Dysfunction of dopaminergic regulation of prolactin in patients with functioning and nonfunctioning pituitary adenomas and craniopharyngiomas

FERTILITY AND STERILITY Copyright 1985 The American Fertility Society

Vol. 44, No.4, October 1985 Printed in U.8A.

Dysfunction of dopaminergic regulation of prolactin in patients with functioning and nonfunctioning pituitary adenomas and craniopharyngiomas

Abraham Martinez-Campos, M.D.*t Judith Cornejo, M.D.:j: Josue Garza-Flores, M.D.* Francisco Velasco, M.D.§ Instituto Nacional de la Nutrici6n, Salvador Zubiran, Hospital General de Mexico, and Centro Medico Nacional, Mexico City, Mexico

The response to domperidone (a dopamine blocking agent) of serum prolactin (P RL) levels was compared in 3 patients with amenorrhea-galactorrhea without evidence of a pituitary tumor, 23 patients with prolactinomas (10 cases with histologic confirmation), 7 patients with histologically verified large nonfunctioning pituitary adenomas with normal or moderately elevated basal PRL levels, and 6 patients with histologically verified craniopharyngiomas (3 with normal basal PRL levels and 3 with elevated PRL levels). The response was compared with that of 10 patients with postpartum hyperprolactinemia and 14 normal women. Ten milligrams of intravenous domperidone induced a rapid rise in PRL that was maximal at 30 to 45 minutes in normal, postpartum, and amenorrhea-galactorrhea patients who had no sign of tumor. In contrast, domperidone failed to induce significant changes in PRL in cases of prolactinoma, nonfunctioning pituitary adenomas, and craniopharyngioma with or without elevated basal PRL levels. The results suggest that dopaminergic control on PRL secretion was impaired in all tumor cases. The mechanisms of this abnormal dopaminergic control, however, may be different. Whereas dopamine control in cases of prolactinoma is altered at the level of pituitary dopamine receptors, alternative explanations must be found for those tumors with normal basal PRL levels and lack of response to domperidone. Fertil SteriI44:471, 1985

Received December 18, 1984; revised and accepted June 14, 1985. *Department of Reproductive Biology, Instituto Nacional de la N utrici6n. tPresent address: Department of Pharmacology, Yale University School of Medicine, New Haven, Connecticut. :j:Department of Endocrinology, Hospital General de Mexico. §Reprint requests: Francisco Velasco, M.D., Division of Neurophysiology, Scientific Research Department, Centro Medico Nacional IMSS, P.O. Box 73-032, Mexico City, Mexico. Vol. 44, No.4, October 1985

The syndrome characterized by menstrual disorders, infertility, and galactorrhea in women and impotence in men occurs in some patients from an increase in prolactin (PRL) secretion. 1 It has been shown more recently l.5 that these endocrine abnormalities are frequently the result of a PRL-secreting pituitary adenoma (prolactinoma) and less commonly associated with craniopharyngiomas. 6 . B In addition, several reports l , 3, 9 suggest that the PRL hypersecretion in patients with

Martinez-Campos et aI. DA·PRL regulation in sellar tumors

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pituitary adenoma (prolactinoma) results from an inappropriate dopaminergic regulation of the adenoma lactotrope. Dopamine (DA) regulation may be reduced because DA infusion to patients with prolactinoma reverses the reduced effectiveness of metoclopramide, a DA-receptor antagonist, on PRL release. 2 To our knowledge, a comparative dynamic study on dopaminergic regulation of PRL in patients with prolactinoma, craniopharyngioma, and nonfunctioning pituitary adenoma (NFP A) in which the basal serum PRL levels are normal or moderately elevated has not been reported. The current study represents an attempt to assess the functional activity of the endogenous dopaminergic system in patients with prolactinoma, compared with patients with

NFP A and craniopharyngioma, through the analysis of PRL response to domperidone, a DAreceptor antagonist. lO MATERIALS AND METHODS

Thirty-nine patients (28 women and 11 men) were studied. All of them had reproductive abnormalities (amenorrhea, galactorrhea, loss of libido, or impotence) with or without other clinical evidence of pituitary tumors. The presence or absence of a tumor was assessed by the size and configuration of the sella turcica as seen in simple skull x-rays and linear tomography in anteriorposterior and lateral projections. Radiologic abnormalities were classified according to Vezina's

Table 1. Clinical Information on Patients Studied Group

Patient no.

