0021-972X/78/4706-1352$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1978 by The Endocrine Society
Vol. 47, No. 6 Printed in U.S.A.
Nomifensine: Diagnostic Test in Hyperprolactinemic States* EUGENIO E. MULLER, ANDREA R. GENAZZANI, AND SERENA MURRU Institute of Pharmacology and Pharmacognosy, University of Cagliari (E.E.M.), 09100 Cagliari; Chair of Obstetric Pathology, University of Siena (A.R.G.), 53100 Siena; and the Department of Obstetric and Gynecology, University of Pisa, 56100 Pisa, Italy ABSTRACT. Nomifensine, an antidepressant agent which activates dopamine (DA) neurotransmission mainly by inhibiting DA reuptake in the central nervous system, was administered either to puerperal lactating women or to subjects with nonpuerperal hyperprolactinemia. In 10 postpartum women and in 7 women with no evidence of PRL-secreting tumor, oral administration of nomifensine (100 or 200 mg, respectively) induced in the following 5 h a clear-cut inhibition of plasma PRL
I
N RECENT years, the studies of the mechanism (s) involved in the neuroendocrine regulation of PRL secretion have led to the introduction of several functional tests in clinical practice. These tests have been used mainly with the aim of differentiating between hyperprolactinemia due to pituitary tumors and so-called "functional" hyperprolactinemia. Early medical diagnosis of hyperprolactinemic states is a noteworthy problem, since it is possible that early treatment may prevent functional hyperprolactinemic disorders from progressing to clinically demonstrable pituitary tumors. So far, the most frequently used stimulation tests include administration of hypothalamic hormones, e.g. TRH or central nervous system (CNS)-active drugs {i.e. dopamine (DA) receptor blockers such as chlorpromazine or sulpiride). The inhibition tests consist of the administration of DA precursor or agonist drugs, e.g. L-dopa or bromocriptine (see Refs. 1 and 2). None of these tests allows accurate discrimination between tumorous and func-
levels; in 10 patients with PRL-secreting tumors, the drug did not lower plasma PRL levels. In 2 of these patients, nonsupressibility of plasma PRL levels to nomifensine was the only indication of the existence of a pituitary microadenoma. It is proposed that acute nomifensine testing may be a valid neuropharmacological tool for discriminating between individuals with and without pituitary adenoma. (J Clin Endocrinol Metab 47: 1352, 1978)
tional hyperprolactinemia (1-3). Also, concomitant evaluation of other pituitary trophic hormone secretions {e.g. gonadotropins) in the resting state or after administration of LRH has been discouraging with regard to this differentiation (see Ref. 4). The differential diagnosis is further compounded by the fact that many cases originally classified as functional, because of the finding of a radiologically normal pituitary fossa, may be due to pituitary microadenomas (5). We propose that nomifensine1 (8-amino-2methyl - 4 - phenyl-1,2,3,4- tetrahy droisoquinoline; Psicronizer, Hoechst S.p.A. Italia), an antidepressant drug which activates DA neurotransmission mainly by inhibiting DA reuptake (6) but with no ability to directly affect DA receptors (7), may be a useful neuropharmacological tool for discriminating functional from tumorous hyperprolactinemia. Materials and Methods
Seventeen informed and consenting volunteers with physiological puerperal hyperprolactinemia (postpartum day 2) and 17 hyperprolactinemic patients were studied. The 17 subjects in the puerpeReceived January 12, 1978. rium were divided into two groups; the first (10 Address requests for reprints to: E. E. Miiller, c/o Department of Pharmacology, University of Milan, Via subjects) underwent acute nomifensine testing, the Vanvitelli, 32, 20129, Milano, Italy. * This work was supported in part by C. N. R. Biology of Reproduction project.
1
Also marketed as Alival.
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NOMIFENSINE TEST IN HYPERPROLACTINEMIA second (7 subjects) served as a control group for evaluating the spontaneous fluctuations in plasma PRL levels. On the basis of clinical, radiological, and biochemical data, the 17 nonpuerperal hyperprolactinemic patients were divided into two groups (Table 1). Group 1 consisted of 7 patients with normal sella turcica and plasma PRL levels which on several occasions were found to be constantly, although moderately, elevated (Table 1). Case 7 had PRL levels up to 80 ng/ml. Three patients (cases 3-5) were obese, and one of them (case 4) was premenopausal. Two patients were oligomenorrheic (cases 2 and 6) and cases 1 and 7 were amenorrheic. Case 7 had taken neuroleptic drugs for at least 2 months. All patients, except for case 5, had galactorrhea. Group 2 was composed of 10 patients with pituitary PRL-secreting tumors. In 8 patients (cases 1-8), the diagnosis of pituitary tumor was made on the basis of highly elevated serum PRL levels and/or an abnormal sella turcica. Case 9 underwent
1353
surgery (see below) only on the basis of elevated plasma PRL levels; case 10a was operated after 1 yr of observation when a double profile of the sella and a further marked rise of plasma PRL (case 10b) occurred. Hypocycloidal polytomography was used in all cases to evaluate the radiomorphology of the sella. Diagnosis of pituitary tumors based on abnormal biochemical and/or radiological findings (group 2, cases 1-8 and 10b) was confirmed in all patients at surgery by the selective removal and histological examination of an adenoma through transsphenoidal microsurgical exploration of the sella. Table 1 summarizes the clinical and laboratory data for the hyperprolactinemic patients. All experiments were performed in the morning after an overnight fast and in menstruating subjects (group 1, cases 2-6) in the early follicular phase. Serial blood specimens were collected through an indwelling polyethylene cannula placed in the antecubital vein and kept open by the slow infusion of 0.9% saline. Starting at 0830-0900 h, subjects
TABLE 1. Clinical and laboratory data and gonadotropin responses of patients without or with evidence of pituitary PRL-secreting tumor
Case no.
