrual cycle on neuroendocrine and behavioral responses to an opiate agonist in humans: Preliminary results
Psychoneuroendocrinology,Vol. 13, No. 4, pp. 339-344, 1988
0306-4530/88 $3.00 + 0.00 © 1988 Pergamon Press plc
Printedin Great Britain
INFLUENCE OF THE MENSTRUAL CYCLE ON NEUROENDOCRINE A N D BEHAVIORAL RESPONSES TO A N OPIATE AGONIST IN HUMANS: PRELIMINARY RESULTS M. HOEHE Psychiatric Hospital, University of Munich, F.R.G. (Received 7 July 1987; in final form 9 December 1987)
SUMMARY Growth hormone (GH), prolacfin (PRL), cortisol, noradrenaline (NA) and euphoric responses to the g opiate receptor agonist Fentanyl (FE) (0.2 mg/70 kg intravenously) were investigated in five healthy, drug-free, female volunteers at menstruation and at ovulation. The plasma GH response to FE was blunted at menstruation relative to the GH response at ovulation. Basal and maximal PRL concentrations were about 1.5 times higher at ovulation than at menstruation. Cortisol and N A concentrations as well as mood and behavioral responses were not influenced by the menstrual cycle. These results confirm earlier reports of a reduced GH response at menstruation to other pharmacological agents. They also demonstrate that the menstrual cycle is an important influence on neuroendocrine responses to opiate challenge.
INTRODUCTION EVIDENCE SUGGESTS that the menstrual cycle influences neuroendocrine responses to pharmacological challenge; in particular, menstruation has been shown to blunt the growth hormone (GH) response in animals (Eriksson & Modigh, 1984) and humans (Frantz & Rabkin, 1965; Merimee & Fineberg, 1971; Matussek et al., 1984). Because reduced responses to pharmacological challenge in psychiatric illness often are interpreted in terms of altered neurotransmitter mechanisms, it seems especially important to control for a possible influence of the menstrual cycle. However, in recent investigations of opiate agonist effects in depressives, an influence of the menstrual cycle has not been considered (Extein et al., 1980; 1981; Judd et al., 1982; Zis et al., 1983; Robertson et al., 1984; Banki & Arato, 1987). An involvement of opiates in the control of gonadotropin secretion has been suggested from animal and human studies (Pang et al., 1977; Blankstein et al., 1981; Grossman et al., 1981; Szekely, 1982; Piva et al., 1984; Yen, 1984), but no studies to date have evaluated the influence of the menstrual cycle on the hormonal and behavioral responses to opiate receptor agonist administration. We therefore investigated GH, prolactin (PRL), cortisol, noradrenaline (NA), mood and behavioral responses to Fentanyl (FE), a potent IXopiate receptor agonist (Wtister et al., 1979) in healthy female volunteers at menstruation and at ovulation. Correspondence to be addressed to: Dr. Margret R. Hoehe, Clinical Neurogenetics Branch, National Institute of Mental Health, Room 10-3N218, Bethesda MD 20892, USA. 339
340
M. HOEHE SUBJECTS AND METHODS
Five healthy female volunteers (mean age 30.4+3.1 years, range 21-36 years) with no metabolic or endocrine disorders, no history of psychiatric disorders, and within 5% of their ideal body weight were studied. Informed consent was obtained according to the declarations of Tokyo (1964) and Helsinki (1975). Study permission was given by the local ethics committee. The volunteers had been free of any drugs, especially from contraceptives and psychotropic drugs, for at least six months. Alcohol intake did not exceed the equivalent of 60 ml ethanol per day. The volunteers were instructed to avoid any alcohol the day before the test, to sleep for at least 7 hr, and to avoid any physical or psychological stress the morning prior to the experiment. They also were instructed to measure their basal temperature every morning throughout a period of at least two months prior to the study, in order to control for normal menstrual cycles and to determine the times of menstruation and ovulation. The experiments were carded out on the second day of menstruation and one day after ovulation. The sequence of tests varied. Thus, each volunteer was subjected to two FE tests at an interval of about two weeks. The FE test was carried out after an overnight fast under basal metabolic conditions. At 0830 h, an indwelling catheter was inserted and the subjects were kept at rest in a supine position. One hour later, FE (0.2 mg/70 kg) was injected intravenously as a bolus over 15 sec. Blood samples for estimation of GH, PRL and cortisol were drawn 60, 30 rain, immediately before, and every 15 min after injection for 2 hr. Blood samples for estimation of NA were drawn immediately before and 5, 15 and 30 