Sex

Age

Hormonal status

Headache

Visual fields

Sella turcica x-rays

yrs

yrs

A_Gd

24 29 21 38

F F F F F F F F F F

Me

18 24 32 17 24 19 26 25 38 17 43

13

M

40

1

F

36

A-G

+

2

F

43

A-G

+

3

F

20

A-G

+

4

F

28

A-G

+

5 6 7 8

F F F F

38 22 26 30

A-G A-G A-G A-G

+ + + +

9

F

36

A-G

+

10

F

34

A-G

+

1b 2b 3b

Probable PRL tumor

1 2 3 4 5 6 7 8 9 lOb

llb 12

Proven PRL tumor

0 0 0 II

F" F F F

Without evidence ofPRL tumor

Length ofHDa

A-G A-G A-G A-G A-G A-G A-G A-G A-G A-G A-G A-G A-G Hypogonadism Hypogonadism

+ + + + + + + + +

Normal Normal Normal Bitemporal hemianopia II Normal II Normal I Normal I Normal I Normal I Normal II Normal I Normal I Normal I Normal (Empty sella Normal turcica) III Bitemporal hemianopia I Normal (Empty sella turcica) IV Bitemporal hemianopia III Bitemporal hemianopia IV Bitemporal hemianopia I Normal I Normal I Normal IV Bitemporal hemianopia III Bitemporal hemianopia II Normal

3 2 3 7 1 5 12 3 2 3 2 4 3 6 8 8 13 20 3 3 8 1 1 4 14

2

aHD, hormonal disorders. bDomperidone responders. cF, female subject. d A-G, amenorrhea -galactorrhea. eM, male subject.

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Martinez-Campos et aI. ·DA-PRL regulation in sellar tumors

Fertility and Sterility

Table 2. Clinical Information of Patients Studied Group

Patient no.

Sex

Age

Mb

61 20 44 43 13 36 38 17 17 19 21 16 23

Hormonal status

Visual fields

Sella turcica x-rays

Craniopharyngioma

1 2 3 4 5 6 7 1 2 3 4 5 6

M M M M M M

Fe

F F

F M M

ofHDa yrs

yrs

Functionless pituitary tumor

Length

Normal Hypogonadism Hypogonadism Hypogonadism Hypogonadism Hypogonadism Hypogonadism Delayed puberty Delayed puberty A_Gd A-G Delayed puberty Delayed puberty

Bitemporal hemianopia Amaurosis Amaurosis Bitemporal hemianopia Amaurosis Bitemporal hemianopia Blindness, left eye Blindness, left eye Bitemporal hemianopia Amaurosis Bitemporal hemianopia

II III IV IV IV III III III II II II III III

2 3 34 10 1/6 8 10 6 6 3 4 5 8

aHD, hormonal disorders. bM, male subject. eF, female subject. d A-G,

amenorrhea-galactorrhea.

criteria. l l Accordingly, the patients were classified into five groups. Group I consisted ofthree women with amenorrhea-galactorrhea without clinical or radiologic evidence of sellar or parasellar tumor. Two patients had normal basal serum PRL levels and one had moderate elevation of basal serum PRL levels. Group II consisted of 13 patients (11 women and 2 men) suspected to have prolactinoma because of the presence of amenorrhea-galactorrhea syndrome in the women and loss of libido and impotence in the men. All of them had elevated plasma PRL levels in serial determinations and radiologic evidence of sellar tumor. Group III consisted of ten women with proven prolactinoma, diagnosed on the basis of the abnormalities described for group II plus the histologic confirmation of the tumor type in samples obtained through transsphenoidal resection. Clinical information for the patients included in groups I to III is described in Table 1. Group IV consisted of seven men with chiasmatic syndrome produced by a large NFP A accompanied by a normal or moderate increase in plasma PRL levels, radiologic erosion of the sella turcica, and histologic confirmation of the tumor type. Group V consisted of six patients (four women and two men) with histologically verified craniopharyngioma. All patients showed some degree of gonadal insufficiency. Three patients showed increased basal plasma PRL levels; and in three patients the radiologic abnormalities suggested a Vol. 44, No.4, October 1985