Without evidence of PRL tumor 1 (24)'' 2(25) 3(37) 4(45) 5(20) 6(23) 7(35) With evidence of PRL tumor 1(26) 2(30) 3(22) 4(41) 5(34) 6(38) 7(25) 8(34) 9(28) 107 (21)" a
b
Length of amenorrhea (yr)a
S, 2 0 — -
0 S, 8 months
S, 2
S,5 S,3 S.15 S, 2 S,20 S, 8 months
S,2 S,3 P, 5
A Maximum (mU/ml) c
Basal hormone levels G A6
Sella turcica x-ray PRL (ng/mJ)
LH (mU/ml) rf
FSH (mU/ml) rf
22.0-26.0 32.0-37.0 18.5-26.0 20.0-24.0 21.0-25.0 14.0-23.0 25.0-80.0
15.0-32.0 2.4-19.0 3.9-4.8 49.0-65.0 11.6-19.0 3.0-6.0 6.0-8.0
6.9-17.0 5.2-14.0 8.2-10.8 33.0-90.0 4.7-5.5 5.7-12.0 7.0-8.0
+ + + + — + +
Normal Normal Normal Normal -Normal Normal Normal
+ + + + + + + +
Enlarged Double profile Enlarged Enlarged Double profile Enlarged Enlarged Double profile Normal
50.0-80.0 230.0-375.0 48.0-60.0 250.0-350.0 28.0-55.0 132.0-156.0 40.0-85.0 28.0-55.0 44.0-65.0
6.0-10.0 4.0-7.0 1.0-8.0 7.0-10.0 2.4 2.8-3.5 2.6
+ +
Normal Double profile
32.0-50.0 90.0-130.0
4.5-8.0 4.0-7.5
P E2 (pg/ml) (pg/ml)e
50 120
400 500
T H
r On
4.4 9.0
60.0 18.0 23.0 76.0 33.0 9.0
71.0 2.0 12.0
13.2 10.2 28.0
130
830
220 100 270 110
980 550 480 900
8.0-14.0 3.0-10.0 7.0-11.0 14.0-20.0
96 12
255 185
12
370
56
664
24.0 28.0 42.0
6.8-10.3
70
480
92.0
54.0
66
500
150 140
600 400
17.5
7.4
4.6-6.0 4.2-7.0
6.2
" S, Secondary; 0, oligomenorrhea; P, polymenorrhea. * Galactorrhea. c Highest plasma LH and FSH levels during LRH testing. d Control values in early follicular phase: LH, 5.9 ± 1.1 mU/ml; FSH, 11.3 ± 2.2 mU/ml. e Progesterone. ^Age (in years) of subject is in parentheses. * a and b refer to examinations performed at 1-yr interval.
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JCE & M • 1978 Vol 47 • No 6
MULLER, GENAZZANI, AND MURRU
1354
Results
received nomifensine (100 or 200 mg) orally in a single administration (see Results). Patients with radiological evidence of a pituitary PRL-secreting tumor or nonsupressibility to acute nomifensine testing (cases 9 and 10a) underwent acute testing with bromocriptine (CB 154 Sandoz; 5.0 mg orally) on separate days. After two baseline blood samples were taken (—30 and 0 min), further blood samples were obtained at 30- to 60-min intervals for 5 h. Plasma was separated, frozen, and stored at —20 C until assayed. Plasma PRL values were assessed with a radioimmunological method, using materials supplied by Biodata (Milan, Italy). One nanogram of the human PRL standard used is equivalent to 23 /xU WHO 71-222, corresponding to 1 ng NIH F-l. The sensitivity of the assay was 1.0 ng/ml and the intraassay variation was 4.3 ± 1.2% (SD). The upper limits of normal in our laboratory were: early follicular phase, 12 ng/ml; ovulatory period, 18 ng/ml; luteal phase, 16 ng/ml (8). In hyperprolactinemic patients, plasma LH and FSH (under basal conditions or after LRH), plasma estradiol (E2), and progesterone were determined by RIA kits supplied by CEA-SORIN (Saluggia, Italy). To evaluate the effect of Nomifensine, results were expressed either as the ratio between plasma PRL levels at each time period (S) and baseline (B) levels (mean of —30- and 0-min values) or as absolute values. The S:B ratio was also used for evaluating spontaneous fluctuations in plasma PRL levels. Results were analyzed using unpaired or paired t tests.
Puerperium Baseline PRL values were 101 ± 2.4 (SEM) ng/ml in control subjects and 199 ± 10.5 ng/ml in subjects undergoing acute testing. No consistent variations were found in plasma PRL levels in the control group receiving placebo during 5 h of observation (range of S:B values, 0.94-1.09; data not presented). Nomifensine (100 mg orally) administration was associated with a significant decrease in plasma PRL levels during the same period; this reduction was present at 120 min (P < 0.001 vs. control group), after which levels progressively declined to reach nadir values at 240-300 min (about 50% inhibition; Fig. 1). Hyperprolactinemic patients In 7 patients with no evidence of PRL-secreting tumor, administration of nomifensine (200 mg orally) was followed by a prompt and clear-cut reduction in plasma PRL levels (about 50% inhibition from 150-300 min), similar to that observed in postpartum women (Fig. 1). In 10 patients with a pituitary PRLsecreting tumor, administration of nomifensine (200 mg orally) did not alter plasma PRL levels (maximal inhibition, 14% at 240 min). In these subjects, in contrast, administration of
S/Bi.2
TUMOR-NOM(IO)
NON TUMOR-NOM(7) POST-PARTUM-NOM (10)
TUMOR-CB 154(10)
60
90
120
150
180
210
240
300 MIN.
FIG. 1. Plasma PRL levels in postpartum women and hyperprolactinemic patients without or with evidence of PRL-secreting tumor given nomifensine (Nom; 100 or 200 mg orally). Also shown are PRL levels in patients with tumor given bromocriptine (CB 154; 5.0 mg orally). Number of subjects is in parentheses. PRL levels are significantly lower (P < 0.05) than values present in tumoral subjects: (in postpartum women given Nom from 120-300 min, in patients without evidence of PRL-secreting tumor given Nom from 30-240 min, and in tumoral subjects given bromocriptine from 60-300 min). In the ordinate, values are expressed as S:B (see text for details).
