Differences in Dopaminergic Regulation of PRL and Aldosterone Secretion

Endocrinol Japon 1992, 39 (2), 169-176

A Patient with a Prolactinoma Associated with an Aldosterone Producing Adrenal Adenoma: Differences in Dopaminergic Regulation of PRL and Aldosterone Secretion

REIKO DEMURA, MITSUHIDE NARUSE, MASAHIRO ISAWA*, NORITAKA ONODA, KIYOKO NARUSE, MINORU YAMAKADO** AND HIROSHI DEMURA Department of Medicine, Institute of Clinical Endocrinology, *Department of Neurosurgery, Neurological Institute, Tokyo Women's Medical College, Tokyo162, and **Department of Medicine, Mitsui Memorial Hospital, Tokyo101, Japan

Abstract. A patient with a rare combination of prolactinoma and aldosterone producing adrenal adenoma (APA) was reported in relation to studies concerning dopaminergic regulation of PRL and aldosterone secretion. The patient is a 38-year-old female with plasma PRL and aldosterone concentrations (PAC) of 563ng/ml and 54ng/dl, respectively. A bolus of 10mg of metoclopramide significantly increased plasma PRL in 6 normal subjects and in 4 patients with APA, whereas the responses were blunted in 7 patients with prolactinoma and in our patient. The response of aldosterone to metoclopramide was less than that of PRL, but similar in all studied subjects, indicating that the dopaminergic inhibition of aldosterone secretion is less than that of PRL in normal subjects and did not change in patients with APA or prolactinoma. Oral administration of 2.5mg of bromocriptine suppressed plasma PRL significantly in all the subjects studied, but did not produce any consistent changes in PAC. Discrepancies in the response of PRL and aldosterone to metoclopramide and to bromocriptine suggest a difference in the dopaminergic regulation of PRL and aldosterone secretion in both normal subjects and patients with prolactinoma and APA. It is unlikely that reduced dopaminergic inhibition is the basis for hypersecretion of PRL and aldosterone in our patient.

Key words: Prolactinoma, APA, Bromocriptine, Metoclopramide.(Endocrinol Japon 39: 169-176, 1992)

DOPAMINERGIC mechanisms are involved in producing adrenal adenoma (APA), a rarely re- the regulation of PRL secretion [1, 2]. Most ported combination [6]. In examining this patient neurologic and pharmacologic evidence suggests we were led to investigate the interrelation be- that secretion of aldosterone is also under the tonic tween dopaminergic control of PRL and aldoster- inhibitory influence of dopamine [3, 4, 5]. Details one secretion. We examined the responses of PRL of the adrenal dopaminergic system, especially its and aldosterone secretion to metoclopramide, a relation with the tubero-infundibular dopa- DA-2 receptor antagonist [7], and bromocriptine, minergic system regulating pituitary PRL secre- a DA-2 receptor agonist [8], in this patient as well tion, remain to be elucidated. Recently, we studied as in normal subjects and in several other patients a patient with a prolactinoma and an aldosterone- with prolactinoma or with APA.

Received: November 20, 1991 Accepted: January 31, 1992 Corresponding to: Dr. Reiko DEMURA, Department of Medi- cine, Institute of Clinical Endocrinology, Tokyo Women's Medical College, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162, Japan. 170 DEMURA et al.