diagnosis of pituitary adenoma, rather than craniopharyngioma. Clinical information for the patients included in groups IV and V is described in Table 2. Ten volunteers who were fully informed and who signed a consent form were studied during the phase of physiologic puerperal hyperprolactinemia (second day after delivery). Their ages ranged between 18 and 30 years. Another 14 healthy volunteers, 8 women and 6 men, whose ages ranged between 20 and 34 years, who had no sign of hormonal abnormalities, and who were not under any medication (including contraceptive medication) were included in the study as a control group. All experiments were performed in the morning after an overnight fast and during the early follicular phase in those women who were menstruating. The tests were started between 8:00 A.M. and 9:00 A.M.; serial blood specimens were collected through an indwelling polyethylene cannula placed in the antecubital vein and maintained by infusion of 0.9% saline. After two baseline samples ( - 30 and 0 minutes), domperidone (10 mg, Janssen Pharmaceuticals, Mexico City, Mexico) was injected rapidly intravenously; blood samples were taken at 30, 45, 60, 90, and 120 minutes. Plasma was separated, frozen, and stored at - 20°C until assayed. Serum PRL levels were assessed by radioimmunoassay with the use of the International Reference Preparation code 75/504 as a standard; all reagents were provided by the matched reagent program of the World Health

Martinez-Campos et al. DA-PRL regulation in sellar tumors

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Figure 1 Pattern of serum PRL changes in patients undergoing domperidone testing. In the ordinate, values are expressed as percentage change from baseline PRL values. Each symbol is the mean of percentage changes from baseline recorded in individual subjects between 30 and 45 minutes after drug administration. The data from the groups of normal and puerperal subjects as well as those without tumor include a symbol that represents the mean ± SD.

Organization. 12 The intraassay and interassay coefficients of variation were estimated to be 7.6% and 5.6%, 6.9% and 21.0%, and 8.2% and 7.9%, respectively, for three different concentrations. The upper limit for normal women with this method is 20 ng/ml. The criteria adopted to define PRL response to domperidone required an increase in baseline PRL levels after drug administration to at least twice the levels before administration. 1 IMMUNOCYTOCHEMICAL STAINING

All the adenomas were studied by immunohistochemistry with the use of the peroxidase antiperoxidase technique, as previously described. 13 Immunostaining for PRL was done in all patients in whom pituitary tissues were obtained; however, growth hormone (GH) and adrenocorticotropic hormone (ACTH) staining was done also in nonfunctioning pituitary tumors. Immunoabsorption was performed for antisera to PRL, GH, and ACTH. Human PRL (NIAMDD) of the amount of 0.004 ,""mollml, 0.0001 to 1.0 nmollml of human 474

Baseline PRL values in normal subjects were 9.2 ± 2.5 (standard error of the mean [SEMD ng/ml in women and 5.4 ± 1.8 (SEM) ng/ml in men. Domperidone administration induced a strong and prompt rise in serum PRL levels, with peak levels occurring 30 to 45 minutes after injection (mean peak ± standard deviation [SD], 112 ± 9.8 ng/ml in women and 68.3 ± 10.1 ng/ml in men). In puerperal women, baseline PRL values were 122 ± 32 ng/ml; administration of domperidone elicited a peak PRL rise as rapid as that which was observed in normal subjects, ranging from 125% to 495% of baseline (mean peak ± SD, 332% ± 118%) (Fig. 1).

PATIENTS WITH ENDOCRINE DISORDERS

Basal PRL Levels Baseline PRL levels in patients in the groups studied were as follows. Levels in patients without evidence of tumor ranged from 12 to 35 ng/ml; with probable prolactinomas, from 68 to 3502 ng/ ml; with proven prolactinomas, from 70 to 1000 ng/ml; with proven NFPA, from 8 to 38 ng/ml; and with proven craniopharyngiomas, from 3 to 102 ng/ml (Fig. 2).