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NOMIFENSINE TEST IN HYPERPROLACTINEMIA bromocriptine (5.0 mg orally) resulted in a striking fall in plasma PRL levels (about 80% at 210-300 min; Fig. 1). Table 2 shows the individual PRL responses to acute nomifensine testing of the 17 patients. No untoward side-effects were noticed in any subject after drug administration. Discussion Nomifensine was effective in lowering plasma PRL levels both in subjects with the functional hyperprolactinemia of the puerperium and those with nonpuerperal hyperprolactinemia without evidence of PRL-secreting tumor. In contrast, it was ineffective in subjects with a PRL-secreting tumor. Although plasma PRL levels in postpartum women reach nonpregnant levels around the third postpartum week, changes recorded in lactat-
ing women after administration of placebo and after nomifensine made it unlikely that the depressant effect of the latter was secondary to spontaneous plasma PRL fluctuations. The same conclusion applies to the PRL-suppressive effect of the drug in patients in whom the existence of a pituitary PRL-secreting tumor could be excluded on the basis of clinical, biochemical, and radiological characteristics. The effectiveness of nomifensine in lowering plasma PRL levels in states of functional hyperprolactinemia contrasts with the inability of the drug to affect PRL secretion in subjects with a pituitary tumor. This fact does not seem to be related to the magnitude of baseline PRL levels; in patients 1-10, nonsupressibility of plasma PRL to nomifensine was present with baseline values ranging from 28-350 ng/ml (Table 2). The nonresponsiveness of the tumor subjects was not due to
TABLE 2. Individual plasma PRL values (nanograms per ml) in patients without or with evidence of pituitary PRLsecreting tumor before and at intervals after administration of 200 mg nomifensine orally Time (min) Case no. Without evidence of PRL tumor 1 2 3 4 5 6 7 With evidence of PRL tumor'' 1" 2 3" 4 5 6 7 8 9 10" a b
0"
30
60
90
120
150
180
210
240
300
24.0 32.5 20.0 20.0 21.0 17.5 30.0
22.0 19.0 17.0 15.5 13.5 16.5 13.0
18.5 19.0 15.5 14.5 13.0 14.0 18.5
20.0 15.5
19.5 16.5 15.2
13.0 14.0 13.0 13.0 15.2 10.5 3.0
11.5 15.0
11.0 21.0 16.0 16.0
12.5 12.5 3.0
10.9 14.5 14.0 15.5 12.0 12.2 3.0
68.25 350.0 58.0 268.5 28.0 156.0 60.0 28.0 58.0
65.0 350.0 50.0 230.0 27.0 136.0 55.0 27.0 55.0
41.5 132.0
46.0 136.0
14.5 11.2 13.0 17.0
9.5 14.0 16.0
13.0 15.5 14.8 13.5 10.5 10.5 3.0
65.0 350.0 54.0 220.0 31.0 144.0 70.0 31.0 55.0
375.0 54.0 220.0 29.0 156.0 57.0 29.0 52.0
60.0 325.0 55.0 220.0 26.0 124.0 57.0 26.0 50.0
55.0 325.0 54.0 210.0 27.0 144.0 46.0 27.0 50.0
67.5 350.0 54.0 180.0 30.0 164.0 53.0 30.0 55.0
67.5 310.0 58.0 250.0 27.0 144.0 56.0 27.0 57.0
55.0 310.0 55.0 210.0 28.0 140.0 46.0 28.0 62.0
65.0 400.0 54.0 200.0
50.0 125.0
50.0 125.0
41.0 138.0
41.0 141.0
34.0 138.0
35.0 128.0
34.0 121.0
32.0 120.0
16.5 3.0
43.0 58.0
Nadir values (min)
10.9 (240)* 14.0 (180) 13.0 (180) 13.0 (180) 9.5 (120) 10.5 (150) 3.0 (150)
55.0 310.0 50.0 180.0 26.0 136.0 43.0 26.0 50.0
(150) (210) (30) (180) (120) (30) (300) (120) (150)
32.0 (300) 120.0 (300)
" Mean of - 3 0 - and 0-min values. * Time at which nadir occurred. '' Patients 1-10 also underwent acute testing with CB 154 (see text and Fig. 1 for details). d Also unresponsive to 300 mg nomifensine orally. e a and b refer to nomifensine testing performed at 1-yr intervals (see Table 1).
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MULLER, GENAZZANI, AND MURRU
1356 DIRECT
PRL
INDIRECT
PRL
PRL
FIG. 2. Hypothetical scheme to explain the mechanism of the suppressive effect on PRL secretion of direct or indirect DA agonist drugs. In the upper part (a and b), the possibility is depicted of a mechanism of control mediated by both DA and PIF; in the lower part (c and d), only the control by DA is reported. For the sake of clarity, an axo-somatic contact between the DA neuron and the PIF neuron has been reported; on neuroanatomical ground, an axo-axonic contact is more likely. Direct DA agonist drugs may affect DA receptor sites located either in the CNS (a) or at pituitary level (a and c). Indirect DA agonist drugs, such as nomifensine, which blocks DA reuptake, may affect DA receptors sites located only in the CNS (b). Panel d envisages the possibility that nomifensine may act by blocking the reuptake of DA released into the portal circulation. This possibility seems to be unlikely, since it is conceivable that presynaptic capture of released DA is not a major mechanism for neurotransmitter removal at median eminence level. DA, Dopaminergic neuron; PIF, prolactin-inhibiting factor neuron, (+), refers to activation of DA neurotransmission
JCE&M • 1978 Vol47 • No 6
refractoriness of the pituitary adenomas to DA stimulation; in the same subjects, bromocriptine, a direct DA agonist drug, induced a striking suppression of the elevated baseline PRL levels. The possibility of an insufficient dosage of nomifensine in subjects with pituitary tumors is also unlikely considering both the sensitivity of DA receptor sites located on the tumorous gland (9) and the finding that in two subjects (cases 1 and 3), a dose as high as 300 mg nomifensine was completely ineffective in lowering plasma PRL levels (data not presented). It is of note that in the functional hyperprolactinemia of the puerperium, despite the presence of higher or similarly elevated baseline PRL levels (mean, 200 ng/ml), even the dose of 100 mg nomifensine markedly lowered plasma PRL levels. Although the inhibitory role of the dopaminergic system(s) in the control of PRL secretion has been unequivocally established (10, 11), it is still not clear whether a PRLinhibiting factor (PIF), whose activity is tonically stimulated by dopaminergic neurons, exists in the hypothalamus or whether the PIF activity of the hypothalamus is entirely accountable by brain DA. DA released from tuberoinfundibular (TIDA) dopaminergic nerve terminals into the hypophyseal portal circulation (12) may act directly at the level of the anterior pituitary, where receptor sites for DA have been located (13, 14) (Fig. 2). Direct DA agonist drugs (such as bromocriptine, apomorphine, piribedil, etc.) may inhibit PRL release either indirectly, by stimulating DA receptors (in the TIDA system?) which then release PIF (Fig. 2a), or by direct stimulation of DA receptors located on pituitary lactotrophs (Fig. 2c). Even though the main site of action of these compounds is presently unknown, on theoretical grounds either a CNS and/or a pituitary site of action is envisaged (13-15). The double site of action of these compounds prevents establishing a CNS or a pituitary etiology of the hyperprolactinemic state. (a and b) or to DA release (d); (—), refers to the inhibitory effect of direct DA agonist drugs on PRL secretion; ||, indicates the block of DA reuptake operated by nomifen-