min after FE injection. Blood for analysis of estradiol was drawn only immediately before FE injection. In parallel, mood and behavioral responses were assessed. One hour before FE administration, mood state was evaluated by the von Zerssen Self-Rating Scales (BfS, BfS') (von Zerssen, 1981) in order to control for menstrual cycle-related mood changes. A visual analogue scale (VAS, 0 mm represented feelings of extreme discomfort, 100 mm represented the maximum of feeling of well-being) was rated by the volunteers immediately before and 15, 30, 45 and 60 min after FE injection, in order to evaluate psychotropic drug effects. A FE questionnaire assessing specific FE effects was given before and 10, 20, 30, 40 and 60 min after injection. The subjects' spontaneous verbal reports were noted. During the experimental procedure, blood pressure, heart rate and respiratory rate were continuously recorded, and symptoms and side effects were noted. GH was estimated by radioimmunoassay (RIA) (Sorin, Biomedica). The intraassay coefficient of variation was 10%, and the interassay coefficient of variation was 14%. PRL was measured by RIA (Diagnostic Products Corporation) with the WHO standard I st IRP 75/504 (32.5 ktlU/ml = 1 ng). The intraassay coefficient of variation was 3%, and the interassay coefficient of variation 5%. Cortisol was estimated by RIA (Diagnostic Products Corporation). The intraassay coefficient of variation was 4%, and the interassay coefficient of variation 6%. NA was measured by HPLC with electrochemical detection (Ackenheil et al., 1982). The intraassay coefficient of variation was 6%, and the interassay coefficient of variation was 7%. Estradiol was determined by RIA (ER 155, Travenol Company). Hormonal and VAS responses to FE were analyzed by considering maximum responses and difference scores (maximum response - basal value at tO). Differences were evaluated by Student's t-test for paired data (twotailed). Data are expressed as mean + SEM. RESULTS
Growth Hormone G H w a s n o t m o d i f i e d b y F E at m e n s t r u a t i o n . A t o v u l a t i o n , h o w e v e r , G H i n c r e a s e d m a x i m a l l y 4 5 - 7 5 m i n a f t e r F E i n j e c t i o n (Fig. 1). I n d i v i d u a l data, m e a n m a x i m u m G H concentrations and difference scores are presented in Table I. M a x i m u m G H responses to FE were higher in four out o f the five subjects at ovulation (t = 2.22, p = 0.09; paired I test). Although b a s e l i n e G H c o n c e n t r a t i o n s w e r e g e n e r a l l y h i g h e r at m e n s t r u a t i o n (Fig. 1), there was no significant correlation b e t w e e n baseline G H concentrations and G H responses. Prolactin The m e a n basal P R L concentration was significantly l o w e r at menstruation than at ovulation ( p < 0 . 0 5 ) (Table I). Similarly, the m e a n m a x i m a l P R L concentration 15-30 min after FE was l o w e r at menstruation (Fig. 1, T a b l e I). Individual menstrual P R L responses were 3 0 % - 5 0 %
MENSTRUAL CYCLE AND RESPONSES TO OPIATE AGONIST T A B L E I. B A S A L A N D M A X I M A L
1 2 3 4 5 .
.
.
.
.
.
.
15.6 3.1 0.5 0.6 9.8 .
.
MW SEM
.
G H A N D P R L V A L U E S A T M E N S T R U A T I O N A N D A T OVULATION.
GH Concentration (ng/ml) Menstruation Ovulation tO t45-75 diff tO t45-75 (lift
Subject No.
.
.
.
.
.
.
.
.
5.9 3.0
5.3 6.6 0.4 0.8 1.8 .
.
.
.
.
.
.
.
.
-10.3 3.5 4). 1 0.2 -8.0 .
.
.
.
3.0 1.2
.
.
.
.
.
.
.
0.4 2.7 7.6 0.6 2.8 .
.
.
.
341
.
-2.9 2.6
.
.
.
30.1 4.7 11.4 5.3 12.5 .
.
.
2.8 1.3
.
.
.
.
.
.
.
.
PRL Concentration (l~IU/ml) Menstruation Ovulation tO t15-30 diff tO t15-30 diff
29.7 2.0 3.8 4.7 9.7 .
.
.
.
.
12.8 4.6
.
.
.
.
.
230 109 237 261 213 .
.
.
10.0 5.1
.
.
.
.
.
.
2250 1958 2075 5797* 2676 .
.
.
.
210 26
.
.
.
.
.
.
.
2020 1849 1838 5536 2463 .
.
.
2951 722
.
.
.
.
.
2741 708
.
397 166 393 288 311 .
.
.
.
.
.
.
.
.
311 42
3984 3952 3277 4385* 3872 .
.
.
.
.
.
.
.
.
.
3894 178
.
3587 3786 2884 4097 3561 .
.
.
.
.
.
3583 199
Basal values (tO), maximal values at timepoints indicated, and corresponding difference scores (dill) are presented. * The abnormally enhanced PRL response to FE in this subject could not be explained by any known medical or endocrine factors.
menstruation
~
ovulation
15
-60
0
60
120 t min
B lOOO 1 602
f
~
lO
8
0/
I 60
f
00
0 60
I 0
I 60
-
I 120
t mi~
I -60
I 0
I 6
I 120 t min
0
300
9nn/ .100~ w -
>~
I I 0 5
I 15
I 30
~ 0/
I I 0 5
I 15
I 15
I 30
I 30
= t min
, I 0
i 15
I 30
I 45
i 60
I 0
I 45
I i. 60 t m i n
FIG. 1: Time courses o f mean plasma GH, PRL, cordsol, N A concentrations and VAS scores (n=5) after injection of FE (0.2 mg/70 kg) at menstruation and ovulation.
