The effect of two dopaminergic drugs on menstrual function and psychological state in hyperprolactinemia *

Transcription

1 FERTILITY AND STERILITY Copyright 1992 The American Fertility Society Printed on acid-free paper in U.S.A. The effect of two dopaminergic drugs on menstrual function and psychological state in hyperprolactinemia * Richard E. Lappohn, M.D., Ph.D.t Harry B. M. van de Wiel, Ph.D.:j: Judith Brownell, M.D. Academisch Ziekenhuis, Groningen, The Netherlands, and Sandoz Ltd., Basel, Switzerland Objective: To investigate the effect of dopaminergic drugs on the well being in hyperprolactinemic patients. Design: A psychometric test for well being, the SCL-90, was applied at baseline and in the 24th week of a double-blind randomized prospective study comparing the effectiveness and safety of the new dopamine d2 agonist CV with bromocriptine. Setting: Outpatient department of a university clinic for obstetrics and gynecology. Patients: Twenty-four women with hyperprolactinemia, 9 of whom had a prolactinoma. Twenty had been treated before, and 11 were known to react unfavorably to bromocriptine. Results: The effectiveness of CV was identical to bromocriptine: its tolerability appeared to be better, especially in the initial phase of treatment. At baseline, the mean scores of the SCL-90 were significantly elevated over the reference values. Sixteen patients had normal scores. The elevations were caused by 8 patients with scores in the range found in psychiatric disease (211 ± 30 [SD] [CV ] and 182 ± 32 [bromocriptinej). They were depressed, anxious, and hostile. At 24 weeks, the patients treated with CV scored better (130 ± 23.5) in the SCL-90 than the patients treated with bromocriptine (149.5 ± 20). Conclusion: The markedly increased well being in patients treated with CV cannot be explained by its better tolerability and is probably caused by a specific central activity of CV Further research into the antidepressive properties of this compound is warranted. Fertil Steril 1992;58:321-7 Key Words: Hyperprolactinemia, depression, bromocriptine, CV Elevated serum prolactin (PRL) levels can be found in a variety of physiological and pathological states. Among others, physical and emotional stress is a PRL releaser (1), but hyperprolactinemia can also be induced by pituitary tumor, disruption of the Received November 19, 1991; revised and accepted March 25, * Financial support for this investigation was obtained from Sandoz Ltd, Basel, Switzerland. t Reprint requests: Richard Lappohn, M.D., Ph.D., Department of Obstetrics and Gynecology, Academisch Ziekenhuis Groningen, Oostersingel 59, 9713 EZ Groningen, The Netherlands. :j: Department of Medical Psychology, Academisch Ziekenhuis. Sandoz Ltd. pituitary stalk, and a number of drugs. Most female patients with hyperprolactinemia exhibit menstrual disturbances; hyperprolactinemic amenorrhea is a frequent cause of involuntary infertility. It is generally accepted that hypothalamic dopamine is the most important inhibitor of pituitary PRL secretion. Probably the PRL reaction to stress is mediated by a decrease in hypothalamic dopaminergic tone. Under these circumstances, serotonin, together with arginin vasopressin, endorphines, and enkephalins, can promote pituitary PRL release (2). Functional disturbances of these neurotransmitters are involved in psychiatric disease. Therefore, specific deviations from normal psychological func- Lappohn et al. Depression in hyperprolactinemia 321

2 tioning may be expected in hyperprolactinemic patients. Indeed, an association of hyperprolactinemia with depressed mood has been described; it also appeared that women with hyperprolactinemia are more distressed and more hostile than controls (3-5). Whether or not excessive PRL secretion is responsible for these symptoms is not clear, not only because of the complexity of PRL regulatory systems and PRL actions but also because the hypogonadism that often accompanies hyperprolactinemia may profoundly affect mood and performance. Prolactin release can be normalized, and normal gonadal function can be restored by the administration of dopaminergic drugs. Bromocriptine (Parlodel/Pravidel; Sandoz, Basel, Switzerland), a semisynthetic ergot alkaloid and