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NOMIFENSINE TEST IN HYPERPROLACTINEMIA
1357
The same conclusion is not valid for drugs Acknowledgments such as Nomifensine, capable of enhancing The participation in these studies of Drs. F. Camanni, dopaminergic neurotransmission without di- F. Massara, and D. Cocchi is gratefully acknowledged. rectly affecting DA receptor sites (Fig. 2b). References Such drugs activate dopaminergic neurotrans- 1. FAGLIA, G., P. BECK-PECCOZ, P. TRAVAGLINI, B. AMBROSI, M. RONDENNA, A. PARACCHI, A. SPADA, G. WEBER, R. BARA, mission via presynaptic events (DA release AND A. ROUZIN, Functional studies in hyperprolactinemic and inhibition of DA reuptake) rather than by states, In Crosignani, P. G., and C. Robyn (eds.), Prolactin and Human Reproduction, New York, Academic Press, 1977, stimulation of postsynaptic DA receptors. p. 225. Thus, they would be expected to inhibit PRL 2. Kleinberg, D. L., G. L. Noel, and A. G. Frantz, Galactorrhea: a study of 235 cases including 48 with pituitary tumors, N secretion in the so-called "functional" hyperEnglJMed 296: 589, 1977. prolactinemia, a condition in which a presyn- 3. JACOBS, H. S., S. FRANKS, M. A. MURRAY, 0. G. R. HULL, S. J. STEELE, AND J. D. N. NABARRO, Clinical and endocrine aptic pool of DA available for release is exfeatures of hyperprolactinemic amenorrhea, Clin Endocrinol pected to be present (Fig. 2b), and ineffective 5: 439, 1976. in lowering PRL in hyperprolactinemic states 4. L'HERMITE, M., A. CAUFRIEZ, AND C. ROBYN, Pathophysiology of human prolactin secretion with special reference to due to a primitive tumor of pituitary lactoprolactin-secreting pituitary adenomas and isolated galactorrhea, In Crosignani, P. G., and C. Robyn (eds.), Prolactin and trophs. It is a common notion, in fact, that the Human Reproduction, New York, Academic Press, 1977, p. normal or pathological mammalian pituitary 179. does not contain the presynaptic neuronal 5. JACOBS, H. S., AND S. FRANKS, Prolactin studies, pituitary tumor, and reproductive function, Br Med J 2: 141, 1975. component (16) through which activation of 6. HUNT, P., M.-H. KANNENGIESSER, AND J.-P. RAYNAUD, Nomifensine: a new potent inhibitor of dopamine uptake into the postsynaptic catecholamine receptor ocsynaptosomes from rat corpus striatum, J Pharm Pharmacol curs physiologically. Thus, drugs which block 26: 370, 1974. DA reuptake should be unable to affect DA 7. GERHARDS, H. G., A. CARENZI, AND E. COSTA, Effects of nomifensine on motor activity, dopamine turnover rate and receptor sites located on the pituitary gland. cyclic 3',5'-adenosine monophosphate concentrations of rat striatum, Naunyn Schmiedebergs Arch Pharmacol 286: 49, However, if one admits that development of 1974. a pituitary tumor takes place as a continuum 8. GENAZZANI, A. R., G. MAGRINI, F. FACCHINETTI, S. ROMAGNINO, C. PINTOR, G. P. FELBER, AND P. FioRETTi, Behavior from a normal cell through hyperplasia and, and origin of plasma androgens throughout the menstrual ultimately, adenoma formation, stages of cycle, In Martini, L., and M. Motta (eds.), Androgens and Antiandrogens, New York, Raven Press, 1977, p. 247. varying degrees of PRL autonomy and, hence, 9. MASHITER, K., E. ADAMS, M. BEARD, AND A. HOLLEY, Broresponsiveness to nomifensine should be exmocryptine inhibits prolactin and growth hormone release by human pituitary tumors in culture, Lancet 2: 197, 1977. pected as the lesion evolves. However, the 10. MEITES, J., Control of prolactin secretion in animals, In Pasobservation that nomifensine failed to lower teels, J. L., and C. Robyn (eds.), Human Prolactin, Amsterdam, Excerpta Medica, 1975, p. 105. PRL in patients with baseline levels as low as 11. MULLER, E. E., G. NISTICO, AND U. SCAPAGNINI, Neurotrans28.0-41.5 ng/ml (group 2, cases 5, 8, and 10a) mitters and Anterior Pituitary Function, New York, Academic Press, 1978. would suggest that P R L autonomy occurs 12. BEN-JONATHAN, N., C. OLIVER, H. J. WEINER, R. S. MICAL, since the early stages of the development of AND J. C. PORTER, Dopamine in hypophysial portal plasma of the rat during the estrous cycle and throughout pregnancy, the pituitary neoplasm. Endocrinology 100: 452, 1977. In conclusion, based on the rationale behind 13. MACLEOD, R. M., AND J. E. LEHEMEYER, Studies on the mechanism of the dopamine-mediated inhibition of prolactin this testing, the present findings suggest that secretion, Endocrinology 94: 1077, 1974. acute nomifensine testing may be the first 14. MACLEOD, R. M., H. KIMURA, AND I. LOGIN. Inhibition of prolactin secretion by dopamine and piribedil (ET-495), In neuropharmacological tool capable of discrimPeciJe, A., and E. E. Muller (eds.), Growth Hormone and inating between individuals with and without Related Peptides, Amsterdam, Excerpta Medica, 1976, p. 433. pituitary adenoma. Its use might be particu- 15. WUTTKE, W., E. CASSELL, AND J. MEITES, Effect of ergocornine on serum prolactin and LH, and on hypothalamic content larly suitable for the early detection of pituiof PIF and LRF, Endocrinology 88: 737, 1971. tary microadenoma in patients with no evi- 16. SAAVEDRA, J. M., M. PALKOVITS, J. S. KIZER, M. J. BROWNSTEIN, AND J. A. ZIVIN, Distribution of biogenic amines and dence of roentgenographical alterations of the related enzymes in the rat pituitary gland, J Neurochem 25: 257, 1975. sella turcica (5, 17). In this vein are the find17. VEZINA, J. L., AND T. S. SUTTON, Prolactin-secreting pituitary ings obtained in two subjects of this study microadenomas, Am J Roentgenol Radium Ther Nucl Med 120: 46, 1974. (group 2, cases 9 and 10).