342
M.HOEHE
reduced in four out of the five subjects (Table I). However, the difference failed to reach statistical significance. Estradiol Estradiol was significantly lower at menstruation than at ovulation; mean plasma concentrations were 29.7 + 6.0 ~tg/1 and 264.0 + 38.0 lxg/1, respectively (p < 0.05). Cortisol Basal cortisol concentrations did not vary over the course of menstrual cycle (Fig. 1). Differences in mean cortisol concentrations 105-120 min after FE (Fig. 1) were not significant. Whereas two subjects showed cortisol decreases in the range of 28%-42% of basal values in each experiment, the other three subjects showed transient cortisol increases 60-120 min after FE both at menstruation and at ovulation. Noradrenaline Basal plasma NA concentrations were 257.2+ 19.3 pg/ml at menstruation and 309.6+26.7 pg/ml at ovulation (Fig. 1). This difference failed to reach statistical significance. The NA concentrations after FE injection were not significantly different (Fig. 1). Mood and Behavioral Responses (BfS + BfS') 1/2 SCOreS did not differ between menstruation (score 6.8+0.5) and ovulation (score 6.0+0.5) and were within the normal nondepressed range. FE significantly increased feelings of well-being 15 min after injection, as indicated by an increase in VAS scores (Fig. 1). No differences were observed between menstruation and ovulation (Fig. 1). Four out of the five subjects expressed feelings of well-being both at menstruation and at ovulation. One subject did not experience any pleasant drug effects at any time. The subjects' spontaneous verbal reports and their responses to the FE questionnaire were in agreement with the VAS scores. Vital Signs FE at a dose of 0.2 mg/70 kg was well tolerated by the subjects. Systolic and diastolic blood pressure, heart rate and respiratory rate did not show any clinically significant changes. Two subjects experienced nausea both at ovulation and at menstruation, and one subject at menstruation. DISCUSSION The plasma GH response to FE challenge showed a pronounced menstrual cycle-related variation. Similar blunted GH responses during menstruation have been reported after arginine and insulin (Frantz & Rabkin, 1965; Merimee & Fineberg, 1971) and after clonidine, an alpha-2 adrenoceptor agonist (Matussek et al., 1984). Also, nonsignificantly increased pre-injection GH concentrations at menstruation have been reported (Matussek et al., 1984). The GH responses to FE were not significantly related to baseline GH concentrations, as has been suggested by Koslow et al. (1982). Furthermore, they were not related to cortisol or glucose concentrations (Brown e t al., 1979). Because mood rating scale scores did not differ over the menstrual cycle and were well within the normal range at menstruation, it seems unlikely that depressive symptomatology might have influenced the GH response. The results suggest that the blunted GH response to FE at menstruation is a state-dependent phenomenon. They have implications for future studies on opiate neuroendocrine responses in psychiatric patients, inasmuch as they identify the menstrual phase of females as an important source of variability. The data also show that both basal PRL concentrations and the PRL responses to FE are
MENSTRUAL CYCLE AND RESPONSES TO OPIATE AGONIST
343
modified by the menstrual cycle. PRL responses were 30%-50% lower in four of the five women at menstruation. Moreover, the PRL responses to FE showed significant sex differences: the responses of men (mean PRL maximum 1269.8+150.6 IzIU/ml, Hoehe et al., 1988) were significantly lower than the responses of women (p<0.01 and p<0.000001, respectively, compared to PIlL responses at menstruation and at ovulation). Thus both, menstrual status and sex are important factors to consider when PRL responses to opiate challenge are evaluated in psychiatric patients. Basal cortisol concentrations and cortisol responses to FE were not modified by the menstrual cycle. Moreover, the responses were not reduced to the same extent - - about 40% of basal values - - as reported for male volunteers (Hoehe et al., 1988). This might be due to the relatively increased number of stress responses in women. The cortisol increases were associated with nausea, which women experienced more frequently than men. Basal NA values appeared to be higher at ovulation, but investigations of an increased number of volunteers and more frequent sampling during the menstrual cycle are needed to draw definite conclusions. NA was not significantly increased by FE, as has been observed in men (Hoehe & Duka, unpublished dam). Possible reasons, e.g. higher NA basal values (Hoehe, unpublished data), remain to be clarified. Euphoric responses to FE as evaluated by VAS scores were not modified by the menstrual cycle. Moreover, no differences between women and men (Hoehe et al., 1988) were noted. Feelings of well-being were expressed by women also who experienced stress, e.g. nausea and other side-effects, during the experiment. Thus, this psychotropic opiate effect did not seem to be influenced by stress. "Euphoria" and "no euphoria" were consistently expressed in all experiments. This is in agreement with our study in male volunteers (Hoehe et al., 1988). A possible trait character of this phenomenon remains to be clarified.
