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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1682-1686
Copyright © 1998 by The Endocrine Society

Original Studies

Hypothalamic Dysfunction in "Cured" Acromegaly Is Treatment Modality Dependent

Steven R. Peacey, Andrew A. Toogood and Stephen M. Shalet

Department of Endocrinology, Christie Hospital, Manchester, United Kingdom M20 4BX

Address all correspondence and requests for reprints to: Prof. S. M. Shalet, Department of Endocrinology, Christie Hospital, Wilmslow Road, Manchester, United Kingdom M20 4BX.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The current definition of cure after treatment for acromegaly stipulates a reduction in GH levels to less than 2 ng/mL (<5 mU/L), as such GH concentrations are believed to be associated with normalization of long term survival. We sought to further define the nature of the cure in such patients, when cure has been achieved by alternative therapeutic modalities, in the expectation that hypothalamic neuroregulatory control of GH secretion might be affected differently by radiotherapy or surgery. In particular we wished to determine the effect of therapy modality on endogenous somatostatin (SMS) tone, using the GH response to iv arginine as a paradigm. We studied 20 patients with cured acromegaly (mean 24-h GH concentration, <2 ng/mL). Eight patients had been cured by surgery only (S; 4 women and 4 men; mean ± SEM age, 52 ± 5 yr), and 12 patients had been cured by radiotherapy (R; 4 women and 8 men; age, 52 ± 3 yr). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age 53 ± 3]. The median (range) GH during 24-h profiles was similar in each group: S, 1.3 (0.7–1.8) ng/mL; R, 0.6 (0.4–1.8) ng/mL; and C, 0.7 (0.4–3.2) ng/mL (P = 0.57). The median incremental GH responses to arginine were significantly lower in the R group compared with those in the S and C groups: S, 6.4 (2.1–16.6) ng/mL; R, 0.1 (0–1.7) ng/mL; and C, 9.2 (0–16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). We conclude that in acromegalic patients deemed to be cured (GH, <2 ng/mL), the mode of therapy has considerable influence on the remaining hypothalamic-somatotroph function. In view of the putative mechanism by which arginine releases GH, we suggest that radiotherapy leads to a reduction or complete loss of endogenous SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH, >2 ng/mL) and who require SMS analog therapy.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE REGULATION of GH release from the normal pituitary gland is predominantly under control of the two hypothalamic hormones, GHRH and somatostatin (SMS) (1, 2). The pulsatile nature of GH release from the somatotroph is thought to be generated by episodic stimulation of the somatotroph by GHRH, augmented by a concomitant reduction in SMS tone, whereas the interpulse GH concentration is thought to reflect the inhibitory tone of SMS (1, 2, 3, 4, 5, 6).

The frequency of GH pulses in acromegaly is increased (7, 8, 9, 10, 11), and this has been interpreted by several authors as evidence that acromegaly is due to a primary hypothalamic abnormality, with secondary development of a pituitary neoplasm (7, 9, 11). Conversely, there is evidence that acromegaly is due to a primary pituitary defect, as the abnormal GH pulsatility in acromegaly may revert to a normal pattern after complete removal of the pituitary tumor (8, 10). Furthermore, somatotroph adenomas are of monoclonal origin (12), and up to 40% have been shown to have an abnormality of the Gs{alpha} subunit (gsp oncogene mutation) (13, 14).

Surgery remains the favored mode of therapy in the majority of patients and may be completely curative, particularly in the case of microadenomas (15, 16, 17). The majority of macroadenomas require further treatment in the form of radiotherapy and/or medical therapy. Radiotherapy is excellent at halting tumor growth, but the slow reduction in GH concentration (18), damage to the normal hypothalamic pituitary axis-necessitating lifelong replacement hormone therapy (19), and the recent evidence to suggest lack of normalization of IGF-1 (20) are obvious disadvantages.

