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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 2 514-517
Copyright © 1997 by The Endocrine Society

Clinical Studies

Acute Effects of Bromocriptine, Cyproheptadine, and Valproic Acid on Plasma Adrenocorticotropin Secretion in Nelson’s Syndrome

Leilani B. Mercado-Asis1, Jack A. Yanovski2, Howard L. Tracer3, Constance L. Chik4 and Gordon B. Cutler, Jr.2

Developmental Endocrinology Branch, National Institute of Child Health and Human Development, and the Office of the Director, Warren Grant Magnuson Clinical Center, National Institutes of Health, Bethesda, Maryland 20892

Address all correspondence and requests for reprints to: Gordon B. Cutler, Jr., M.D., Developmental Endocrinology Branch, National Institute of Child Health and Human Development, Section on Developmental Endocrinology, Building 10, Room 10N262, 10 Center Drive, MSC 1862, Bethesda, Maryland 20892-1862.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Previous studies have found that bromocriptine, cyproheptadine, and valproic acid can reduce ACTH secretion in Nelson’s syndrome, but none of these agents has achieved widespread use due to their failure to normalize ACTH in most patients. The current study was undertaken to determine whether these three agents, which act through different mechanisms, decrease plasma ACTH synergistically when administered together. Six adult female patients (mean age, 41 yr) with Nelson’s syndrome were studied. ACTH was measured every 20 min for 8 h, 2 h before and 6 h after each of the following six treatments: placebo, bromocriptine (2.5 mg), cyproheptadine (8 mg), valproic acid (1 g), cyproheptadine plus valproic acid, and the combination of all three drugs. The sequence of treatments was determined randomly, and there was an interval of at least 2 days between each treatment. The hourly ACTH values were averaged, and the percent maximal suppression of plasma ACTH, relative to the baseline values before drug administration, was compared among the six treatments. Basal plasma ACTH levels in the six patients ranged from 40–3324 pmol/L (normal range, 1–8). The percent maximal suppression of ACTH after administration of placebo (6 ± 11%), cyproheptadine (17 ± 15%), valproic acid (37 ± 10%), or the combination of cyproheptadine and valproic acid (19 ± 14%) did not achieve statistical significance. Bromocriptine, on the other hand, caused a significant decrease in plasma ACTH (52 ± 8%; P < 0.05), as did the combination of bromocriptine, cyproheptadine, and valproic acid (58 ± 12%; P < 0.05). However, the combined effect of the three drugs did not significantly exceed the effect of bromocriptine alone. We conclude that at the doses studied, bromocriptine had the greatest acute effect in suppressing ACTH secretion in Nelson’s syndrome, and that combined administration with valproic acid and cyproheptadine did not further increase this acute ACTH-suppressive effect.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
NELSON AND colleagues in 1958 (1) described the syndrome of hyperpigmentation, marked ACTH hypersecretion, and an enlarging pituitary tumor after bilateral adrenalectomy for Cushing’s disease. Current treatment for this condition is transsphenoidal resection of the tumor and/or irradiation (2, 3). Although most patients respond well to this approach, a minority have progressive tumor growth and rising ACTH levels (4, 5, 6).

An alternative management approach for such patients is medical treatment to suppress ACTH (7). Valproic acid (8), cyproheptadine (9), and bromocriptine (10, 11) have each been shown to reduce ACTH in some patients with Nelson’s syndrome. None of these agents has achieved widespread use, however, due to the limited data on their abilities to normalize ACTH secretion.

The distinct mechanisms of action of bromocriptine, cyproheptadine, and valproic acid led us to hypothesize that they might have additive or synergistic effects in suppressing plasma ACTH. Bromocriptine, a dopamine agonist, is thought to exert its effects through pituitary dopamine receptors (10, 11, 12, 13, 14, 15, 16, 17, 18). Cyproheptadine, a serotonin antagonist, was originally proposed to suppress ACTH through a hypothalamic site of action (19, 20, 21, 22, 23), but may also have direct effects on ACTH-secreting tumor cells (12, 22, 24, 25, 26). Valproic acid, an inhibitor of {gamma}-aminobutyric acid reuptake, is presumed to act by enhancing {gamma}-aminobutyric acid inhibition of hypothalamic CRH release (8, 27, 28, 29, 30, 31, 32, 33, 34, 35). To evaluate the potential synergism of multidrug regimens in the treatment of Nelson’s syndrome, we determined the acute effects of single doses of bromocriptine, cyproheptadine, and valproic acid, separately and in combination, in patients with Nelson’s syndrome.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Clinical features of the patients

Six women (mean age, 41 yr; range, 29–59 yr) were studied 2–25 yr after bilateral adrenalectomy for Cushing’s disease. All six had a radiologically detected pituitary adenoma at presentation, which was pathologically confirmed as corticotropinoma in the five patients who underwent surgery (Table 1Go). None had evidence of ectopic secretion of ACTH or CRH. All patients were diagnosed as having Nelson’s syndrome on the basis of hyperpigmentation and elevated basal plasma ACTH levels at the time of study. When enrolled in this study, patients 1, 4, 5, and 6 had magnetic resonance imaging evidence of extrasellar extension of their pituitary tumor, whereas patients 2 and 3 had no obvious evidence of residual pituitary tumor. Five subjects had undergone transsphenoidal surgery (patients 1, 2, 4, 5, and 6) or pituitary irradiation (patients 1, 2, 3, 5, and 6) 1–12 yr before study, and all except patient 2 were receiving treatment for secondary hypothyroidism, hypogonadism, or diabetes insipidus. The protocol was approved by the institutional review board of the NICHHD, and informed consent was obtained from each subject.