ng/ml/h before and 0.2ng/ml/h after). A solitary Materials and Methods adenoma was found in the left adrenal gland on Case report CT and magnetic resonance imaging (MRI). These data supported the diagnosis of a prolacti- The patient was a 38-year-old female with noma associated with an APA. increased plasma PRI, (563ng/ml) and a pituitary The course after admission is summarized in macroadenoma on computerized tomographic Fig. 1. Nifedipine, a calcium channel blocker, scan (CT). The results of pituitary function tests, lowered blood pressure to 150/90mmHg, while summarized in Table 1. indicate that reserves are PRI, and PAC remained high. After initiation of partially impaired. Serum PRL levels did not bromocriptine therapy (5.0 to 7.5mg/day), plasma significantly change in response to administration PRL levels decreased strikingly and attained nor- of TRH. The patient also had hypertension mal levels within 2-3 weeks. Although PAC (210/110mmHg) associated with suppressed levels tended to decrease after initiation of bromocrip- of plasma renin activity (PRA, 0.1ng/ml/h), and an tine treatment, it remained high in sharp contrast elevated plasma aldosterone concentration (PAC, to that of PRL. Bromocriptine did not alter the 54ng/dl) after overnight recumbency while con- response of PAC to intravenous injection of suming an unrestricted diet. PRA remained sup- furosemide followed by standing for 2h (36.8 pressed even after intravenous administration of ng/dl before and 38.2 ng/dl after). Intravenous 40mg of furosemide and standing for 2 h (0.2 injection of synthetic 1-24 ACTH resulted in a rise

Table 1. Pituitary function test

* ITT . Insulin Tolerance Test.

Fig. 1. Clinical course of the patient with a prolactinoma and an APA. DOPAMINE ON PRL AND ALDOSTERONE 171 in plasma aldosterone of 16.0ng/dl before and tration to minimize gastrointestinal symptoms. 91.3 ng/d/ during bromocriptine treatment. A left Plasma was separated immediately and stored at adrenalectomy was performed one month after - 20•Ž until the assay. The hormones were deter- admission and a golden yellow adenoma, 16×9× mined by radioimmunoassay with commercially 8mm in size, was extirpated with normal adjacent available kits. PRL and aldosterone kits were adrenal tissues. The histological findings were obtained from Eiken ICL (Tokyo, Japan) and PRA compatible with the diagnosis of APA. The serum kits were obtained from Dainabot RI Laboratories potassium concentration, PAC, and blood pres- (Tokyo, Japan). Normal values for PRL, aldoster- sure were normal within 2 weeks after surgery. one and PRA were 2-20ng/ml, 2.2-15ng/dl and Plasma PRL remained suppressed and there was a 0.5-3.0ng/ml/h. The inter- and intra-assay varia- marked reduction in the size of the pituitary tions for all of the assays were within 10%. tumor on brain CT and MRI with continued Statistical analysis was performed by ANOVA administration of bromocriptine after adre- followed by Duncan's multiple range test. nalectomy. Menstruation resumed about 2 months after surgery.

Results Metoclopramide test The responses of PRL and aldosterone concen- A metoclopramide test was performed in this trations to metoclopramide are shown in Figs. 2 patient and in 6 normal subjects (25-48 yr), 7 and 3, respectively, and the maximal percent patients (18-51 yr) with prolactinoma (aldosterone changes are shown in Fig. 5. Plasma PRL levels samples were not available from 4 of 7 normal increased significantly in normal subjects (M•}SD, subjects), and 7 patients (30-58yr) with APA. All 1146•}198%) and in patients with APA patients and normal subjects were studied while (615•}360%), while the response was blunted in they were consuming a diet unrestricted in sodium the present patient (126%) and in patients with after an overnight fast, and following assumption prolactinoma (118•}30%). The responses of aldos- of a supine position for at least 1h prior to basal terone to metoclopramide at 30 min were sampling. A bolus of 10mg of metoclopramide 156•}43% in normal subjects, 174•}60% in pa- was injected intravenously between 0900 h and tients with prolactinoma, 154•}30% in patients 0930 h. Plasma samples were obtained before and with APA, and 140% in the present patient. 30 min after injection, since published reports [7] The acute effects of bromocriptine on PRL and and our preliminary studies have shown that both aldosterone levels are shown in Fig. 4 and percent PRL and PAC reach their peak values 30 min after changes at 6 h are shown in Fig. 5. Plasma levels of intravenous injection of metoclopramide. PRL were suppressed by a single administration of