dopamine receptor stimulator, is the most extensively used drug in the treatment of hyperprolactinemia. A double-blind, placebo-controlled crossover study with bromocriptine showed that distress decreased and well-being increased in parallel with the fall in PRL levels (6). Another double-blind study with untreated matched controls gave identical results (7). The improvement of depression is not specific for bromocriptine: it was also noted with pergolide, a more potent dopaminergic drug (5). The known side effects of dopaminergic drugs (nausea, headache, orthostatic hypotension, and nasal stuffiness) were more severe in the bromocriptine group and prevented a dosage increase to the optimal therapeutic level in two patients. Patients who do not respond satisfactorily to the PRL-Iowering action of dopaminergic drugs are not rare. In some, drug intolerance is the main problem; in others, especially those with a prolactinoma, drug resistance may be caused by a decreased density of dopamine receptors in the tumor (8, 9). To diminish the problem of drug intolerance, efforts have been made to find a drug with fewer adverse reactions. CV , an octahydrobenzo[g]quinoline (Sandoz), is a new long-acting nonergot dopamine agonist that effectively inhibits PRL secretion in animal models (10) and in hyperprolactinemic women (11-13). Our participation in a long-term, double-blind comparative study with bromocriptine for efficacy and tolerability prompted the formulation of three additional research questions: (1) Can a differe~ce between hyperprolactinemic patients and the normal population with respect to psychological factors such as fear, hostility, and depressive mood be confirmed? (2) If so, can treatment with a dopaminergic drug influence well-being in a positive way? and (3) Is there a difference between CV and bromocriptine in effects on such psychometric measures? Subjects MATERIALS AND METHODS Twenty-four women with persistent hyperprolactinemia, 22 to 42 years of age (median 35 years), volunteered to participate in the study. All women had been fully informed and gave their consent in writing. Twenty had originally presented with secondary amenorrhea of 8 to 64 months' duration, 2 had oligomenorrhea with menstrual intervals of 3 to 8 months, and 2 had an irregular cycle with galactorrhea. All but 4 women had been treated with bromocriptine before; 11 had poorly tolerated this drug, preventing administration of a dose large enough to normalize PRL levels in 3 of them. Three women had also participated in an earlier 12-month study concerning the effectiveness of CV (13). Earlier bromocriptine therapy had lasted for 8 to 72 months (median 20 months) in daily doses of between 3.75 and 12.5 mg (median 5 mg). The interval between earlier bromocriptine or CV treatment and the start of this study was at least 3 months. For 6 weeks before the study was started, no patient received any drug that could interfere with PRL secretion. At the baseline visit after the prestudy washout, 14 patients were amenorrheic, 8 had oligomenorrhea, and 2 profuse galactorrhea with an irregular cycle (Table 1). One patient (no. 9) had a macroprolactinoma expanding into the sphenoidal sinus. Small prolactinomas had been demonstrated by computer tomography in four women (nos. 5, 12, 14, and 22) and in three (nos. 10, 17, and 24) by magnetic resonance imaging (MRI). Patient 23 had severe abnormalities of the pituitary region, but in the MRI the signal intensity was homogeneous, which made the presence of pituitary tumor unlikely. Repeated visual field determinations were normal. One patient (no. 13) with macroprolactinoma had been irradiated, which we did not know at admission to the study. She was withdrawn at week 4. In two women with moderate hyperprolactinemia pituitary imaging has not been performed. No patient had an urgent desire for pregnancy, and all used mechanical forms of contraception during the study. Methods Prolactin was measured by immunoradiometric assay using the Serono Maia clone (Serono Inc, 322 Lappohn et ai. Depression in hyperprolactinemia Fertility and Sterility