Recent studies have suggested that GH levels below 2 ng/mL are associated with normalization of insulin-like growth factor I (IGF-I) (21, 22). Similarly, patients who achieve such GH levels after treatment have improved long term survival (23), predominantly as a result of a reduction in the excess cardiovascular mortality associated with acromegaly (23, 24, 25, 26, 27, 28). Thus, the current definition of "cure" in acromegaly stipulates a reduction in mean GH concentrations to less than 2 ng/mL (<5 mU/L) (23, 29). However, we hypothesized that in patients in whom such GH levels had been achieved, hypothalamic neuroregulatory control of GH secretion might be affected differently by the alternative modes of therapy used to produce a cure.

We, therefore, sought to further define the nature of the cure in those patients who achieve a mean GH concentration below 2 ng/mL by different therapeutic interventions, i.e. those cured by surgery only or by radiotherapy. We have assessed this in terms of the ability of the somatotroph to release GH in response to arginine. Arginine was chosen because it is generally accepted that arginine predominantly, although not exclusively (30), causes GH release by the inhibition of SMS (31, 32); the test can safely be used in patients of any age; and the GH response is not age dependent (33, 34). We hypothesized that the GH response to arginine in cured acromegalics could be used to reflect the underlying SMS tone and any existing hypothalamic dysregulation of GH secretion.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
We reviewed the case notes of all our acromegalic patients. All 26 patients who had achieved GH levels below 2 ng/mL during an oral glucose tolerance test or a GH profile (usually hourly samples, for 5–8 h) and who were not receiving medical therapy for their acromegaly, were approached and asked to participate in this study. Of these, 20 patients agreed to be studied, and the mean GH concentration over 24 h (using every 20 min sampling) was determined in these patients (see Results). Eight patients had been cured by surgery only [S; 4 women and 4 men; mean ± SEM age, 52 ± 5 yr; body mass index (BMI), 28 ± 1 kg/m2], and 12 patients had been cured by radiotherapy (R), 7 of whom had undergone previous surgery, which had been unsuccessful (4 women and 8 men; age, 52 ± 3 yr; BMI, 32 ± 1 kg/m2). Sixteen healthy subjects were studied as a control group (C; 6 women and 10 men; age, 53 ± 3 yr; BMI, 27 ± 1 kg/m2). Two of the 8 surgically cured patients and 11 of the 12 radiotherapy cured patients had macroadenomas at diagnosis. Nine of the radiotherapy cured (but none of the surgically cured patients), had additional anterior pituitary hormone deficits and were receiving conventional hormone replacement at the time of study. Seven surgically cured patients had transsphenoidal surgery (1 had transethmoidal surgery). Eleven radiotherapy cured patients received external beam radiotherapy (2000–4500 cGY); 1 of these patients had also previously received an yttrium implant, and the remaining radiotherapy cured patient was treated with an yttrium implant alone. Details of previous therapy and pituitary hormone deficits are given in Tables 1, a and b.

Each subject fasted from 2200 h and had an iv cannula inserted into the antecubital fossa. The following morning at 0900 h, each subject underwent an arginine stimulation test (20 g arginine/m2 given iv over 30 min from 0 min). Blood was sampled for GH at time zero and every 30 min for 150 min. GH was measured using a two-site immunoradiometric assay, with a limit of detection of 0.4 ng/mL. Interassay coefficients of variation were 8.8%, 5.5%, and 6% at GH concentrations of 2, 10, and 26 ng/mL, respectively. Blood was also sampled for IGF-I at 0 min.

