J. Endocrinol. Invest. 13: 217 -220, 1990

The growth hormone response to growth hormone releasing hormone in patients previously treated with bilateral adrenalectomy alone for Cushing's disease H.M. Whitehead*, J.A McKnight*, B. Sheridan**, AL. Kennedy*, D.R. Hadden*, and

AB. Atkinson*

* Sir George E. CIRrk Metabolie Unit, and **Regional Endocrine Laboratory, Royal Victoria Hospital, Belfast, Northern Ireland ABSTRACT. Human growth hormone releasing hormone (GHRH) fails to stimulate human growth hormone (GH). in hypereortisolism. In order to study whether the responsiveness to GHRH stimulation returns after eure of the hypercortisolism, the GH response to GHRH was examined in 8 patients at least 5 yr after they had undergone bilateral adrenalectomy as their sole treatment for Cushing's disease. None had current evidence of a pituitary macroadenoma. A group of 8 healthy subjects matched for age and sex formed the control group. All patients and subjects received an iv injedion

of GHRH 1 j..Lg/kg, after an overnight fast, blood sampl,es were taken before and at 15, 30, 45, 60; 90 and 120 min, There was no statistical difference between the peak GH or area under curve (AUC) response (median, range) in the two gr9ups studied (adrenalectomized peak GH 9.2 (4.6-32.0) vs 16.5 (7.5-63) mU I I, adrenalectomized AUC response 647.5 (344.2-1489.5) vs 1103.5 (339.75188.5) mUlI. Patients with Cushing's disease once cured of hypercortisolism, have a GH response to GHRH.

INTRODUCTION There has been considerable debate regarding the aetiology and pathogenesis of Cushing's disease (1 -9). This has centered on whether the pituitary ACTH hypersecretion is a consequence of a higher CNS abnormality or is the result of the development of an autonomous pituitary tumor, Krieger and Gewirtz (4) reported a persistent lack of growth hormone (GH) response to insulin-induced hypoglycemia and absence of nocturnal GH release during active hypercortisolism (5). In support of a higher CNS theory, they provided evidence that the GH abnormalities persisted after eure of hypercortisolism in Cushing's disease, where as, in contrast, they reported that patients with the syndrome secondary to an adrenocortical

adenoma responded normally to both- stimuli after rem oval of the adenoma (4). However, Krieger's patients with Cushing's disease all had pituitarydirected therapy in addition to bilateral adrenalectomy. More recently, we found that both the nocturnal and the insulin-stimulated release of GH had returned to normal 6 yr after bilateral adrenalectomy for Cushing's disease (9). In contrast to the patients studied by Krieger, none of ours had had any pituitary-directed therapy. Other workers have demonstrated a normal response to insulin-induced hypoglycemia after correction of hypercortisolism by pituitary surgery in Cushing's disease and after correction of other forms of Cushing's syndrome (10-12). Smals et al. (13) have shown that human growth hormone releasing hormone fails to stimulate human growth hormone in patients with active hypercortisolism. In order to elucidate further any possible abnormality of GH secretion in Cushing's disease after cure of the hypercortisolism, we have assessed the growth hormone response to growth hormone releasing hormone in a group of patients cured of Cushing's disease by bilateral adrenalectomy alone.

Key-words.· Growth hormone. growth hormone releaslng hormone. hypercortlsollsm. Cushlng's disease. bilateral adrenaleetomy. Correspondenee.· Dr. Helen M. Whltehead. Sir George E Clark Metabolie Unlt. Royal Vietoria Hospital. Grosvenor Road. Beilast. Northern Ireland, BT126BA

Reeeived July 17. 1989. aeeepted December 8. 1989

217

H.M. Whitehead, J.A. McKnight, B. Sheridan, et al.

for age and sex were studied as controls (mean age 45.8, range 33-55 yr). Informed written consent was obtained fram all patients and control subjects. All patients and controls were studied at 09:00 h, after an overnight fast. The morning dose of hydrocortisone was omitted in the seven patients receiving this therapy. An intravenous heparin lock cannula was inserted, and patients rested in bed for 30 min. At 09:30 h all subjects received human growth hormone releasing factor 1-44 (Sanofi, Wythenshawe, Manchester) 1 jlg/kg by bolus iv injection. Blood sampies were collected before and at 15, 30, 45, 60, 90 and 120 min after the injection. Plasma HGH was measured by radioimmunoassay (14). Area under curve (AUC) was calculated using the trapezoid method. Statistical comparisons were made using the non-parametric Mann-Whitney U test. Results are expressed as median and ranges. Approval for the study was obtained from the Oueen's University of Belfast Ethical Committee.

Table 1 - Clinical data for patients previously treated for Cushing's disease. Time since bilateral adrenalectomy (yr)

CT scan

Patient (no.)

Age/Sex

1

4

48/M 47/F 33/F 341M

21

1 LD « 5 mm)

5

51/F

15

2 LD (1 x 1 mm)

6

58/F

34

2 LD(2 x 2 mm)

7

47 IM

13

Normal

8

40/F

5

Normal

2 3

15

1 LD «2 mm)

11

1 LD « 2 mm)

11

1 LD « 5 mm)

LD - Iucen! defec!

In all cases the operation had been performed at least 5 yr previously. We again used patients who had had no pituitary operation or irradiation, and who at the time of study had no evidence of a large pituitary adenoma.

