neuroleptics and prolactin secretion

zyxwvuts zyxwvu zyx zyxwvu Clinical Endocrinology (1976) 5, 273-282. EFFECT O F ACUTE AND CHRONIC NEUROLEPTIC T H E R A P Y O N S E R U M P R O L A C T I N LEVELS I N MEN AND WOMEN O F D I F F E R E N T AGE GROUPS JOSE LUIS DE RIVERA, S A M A R T H J I LAL, PRAKASH ETTIGI, SLAVOJ HONTELA, H E R B E R T F . M U L L E R AND HENRY G. FRIESEN Departments of Psychiatry, Douglas Hospital, Montreal General Hospital, Queen Mary Veterans’ Hospital, and Department of Physiology, University of Manitoba (Received 20 October 1975; revised 21 January 1976; accepted 28 January 1976) SUMMARY A single fasting level of serum prolactin was measured in each of sixty control subjects and eighty-three psychiatric patients of both sexes who had been on neuroleptic therapy for 2-4 weeks (acute treatment) or at least 5 years (chronic treatment) and who were aged either 17-45 or 48-85 years. All groups of patients had significantly higher mean prolactin levels than controls. Gender, age group of women, and exposure to acute or chronic treatment were significant variables determining the magnitude of neuroleptic-induced elevation of prolactin. In some of the groups, dose, duration of chronic therapy, and concomitant administration of anticholinergic drugs also influenced prolactin levels. Whereas all acutely treated women had prolactin values above the control range, one out of twelve (8.3%) of the women aged 17-45 years and six out of fourteen (42.9%) of the women aged 48-85 years who were under chronic treatment had normal values. Normal prolactin levels were also found in five out of sixteen (31.2%) of the acutely treated and nine out of twenty-four (37.5%) of the chronically treated men aged 17-85 years. INTRODUCTION Serum prolactin levels increase following the administration of neuroleptic drugs to healthy volunteers (Kleinberg et al., 1971; Friesen et al., 1972) or to psychiatric patients (Kleinberg & Frantz, 1971; Turkington, 1972; Bryant & Greenwood, 1972; Meltzer et al., 1975). In most reports the drug has either been administered as a single dose or for periods of less than 8 weeks. The effect of neuroleptics on serum prolactin levels after more protracted periods of treatment has been less completely studied (Kleinberg & Frantz, 1971; Beumont et al., 1974a, b; Wilson et al., 1975). This is of interest in view of a possible role of prolactin in human breast cancer (Salih et al., 1972; Flax et al., 1973; Smithline et al., 1975) and the zy zyxwvutsrq Correspondence: Dr S . Lal, Department of Psychiatry, Montreal General Hospital, Montreal H3G 1A4, P.Q., Canada. 273 274 zyxwvuts zyxwvu zyxw zyxwv Jose Luis de Rivera et al. recommendation by some authors for caution in the use of drugs that increase prolactin in patients with mammary malignancies (Palmer & Maurer, 1972). The present study was undertaken to investigate the effect of acute and chronic exposure to therapeutic doses of neuroleptics on serum prolactin levels in men and women of different age groups. METHODS Serum prolactin levelswere measured in men and women of two age groups, 17-45 years (young patients) and 48-85 years (older patients), who were either on acute or chronic neuroleptic therapy (phenothiazines, thioxanthenes or butyrophenones). These neuroleptic agents included chlorpromazine, levomepromazine, trifluoperazine, perphenazine, fluphenazine, prochlorperazine, thioridazine, pericyazine, thioxthixene and haloperidol. In addition, prolactin was measured in healthy volunteers on no medication. Patients receiving acute neuroleptic therapy consisted of individuals admitted consecutively to a psychiatric ward of a general hospital and who were on neuroleptic medication for 2-4 weeks at the time of blood sampling. One of the additional criteria for selection required that none of these patients had received major tranquillizers, antidepressants or other drugs known to elevate serum prolactin levels (Turkington, 1972) for at least 1 year prior to admission. Most subjects in this group were treated with neuroleptics