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  		Table 1. Clinical features of six patients with Nelson’s syndrome

 
Protocol

Data were collected for six different test periods: placebo, bromocriptine (2.5 mg), cyproheptadine (8 mg), valproic acid (1 g), the combination of cyproheptadine (8 mg) and valproic acid (1 g), and the combination of cyproheptadine (8 mg), valproic acid (1 g), and bromocriptine (2.5 mg). The sequence of the six tests was randomized, and the interval between tests was at least 2 days. The cortisol maintenance dose was withheld on test days until after the 8-h sampling period (1600 h). Blood samples for determination of plasma ACTH were collected every 20 min for 8 h starting at 0800 h (2 h before and 6 h after administration of the test medication). The basal ACTH level for each test period was determined by averaging the seven successive ACTH measurements obtained every 20 min between 0800–1000 h before administration of the study medication.

Plasma ACTH was measured by polyclonal RIA after extraction (36). The sensitivity of the ACTH assay ranged from 0.9–2.2 pmol/L. The intra- and interassay variabilities were 7–12% and 12–25%, respectively. All samples from a given day were measured in the same assay.

Statistical analysis

Data are presented as the mean ± SEM. To analyze drug effects on ACTH, for each study medication we first determined the mean ACTH level during the initial 2 h before drug administration (the average of the seven successive baseline ACTH values obtained every 20 min between 0800–1000 h) and then found the hourly mean ACTH (the average of the three ACTH values obtained during that hour) for each of the 6 h after administration of the study medication. The percent maximal suppression (PMS) of ACTH was determined from the lowest mean hourly ACTH level during the 6 h after drug administration. PMS data were subjected to an arc-sine-square root transformation before one-way ANOVA with repeated measures. Post-hoc paired Fisher’s least significant differences test was used to determine significance among the various medications using the Bonferroni adjustment for multiple comparisons. Nominal P values are reported.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
ANOVA with repeated measures demonstrated a significant effect of medication (Fig. 1Go; P < 0.05). Administration of placebo caused no significant change in plasma ACTH (PMS, 6 ± 11%), whereas bromocriptine caused a significant decrease in plasma ACTH (52 ± 8%; P < 0.05 vs. placebo). The maximal decrease in plasma ACTH did not achieve statistical significance after administration of cyproheptadine (17 ± 15%), valproic acid (37 ± 10%), or the combination of cyproheptadine and valproic acid (19 ± 14%). Although the greatest suppression of plasma ACTH was observed when all three medications (bromocriptine, cyproheptadine, and valproic acid) were given together (58 ± 12%; P < 0.05 vs. placebo), the difference between the suppression induced by bromocriptine alone and that induced by the combination of all three agents was not statistically significant. The time of maximal ACTH suppression was 4.8 ± 0.5 h (mean ± SEM) after bromocriptine administration and 3.8 ± 0.7 h after the administration of all three drugs (P = NS).



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  		Figure 1. PMS of plasma ACTH (relative to the mean level at 0800–1000 h) in six patients with Nelson’s syndrome after single doses of bromocriptine (2.5 mg), cyproheptadine (8 mg), valproic acid (1 g), cyproheptadine plus valproic acid (Cypro + Valpro), or the combination of all three drugs. Solid bars represent the mean ± SEM. Each subject’s data points are indicated by the symbols to the left of each solid bar. *, P < 0.05 vs. placebo treatment.

 
Adverse effects of the study drugs included moderate orthostatic hypotension in five patients (patients 1–5) after bromocriptine ingestion. Patient 4 had severe dizziness, nausea, and vomiting in response to the combination of the three drugs, and patient 2 experienced sleepiness.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Among the three drugs evaluated, each of which has been shown in previous reports to suppress ACTH secretion in patients with Nelson’s syndrome, only bromocriptine (2.5 mg) suppressed ACTH levels acutely at the dose used in this study. Our results support earlier observations on the suppressive effects of bromocriptine on ACTH secretion (10, 11, 12, 13, 14, 15, 16, 17, 18), but did not demonstrate the efficacy of cyproheptadine (19, 20, 21, 22, 23, 24, 25, 26) or valproic acid (27, 28, 29, 30, 31, 32, 33, 34, 35). Moreover, contrary to our hypothesis, the combination of bromocriptine, cyproheptadine, and valproic acid did not produce greater acute ACTH-suppressive effects than bromocriptine alone. Thus, this acute, single dose study did not provide a rationale for the combined use of these agents in the management of Nelson’s syndrome.

Although this study found no synergism among these drugs when administered acutely, it remains possible that additive or synergistic effects might be observed in longer term studies or with different dosing regimens. For example, Krieger and colleagues suggested that the maximal response to cyproheptadine requires at least 3 weeks of treatment at a dose of 24 mg/day (9, 20, 37). Thus, the issue of whether the combined use of these drugs for longer periods might have additive or synergistic effects will have to be resolved through longer term studies.

The patient with Nelson’s syndrome who is refractory to transsphenoidal surgery and pituitary irradiation remains a difficult treatment problem. For these patients, continued research is needed to develop a medical therapy that approaches the effectiveness of the medical treatments for prolactinomas (38) and somatotroph adenomas (39).


   Footnotes
 
1 Current address: Section of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine and Surgery, University of Santo Tomas, Espana, Manila, Philippines. Back

2 Commissioned officer, USPHS. Back

3 Current address: 8300 Corporate Drive, Landover, Maryland 20785. Back

4 Current address: Room 362, HMRC, Division of Endocrinology and Metabolism, Department of Medicine, University of Alberta, Edmonton, Alberta Canada T6G 2S2. Back

Received July 15, 1996.

Revised September 19, 1996.

Accepted October 10, 1996.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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