Acknowledgements:
The author thanks Prof. Dr. N. Matussek, Psychiatric Hospital, University of Munich, for his support in publication of this manuscript and Prof. Dr. Kuss, I. Frauenklinik, University of Munich, for the determination of estradiol. This work was supported by the DeutscheForschungsgemeinschaft.
REFERENCES Ackenheil M, Fr6hler M, Goldig G, Rail G, Welte~D (1982) Catecholamin-Bestimmungin Blut und Liquor mit Hochdruckfliissigkeitschromatographieund eleku'ochemischemDetektor. Arzneim-ForschlDrug Res (1I) 32: 893. Banki CM, Arato M (1987) Multiple hormonal responses to morphine: relationship to diagnosis and dexaroethasone suppression. Psychoneuroendocrinology 12: 3-11. Blankstein J, Winter JSD, Feiman C (1981) Endorphins and the regulation of the human menstrual cycle. Clin Endocrino114: 287-294. Brown GM, Friend WC, Chambers JW (1979) Neuropharmacologyof hypothalamic-pitultary regulation. In: Tolls G, Labile F, Martin JB, Naftolin F (Eds) Clinical Neuroendocrinology: A Pathophysiological Approach. Raven Press, New York, pp 47-81. Eriksson E, Modigh K (1984) Depression, alpha 2-receptors and sex hormones: neuroendocrine studies in rat. In: Usdin E, Asberg M, Bertilsson L, Sj6qvist F (Eds) Frontiers in Biochemical and Pharmacological Research in Depression. Raven Press, New York, pp 161-178. Extein I, Pottash ALC, Gold MS, SweeneyDR, Martin DM, Goodwin RK (1980) Deficient prolactin response to morphine in depressed patients. Am J Psychiatry 137: 845-846. Extein I, Pickar D, Gold MS, Gold PW, Pottash ALC, Sweeney DR, Ross RJ, Rebard R, Martin DM, GoodwmFK (1981) Methadone and morphine in depression. Psychopharmacol Bull 17: 29-33. Frantz AG, Rabkin MT (1965) Effects of estrogen and sex.differences on secretion of human growth hormone. J Clin Endocrinol Metab 25: 1470-1480. Grossman A, Moult PJA, Galliard RC, Delitala G, Toff WD, Rees LH, Besser GM (1981) The opioid control of LH and FSH release: effects of a met-enkephalin analogue and naloxone. Clin Endocrino114: 41-47.
344
M. HOEHE
Hoehe M, Duka T, Docnicke A (1988) Human studies on the g opiate receptor agonist fentanyl: neurccndocrine and behavioral responses. Psychoneuroendocrinology,in press. Judd LL, Risch SC, Parker DC, Janowsky DS, Segal DS, Huey LY (1982) Endogenous opioid mechanism in neurt~ndocrine regulation in normal and psychopathological states. PsychopharmacolBull 18: 204-207. Koslow SH, Stokes PE, Mendels J, Ramsey A, Casper R (1982) Insulin tolerance test: human growth hormone response and insulinresistance in primary unipolar depressed, bipolar depressed and normal subjects. Psychol Meal 12: 45-55. Matussek N, Ackenheil M, Herz M (1984) The dependence of the clonidine growth hormone test on alcohol drinking habits and the menstrual cycle. Psychoneuroendocrinology9: 173-177. Medmee TJ, Fineberg SE (1971) Studies of the sex based variation of human growth hormone secretion. J Clin Endocrinol Metal) 33: 896-902. Pang CN, Zimmermann E, Sawyer CH (1977) Morphine inhibition of the preovulation surges of plasma luteinizing hormone and follicle stimulating hormone in the rat. Endocrinology 101: 1726-1732. Piva F, Limonta P, Maggi R, Martini L (1984) Dual effects of the opioids in the control of gonadotropin secretion. In: Delitala G, Motta M, Serio M (Eds) Opioid Modulation of Endocrine Function. Raven Press, New York, pp 155-169. Robettson AG, Jackman H, Meltzer H (1984) Prolactin response to morphine in depression. Psych/airy Res 11: 353-364. Szekely J (1982) Opioid peptides and the neuroendocrine functions. In: Szekely J, Ronai AZ (Eds) Opioid Peptides, Vol. IL CRC Press, Boca Raton, Florida, pp 208-228. Von Zcrssen D (1981) Befindlichkeitsskala. In: CIPS (Eds) Internationale Skalenfiir Psychiatrie. Beltz Test GmbH, Weinheim. WUster M, Schulz R, Herz A (1979) Specificity of opioids towards the g, 8- and Y-opiate receptors. Neurosci Lett 15: 193-198. Yen SSC (1984) Opiates and reproduction: studies in women. In: Dclitala G, Motta M, Sexio M (Eds) Opioid Modulation of Endocrine Function. Raven Press, New York, pp 191-209. Zis AP, Haskett RF, Albala AA, CarroU BJ (1983) Escape from dexamcthasone suppression: possible role of an impaired inhibitory opioid mechanism. Progr Neuro-PsychopharmacolBiol Psychiat 7: 563-568.