PRL Response to Domperidone As depicted in Figure 1, administration of domperidone in normal subjects and patients in group I without evidence of tumor induced a clear-cut rise in serum PRL levels, with peak levels observed 30 to 45 minutes after drug administration. The maximum percentage change of basal PRL ranged from 810% to 1042% (mean, 945%). In two patients in the group with probable prolactinomas, domperidone was able to induce change in basal PRL levels above 100% (295% and 278%). In the remaining patients, the highest change in basal PRL levels was 90%. In the group with proven PRL tumors, baseline serum PRL levels were not modified significantly (Fig. 1).

Martinez-Campos et al. DA-PRL regulation in sellar tumors

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The same lack of response was observed in patients with NFPA in which PRL levels were normal or moderately elevated. The presence of normal or moderately elevated basal PRL levels in our group of NFPA patients indicates the presence of PRL-secreting tissue. We do not feel, however, that these tumors were prolactinomas because (1) the serum PRL levels were only moderately elevated in the presence of large tumor mass and far lower than the levels seen in most prolactinomas; (2) histologic studies of multiple sections of surgical specimens in these cases failed to reveal positive staining for PRL, GH, or ACTH with the use of the immunoperoxidase technique; and (3) the tumor behaved clinically as NFP A in all cases. In vitro observations of NFPA tissue offer an alternative explanation for this lack of response to domperidone. A high concentration of nonsaturable binding (40 nmol [3H+] domperidone) has been found in tumorous tissue, suggesting either the presence of different types of DA receptors or the absence of domperidone receptors in that type 1300

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The data obtained clearly showed that domperidone was effective in increasing serum PRL levels in normal subjects and in patients with functional hyperprolactinemia of the puerperium and in patients without evidence of sellar and parasellar tumor. On the contrary, domperidone was ineffective in most patients with unproven prolactinomas and in all patients with proven PRL-secreting tumors, as has been reported previously. 1. 14 This lack of response to domperidone has been interpreted as evidence of defective hypothalamic-pituitary DA control upon inhibition of PRL release. Vol. 44, No.4, October 1985

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Figure 3 Pattern of serum PRL changes in patients with proven tumor who underwent domperidone testing. In the ordinate, values are expressed as percentage change from baseline PRL values. Each symbol is the mean of percentage changes from baseline recorded in individual subjects between 30 and 45 minutes after drug administration. Also shown are data corresponding to groups of normal subjects (women and men) and puerperal subjects, in whom the symbol represents the mean ± SD.

Martinez-Campos et al. DA-PRL regulation in sellar tumors

475

oftumor. 9 Therefore, there may be other compensatory mechanisms in the control of PRL release. On the other hand, lack of response to DA-receptor antagonist and rise in serum PRL has been reported l5 • 16 in hypopituitarism secondary to hypothalamic lesion. It is possible that the lack of response to domperidone in our NFPA patients may indicate a hypothalamic dysfunction of DA production, because all tumors had extrasellar extensions that may have damaged the hypothalamus. Finally, it is possible that the NFPA had caused a mechanical blockage of hypothalamicpituitary portal circulation, therefore interrupting the transportation of hypothalamic DA to the pituitary gland. The presence of amenorrhea-galactorrhea in craniopharyngioma is uncommon,6-8, 17 and PRL secretion mechanisms have been rarely studied in those cases. It may be expected, in view of the proximity of craniopharyngiomas to the pituitary stalk and anterior hypothalamus, that these tumors may interfere with the portal system circulation and later DA inhibition of PRL secretion, which in turn yields to increased serum PRL levels. This interference may explain the lack of response to domperidone in patients with craniopharyngioma, amenorrhea-galactorrhea, and elevated serum PRL levels. However, it does not explain the lack of response to domperidone in those patients with craniopharyngioma who have normal or moderately elevated basal PRL levels. An alternative explanation for those patients with craniopharyngioma and delayed puberty, who presumably have decreased estrogen secretion, may be that, because estrogens increase PRL synthesis and release and PRL response to DA-blocking receptor drugs,18 the lack of response to domperidone is caused by a decrease in estrogen secretion. Acknowledgments. We thank Priscilla S. Dannies, Ph.D., for critically reviewing this manuscript. Domperidone was provided by Janssen Pharmaceuticals, Mexico City, D.F. Mexico.