3 Table 1 Clinical Data in Basal Situation and During Treatment With CV and Bromocriptine Patient no. PRL Baseline Week 4 Symptoms * PRL Bleeding P PRL Week 8 Bleeding P PRL Week 12 Bleeding P Week 24 PRL Bleeding P Dose CV Bromocriptine miu/l 2,148 1,374 3,256 1,245 1,671 1,533 1,316 2,084 1,843 1,639 1,711 1,526 Idiop; amend Micro; oligo Micro; amend Idiop; amend Idiop; ameno Micro; galact Idiop; ameno Micro; ameno , , , , NDt , , mg , , ,314 Idiop; amend Discontinued: pregnant 5.0 1,679 Idiop; amend ,280 Idiop; amend , , ,315 Idiop; ameno 988 Dropout: adverse effects ,098 Macro; ameno 4,356 1,263 1, ,580 Micro; oligo Macro; oligo 115 Dropout: protocol violation/adv. eft' ,297 Micro; amend 841 Discontinuation: moved away ,320 ldiop; oligo ,667 Idiop; galact ,163 Macro; amend ,839 Micro; amend ND * idiop, idiopathic hyperprolactinemia; micro, microproiactinoma; macro, macroprolactinoma; ameno, amenorrhea; oligo, oligomenorrhea; galact, galactorrhea. t ND, not determined. Rome, Italy) kit with the International Reference Preparation hprl 75/504 as a standard. The upper normal value for women of reproductive age is 600 miu/l. To evaluate changes in psychological state, the Symptom Checklist with 90 items (SCL-90) (14) in its Dutch version (15) was administered immediately before the start of the study and in the last week of treatment. This broad-based questionnaire evolved from the earlier Hopkins Symptom Checklist and is intended for outpatient use. For each of the 90 items, the respondent is instructed to rate "How much that problem has bothered and/or distressed you during the past including today" on a 5-point scale, from 0 (not at all) to 4 (extremely). The Dutch version of the checklist has nine factors: agoraphobic anxiety, anxiety, depression, somatic complaints, hostility, insufficient thinking and acting, mistrust and interpersonal sensitivity, sleeping disorders, and psychoneuroticism. Sample items are: "feeling afraid to go out of your house alone," "pains in heart or chest," "sleep that is restless or disturbed," and "feelings of guilt." The upper values of the mean scores from tests in 577 psychologically normal women were used as a reference. Patients were randomized in groups of four, so that two received bromocriptine and two received CV for a period of 6 months. The starting dose of bromocriptine was 1.25 mg/d and that of CV was mg/d. After the starting package, dosages were increased to 2.5 mg bromocriptine two times daily and mg CV at bedtime. Capsules were taken with breakfast and at bedtime with a snack. Patients on CV received placebo capsules at breakfast. Doses up to mg/d of CV and 10 mg/d bromocriptine could be given by week 12 if serum PRL levels had not normalized at the preceding visit and if tolerability allowed. Prolactin levels were determined at baseline and at weeks 4, 8, 12, and 24. Blood samples were drawn between 9 A.M. and 11 A.M., and patients had been instructed to ingest their capsules afterward. At the baseline and after weeks 12 and 24, extensive laboratory safety tests were done and electrocardiograms were recorded. At each visit adverse events were noted, menstrual history was taken, and the normality of the cycle was assessed by measurement of plasma progesterone (P) concentrations in the second half of the cycle from women with regular menstrual bleeding. Midluteal P levels> 30 nmoljl and levels > 10 nmoljl in the early and late luteal phase were considered to be indicative of normal ovarian function. The scores on the SCL-90 test were computed before the randomization code was broken. In the Lappohn et al. Depression in hyperprolactinemia 323

4 Table 2 Score of Adverse Events During Treatment With CV and Bromocriptine* CV Patient Week 4 Week 8 Week 12 Week t 4t 0:1: t * Main adverse events: nausea, dizziness, nasal congestion. Severe = 3 points; moderate = 2; slight = 1 point. Minor adverse events: irritability, headache, tiredness. Severe = 2 points; moderate = 1; slight = 0 points. Bromocriptine Patient Week 4 Week 8 Week 12 Week Pregnant It Dropout ot ot Dropout 14 0 Discontinued Pregnant t Dosage increase. :I: Dosage decrease. statistical analysis, one-way ANOV A and Student's t-test (one- and two-tailed) for paired and independent data were used. Nonparametric tests (Wilcoxon's rank sum test for paired and independent data [16]) were used whenever the sample