Results are expressed as medians (with the ranges in parentheses) and were analyzed using ANOVA; comparisons were made using Dunn’s test. P < 0.05 was considered statistically significant. For purposes of analysis a reported GH value of less than 0.4 ng/mL was regarded as 0.4 ng/mL. Ethical approval was granted by the South Manchester Medical research ethics committee.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
GH and IGF-I

The median (range) GH during a 24-h profile was similar in each group: S, 1.3 (0.7–1.8) ng/mL; R, 0.6 (0.4–1.8) ng/mL; and C, 0.7 (0.4–3.2) ng/mL (P = 0.57; Fig. 1Go). The median IGF-I level was significantly elevated in the R group compared with that in C subjects, whereas the median IGF-I level in the S patients was not significantly different from that in either the C or the R group: S, 219 (124–853) ng/mL; R, 273 (100–792) ng/mL; and C, 156 (89–342) ng/mL (P < 0.02; S vs. R, P > 0.05; S vs. C, P > 0.05; R vs. C, P < 0.05; Fig. 2Go).



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  		Figure 1. Individual mean GH concentrations during a 24-h profile (bar = median).

 


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  		Figure 2. Individual IGF-I concentrations (bar = median).

 
Arginine stimulation

Basal GH concentrations were similar: S, 0.6 (0.4–2.2) ng/mL; R, 1.0 (0.4–4.5) ng/mL; and C, 0.6 (0.4–4.7) ng/mL (P = 0.94). Median incremental GH responses were significantly lower in the R group compared with those in the S or C group: S, 6.4 (2.1–16.6) ng/mL; R, 0.1 (0–1.7) ng/mL; and C, 9.2 (0–16.1) ng/mL (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001; Fig. 3Go). The total area under the curve from 0–150 min revealed similar results: S, 580 (275–1264) ng/mL·min; R, 154 (60–390) ng/mL·min; and C, 635 (60–1476) ng/mL·min (P = 0.0002; S vs. R, P < 0.01; S vs. C, P > 0.05; R vs. C, P < 0.001). No correlation was found between the IGF-I level and the incremental GH response to arginine for either the patients or controls.



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  		Figure 3. Individual basal and peak GH concentration during an arginine stimulation test in radiotherapy cured patients (a), surgically cured patients (b), and controls (c). S vs. R, P < 0.01; S vs. C, P = > 0.05; R vs. C, P < 0.001.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Each patient in this study had a mean GH concentration during 24 h of less than 2 ng/mL, and as such they represent patients with cured acromegaly, adopting current biochemical and epidemiological definitions. Although GH concentrations at this level have been associated with normalization of IGF-I (21, 22), clearly such a definition of cure does not necessarily equate with a normal IGF-I for a given individual, as the mean GH concentration during a GH profile does not reveal the pattern of GH release, which may continue to be abnormal (22). This point has been emphasized by Barkan et al. recently (20). Thus, although the median IGF-I concentration was similar in S and C groups, the S group clearly included individuals with an elevated IGF-I, who might therefore be considered to have active acromegaly and still have adenomatous cells present, albeit with relatively low GH secretory activity. Similar examples exist in the R group.

The major finding of this study, is the striking difference in the GH response to arginine between the R and S acromegalic patients. All of the S acromegalic patients had an incremental GH response in excess of the incremental GH response of every patient in the R group. Indeed, most patients in the R group exhibited only a minimal GH response to arginine, and six patients had no GH response. It is known that both the normal somatotroph and GH-secreting adenomas release GH in response to arginine (35, 36), and it has been postulated that this occurs primarily through the inhibition of SMS from the hypothalamus (31, 32), although contributions via the release of GHRH (30) and possibly the putative endogenous GH-releasing peptide cannot be totally excluded (37). The lack of a GH response to arginine in the R group therefore suggests either hypothalamic dysfunction or complete destruction of both normal and abnormal somatotrophs of the pituitary by radiotherapy. Some of the patients in the radiotherapy group had mean 24-h GH concentrations below 0.4 ng/mL, and thus the lack of response to arginine stimulation may represent a complete absence of normal and abnormal somatotrophs. However, other patients in this group have clear evidence of GH secretion during 24 h, with or without an elevated IGF-I, and yet no GH response to arginine occurred. Furthermore, there was no differentiation in the arginine-induced GH response between those radiotherapy treated patients with detectable GH and a raised IGF-I level and the four patients who had an undetectable GH concentration during a 24-h profile. In view of the putative mechanism of GH release during arginine stimulation, it can be inferred from the above results that damage has occurred to the SMS-producing cells of the hypothalamus (and possibly to the GHRH neurons also). In view of the similar GH responses to arginine in the S and C groups, this suggests that radiotherapy per se has caused damage to the SMS-producing cells of the hypothalamus.