2.5mg of bromocriptine to 12•}5% of the basal Bromocriptine test levels in normal subjects, 27•}9% in patients with

prolactinoma and 23•}5% in patients with APA. The changes in plasma PRL and aldosterone No significant differences were observed among concentrations in response to bromocriptine admi- the 3 groups. Bromocriptine suppressed our pa- nistration were examined in this patient, 5 normal tient's plasma PRL from 563 ng/ml to 51 ng/ml subjects (aldosterone samples were not available (9%) with the lowest value at 6 h. from 2 of these 5 subjects), 5 patients with In contrast to changes in plasma PRL levels, prolactinoma and 4 patients with APA. Bromo- bromocriptine did not produce any significant criptine (2.5mg) was administered orally at 0900 changes in PAC in normal subjects (92•}11%) or in

h. Plasma samples for assay of PRL and aldoster- patients with prolactinoma (83•}39%), although one were obtained at 0, 2, 4, and 6 h. In addition mean levels tended to decrease. Bromocriptine samples were obtained from some patients at 1, 8, administration was followed by large fluctuations 12 and 24 h. The study conditions were the same of plasma aldosterone levels in 2 of 4 patients with as those for the metoclopramide test except that all APA. PAC decreased after 1h and then peaked at patients and normal subjects were allowed to have 2 and 4h and subsequently fell to below the basal a light meal at the time of bromocriptine adminis- level at 6h in the present patient. There were no 172 DEMURA et al.

(a) Normal Subjects (b) Prolactinoma (c) APA

Fig. 2. PRL levels before and 30min after iv administration of 10mg of metoclopramide to 6 normal subjects, 7 patients with prolactinoma and 7 patients with APA. The points connected by a dashed line indicate the results for the patient described in this report.

(a) Normal Subjects (b) Prolactinoma (c) APA

Fig. 3. PAC before and 30 min after iv administration of 10mg of metoclopramide to 6 normal subjects, 3 patients with prolactinoma and 6 patients with APA. The points connected by a dashed line indicate the results for the patient described in this report. DOPAMINE ON PRL AND ALDOSTERONE 173

(a) Prolactin (b) Aldosterone

Fig. 4. Changes in plasma levels of PRL and aldosterone after oral administration of 2.5mg of bromocriptine to 5 patients with prolactinoma (•œ-•œ), 4 patients with APA (•›-•›) and the present patient (•›----•›). The shadow area includes the mean•}SD for normal subjects.

(a) metoclopramide test (b)bromocriptine test concomitant changes in PRA, or serum potassium concentrations (data not shown).

Discussion

The results of the present study demonstrate that there are differences in the response of PRL and aldosterone to metoclopramide as well as to bromocriptine in normal subjects and in patients with prolactinoma or APA and in one patient with a prolactinoma and an APA. The aldosterone responses to metoclopramide were significantly lower than the responses of PRL to metoclopramide in normal subjects and in patients with APA. Assessing metoclopramide response as an index of the extent of dopaminergic inhibition, the findings suggest that dopaminergic inhibition is less important in deter- mining the secretion of aldosterone than in deter- mining the secretion of PRL in normal subjects