values appeared not to be normally distributed or when the variance differences were large. The study protocol has been approved by the Ethical Committee of the University Hospital, Groningen, The Netherlands. RESULTS Clinical Efficacy and Serum PRL All patients assigned to treatment with CV and 8 of the patients assigned to bromocriptine completed the 24-week study. Table 1 gives an overview of the clinical status and serum PRL levels during the study. The initial PRL levels in the two groups were not significantly different (Wilcoxon's: 2a > 0.10). As indicated in Table 1, final PRL became normal in 8 patients on CV and 8 on bromocriptine, with cyclic vaginal blood loss occurring in 10 and 9 of the CV and bromocriptine-treated patients, respectively. In the CV group, 2 patients had <50% lowering of the PRL level at the final dose used; one of these (no. 11) was known to have reacted insufficiently to bromocriptine as well. The other (no. 10) did not tolerate a dose increase at week 8 and thereby remained hyperprolactinemic and amenorrheic. Patient 8 in the bromocriptine group, who also had reacted insuffi- ciently to bromocriptine at earlier treatment, discontinued while still hyperprolactinemic; another patient with a high PRL level in week 24 (no. 7) had not used the drug for 3 days while in the luteal phase of the cycle. Patient 24 was in the periovulatory phase of the cycle when her PRL was last measured. Progesterone values compatible with cyclic ovarian function were found in nine (CV ) and eight (bromocriptine) patients. Two pregnancies occurred during week 16 and 24 of bromocriptine treatment (contraception failures). Patient 9 (bromocriptine), who remained amenorrheic during the study, started to menstruate regularly from week 26 (after the code had been broken). There were no differences between the PRL results obtained in the CV and bromocriptine groups, and there was no evidence for a different efficacy of the drugs. Tolerability and Safety Adverse events were recorded in both treatment groups. They are listed as a score in Table 2. There were significantly higher adverse effect scores in the bromocriptine group at week 4 (Wilcoxon's; 2a < 0.05). Adverse effects led to study discontinuation before week 8 in patient 8 (bromocriptine). Both she and patient 14, (bromocriptine) who was withdrawn from the study in week 4 and who also complained of intolerable adverse effects, had been poor tolerators before. From week 8, there were no differences between the adverse effect scores of the two groups. With exception of three women, severe or moderate adverse events while using bromocriptine 324 Lappohn et al. Depression in hyperprolactinemia Fertility and Sterility

5 were reported by earlier poor tolerators; two had minor complaints when again using the drug. Patients on CV appeared to have a better tolerance for this drug; three earlier poor tolerators of bromocriptine reported only slight side effects while using CV The only more serious adverse event, reported by 6 CV users, was nausea at night or early in the morning. It had disappeared by week 8 in four women. In patient 10, persistent severe nausea prevented a dose increase. Vital signs, electrocardiogram, and safety laboratory tests remained normal throughout, and no changes from baseline were recorded in physical, electrocardiographic, or blood and urine safety tests in any patient. Psychological Function The SCL-90 was completed by all women at baseline and by all but one (bromocriptine; moved away) after 24 weeks of treatment or at early discontinuation (Table 1). No differences were seen between the baseline scores of women with amenorrhea (supposed to be hypogonadal) and with oligomenorrhea, between those with and without demonstrable pituitary disease, and between the CV and bromocriptine groups. Sixteen patients had 250 Points # # # # t- r- - ~ ~ ~ '-'-- '--'-- ~~ ~~ - * - -:- 1 nls 1 hi 2 nls 2 hi I - CV D Bromocripline I Figure 1 Total scores of SCL-90 tests. The horizontal line indicates the upper normal level of the SCL = base line result 2 = week 24 or end of treatment. nls = mean result of wome~ with normal SCL 90; hi = mean result of women with pathological test result. *Significant (P = <0.05) difference between first and second test; #Significantiy (P = <0.05) different from normal Points I - CV Bromocriptin I 20 * 10 feor 1 fear 2 depression 1 depression 2 hostility 1 hostility 2 Figure 2 Significant items in the SCL-90. Reference population upper normal values are drawn as horizontal lines. 