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Hardina, RL Singhal. Amsterdam, Croom Helm Ltd., 1981, p 53 2. Quigley ME, Judd SJ, Guilliland JB, Yen SSC: Spiperone binding to human anterior pituitaries and pituitary adenomas secreting prolactin, growth hormone and adrenocorticotropic hormone. J Clin Endocrinol Metab 50:994, 1980 3. Quigley ME, Judd SJ, Guilliland JB, Yen SSC: Effects of a dopamine antagonist on the release of gonadotropin and prolactin in normal women and women with hyperprolactinemic anovulation. J Clin Endocrinol Metab 48:718, 1979 4. Chang RJ, Keye WR Jr, Young JR, Wilson CB, Jaffe RB: Detection, evaluation and treatment of pituitary microadenomas in patients with galactorrhea and amenorrhea. Am J Obstet Gynecol 128:356, 1977 5. Thorner MO: Prolactin: clinical physiology and the significance and management of hyperprolactinaemia. In Clinical Neuroendocrinology, Edited by L Martini, GM Besser. New York, Academic Press, 1977, p 319 6. Kapcala LP, Molitch ME, Post KD, Biller BJ, Prager RJ, Jackson IMD, Reichlin S: Galactorrhea, oligoamenorrhea, and hyperprolactinemia in patients with craniopharyngioma. J Clin Endocrinol Metab 51:798, 1980 7. Banna M: Craniopharyngioma in adults. Surg Neurol 1:202, 1973 8. Trokoudes KM, Walfish PG, Holgate RC, Pritzker KPH, Schwartz ML, Koracs K: Sellar enlargement with hyperprolactinemia and a Rathke's pouch cyst. JAMA 240:471, 1978 9. Bression D, Brandi AM, Martres MP, Nousbaum A, Casselin F, Rocadot J, Peillon F: Dopaminergic receptors in human prolactin-secreting adenomas: a quantitative study. J Clin Endocrinol Metab 51:1037, 1980 10. Denef C, Follebouckt JJ: Differential effects of dopamine antagonists on prolactin secretion from cultured rat pituitary cells. Life Sci 23:431, 1978 11. Vezina JL: Prolactin-secreting pituitary adenomas: radiologic diagnosis. In Progress in Prolactin Physiology and Pathology, Edited by C Robyn, M Harter. Amsterdam, Elsevier-North Holland, 1978, p 351 12. World Health Organization: Programme for the Provision of Matched Reagents for the Radioimmunoassay of Hormones in Reproductive Physiology: Method Manual 1979, Third edition. Geneva, World Health Organization, 1979, p 76 13. Vandesande F: Peroxidase-antiperoxidase techniques. In Immunohistochemistry, Vol 3, Edited by AA Cuello. New York, International Brain Research Organization, 1983, p 101 14. Scanlon MF, Rodriguez-Arnao MD, McGregor AM, Weightman D, Lewis M, Cook DB, Gomez-Pan A, Hall R: Altered dopaminergic regulation of thyrotrophin release in patients with prolactinomas: comparison with other tests of hypothalamic-pituitary function. Clin Endocrinol (OxO 14:133, 1981 15. Tolis G, Goldstein M, Friesen HG: Functional evaluation of prolactin secretion in patients with hypothalamic pituitary disorders. J Clin Invest 52:783, 1973 16. WoolfPD, Jacobs LS, Donofrio R, Burday SZ, Schalch DS: Secondary hypopituitarism evidence for continuing regulation of hormone release. J Clin Endocrinol Metab 38:71, 1974

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17. Jenkins JS, Gilbert CJ, Ang V: Hypothalamic-pituitary function in patients with craniopharyngiomas. J Clin Endocrinol Metab 43:394, 1976 18. Martinez-Campos A, Moctezuma 0, Larrea F: Interaction of estrogens with dopamine and calcium in the regulation

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of prolactin release in vivo. In Prolactin Secretion: A Multidisciplinary Approach, Edited by F Mena, RC Valverde. New York, Academic Press, 1984, p 263

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