for the first time. Patients receiving chronic neuroleptic therapy were patients in a large mental hospital who were on continuous treatment with major tranquillizers for at least 5 years and who had been hospitalized throughout this period of time. All patients were physically well and without clinical evidence of an endocrinopathy or organic brain disease. Patients with a previous lobotomy were excluded from the study. None of the subjects were on hormonal therapy. Seventy-six of the eighty-three patients were suffering from schizophrenia. Thirty-four of these patients were receiving anticholinergic antiparkinsonian drugs (trihexyphenidyl HCl, benztropine mesylate or procyclidine HC1) and eighteen, minor tranquilizers (diazepam) and/or hypnotic agents (flurazepam, dichloralphenazone or chloral hydrate) in addition to their neuroleptic medication. The subjects on these additional drugs were fairly evenly distributed amongst the groups under comparison. Many of the patients were on more than one neuroleptic agent. In the acutely treated patients doses as well as specific neuroleptic agent were changed during the 2-4 week period in several of the patients but were constant for 48 h prior to drawing blood for prolactin estimation. In the case of chronically treated patients, the medication had been unchanged for at least 3 months and in most cases 6 months. Dosage of medication varied widely between subjects. In order to compare doses of neuroleptics, the daily dose of neuroleptic taken by the acutely treated subjects over the previous 48 h and over the previous 3 months by the chronically treated patients were converted to millimoles of chlorpromazine. This conversion was based on the equivalence of antipsychotic potency, if known (Hollister, 1970). Data on age, dose and duration of neuroleptic therapy are given in Table 1. All the older women on neuroleptic therapy were aged 50 or over except for one of the acutely treated subjects who was 48. The youngest chronically treated patient was 23. The control subjects were mainly medical and paramedical personnel in the two hospitals or individuals living in a neighbouring boarding home for the elderly. These subjects were Group (age range, years) 1745 Acute neuroleptic therapy Age (years) Duration on neuroleptics Daily dose of neuroleptics (chlorpromazine equivalents, mm01es)~ 48-85 Age (years) Duration on neuroleptics Daily dose of neuroleptics (chlorpromazine equivalents, mmoles) Chronic neuroleptic therapy - Women (n) Men (n) Women (n) Men (n) 30.7k2.4 (14) 30.1f2.2 (14) 35.0k1.1 (12) 35.3k2.1 (12) + 2.9 0.2 weeks 2.7 t 0.2 weeks 4.15& 1.063 3.09 f 0.404 9.3 1.2 years 9.9 f 1.2 years % F 4.46 & 0.69y11) 3 0 50.3 2 1.2 (3) 51.5 (2) 3.0k0.6 weeks 3 weeks 1.88 k0.62 2.50, 5.01 264 f0.52’ 63.1 k2.5 (14) 64.4f2.8 (12) 15.5k 1.4’ years 12.2f 1.6 years 0.93 f0.22 92 Q K 2 0 1.40f0.40 cc. Data expressed as meanfstandard error of mean; n = number of subjects. Conversion of neuroleptic doses to millimoles of chlorpromazine based on dose equivalence given by Hollister (1970). 1 mmol chlorpromazine than chronically treated than chronically treated than chronically treated than chronically treated 320 men (P<0.05) and women (Pc0.01) aged 48-85 years. men (P<O.Ol) and women (P.:O.001) aged 48-85 years. women aged 48-85 years (P<0.01). women aged 17-45 years (P<O.O5) and chronically treated men (P<0.001) and women (P<0.001) aged than chronically treated women aged 17-45 years (P<O.Ol) and chronically treated men aged 1 7 4 5 years [P<0.01). R s’ rrc = mg. Significantly greater Significantly greater Significantly greater Significantly greater 48-85 years. Significantly greater z zy zyxwvu zyxwv zy zyxwvutsrqp zyxwvutsrqp zy zyxwvutsrqp z TABLE 1. Age, dose and duration of neuroleptic therapy’ zyxw zyxw Jose Luis de Rivera et al. zyxw zyxw physically well and without known psychiatric illness. None of the control subjects was on medication and none had received drugs which are known to affect prolactin levels over the preceding year. Fasting blood samples were drawn