Fig. 5. Maximal responses of PRL (above) and aldosterone (below) to (a) metoclopramide and (b) bromocriptine in all patients and normal subjects studied. The mean maximal responses for each group are indicated by short horizontal lines. The significance of differences between groups are shown (*, P<0.01; NS, not significant). 174 DEMURA et al. and in patients with APA. These observations are the patients or normal subjects studied. Most similar to those made in earlier studies of normal earlier reports describe a discrepancy between the subjects [9-14]. The small aldosterone release in responses of PRL and aldosterone to bromocrip- response to metoclopramide seen in normal sub- tine [26, 27, 28, 29]. While plasma aldosterone jects and in patients with APA was similar to that concentrations at times varied after bromocriptine seen in our patient and in patients with prolacti- administration to normal subjects and patients noma. with prolactinoma and APA, no consistent changes In contrast to the results in normal subjects and were observed. Since changes in PRA and in patients with APA, the maximal percentage re- serum potassium levels were not associated with sponse of PRL to metoclopramide was significantly changes in plasma aldosterone levels after bromoc- attenuated in patients with prolactinoma and also riptine administration, the renin-angiotensin sys- was minimal in our patient, indicating that the tem and changes in serum potassium concentra- dopaminergic inhibition of PRL secretion is re- tions could not account for the variations observed duced in patients with prolactinoma. Diminished in the plasma aldosterone concentration. Changes response of PRL to metoclopramide was reported in ACTH levels cannot be ruled out as a cause for earlier in patients with prolactinoma and in pa- the observed changes in plasma aldosterone levels. tients with hypothalamic lesions [15, 16]. Impaired Although both adrenal and pituitary DA recep- tubero-infundibular dopaminergic neurons or an tors have been reported to be of the DA-2 type [22, increased turnover of dopamine in the hypothala- 23, 30, 31], Carey et al. [11, 12] have suggested that mus and/or pituitary have been postulated to the differences in response could be attributed to explain these findings. differences in the subtypes of dopamine receptors There have been some inconsistencies concern- on the adrenals and the pituitary. A recent study ing the changes in dopamine tone modulating with receptor gene expression reported that no aldosterone secretion in patients with APA: both DA-2 receptors or dopamine- and adenylate cyc- increased [17, 18] and unchanged [19, 20, 21] lase-regulated phosphoprotein (DARPP-32), a dopamine tone have been reported. The results of presumptive marker for D-1-receptive neurons, the present study showed that the responses of were found in the adrenal cortex of rats, though plasma aldosterone to metoclopramide in patients DA-2 receptors were found in the adrenal medulla with APA are approximately the same as those in of these animals [25]. DA receptors in the adrenal normal subjects, suggesting that dopaminergic cortex may be few in number and/or different in tone is not greatly altered in the adrenals of type from those in the pituitary. patients with APA. The lower aldosterone response to metoclopra- In addition to the results obtained with metoc- mide and the poor suppression of aldosterone by lopramide, there were differences in the responses bromocriptine compared to the response and of PRL and aldosterone to the administration of suppression of PRL, may be attributed to less bromocriptine. Our results together with most dopaminergic innervation and fewer dopa- earlier reports [1, 2, 7] show some degree of minergic receptors in the adrenals compared to suppression of PRL in response to bromocriptine the pituitary. Dopaminergic regulation of PRL in all normal subjects and patients studied. Dopa- and aldosterone must be independent of each mine receptors in the pituitary gland have been other in normal subjects, in patients with APA, well characterized in ligand-binding studies [22, and in prolactinoma. It would seem physiologically 23] and PET analysis [24]. DA-2 receptors have appropriate for regulation of aldosterone and been found on normal lactotrophs and in prolacti- PRL release to be independent. Dopamine is the noma tissues [22, 23]. The affinity and the concen- most potent physiological PRL release inhibiting tration of binding sites in pituitary adenomas were factor, while many factors other than dopamine roughly the same as those in normal lactotrophs. such as the renin-angiotensin system, potassium, More recently, gene expression of DA-2 receptor and ACTH regulate the secretion of aldosterone. has been demonstrated by in situ hybridization In our patient the changes in PRL and aldoster- [25]. one in response to metoclopramide and bromoc- In contrast, there was relatively little effect of riptine, respectively, were similar to those in bromocriptine on aldosterone secretion in any of patients with prolactinoma and with APA, respec- DOPAMINE ON PRL AND ALDOSTERONE 175 tively. It is unlikely that reduced dopaminergic Acknowledgments inhibition is the basis for hypersecretion of PRL and aldosterone in our patient. The coexistence of The authors thank Mrs. K. Terasaki, Mrs. H. a prolactinoma and an APA found in this case may Murayoshi, Miss Y. Kato, Mrs. S. Tajima and Mr. be coincidental. T. Suzuki for their able technical assistance. We also thank Dr. C. A. Nugent for revising the manuscript. This work was partly supported by a grant-in-aid for Specific Diseases from the Minis- try of Health and Welfare, Japan.

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