0306-4530/88 $3.00 + 0.00 © 1988 Pergamon Press plc
Printedin Great Britain
INFLUENCE OF THE MENSTRUAL CYCLE ON NEUROENDOCRINE A N D BEHAVIORAL RESPONSES TO A N OPIATE AGONIST IN HUMANS: PRELIMINARY RESULTS M. HOEHE Psychiatric Hospital, University of Munich, F.R.G. (Received 7 July 1987; in final form 9 December 1987)
SUMMARY Growth hormone (GH), prolacfin (PRL), cortisol, noradrenaline (NA) and euphoric responses to the g opiate receptor agonist Fentanyl (FE) (0.2 mg/70 kg intravenously) were investigated in five healthy, drug-free, female volunteers at menstruation and at ovulation. The plasma GH response to FE was blunted at menstruation relative to the GH response at ovulation. Basal and maximal PRL concentrations were about 1.5 times higher at ovulation than at menstruation. Cortisol and N A concentrations as well as mood and behavioral responses were not influenced by the menstrual cycle. These results confirm earlier reports of a reduced GH response at menstruation to other pharmacological agents. They also demonstrate that the menstrual cycle is an important influence on neuroendocrine responses to opiate challenge.
INTRODUCTION EVIDENCE SUGGESTS that the menstrual cycle influences neuroendocrine responses to pharmacological challenge; in particular, menstruation has been shown to blunt the growth hormone (GH) response in animals (Eriksson & Modigh, 1984) and humans (Frantz & Rabkin, 1965; Merimee & Fineberg, 1971; Matussek et al., 1984). Because reduced responses to pharmacological challenge in psychiatric illness often are interpreted in terms of altered neurotransmitter mechanisms, it seems especially important to control for a possible influence of the menstrual cycle. However, in recent investigations of opiate agonist effects in depressives, an influence of the menstrual cycle has not been considered (Extein et al., 1980; 1981; Judd et al., 1982; Zis et al., 1983; Robertson et al., 1984; Banki & Arato, 1987). An involvement of opiates in the control of gonadotropin secretion has been suggested from animal and human studies (Pang et al., 1977; Blankstein et al., 1981; Grossman et al., 1981; Szekely, 1982; Piva et al., 1984; Yen, 1984), but no studies to date have evaluated the influence of the menstrual cycle on the hormonal and behavioral responses to opiate receptor agonist administration. We therefore investigated GH, prolactin (PRL), cortisol, noradrenaline (NA), mood and behavioral responses to Fentanyl (FE), a potent IXopiate receptor agonist (Wtister et al., 1979) in healthy female volunteers at menstruation and at ovulation. Correspondence to be addressed to: Dr. Margret R. Hoehe, Clinical Neurogenetics Branch, National Institute of Mental Health, Room 10-3N218, Bethesda MD 20892, USA. 339
340
M. HOEHE SUBJECTS AND METHODS
Five healthy female volunteers (mean age 30.4+3.1 years, range 21-36 years) with no metabolic or endocrine disorders, no history of psychiatric disorders, and within 5% of their ideal body weight were studied. Informed consent was obtained according to the declarations of Tokyo (1964) and Helsinki (1975). Study permission was given by the local ethics committee. The volunteers had been free of any drugs, especially from contraceptives and psychotropic drugs, for at least six months. Alcohol intake did not exceed the equivalent of 60 ml ethanol per day. The volunteers were instructed to avoid any alcohol the day before the test, to sleep for at least 7 hr, and to avoid any physical or psychological stress the morning prior to the experiment. They also were instructed to measure their basal temperature every morning throughout a period of at least two months prior to the study, in order to control for normal menstrual cycles and to determine the times of menstruation and ovulation. The experiments were carded out on the second day of menstruation and one day after ovulation. The sequence of tests varied. Thus, each volunteer was subjected to two FE tests at an interval of about two weeks. The FE test was carried out after an overnight fast under basal metabolic conditions. At 0830 h, an indwelling catheter was inserted and the subjects were kept at rest in a supine position. One hour later, FE (0.2 mg/70 kg) was injected intravenously as a bolus over 15 sec. Blood samples for estimation of GH, PRL and cortisol were drawn 60, 30 rain, immediately before, and every 15 min after injection for 2 hr. Blood samples for estimation of NA were drawn immediately before and 5, 15 and 30 min after FE injection. Blood for analysis of estradiol was drawn only immediately