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Vol. 47, No. 6 Printed in U.S.A.
Nomifensine: Diagnostic Test in Hyperprolactinemic States* EUGENIO E. MULLER, ANDREA R. GENAZZANI, AND SERENA MURRU Institute of Pharmacology and Pharmacognosy, University of Cagliari (E.E.M.), 09100 Cagliari; Chair of Obstetric Pathology, University of Siena (A.R.G.), 53100 Siena; and the Department of Obstetric and Gynecology, University of Pisa, 56100 Pisa, Italy ABSTRACT. Nomifensine, an antidepressant agent which activates dopamine (DA) neurotransmission mainly by inhibiting DA reuptake in the central nervous system, was administered either to puerperal lactating women or to subjects with nonpuerperal hyperprolactinemia. In 10 postpartum women and in 7 women with no evidence of PRL-secreting tumor, oral administration of nomifensine (100 or 200 mg, respectively) induced in the following 5 h a clear-cut inhibition of plasma PRL
I
N RECENT years, the studies of the mechanism (s) involved in the neuroendocrine regulation of PRL secretion have led to the introduction of several functional tests in clinical practice. These tests have been used mainly with the aim of differentiating between hyperprolactinemia due to pituitary tumors and so-called "functional" hyperprolactinemia. Early medical diagnosis of hyperprolactinemic states is a noteworthy problem, since it is possible that early treatment may prevent functional hyperprolactinemic disorders from progressing to clinically demonstrable pituitary tumors. So far, the most frequently used stimulation tests include administration of hypothalamic hormones, e.g. TRH or central nervous system (CNS)-active drugs {i.e. dopamine (DA) receptor blockers such as chlorpromazine or sulpiride). The inhibition tests consist of the administration of DA precursor or agonist drugs, e.g. L-dopa or bromocriptine (see Refs. 1 and 2). None of these tests allows accurate discrimination between tumorous and func-
levels; in 10 patients with PRL-secreting tumors, the drug did not lower plasma PRL levels. In 2 of these patients, nonsupressibility of plasma PRL levels to nomifensine was the only indication of the existence of a pituitary microadenoma. It is proposed that acute nomifensine testing may be a valid neuropharmacological tool for discriminating between individuals with and without pituitary adenoma. (J Clin Endocrinol Metab 47: 1352, 1978)
tional hyperprolactinemia (1-3). Also, concomitant evaluation of other pituitary trophic hormone secretions {e.g. gonadotropins) in the resting state or after administration of LRH has been discouraging with regard to this differentiation (see Ref. 4). The differential diagnosis is further compounded by the fact that many cases originally classified as functional, because of the finding of a radiologically normal pituitary fossa, may be due to pituitary microadenomas (5). We propose that nomifensine1 (8-amino-2methyl - 4 - phenyl-1,2,3,4- tetrahy droisoquinoline; Psicronizer, Hoechst S.p.A. Italia), an antidepressant drug which activates DA neurotransmission mainly by inhibiting DA reuptake (6) but with no ability to directly affect DA receptors (7), may be a useful neuropharmacological tool for discriminating functional from tumorous hyperprolactinemia. Materials and Methods
Seventeen informed and consenting volunteers with physiological puerperal hyperprolactinemia (postpartum day 2) and 17 hyperprolactinemic patients were studied. The 17 subjects in the puerpeReceived January 12, 1978. rium were divided into two groups; the first (10 Address requests for reprints to: E. E. Miiller, c/o Department of Pharmacology, University of Milan, Via subjects) underwent acute nomifensine testing, the Vanvitelli, 32, 20129, Milano, Italy. * This work was supported in part by C. N. R. Biology of Reproduction project.
1
Also marketed as Alival.
1352
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NOMIFENSINE TEST IN HYPERPROLACTINEMIA second (7 subjects) served as a control group for evaluating the spontaneous fluctuations in plasma PRL levels. On the basis of clinical, radiological, and biochemical data, the 17 nonpuerperal hyperprolactinemic patients were divided into two groups (Table 1). Group 1 consisted of 7 patients with normal sella turcica and plasma PRL levels which on several occasions were found to be constantly, although moderately, elevated (Table 1). Case 7 had PRL levels up to 80 ng/ml. Three patients (cases 3-5) were obese, and one of them (case 4) was premenopausal. Two patients were oligomenorrheic (cases 2 and 6) and cases 1 and 7 were amenorrheic. Case 7 had taken neuroleptic drugs for at least 2 months. All patients, except for case 5, had galactorrhea. Group 2 was composed of 10 patients with pituitary PRL-secreting tumors. In 8 patients (cases 1-8), the diagnosis of pituitary tumor was made on the basis of highly elevated serum PRL levels and/or an abnormal sella turcica. Case 9 underwent
1353
surgery (see below) only on the basis of elevated plasma PRL levels; case 10a was operated after 1 yr of observation when a double profile of the sella and a further marked rise of plasma PRL (case 10b) occurred. Hypocycloidal polytomography was used in all cases to evaluate the radiomorphology of the sella. Diagnosis of pituitary tumors based on abnormal biochemical and/or radiological findings (group 2, cases 1-8 and 10b) was confirmed in all patients at surgery by the selective removal and histological examination of an adenoma through transsphenoidal microsurgical exploration of the sella. Table 1 summarizes the clinical and laboratory data for the hyperprolactinemic patients. All experiments were performed in the morning after an overnight fast and in menstruating subjects (group 1, cases 2-6) in the early follicular phase. Serial blood specimens were collected through an indwelling polyethylene cannula placed in the antecubital vein and kept open by the slow infusion of 0.9% saline. Starting at 0830-0900 h, subjects
TABLE 1. Clinical and laboratory data and gonadotropin responses of patients without or with evidence of pituitary PRL-secreting tumor
Case no.