in the morning approximately 10 h after the last dose of neuroleptic and centrifuged immediately and the serum stored at - 20°C until assayed for prolactin. Prolactin was assayed by homologous radioimmunoassay (Hwang et al., 1971). In most cases samples from controls and drug-treated patients were measured simultaneously. Data were analysed by standard statistical techniques (Ferguson, 1966), namely, the twotailed t test and the Pearson product moment correlation coefficient. RESULTS All control values of serum prolactin for both sexes and age groups were less than 20 pg/l (Table 2). There were no differences between control men and women of the same age TABLE 2. Effect of acute and chronic neuroleptic treatment on serum prolactin levels' Age (years) 17-45 48-85 Controls Women' Men' 8.4+ 1.13 (4-1 7) n = 16 6.9k0.9 (4-1 5) n=14 8.2+ 1.13 (4-15) n = 12 5.6k0.4 (4-10) n=18 Acute neuroleptic therapy Women Men 89.4+_10.24 35.0k4.2' (14-60) (28-140) n = 14 n = 14 46.7+_5.g7 4, 16 (39-58) n=3 n=2 Chronic neuroleptic therapy zy Women Men 41.6+6.96 (7-85) n = 12 226k3.0 (10-40) n = 14 24.7k3.6 (8-48) n = 12 16.9k2.5 (7-31) n = 12 Values expressed as ,ug/l, meankstandard error of the mean; range in parentheses; n = number of subjects. Controls = subjects on no medication; acute neuroleptic therapy = subjects on continuous neuroleptic therapy for 2-4 weeks; chronic neuroleptic therapy = subjects on continuous neuroleptic therapy for at least 5 years. * Significantly less than corresponding acutely and chronically treated subjects ( P < 0.001). Significantly higher than male controls aged 48-85 years (P<0.05). Significantly higher than acutely treated men aged 17-45 years (P<O.OOl), and chronically treated men and women of either age group (P<O.OOl). Significantly higher than chronically treated women (P<0.05) and men (P<O.Ol) 48-85 years. Significantlyhigher than chronically treated men aged 1 7 4 5 years (Pc0.05) and 48-85 years (P<O.O1) as well as chronically treated women 48-85 years (P<0.05). Significantlyhigher than chronically treated men aged 17-45 years (P<0.05) and 48-85 years (P<O.OOl) and chronically treated women 48-85 years (P<O.Ol). group. However, the values for men and women aged 17-45 years were both significantly higher than for control men aged 48-85 years (P<0-05). In subjects receiving acute or chronic neuroleptic therapy the mean values were significantly higher than those in the corresponding control groups ( P <0.001). All acutely treated women of both age groups had values above the respective control range. In contrast, in women receiving chronic neuroleptic therapy, one out of twelve of the young women Neuroleptics and prolactin zyxw 277 (8.3%) and six out of fourteen of the older women (42.9%) had values within the range of the age-matched controls. Two of the fourteen men (14.3%) aged 17-45 years and one of the two men aged 48-86 years receiving acute neuroleptic therapy had values within the range of the corresponding control groups. Amongst the chronically treated men, four out of twelve (33.3%) aged 17-45 years and five out of twelve (41.7%) aged 48-85 years had values within the control range. Sex, age group (17-45 years or 48-85 years) as well as acute (2-4 weeks) versus chronic ( 5 or more years) treatment were significant variables influencing the magnitude of neuroleptic induced elevation of serum prolactin. The mean serum prolactin value was highest in the acutely treated young women (approximately 90 pg/l) (Table 2). Levels of approximately 40 pg/l were found amongst the acutely treated older women, chronically treated young women and acutely treated men aged 17-45 years. Chronically treated men aged 17-45 years and 48-85 years as well as chronically treated older women had mean prolactin levels of approximately 20 pg/l. The latter values were approximately three times the mean control values. There were insufficient numbers of acutely treated men aged 48-85 to draw conclusions. Acutely treated young women had significantly higher concentrations of serum prolactin than