before FE injection. In parallel, mood and behavioral responses were assessed. One hour before FE administration, mood state was evaluated by the von Zerssen Self-Rating Scales (BfS, BfS') (von Zerssen, 1981) in order to control for menstrual cycle-related mood changes. A visual analogue scale (VAS, 0 mm represented feelings of extreme discomfort, 100 mm represented the maximum of feeling of well-being) was rated by the volunteers immediately before and 15, 30, 45 and 60 min after FE injection, in order to evaluate psychotropic drug effects. A FE questionnaire assessing specific FE effects was given before and 10, 20, 30, 40 and 60 min after injection. The subjects' spontaneous verbal reports were noted. During the experimental procedure, blood pressure, heart rate and respiratory rate were continuously recorded, and symptoms and side effects were noted. GH was estimated by radioimmunoassay (RIA) (Sorin, Biomedica). The intraassay coefficient of variation was 10%, and the interassay coefficient of variation was 14%. PRL was measured by RIA (Diagnostic Products Corporation) with the WHO standard I st IRP 75/504 (32.5 ktlU/ml = 1 ng). The intraassay coefficient of variation was 3%, and the interassay coefficient of variation 5%. Cortisol was estimated by RIA (Diagnostic Products Corporation). The intraassay coefficient of variation was 4%, and the interassay coefficient of variation 6%. NA was measured by HPLC with electrochemical detection (Ackenheil et al., 1982). The intraassay coefficient of variation was 6%, and the interassay coefficient of variation was 7%. Estradiol was determined by RIA (ER 155, Travenol Company). Hormonal and VAS responses to FE were analyzed by considering maximum responses and difference scores (maximum response - basal value at tO). Differences were evaluated by Student's t-test for paired data (twotailed). Data are expressed as mean + SEM. RESULTS
Growth Hormone G H w a s n o t m o d i f i e d b y F E at m e n s t r u a t i o n . A t o v u l a t i o n , h o w e v e r , G H i n c r e a s e d m a x i m a l l y 4 5 - 7 5 m i n a f t e r F E i n j e c t i o n (Fig. 1). I n d i v i d u a l data, m e a n m a x i m u m G H concentrations and difference scores are presented in Table I. M a x i m u m G H responses to FE were higher in four out o f the five subjects at ovulation (t = 2.22, p = 0.09; paired I test). Although b a s e l i n e G H c o n c e n t r a t i o n s w e r e g e n e r a l l y h i g h e r at m e n s t r u a t i o n (Fig. 1), there was no significant correlation b e t w e e n baseline G H concentrations and G H responses. Prolactin The m e a n basal P R L concentration was significantly l o w e r at menstruation than at ovulation ( p < 0 . 0 5 ) (Table I). Similarly, the m e a n m a x i m a l P R L concentration 15-30 min after FE was l o w e r at menstruation (Fig. 1, T a b l e I). Individual menstrual P R L responses were 3 0 % - 5 0 %
MENSTRUAL CYCLE AND RESPONSES TO OPIATE AGONIST T A B L E I. B A S A L A N D M A X I M A L
1 2 3 4 5 .
.
.
.
.
.
.
15.6 3.1 0.5 0.6 9.8 .
.
MW SEM
.
G H A N D P R L V A L U E S A T M E N S T R U A T I O N A N D A T OVULATION.
GH Concentration (ng/ml) Menstruation Ovulation tO t45-75 diff tO t45-75 (lift
Subject No.
.
.
.
.
.
.
.
.
5.9 3.0
5.3 6.6 0.4 0.8 1.8 .
.
.
.
.
.
.
.
.
-10.3 3.5 4). 1 0.2 -8.0 .
.
.
.
3.0 1.2
.
.
.
.
.
.
.
0.4 2.7 7.6 0.6 2.8 .
.
.
.
341
.
-2.9 2.6
.
.
.
30.1 4.7 11.4 5.3 12.5 .
.
.
2.8 1.3
.
.
.
.
.
.
.
.
PRL Concentration (l~IU/ml) Menstruation Ovulation tO t15-30 diff tO t15-30 diff
29.7 2.0 3.8 4.7 9.7 .
.
.
.
.
12.8 4.6
.
.
.
.
.
230 109 237 261 213 .
.
.
10.0 5.1
.
.
.
.
.
.
2250 1958 2075 5797* 2676 .
.
.
.
210 26
.
.
.
.
.
.
.
2020 1849 1838 5536 2463 .
.
.
2951 722
.
.
.
.
.
2741 708
.
397 166 393 288 311 .
.
.
.
.
.
.
.
.
311 42
3984 3952 3277 4385* 3872 .
.
.
.
.
.
.
.
.
.
3894 178
.
3587 3786 2884 4097 3561 .
.
.
.
.
.
3583 199
Basal values (tO), maximal values at timepoints indicated, and corresponding difference scores (dill) are presented. * The abnormally enhanced PRL response to FE in this subject could not be explained by any known medical or endocrine factors.
menstruation
~
ovulation
15
-60
0
60
120 t min
B lOOO 1 602
f
~
lO
8
0/
I 60
f
00
0 60
I 0
I 60
-
I 120
t mi~
I -60
I 0
I 6
I 120 t min
0
300
9nn/ .100~ w -
>~
I I 0 5
I 15
I 30
~ 0/
I I 0 5
I 15
I 15
I 30
I 30
= t min
, I 0
i 15
I 30
I 45
i 60
I 0
I 45
I i. 60 t m i n
FIG. 1: Time courses o f mean plasma GH, PRL, cordsol, N A concentrations and VAS scores (n=5) after injection of FE (0.2 mg/70 kg) at menstruation and ovulation.