Without evidence of PRL tumor 1 (24)'' 2(25) 3(37) 4(45) 5(20) 6(23) 7(35) With evidence of PRL tumor 1(26) 2(30) 3(22) 4(41) 5(34) 6(38) 7(25) 8(34) 9(28) 107 (21)" a
b
Length of amenorrhea (yr)a
S, 2 0 — -
0 S, 8 months
S, 2
S,5 S,3 S.15 S, 2 S,20 S, 8 months
S,2 S,3 P, 5
A Maximum (mU/ml) c
Basal hormone levels G A6
Sella turcica x-ray PRL (ng/mJ)
LH (mU/ml) rf
FSH (mU/ml) rf
22.0-26.0 32.0-37.0 18.5-26.0 20.0-24.0 21.0-25.0 14.0-23.0 25.0-80.0
15.0-32.0 2.4-19.0 3.9-4.8 49.0-65.0 11.6-19.0 3.0-6.0 6.0-8.0
6.9-17.0 5.2-14.0 8.2-10.8 33.0-90.0 4.7-5.5 5.7-12.0 7.0-8.0
+ + + + — + +
Normal Normal Normal Normal -Normal Normal Normal
+ + + + + + + +
Enlarged Double profile Enlarged Enlarged Double profile Enlarged Enlarged Double profile Normal
50.0-80.0 230.0-375.0 48.0-60.0 250.0-350.0 28.0-55.0 132.0-156.0 40.0-85.0 28.0-55.0 44.0-65.0
6.0-10.0 4.0-7.0 1.0-8.0 7.0-10.0 2.4 2.8-3.5 2.6
+ +
Normal Double profile
32.0-50.0 90.0-130.0
4.5-8.0 4.0-7.5
P E2 (pg/ml) (pg/ml)e
50 120
400 500
T H
r On
4.4 9.0
60.0 18.0 23.0 76.0 33.0 9.0
71.0 2.0 12.0
13.2 10.2 28.0
130
830
220 100 270 110
980 550 480 900
8.0-14.0 3.0-10.0 7.0-11.0 14.0-20.0
96 12
255 185
12
370
56
664
24.0 28.0 42.0
6.8-10.3
70
480
92.0
54.0
66
500
150 140
600 400
17.5
7.4
4.6-6.0 4.2-7.0
6.2
" S, Secondary; 0, oligomenorrhea; P, polymenorrhea. * Galactorrhea. c Highest plasma LH and FSH levels during LRH testing. d Control values in early follicular phase: LH, 5.9 ± 1.1 mU/ml; FSH, 11.3 ± 2.2 mU/ml. e Progesterone. ^Age (in years) of subject is in parentheses. * a and b refer to examinations performed at 1-yr interval.
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JCE & M • 1978 Vol 47 • No 6
MULLER, GENAZZANI, AND MURRU
1354
Results
received nomifensine (100 or 200 mg) orally in a single administration (see Results). Patients with radiological evidence of a pituitary PRL-secreting tumor or nonsupressibility to acute nomifensine testing (cases 9 and 10a) underwent acute testing with bromocriptine (CB 154 Sandoz; 5.0 mg orally) on separate days. After two baseline blood samples were taken (—30 and 0 min), further blood samples were obtained at 30- to 60-min intervals for 5 h. Plasma was separated, frozen, and stored at —20 C until assayed. Plasma PRL values were assessed with a radioimmunological method, using materials supplied by Biodata (Milan, Italy). One nanogram of the human PRL standard used is equivalent to 23 /xU WHO 71-222, corresponding to 1 ng NIH F-l. The sensitivity of the assay was 1.0 ng/ml and the intraassay variation was 4.3 ± 1.2% (SD). The upper limits of normal in our laboratory were: early follicular phase, 12 ng/ml; ovulatory period, 18 ng/ml; luteal phase, 16 ng/ml (8). In hyperprolactinemic patients, plasma LH and FSH (under basal conditions or after LRH), plasma estradiol (E2), and progesterone were determined by RIA kits supplied by CEA-SORIN (Saluggia, Italy). To evaluate the effect of Nomifensine, results were expressed either as the ratio between plasma PRL levels at each time period (S) and baseline (B) levels (mean of —30- and 0-min values) or as absolute values. The S:B ratio was also used for evaluating spontaneous fluctuations in plasma PRL levels. Results were analyzed using unpaired or paired t tests.
Puerperium Baseline PRL values were 101 ± 2.4 (SEM) ng/ml in control subjects and 199 ± 10.5 ng/ml in subjects undergoing acute testing. No consistent variations were found in plasma PRL levels in the control group receiving placebo during 5 h of observation (range of S:B values, 0.94-1.09; data not presented). Nomifensine (100 mg orally) administration was associated with a significant decrease in plasma PRL levels during the same period; this reduction was present at 120 min (P < 0.001 vs. control group), after which levels progressively declined to reach nadir values at 240-300 min (about 50% inhibition; Fig. 1). Hyperprolactinemic patients In 7 patients with no evidence of PRL-secreting tumor, administration of nomifensine (200 mg orally) was followed by a prompt and clear-cut reduction in plasma PRL levels (about 50% inhibition from 150-300 min), similar to that observed in postpartum women (Fig. 1). In 10 patients with a pituitary PRLsecreting tumor, administration of nomifensine (200 mg orally) did not alter plasma PRL levels (maximal inhibition, 14% at 240 min). In these subjects, in contrast, administration of
S/Bi.2
TUMOR-NOM(IO)
NON TUMOR-NOM(7) POST-PARTUM-NOM (10)
TUMOR-CB 154(10)
60
90
120
150
180
210
240
300 MIN.
FIG. 1. Plasma PRL levels in postpartum women and hyperprolactinemic patients without or with evidence of PRL-secreting tumor given nomifensine (Nom; 100 or 200 mg orally). Also shown are PRL levels in patients with tumor given bromocriptine (CB 154; 5.0 mg orally). Number of subjects is in parentheses. PRL levels are significantly lower (P < 0.05) than values present in tumoral subjects: (in postpartum women given Nom from 120-300 min, in patients without evidence of PRL-secreting tumor given Nom from 30-240 min, and in tumoral subjects given bromocriptine from 60-300 min). In the ordinate, values are expressed as S:B (see text for details).