acutely treated men (P<O.OOl) and chronically treated men and women of either age range (P<O.OOl) (Table 2). There were only three subjects in the group of acutely treated older women; the mean serum prolactin was lower than that of the acutely treated young women but the difference was not statistically significant. The values for the acutely treated older women were significantly higher than those of the chronically treated older women (P<0.0 l), chronically treated men of either age group (P<O.O5 to <0.001) but not those of chronically treated young women or acutely treated men aged 17-45 years. Chronically treated young women had significantly higher values than the chronically treated older women (P<0.05) and chronically treated men of either age group (P<0*05to <0.01). There were no significant differences between the chronically treated older women and chronically treated men of either age group. Acutely treated men aged 17-45 years had significantly higher serum prolactin levels than chronically treated men ( P <0.01) or women (P<0.05) aged 48-85 years but not significantly different values from chronically treated men or women aged 17-45 years. There was no significant difference between chronically treated men aged 17-45 years and those aged 48-85 years. The statistical differences noted could not in many cases be attributed to differences in daily dosage of neuroleptic medication. Thus, amongst the four groups of patients aged 17-45 years there was no statistical difference in dose of neuroleptic administered with the exception that the chronically treated men received significantly higher neuroleptic doses than the chronically treated women (P<0-05)(Table 1). Despite the lower neuroleptic dose, these chronically treated women had significantly higher prolactin concentrations than the chronically treated men. The neuroleptic doses received by patients in the four groups aged 17-45 years were all significantly higher than the chronically treated men and women aged 48-85 years (Table 1). None of the groups of women showed a significant correlation between serum prolactin concentration and dose of neuroleptic (Table 3). However, amongst the chronically treated zyx zyx zyxwvuts 278 zyxwvuts zyx Jose Luis de Rivera et al. men there was a significant positive correlation between prolactin levels and dose of neuroleptic for patients aged 17-45 (P<0*05)and 17-85 years (P<O.Ol) (Table 3). zyxwvutsr zyxwvut TABLE3. Correlation between fasting serum prolactin levels and age, dose, and duration of neuroleptic therapy' GroupZ (age range, years) Prolactin and dose of neuroleptic Prolactin and age Prolactin and duration of neuroleptic therapy - r Acutely treated women 1745 +0.11 17-85 -0.23 df 12 15 P r NS NS +0.16 0.23 + 12 15 P r - - NS NS P df - - - zyxwvu Chronically treated women 1745 -0.08 48-85 -0.12 17-85 -0.56 10 12 24 NS NS < 0.01 Acutely treated men 1745 17-85 12 14 10 10 22 -0.41 -0.62 Chronically treated men 17-45 -0.19 0.05 48-85 17-85 -0.34 + df + 0.04 +0.25 +0.32 10 12 24 NS NS NS -0.44 -0.01 -0.43 10 12 24 NS NS < 0.05 NS < 0.01 +0.34 +0.23 12 14 NS NS - - - - NS NS NS + 0.68 +0.43 + 0.68 9 10 21 < 0.05 NS -0.52 +0.05 -0.28 10 10 22 NS NS NS < 0.01 - ' r = correlation coefficient; df = degrees of freedom; P = probability based on significance of correlation coefficient; NS = not significant. * Acutely treated patients were on continuous neuroleptic medication for 2-4 weeks ; chronically treated patients were on continuous neuroleptic medication for at least 5 years. TABLE4. Effect of antiparkinsonian medication on neuroleptic-induced increase in serum prolactin' Women Treatment age group (years) Acute neuroleptic therapy 1745 Chronic neuroleptic therapy 1745 48-85 + Men - ___- zyxwv + Antiparkinsonian drugs2 Antiparkinsonian drugs 72.2 k 17(5) 99.0 t 12.2(9) P = NS3 38.6+ 5.4(9) 31.0+69(5) P = NS 55.2+ 9.5(6) 27.02 6.5(6) P < 0.05 26.3 2 5.7(6) 23.02 4.8(6) P = NS 15.0+2.8(4) 25.7+3.7(10) P = NS 24.8 2 2.9(4) 13.0+ 2.4(8) P < 0.05 - zyx Values expressed as pg/l, mean k standard error