These findings are consistent with previous findings that radiotherapy causes hypopituitarism by inducing damage primarily within the hypothalamus rather than the pituitary gland (38, 39, 40); thus, the hypothalamus is more radiosensitive than the pituitary (41). Two of the patients received yttrium implantation as primary therapy (one of whom subsequently also received external beam radiotherapy). Both of these patients had mean GH levels below 0.4 ng/mL and had no response to arginine. This may represent hypothalamic damage, but is more likely to represent complete pituitary somatotroph destruction, as yttrium is conventionally thought to cause less damage to the hypothalamus (42).

Few studies have examined the GH response to arginine in patients with acromegaly who have been treated with radiotherapy. Where the individual GH results have been documented, the patients have shown varying GH responses to arginine. Such patients have not, however, been cured acromegalics, and the time after radiotherapy has not been stated in these studies (35, 36). Clearly, the time from radiotherapy may be an important factor in the development of hypothalamic damage.

Recently, using an ultrasensitive chemiluminescent GH assay, it has been shown that GH release remains pulsatile in GH-deficient patients with pituitary disease who have undergone surgery and radiotherapy (43). Similarly, it has been suggested that radiotherapy reduces, but does not completely abolish, SMS and GHRH release (44). These studies suggest that although SMS and GHRH release may be greatly reduced by radiotherapy, they continue to be secreted, albeit perhaps at low concentrations. Such findings are compatible with the results of this study. It should be noted, however, that 3 of 16 healthy control subjects also had minimal or no GH response to arginine stimulation. This is consistent with previous reports in normal subjects using this test (33, 34) and confirms that for a given individual, the lack of a GH response to arginine may not necessarily indicate hypothalamic or pituitary disease.

Somatotroph tumors are known to express SMS receptors to a variable degree, and as such, patients with acromegaly show variable GH suppression during SMS analog therapy (45). If radiotherapy induces damage or destruction of the SMS-producing cells of the hypothalamus, then this may induce an alteration of SMS receptor expression by the tumor. We hypothesize that such an alteration of SMS receptor expression might alter the sensitivity of those radiotherapy-treated tumors to exogenous SMS analog therapy compared to that of those tumors that have been treated with surgery only. Similarly, if such a change in receptor expression does follow radiotherapy, then the exact timing of this change is unknown, i.e. how long after radiotherapy does endogenous SMS production decline. Further studies are required to answer these questions, as the effectiveness and dose-response relationship of subsequent SMS analog therapy may be influenced by prior pituitary radiotherapy.

In conclusion, we have shown that in acromegalic patients deemed to be cured (GH <2 ng/mL), the mode of therapy has considerable influence on remaining hypothalamic-somatotroph function. We suggest that radiotherapy leads to a reduction or complete loss of endogenous hypothalamic SMS tone. This may have implications for the treatment of those acromegalic patients who are not cured (GH >2 ng/mL) and who require SMS analog therapy.


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  		Table 1A. Patient details of surgically cured acromegalic patients

 

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  		Table 1B. Patient details of radiotherapy cured acromegalic patients

 
Received December 5, 1997.

Revised February 3, 1998.

Accepted February 11, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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QJM, January 1, 2000; 93(1): 1 - 6.
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P. U. Freda, K. D. Post, J. S. Powell, and S. L. Wardlaw
Evaluation of Disease Status with Sensitive Measures of Growth Hormone Secretion in 60 Postoperative Patients with Acromegaly
J. Clin. Endocrinol. Metab., November 1, 1998; 83(11): 3808 - 3816.
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