342
M.HOEHE
reduced in four out of the five subjects (Table I). However, the difference failed to reach statistical significance. Estradiol Estradiol was significantly lower at menstruation than at ovulation; mean plasma concentrations were 29.7 + 6.0 ~tg/1 and 264.0 + 38.0 lxg/1, respectively (p < 0.05). Cortisol Basal cortisol concentrations did not vary over the course of menstrual cycle (Fig. 1). Differences in mean cortisol concentrations 105-120 min after FE (Fig. 1) were not significant. Whereas two subjects showed cortisol decreases in the range of 28%-42% of basal values in each experiment, the other three subjects showed transient cortisol increases 60-120 min after FE both at menstruation and at ovulation. Noradrenaline Basal plasma NA concentrations were 257.2+ 19.3 pg/ml at menstruation and 309.6+26.7 pg/ml at ovulation (Fig. 1). This difference failed to reach statistical significance. The NA concentrations after FE injection were not significantly different (Fig. 1). Mood and Behavioral Responses (BfS + BfS') 1/2 SCOreS did not differ between menstruation (score 6.8+0.5) and ovulation (score 6.0+0.5) and were within the normal nondepressed range. FE significantly increased feelings of well-being 15 min after injection, as indicated by an increase in VAS scores (Fig. 1). No differences were observed between menstruation and ovulation (Fig. 1). Four out of the five subjects expressed feelings of well-being both at menstruation and at ovulation. One subject did not experience any pleasant drug effects at any time. The subjects' spontaneous verbal reports and their responses to the FE questionnaire were in agreement with the VAS scores. Vital Signs FE at a dose of 0.2 mg/70 kg was well tolerated by the subjects. Systolic and diastolic blood pressure, heart rate and respiratory rate did not show any clinically significant changes. Two subjects experienced nausea both at ovulation and at menstruation, and one subject at menstruation. DISCUSSION The plasma GH response to FE challenge showed a pronounced menstrual cycle-related variation. Similar blunted GH responses during menstruation have been reported after arginine and insulin (Frantz & Rabkin, 1965; Merimee & Fineberg, 1971) and after clonidine, an alpha-2 adrenoceptor agonist (Matussek et al., 1984). Also, nonsignificantly increased pre-injection GH concentrations at menstruation have been reported (Matussek et al., 1984). The GH responses to FE were not significantly related to baseline GH concentrations, as has been suggested by Koslow et al. (1982). Furthermore, they were not related to cortisol or glucose concentrations (Brown e t al., 1979). Because mood rating scale scores did not differ over the menstrual cycle and were well within the normal range at menstruation, it seems unlikely that depressive symptomatology might have influenced the GH response. The results suggest that the blunted GH response to FE at menstruation is a state-dependent phenomenon. They have implications for future studies on opiate neuroendocrine responses in psychiatric patients, inasmuch as they identify the menstrual phase of females as an important source of variability. The data also show that both basal PRL concentrations and the PRL responses to FE are
MENSTRUAL CYCLE AND RESPONSES TO OPIATE AGONIST
343
modified by the menstrual cycle. PRL responses were 30%-50% lower in four of the five women at menstruation. Moreover, the PRL responses to FE showed significant sex differences: the responses of men (mean PRL maximum 1269.8+150.6 IzIU/ml, Hoehe et al., 1988) were significantly lower than the responses of women (p<0.01 and p<0.000001, respectively, compared to PIlL responses at menstruation and at ovulation). Thus both, menstrual status and sex are important factors to consider when PRL responses to opiate challenge are evaluated in psychiatric patients. Basal cortisol concentrations and cortisol responses to FE were not modified by the menstrual cycle. Moreover, the responses were not reduced to the same extent - - about 40% of basal values - - as reported for male volunteers (Hoehe et al., 1988). This might be due to the relatively increased number of stress responses in women. The cortisol increases were associated with nausea, which women experienced more frequently than men. Basal NA values appeared to be higher at ovulation, but investigations of an increased number of volunteers and more frequent sampling during the menstrual cycle are needed to draw definite conclusions. NA was not significantly increased by FE, as has been observed in men (Hoehe & Duka, unpublished dam). Possible reasons, e.g. higher NA basal values (Hoehe, unpublished data), remain to be clarified. Euphoric responses to FE as evaluated by VAS scores were not modified by the menstrual cycle. Moreover, no differences between women and men (Hoehe et al., 1988) were noted. Feelings of well-being were expressed by women also who experienced stress, e.g. nausea and other side-effects, during the experiment. Thus, this psychotropic opiate effect did not seem to be influenced by stress. "Euphoria" and "no euphoria" were consistently expressed in all experiments. This is in agreement with our study in male volunteers (Hoehe et al., 1988). A possible trait character of this phenomenon remains to be clarified.