of the mean; number of subjects in parentheses. = on antiparkinsonian medication; - = not on antiparkinsonian medication. P = probability based on Student's 'f' test; NS = not significant. + zyxw zyxwvut Neuroleptics and prolactin 279 Within each group of patients there was no correlation between concentration of serum prolactin and age (Table 3). However, for the combined patients aged 17-85 years there was a significant negative correlation between prolactin levels and age of chronically treated women (P<O.Ol) and age of acutely treated men (P<O.Ol). Amongst patients treated for at least 5 years there was a significant negative correlation between prolactin concentration and duration of treatment for women patients aged 17-85 years (Table 3). Amongst acutely treated patients, simultaneous administration of anticholinergic agents used as antiparkinsonian drugs did not affect fasting serum prolactin levels (Table 4). However, women aged 17-45 and men aged 48-85 years who were on antiparkinsonian agents as well as chronic neuroleptic therapy had significantly higher prolactin levels than age-matched patients on neuroleptics alone (P<0.05). DISCUSSION zyxw There is evidence that prolactin secretion is modulated by dopaminergic mechanisms in man (Martin et al., 1974). Neuroleptics are believed to increase prolactin secretion by blocking dopamine receptors in the hypothalamus (Daughaday & Jacobs, 1972) or possibly pituitary (Shaar & Clemens, 1974). Most studies on neuroleptic-induced serum prolactin increase have been conducted over short periods of drug administration (Kleinberg et al., 1971 ; Friesen et al., 1972; Bryant & Greenwood, 1972; Meltzer et al., 1975), periods of 2-12 weeks (Turkington, 1972; Kleinberg & Frantz, 1971) or, in the exceptional case, following 18 months drug treatment (Kleinberg & Frantz, 1971). Recently, Beumont et al. (1974a, b) have provided data on serum prolactin levels following more extensive periods of phenothiazine exposure. These authors found that fourteen out of sixteen premenopausal women (aged 18-48) treated for 3 weeks to 14 years and three out of four postmenopausal women (aged 49-57) treated for 10 years had elevated serum prolactin levels whereas no increase was noted in five men treated for 10 years. In the study by Wilson et al. (1975) on female psychiatric patients, with an average age of over 70, and treated for up to 8 years with neuroleptics, the mean prolactin levels were elevated; several of the subjects had values within the control range. In the present study all groups of neuroleptic treated patients had significantly higher mean prolactin concentrations than controls. Unlike the findings of Beumont et al. (1974b), over 50% of our chronically treated men had elevated prolactin levels. In addition, normal prolactin levels were found equally in chronically treated women aged 48-85 (six out of fourteen) and chronically treated men of a similar age group (five out of twelve). Gender and age group of women were found to be important factors determining the magnitude of neuroleptic-induced elevation of basal serum prolactin levels. Acute (2-4 weeks) and chronically treated (> 5 years) women aged 17-45 had significantly higher prolactin levels than did men matched for age and duration of neuroleptic therapy. This sex difference could not be accounted for by differences in neuroleptic dose. Thus, though the mean prolactin concentration was significantly higher in chronically treated women aged 17-45 years than in chronically treated men the latter were on significantly higher doses of neuroleptics. The sex difference was no longer evident when chronically treated women aged 48-85 zyxwvu zyxwvu zyxw Jose Luis de Rivera et al. years were compared to chronically treated men whose dose and duration of neuroleptic therapy were similar. The chronically treated women aged 17-45 years had significantly higher prolactin levels than chronically treated women aged 48-85 years. This difference between the two age groups may reflect an effect of pre- and post-menopausal