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1355
NOMIFENSINE TEST IN HYPERPROLACTINEMIA bromocriptine (5.0 mg orally) resulted in a striking fall in plasma PRL levels (about 80% at 210-300 min; Fig. 1). Table 2 shows the individual PRL responses to acute nomifensine testing of the 17 patients. No untoward side-effects were noticed in any subject after drug administration. Discussion Nomifensine was effective in lowering plasma PRL levels both in subjects with the functional hyperprolactinemia of the puerperium and those with nonpuerperal hyperprolactinemia without evidence of PRL-secreting tumor. In contrast, it was ineffective in subjects with a PRL-secreting tumor. Although plasma PRL levels in postpartum women reach nonpregnant levels around the third postpartum week, changes recorded in lactat-
ing women after administration of placebo and after nomifensine made it unlikely that the depressant effect of the latter was secondary to spontaneous plasma PRL fluctuations. The same conclusion applies to the PRL-suppressive effect of the drug in patients in whom the existence of a pituitary PRL-secreting tumor could be excluded on the basis of clinical, biochemical, and radiological characteristics. The effectiveness of nomifensine in lowering plasma PRL levels in states of functional hyperprolactinemia contrasts with the inability of the drug to affect PRL secretion in subjects with a pituitary tumor. This fact does not seem to be related to the magnitude of baseline PRL levels; in patients 1-10, nonsupressibility of plasma PRL to nomifensine was present with baseline values ranging from 28-350 ng/ml (Table 2). The nonresponsiveness of the tumor subjects was not due to
TABLE 2. Individual plasma PRL values (nanograms per ml) in patients without or with evidence of pituitary PRLsecreting tumor before and at intervals after administration of 200 mg nomifensine orally Time (min) Case no. Without evidence of PRL tumor 1 2 3 4 5 6 7 With evidence of PRL tumor'' 1" 2 3" 4 5 6 7 8 9 10" a b
0"
30
60
90
120
150
180
210
240
300
24.0 32.5 20.0 20.0 21.0 17.5 30.0
22.0 19.0 17.0 15.5 13.5 16.5 13.0
18.5 19.0 15.5 14.5 13.0 14.0 18.5
20.0 15.5
19.5 16.5 15.2
13.0 14.0 13.0 13.0 15.2 10.5 3.0
11.5 15.0
11.0 21.0 16.0 16.0
12.5 12.5 3.0
10.9 14.5 14.0 15.5 12.0 12.2 3.0
68.25 350.0 58.0 268.5 28.0 156.0 60.0 28.0 58.0
65.0 350.0 50.0 230.0 27.0 136.0 55.0 27.0 55.0
41.5 132.0
46.0 136.0
14.5 11.2 13.0 17.0
9.5 14.0 16.0
13.0 15.5 14.8 13.5 10.5 10.5 3.0
65.0 350.0 54.0 220.0 31.0 144.0 70.0 31.0 55.0
375.0 54.0 220.0 29.0 156.0 57.0 29.0 52.0
60.0 325.0 55.0 220.0 26.0 124.0 57.0 26.0 50.0
55.0 325.0 54.0 210.0 27.0 144.0 46.0 27.0 50.0
67.5 350.0 54.0 180.0 30.0 164.0 53.0 30.0 55.0
67.5 310.0 58.0 250.0 27.0 144.0 56.0 27.0 57.0
55.0 310.0 55.0 210.0 28.0 140.0 46.0 28.0 62.0
65.0 400.0 54.0 200.0
50.0 125.0
50.0 125.0
41.0 138.0
41.0 141.0
34.0 138.0
35.0 128.0
34.0 121.0
32.0 120.0
16.5 3.0
43.0 58.0
Nadir values (min)
10.9 (240)* 14.0 (180) 13.0 (180) 13.0 (180) 9.5 (120) 10.5 (150) 3.0 (150)
55.0 310.0 50.0 180.0 26.0 136.0 43.0 26.0 50.0
(150) (210) (30) (180) (120) (30) (300) (120) (150)
32.0 (300) 120.0 (300)
" Mean of - 3 0 - and 0-min values. * Time at which nadir occurred. '' Patients 1-10 also underwent acute testing with CB 154 (see text and Fig. 1 for details). d Also unresponsive to 300 mg nomifensine orally. e a and b refer to nomifensine testing performed at 1-yr intervals (see Table 1).
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MULLER, GENAZZANI, AND MURRU
1356 DIRECT
PRL
INDIRECT
PRL
PRL
FIG. 2. Hypothetical scheme to explain the mechanism of the suppressive effect on PRL secretion of direct or indirect DA agonist drugs. In the upper part (a and b), the possibility is depicted of a mechanism of control mediated by both DA and PIF; in the lower part (c and d), only the control by DA is reported. For the sake of clarity, an axo-somatic contact between the DA neuron and the PIF neuron has been reported; on neuroanatomical ground, an axo-axonic contact is more likely. Direct DA agonist drugs may affect DA receptor sites located either in the CNS (a) or at pituitary level (a and c). Indirect DA agonist drugs, such as nomifensine, which blocks DA reuptake, may affect DA receptors sites located only in the CNS (b). Panel d envisages the possibility that nomifensine may act by blocking the reuptake of DA released into the portal circulation. This possibility seems to be unlikely, since it is conceivable that presynaptic capture of released DA is not a major mechanism for neurotransmitter removal at median eminence level. DA, Dopaminergic neuron; PIF, prolactin-inhibiting factor neuron, (+), refers to activation of DA neurotransmission
JCE&M • 1978 Vol47 • No 6
refractoriness of the pituitary adenomas to DA stimulation; in the same subjects, bromocriptine, a direct DA agonist drug, induced a striking suppression of the elevated baseline PRL levels. The possibility of an insufficient dosage of nomifensine in subjects with pituitary tumors is also unlikely considering both the sensitivity of DA receptor sites located on the tumorous gland (9) and the finding that in two subjects (cases 1 and 3), a dose as high as 300 mg nomifensine was completely ineffective in lowering plasma PRL levels (data not presented). It is of note that in the functional hyperprolactinemia of the puerperium, despite the presence of higher or similarly elevated baseline PRL levels (mean, 200 ng/ml), even the dose of 100 mg nomifensine markedly lowered plasma PRL levels. Although the inhibitory role of the dopaminergic system(s) in the control of PRL secretion has been unequivocally established (10, 11), it is still not clear whether a PRLinhibiting factor (PIF), whose activity is tonically stimulated by dopaminergic neurons, exists in the hypothalamus or whether the PIF activity of the hypothalamus is entirely accountable by brain DA. DA released from tuberoinfundibular (TIDA) dopaminergic nerve terminals into the hypophyseal portal circulation (12) may act directly at the level of the anterior pituitary, where receptor sites for DA have been located (13, 14) (Fig. 2). Direct DA agonist drugs (such as bromocriptine, apomorphine, piribedil, etc.) may inhibit PRL release either indirectly, by stimulating DA receptors (in the TIDA system?) which then release PIF (Fig. 2a), or by direct stimulation of DA receptors located on pituitary lactotrophs (Fig. 2c). Even though the main site of action of these compounds is presently unknown, on theoretical grounds either a CNS and/or a pituitary site of action is envisaged (13-15). The double site of action of these compounds prevents establishing a CNS or a pituitary etiology of the hyperprolactinemic state. (a and b) or to DA release (d); (—), refers to the inhibitory effect of direct DA agonist drugs on PRL secretion; ||, indicates the block of DA reuptake operated by nomifen-