1 = base line result; 2 = week 24 or end of treatment. *Significant (P = <0.05) difference between first and second test. normal results, but patients 5, 6, 16, and 19 on CV and 2, 4, 14, and 20 on bromocriptine had a pathological score of the baseline SCL. They caused the mean ± SD total scores of the CV group (151.4 ± 48.6) and those ofthe bromocriptine group (142.4 ± 56.8) to be significantly higher (P = 0.05) than the upper mean values in the normal population (Fig. 1). The mean scores of the normal patients were ± 15.9 (CV ) and ± 11.9 (bromocriptine). The mean scores ofthe patients with pathological scores were 211 ± 30 (CV ) and 182 ± 32 (bromocriptine). The items of fear (P = 0.03), depression (P = 0.05), and hostility (P = 0.05) were the significant contribuants to the difference (Fig. 2). At the end of the treatment period, the effect of the drugs was first investigated with a one-way ANOV A. In the 16 patients with normal baseline total SCL scores, no significant changes or differences were found. The initial and final scores of the 8 patients with high baseline SCL scores were significantly different: F = 6.677, P = In these patients, the effects were investigated in a withinsubject design: the scores were compared with twosided paired t-tests. The four patients on CV showed a significant lowering of their total score: 130 ± 23.5 (t = 4.61, P = 0.019). The total score of the bromocriptine group was almost significantly lower: ± 20 (t = 2.63, P = 0.08). In the patients on CV , significant improvements were found for the items offear (t = 3.36, P = 0.04) and depression (t = 3.14, P = 0.05), but there was no significant * Lapptihn et al. Depression in hyperprolactinemia 325

6 change of the item hostility (t = 2.00, P = 0.14). In the bromocriptine group, the only improvement was in the item hostility (t = 5.17, P = 0.002). Significant correlations between PRL levels and SCL score could not be demonstrated at baseline or at the end of the treatment period. Likewise, there was no correlation between adverse event scores and PRL levels. DISCUSSION CV appears to be an equally effective and safe drug as bromocriptine. It can be given once daily at bedtime and has significantly less severe initial side effects. Notably, nasal stuffiness, dizziness, and orthostatic hypotension (all considered to be d-1 agonistic effects) were not found in our patients. On the other hand, patients who had been resistant to the PRL-Iowering action ofbromocriptine remained so while treated with CV Significant deviations from normal psychological functioning (depressive feelings, fearfulness, and hostility) in patients with hyperprolactinemia, as reported in the literature (3-5), were found in 8 of our 24 cases. This proportion, though relatively high, does not confirm that depression, fearfulness, and hostility are general features of hyperprolactinemic syndromes. One possible explanation for the findings in earlier studies is selection bias. Because we had only four patients with recently started signs of hyperprolactinemia in our study, we cannot rule out the possibility that hyperprolactinemia does cause psychological disturbances, but that these wear off, whereas the somatic syndrome persists. On the other hand, we found no evidence for hypogonadism as a cause of depression because the mean baseline SCL score in patients with amenorrhea/hypogonadism was unremarkable. We found a significant improvement of the second SCL-90 score in depressed patients treated with CV , whereas the improvement in those treated with bromocriptine failed to reach significance, with exception of the item hostility. Prolactin levels and initial SCL-90 scores were identical in the two groups, so there is no evidence for bias through incorrect randomization. The finding of a difference is remarkable because in all earlier reports the patients' increased well-being in parallel with the falling PRL levels was stressed. Our clinical