status. Though the older women were on significantly lower doses of neuroleptic than the young women this is not a sufficient explanation for the difference as there was no significant correlation between dose of neuroleptic and serum prolactin levels for these groups of women patients. The duration of neuroleptic therapy was, however, significantly longer in the older women than in the young women. This factor may have contributed to some of the difference between the two groups as a significant negative correlation was found between the duration of neuroleptic therapy received by the combined group of chronically treated women aged 17-85 and serum prolactin level. The sex difference in serum prolactin levels between subjects aged 17-45 years and absence of an effect of gender in the older age groups suggests that oestrogens enhance the neuroleptic effect on prolactin secretion. Such an explanation is in keeping with the findings of Buckman & Peake (1973) who found that in normal subjects perphenazine-induced elevation of prolactin was greater in women than in men and that administration of exogenous oestrogens augments this response in both sexes. Acute administration of neuroleptics (2-4 weeks) resulted in significantly higher prolactin levels than chronic therapy (5 years or more) with similar daily doses, in both the young and older women. Whereas all acutely treated women had elevated serum prolactin levels, seven out of twenty-six of the chronically treated women (six of whom were 17-45 years) had normal levels. Also, the chronically treated women (aged 17-85 years) showed a significant negative correlation between prolactin level and duration of treatment. These data suggest that a degree of adaptation to neuroleptic blockade of hypothalamic dopamine receptors occurs with chronicity of drug administration, at least in women. In this regard, adaptation to neuroleptic action has been demonstrated in the rat with respect to blockade of striatal dopaminergic receptors (Asper et al., 1973). The absence of a chronicity effect of neuroleptic treatment for men aged 17-45 suggests that adaptation only occurs with respect to the oestrogen-enhancing mechanism. The lower levels of prolactin in chronically treated men aged 48-85 compared with acutely treated men aged 17-45 appears to be related to differences in neuroleptic dose. It is possible that normal prolactin levels in some subjects were the result of non-compliance in swallowing medication or inadequate absorption of neuroleptic from the gut. Normal fasting levels might also occur if only short-lasting secretory bursts of prolactin follow each dose of neuroleptic. Acute schizophrenia is not associated with an alteration of serum prolactin levels (Meltzer et al., 1975) but whether chronicity of the psychosis affects neurohormonal responsiveness is unknown. Amongst the acutely treated men and chronically treated women aged 17-85 years there was a significant negative correlation between age and serum prolactin level. In the case of women the decline in prolactin response with age may be a reflection of the effect of menopausal status. There is evidence from animal research that cholinergic mechanisms decrease prolactin secretion (Meites, 1974). In the present study anticholinergic drugs increased the prolactin response in some groups but not in others. zyxwvuts zyxwvuts Neuroleptics and prolactin 28 1 zy zyxw zyx It is evident from the present study that in the clinical treatment setting many interacting variables influence the effect of neuroleptics on serum prolactin levels. It is also clear that in the majority of cases elevated prolactin levels persist despite chronicity of neuroleptic exposure. Thus, if elevated serum prolactin levels play a role in human breast cancer then subjects exposed to long-term neuroleptic treatment might be expected to have a higher incidence of this malignancy. Evidence for this, however, is lacking (Ettigi et al., 1973). ACKNOWLEDGMENTS This work was supported by grants from the Medical Research Council (Canada) and