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NOMIFENSINE TEST IN HYPERPROLACTINEMIA
1357
The same conclusion is not valid for drugs Acknowledgments such as Nomifensine, capable of enhancing The participation in these studies of Drs. F. Camanni, dopaminergic neurotransmission without di- F. Massara, and D. Cocchi is gratefully acknowledged. rectly affecting DA receptor sites (Fig. 2b). References Such drugs activate dopaminergic neurotrans- 1. FAGLIA, G., P. BECK-PECCOZ, P. TRAVAGLINI, B. AMBROSI, M. RONDENNA, A. PARACCHI, A. SPADA, G. WEBER, R. BARA, mission via presynaptic events (DA release AND A. ROUZIN, Functional studies in hyperprolactinemic and inhibition of DA reuptake) rather than by states, In Crosignani, P. G., and C. Robyn (eds.), Prolactin and Human Reproduction, New York, Academic Press, 1977, stimulation of postsynaptic DA receptors. p. 225. Thus, they would be expected to inhibit PRL 2. Kleinberg, D. L., G. L. Noel, and A. G. Frantz, Galactorrhea: a study of 235 cases including 48 with pituitary tumors, N secretion in the so-called "functional" hyperEnglJMed 296: 589, 1977. prolactinemia, a condition in which a presyn- 3. JACOBS, H. S., S. FRANKS, M. A. MURRAY, 0. G. R. HULL, S. J. STEELE, AND J. D. N. NABARRO, Clinical and endocrine aptic pool of DA available for release is exfeatures of hyperprolactinemic amenorrhea, Clin Endocrinol pected to be present (Fig. 2b), and ineffective 5: 439, 1976. in lowering PRL in hyperprolactinemic states 4. L'HERMITE, M., A. CAUFRIEZ, AND C. ROBYN, Pathophysiology of human prolactin secretion with special reference to due to a primitive tumor of pituitary lactoprolactin-secreting pituitary adenomas and isolated galactorrhea, In Crosignani, P. G., and C. Robyn (eds.), Prolactin and trophs. It is a common notion, in fact, that the Human Reproduction, New York, Academic Press, 1977, p. normal or pathological mammalian pituitary 179. does not contain the presynaptic neuronal 5. JACOBS, H. S., AND S. FRANKS, Prolactin studies, pituitary tumor, and reproductive function, Br Med J 2: 141, 1975. component (16) through which activation of 6. HUNT, P., M.-H. KANNENGIESSER, AND J.-P. RAYNAUD, Nomifensine: a new potent inhibitor of dopamine uptake into the postsynaptic catecholamine receptor ocsynaptosomes from rat corpus striatum, J Pharm Pharmacol curs physiologically. Thus, drugs which block 26: 370, 1974. DA reuptake should be unable to affect DA 7. GERHARDS, H. G., A. CARENZI, AND E. COSTA, Effects of nomifensine on motor activity, dopamine turnover rate and receptor sites located on the pituitary gland. cyclic 3',5'-adenosine monophosphate concentrations of rat striatum, Naunyn Schmiedebergs Arch Pharmacol 286: 49, However, if one admits that development of 1974. a pituitary tumor takes place as a continuum 8. GENAZZANI, A. R., G. MAGRINI, F. FACCHINETTI, S. ROMAGNINO, C. PINTOR, G. P. FELBER, AND P. FioRETTi, Behavior from a normal cell through hyperplasia and, and origin of plasma androgens throughout the menstrual ultimately, adenoma formation, stages of cycle, In Martini, L., and M. Motta (eds.), Androgens and Antiandrogens, New York, Raven Press, 1977, p. 247. varying degrees of PRL autonomy and, hence, 9. MASHITER, K., E. ADAMS, M. BEARD, AND A. HOLLEY, Broresponsiveness to nomifensine should be exmocryptine inhibits prolactin and growth hormone release by human pituitary tumors in culture, Lancet 2: 197, 1977. pected as the lesion evolves. However, the 10. MEITES, J., Control of prolactin secretion in animals, In Pasobservation that nomifensine failed to lower teels, J. L., and C. Robyn (eds.), Human Prolactin, Amsterdam, Excerpta Medica, 1975, p. 105. PRL in patients with baseline levels as low as 11. MULLER, E. E., G. NISTICO, AND U. SCAPAGNINI, Neurotrans28.0-41.5 ng/ml (group 2, cases 5, 8, and 10a) mitters and Anterior Pituitary Function, New York, Academic Press, 1978. would suggest that P R L autonomy occurs 12. BEN-JONATHAN, N., C. OLIVER, H. J. WEINER, R. S. MICAL, since the early stages of the development of AND J. C. PORTER, Dopamine in hypophysial portal plasma of the rat during the estrous cycle and throughout pregnancy, the pituitary neoplasm. Endocrinology 100: 452, 1977. In conclusion, based on the rationale behind 13. MACLEOD, R. M., AND J. E. LEHEMEYER, Studies on the mechanism of the dopamine-mediated inhibition of prolactin this testing, the present findings suggest that secretion, Endocrinology 94: 1077, 1974. acute nomifensine testing may be the first 14. MACLEOD, R. M., H. KIMURA, AND I. LOGIN. Inhibition of prolactin secretion by dopamine and piribedil (ET-495), In neuropharmacological tool capable of discrimPeciJe, A., and E. E. Muller (eds.), Growth Hormone and inating between individuals with and without Related Peptides, Amsterdam, Excerpta Medica, 1976, p. 433. pituitary adenoma. Its use might be particu- 15. WUTTKE, W., E. CASSELL, AND J. MEITES, Effect of ergocornine on serum prolactin and LH, and on hypothalamic content larly suitable for the early detection of pituiof PIF and LRF, Endocrinology 88: 737, 1971. tary microadenoma in patients with no evi- 16. SAAVEDRA, J. M., M. PALKOVITS, J. S. KIZER, M. J. BROWNSTEIN, AND J. A. ZIVIN, Distribution of biogenic amines and dence of roentgenographical alterations of the related enzymes in the rat pituitary gland, J Neurochem 25: 257, 1975. sella turcica (5, 17). In this vein are the find17. VEZINA, J. L., AND T. S. SUTTON, Prolactin-secreting pituitary ings obtained in two subjects of this study microadenomas, Am J Roentgenol Radium Ther Nucl Med 120: 46, 1974. (group 2, cases 9 and 10).
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