Acknowledgements:
The author thanks Prof. Dr. N. Matussek, Psychiatric Hospital, University of Munich, for his support in publication of this manuscript and Prof. Dr. Kuss, I. Frauenklinik, University of Munich, for the determination of estradiol. This work was supported by the DeutscheForschungsgemeinschaft.
REFERENCES Ackenheil M, Fr6hler M, Goldig G, Rail G, Welte~D (1982) Catecholamin-Bestimmungin Blut und Liquor mit Hochdruckfliissigkeitschromatographieund eleku'ochemischemDetektor. Arzneim-ForschlDrug Res (1I) 32: 893. Banki CM, Arato M (1987) Multiple hormonal responses to morphine: relationship to diagnosis and dexaroethasone suppression. Psychoneuroendocrinology 12: 3-11. Blankstein J, Winter JSD, Feiman C (1981) Endorphins and the regulation of the human menstrual cycle. Clin Endocrino114: 287-294. Brown GM, Friend WC, Chambers JW (1979) Neuropharmacologyof hypothalamic-pitultary regulation. In: Tolls G, Labile F, Martin JB, Naftolin F (Eds) Clinical Neuroendocrinology: A Pathophysiological Approach. Raven Press, New York, pp 47-81. Eriksson E, Modigh K (1984) Depression, alpha 2-receptors and sex hormones: neuroendocrine studies in rat. In: Usdin E, Asberg M, Bertilsson L, Sj6qvist F (Eds) Frontiers in Biochemical and Pharmacological Research in Depression. Raven Press, New York, pp 161-178. Extein I, Pottash ALC, Gold MS, SweeneyDR, Martin DM, Goodwin RK (1980) Deficient prolactin response to morphine in depressed patients. Am J Psychiatry 137: 845-846. Extein I, Pickar D, Gold MS, Gold PW, Pottash ALC, Sweeney DR, Ross RJ, Rebard R, Martin DM, GoodwmFK (1981) Methadone and morphine in depression. Psychopharmacol Bull 17: 29-33. Frantz AG, Rabkin MT (1965) Effects of estrogen and sex.differences on secretion of human growth hormone. J Clin Endocrinol Metab 25: 1470-1480. Grossman A, Moult PJA, Galliard RC, Delitala G, Toff WD, Rees LH, Besser GM (1981) The opioid control of LH and FSH release: effects of a met-enkephalin analogue and naloxone. Clin Endocrino114: 41-47.
344
M. HOEHE
Hoehe M, Duka T, Docnicke A (1988) Human studies on the g opiate receptor agonist fentanyl: neurccndocrine and behavioral responses. Psychoneuroendocrinology,in press. Judd LL, Risch SC, Parker DC, Janowsky DS, Segal DS, Huey LY (1982) Endogenous opioid mechanism in neurt~ndocrine regulation in normal and psychopathological states. PsychopharmacolBull 18: 204-207. Koslow SH, Stokes PE, Mendels J, Ramsey A, Casper R (1982) Insulin tolerance test: human growth hormone response and insulinresistance in primary unipolar depressed, bipolar depressed and normal subjects. Psychol Meal 12: 45-55. Matussek N, Ackenheil M, Herz M (1984) The dependence of the clonidine growth hormone test on alcohol drinking habits and the menstrual cycle. Psychoneuroendocrinology9: 173-177. Medmee TJ, Fineberg SE (1971) Studies of the sex based variation of human growth hormone secretion. J Clin Endocrinol Metal) 33: 896-902. Pang CN, Zimmermann E, Sawyer CH (1977) Morphine inhibition of the preovulation surges of plasma luteinizing hormone and follicle stimulating hormone in the rat. Endocrinology 101: 1726-1732. Piva F, Limonta P, Maggi R, Martini L (1984) Dual effects of the opioids in the control of gonadotropin secretion. In: Delitala G, Motta M, Serio M (Eds) Opioid Modulation of Endocrine Function. Raven Press, New York, pp 155-169. Robettson AG, Jackman H, Meltzer H (1984) Prolactin response to morphine in depression. Psych/airy Res 11: 353-364. Szekely J (1982) Opioid peptides and the neuroendocrine functions. In: Szekely J, Ronai AZ (Eds) Opioid Peptides, Vol. IL CRC Press, Boca Raton, Florida, pp 208-228. Von Zcrssen D (1981) Befindlichkeitsskala. In: CIPS (Eds) Internationale Skalenfiir Psychiatrie. Beltz Test GmbH, Weinheim. WUster M, Schulz R, Herz A (1979) Specificity of opioids towards the g, 8- and Y-opiate receptors. Neurosci Lett 15: 193-198. Yen SSC (1984) Opiates and reproduction: studies in women. In: Dclitala G, Motta M, Sexio M (Eds) Opioid Modulation of Endocrine Function. Raven Press, New York, pp 191-209. Zis AP, Haskett RF, Albala AA, CarroU BJ (1983) Escape from dexamcthasone suppression: possible role of an impaired inhibitory opioid mechanism. Progr Neuro-PsychopharmacolBiol Psychiat 7: 563-568.