from the U.S. Public Health Service Child Health and Human Development Institute. Additional support was received from Merck Sharp and Dohme, Canada Ltd, Montreal, Canada. zyxwv zyxw zyxwvutsr zyxw REFERENCES ASPER,H., BAGGIOLINI, M., BURKI,H.R., LAUENER, H., RUCH,W. & STILLE,G. (1973) Tolerance phenomena with neuroleptics, catalepsy apomorphine stereotypies and striatal dopamine metabolism in the rat after single and repeated administration of loxapine and haloperidol. European Journal of Pharmacology, 22,287-294. BEUMONT, P.J.V., GELDER, M.G., FRIESEN, H.G., HARRIS,G.W., MACKINNON, P.C.B., MANDELBROTE, B.M. & WILES,D.H. (1974a) The effects of phenothiazines on endocrine function. 1 . Patients with inappropriate lactation and amenorrhoea. British Journal of Psychiatry, 124,413419. BEUMONT, P.J.V., CORKER, C.S., FRIESEN, H.G., KOLAKOWSKA, T., MANDELBROTE, B.M., MARSHALL, J., MURRAY,M.A.F. & WILES, D.H. (1974b) The effects of phenothiazines on endocrine function. 2. Effects in men and postmenopausal women. British Journal of Psychiatry, 124,420430. BRYANT, G.D. & GREENWOOD, F.C. (1972) The concentrations of human prolactin in plasma measured by radioimmunoassay: experimental and physiological modifications. Lactogenic Hormones (ed. by G. E. W. Wolstenholme and J. Knight), pp. 197-206. Churchill Livingstone, Edinburgh. BUCKMAN, M.T. & PEAKE,G.T. (1973) Estrogen potentiation of phenothiazine-induced prolactin secretion in man, Journal of Cfinical Endocrinology and Metabolism, 37,977-980. DAUGHADAY, W.H. & JACOBS, L.S. (1972) Human prolactin. Ergebnisse der Physiologie, 67, 169-194. ETTIGI,P., LAL,S. & FRIESEN, H.G. (1973) Prolactin, phenothiazines, admission to mental hospital, and carcinoma of the breast. Lancet, ii, 266-267. FERGUSON, G.A. (1966) Statistical Analysis in Psychology and Education, 2nd edn. McGraw-Hill, Toronto. FLAX,H., SALIH,H., NEWTON,K.A. & HOBBS,J.R. (1973) Are some women’s breast cancers androgen dependent? Lance?, i, 1204-1207. FRIESEN, H., GUYDA, H., HWANG, P., TYSON, J.E. & BARBEAU, A. (1972) Functional evaluation of prolactin secretion: a guide to therapy. Journal of Clinical Investigation, 51, 706-709. HOLLISTER, L.E. (1970) Choice of antipsychotic drugs. American Journat of Psychiatry, 127, 186-190. HWANG, P., GUYDA, H. & FRIESEN, H. (1971) A radioimmunoassay for human prolactin. Proceedings of the National Academy of Sciences, 68, 1902-1906. KLEINBERG, D.L. & FRANTZ, A.G. (1971) Human prolactin: Measurement in plasma by in vitro bioassay. Journal of Clinical Investigation, 50, 1557-1568. KLEINBERG, D.L., NOEL,G.L. & FRANTZ, A.G. (1971) Chlorpromazine stimulation and L-dopa suppression of plasma prolactin in man. Journal of Clinical Endocrinology and Metabolism, 33, 873-876. MARTIN, J.B., LAL,S., TOLIS,G. & FRIESEN, H.G. (1974) Inhibition by apomorphine of prolactin secretion in patients with elevated serum prolactin. Journal of Clinical Endocrinology and Metabolism, 39, 180182. MEITES, J. (1974) Neuroendocrinology of lactation. Journal of Investigative Dermatology, 63, 119-124. MELTZER, H.Y., SACHAR, E.J. & FRANTZ,A.G. (1975) Dopamine antagonism by thioridazine in schizophrenia. Biologicaf Psychiatry, 10,53-57. L.H. (1972) Prolactin and breast cancer. Lancet, ii, 1036. PALMER, J. & MAURER, 282 zyxwvuts zyxw zyxwvuts Jose Luis de Rivera et al. SALIH,H., FLAX,H., BRANDER, W. & HOBBS,J.R. (1972) Prolactin dependence in human breast cancers. Lancet, ii, 1103-1105. SHAAR, C.J. & CLEMENS, J.A. (1974) The role of catecholamines in the release of anterior pituitary prolactin in vitro. Endocrinology, 95, 1202-1212. SMITHLINE, F., SHERMAN, L. & KOLODNY, H.D. (1975) Prolactin and breast carcinoma. New EngZand Journal of Medicine, 292, 784-792. TURKINGTON, R.W. (1972) Prolactin secretion in patients treated with various drugs. Archives of Internal Medicine, 130, 349-354. WILSON, R.G., HAMILTON, J.R., BOYD,W.D., FORREST, A.P.M., COLE,E.N., BOYNS, A.R. & GRIFFITHS, K. (1975) The effect of longterm phenothiazine therapy on plasma prolactin. British Journat ofPsychiatry, 127, 71-74.