results in terms of return of cyclic ovarian function and the PRL levels reached in the CV group were no better than those obtained in the bromo- criptine group, so the normalization of the hormonal factors cannot explain the greatly improved sense of well-being in these patients. Better tolerability of CV , which may be related to the once daily administration of active drug at bedtime with resulting peak drug concentrations during sleep, can hardly account for the observed difference with bromocriptine because tolerability only appeared to play a role in the early weeks of treatment. The failure of the CV group to improve on the item hostility is of concern: it might indicate a second-order error (failure to disclose a real difference because the sample is too small). However, fear and depression are intrapersonal psychological factors, whereas hostility is a social one. We noticed that uncertainty about the type of medication in these otherwise greatly improved patients evoked some irritation toward the study and the treating physician, which may well have influenced the hostility score in a negative sense. We conclude that CV and bromocriptine, significantly less so, has a beneficial influence on well-being in depressed hyperprolactinemic patients. The effect appears not to be related to the recurrence of ovulatory cycles. One factor may be its good penetration of the blood-brain barrier, another its structural resemblance to apomorphine. Further research into the antidepressive properties of CV is warranted. REFERENCES 1. Robyn C, Meuris S. The state of the art in human prolactin. In: K. Hoshino, editor. The prolactin gene family and its receptors. Amsterdam: Elsevier Science Publishers, 1988: MacLeod RM, Judd AM, Spangelo BL, Ross PC, Jarvis WD, Login LS. Systems that regulate prolactin release. In: K. Hoshino, editor. The prolactin gene family and its receptors. Amsterdam: Elsevier Science Publishers, 1988: Fava GA, Fava M, Kellner R, Serafini E, Mastrogiacomo I. Depression, hostility and anxiety in hyperprolactinemic amenorrhea. Psychother Psychosom 1981;36: Kellner R, Buckman MT, Fava GA, Pathak D. Hyperprolactinemia, distress and hostility. Am J Psychiatry 1984;141: Mattox JH, Buckman MT, Bernstein J, Pathak D, Kellner R. Dopamine agonists for reducing depression associated with hyperprolactinemia. J Reprod Med 1986;31: Buckman MT, Kellner R. Reduction of distress in hyperprolactinemia with bromocriptine. Am J Psychiatry 1985;142: Koppelman MCS, Parry BL, Hamilton JA, Alagna SW, Loriaux DL. Effect of bromocriptine on affect and libido in hyperprolactinemia. Am J Psychiatry 1987;144: Lappohn et al. Depression in hyperprolactinemia Fertility and Sterility

7 8. Grossman A, Wass JAH, Besser GM. The rapid diagnosis of sensitivity or resistance to dopamine agonists with depot bromocriptine. Acta Endocrinol (Copenh) 1987;116: Pellegrini I, Rasolonjanahari R, Gunz G, Bertrand P, Delivet S, Jelynak CP, et al. Resistance to bromocriptine in prolactinomas. J Clin Endocrinol Metab 1989;69: Fliickiger E. Pharmacological profile of dopaminergic agents. In: Molinatti GM, and Martini L, editors. Endocrinology Amsterdam: Elsevier Science Publishers, 1986; Gaillard RC, Nordmann R, Petcher TJ, Brownell J. A novel octahydrobenzo[g]quinoline, CV , with potent dopamine agonist properties. In: Molinatti GM, Martini L, editors. Endocrinology Amsterdam: Elsevier Science Publishers, 1986; Rasmussen C, Bergh T, Wide L, Brownell J. Long-term treatment with a new non-ergot long-acting dopamine agonist, CV , in women with hyperprolactinaemia. Clin Endocrinol (OxO 1988;29: Van der Heijden PFM, Lappiihn RE, Corbey RS, de Goeij WBKMV, Brownell J, Rolland R. The effectiveness, safety, and tolerability of CV in hyperprolactinemic women: a 12 month study. Fertil Steril 1989;52: Derogatis LR. SCL-90: administration, scoring and procedures manual for the revised version. Baltimore: Johns Hopkins University School of Medicine Clinical Psychometric Unit, Arrindell WA, Ettema JHM. Klachtenlijst (SCL 90). Lisse, The Netherlands: Swets and Zeitlinger B.V., Wabeke P, van Eeden C. Manual for the Wilcoxon test. Report S176 (M65-65A). Amsterdam: Mathematical Centre, Lappohn et al. Depression in hyperpro/actinemia 327