RESULTS MATERIALS AND METHODS

A wide range of response of GH to GHRH was observed in both groups of patients (Fig. 1). There was no statistical difference between the median peak GH or area under curve response in the two groups studied (Fig. 2) : 1) Peak GH (adrenalectomized 9.2 (4.6-32.0) vs 16.5 (7.5-63) mUli) (Table 2); 2) Area under curve response (adrenalectomized 647.5 (344-1489.5) vs 1103.5 (339.7-5188.5).

Eight patients were studied, all of whom had undergone bilateral adrenalectomy between 5 and 34 yr previously (total in 6, subtotal in 2) for treatment of Cushing's disease without pituitary-directed therapy. Their ages ranged from 33-58 yr, mean 45.3 yr. All patients were receiving standard replacement doses of corticosteroids, with the exception of patient 6 (subtotal adrenalectomy), who was on none. None of the patients had evidence of a macroadenoma (Iucent defect > 10 mm diameter) on coronal fourth generation (Siemens DR3) CT scan of the pituitary. Six patients had small lucent defects less than 5 mm diameter (Table 1). None of the patients had a visual field loss and none had active Cushing's syndrome. A group of 8 normal volunteers, matched

70 Serum hGH mUli

DISCUSSION This study demonstrates that in patients cured of Cushing's disease without pituitary-directed therapy, the GH responsiveness to GHRH can revert to normal after cure of the hypercortisolism This finding lends support to the theory that alterations in growth hormone physiology occur as a conse-

70

50 30

o

30 60 90 120 Time (min)

o

30 60 90 120 Time (min)

218

Fig 1 - The hGH response to GHRH in 8 pa/ients with Cushing's disease (Ieft) and 8 normal contral subjects (right).

GH response to GHRH in Cushing's disease

GH 70

reactive GHRH measured by RIA was significantly decreased in comparison with untreated rats (15). A similar mechanism in humans could adequately explain the impaired GH release following both insulin-induced hypoglycemia and GHRH stimulation associated with hypercortisolism, as the GH response to hypoglycemia may be mediated by both an increase in GHRH and a reduced somatostatin release (16), while in contrast, the GH response to exogenous GHRH will depend upon the degree of endogenous somatostatin release. It is conceivable that if after cure of hypercortisolism the hypothalamic content of somatostatin were to remain elevated, whilst that of endogenous GHRH returned to normal, a discrepant responsiveness to insulin-induced hypoglycemia and exogenous GHRH could result, as has occurred in a number of our patients. The GH response to GHRH in any given group is variable and difficulty arises in proving statistical differences. The 95% confidence intervals for the ratio of peak GH response in cases and controls in this study is 22% to 107%. The corresponding interval for AUC response is 27% to 131 %. We cannot exclude the possibility of a subtle remaining abnormality of GH secretion in our group of patients, but this would be very difficult to prove, because to have 90% power to detect a 34% reductionin peak GH or AUC response as statistically significant (p< 0.05; two-tailed) would require a study of 70 cases and 70 controls. Such a large study of homogenous patients such as those included in the present paper would be very difficult to organize, especially since many centres routinely advocate external pituitary irradiation after bilateral adrenalectomy for Cushing's disease.

mUli



60



50

40



30

•• • I

.•

Patiel)ts

Controls

20 10

~.-



Fig. 2 - The maximum HGH response to GHRH in patients with Cushing's disease (Ieft) and normal controls (right), n = 8.

quence of hypercortisolism per se, and argues against a higher CNS abnormality in these patients. All of our patients cured of hypercortisolism responded to GHRH with a rise in GH. This is in striking contrast to the response observed by Smals et al. (13) when assessing patients with hypercortisolism and suggests that the abnormality can be reversible. In 4 of the 8 patients we studied, the response was considerably biunted as compared with their age and sex matched controls (Table 2), perhaps reflecting a higher resting somatostatin tone. Three of these patients had previously been assessed with insulin-stimulated hypoglycemia, all had a normal response (peak rise 30-75 mUli) (9). It has been demonstrated in female rats that dexamethasone consistently suppressed serum GH levels. In these rats the hypothalamic content of immunoreactive somatostatin measured by ELiSA was significantly increased, whereas that of immuno-

Table 2 - Maximum GH and AUC response to GHRH in patients and their age/sex matched controls. Patient (no.)

Age/Sex

1

48/M 47/F 33/F 341M 51/F 58/F 47/M 40/F

2 3 4 5 6 7 8

Response to GHRH AUC Maximum (mUli) GH (mUli) 4.9

364.5

Contra I

Age/Sex

1

52/M 45/F 33/F 331M 55/F 55/F 52/M 38/F

16.0

1294.5

2

18.5

1489.5

3

4.6

434.3

4

7.3

477.8

5

11.0

816.0

6

32.0

1271.3

7

5.2

344.3

8

Aue - area under curve

219

Response to GHRH AUC Maximum (mUli) GH (mUli) 16.5

1177.5

10.5

630.7

16.0

836.3

16.5

1143.7

47.5

25523

7.5

339.8

63.0

5188.5

19.0

1064.3

H.M. Whitehead, J.A. McKnight, B. Sheridan, et al.

8. Fitzgerald PA, Aron D.C., Findling J.w., Tyrrell J.B., Brooks R.M., Wilson C.B., Forsham P.H. Cushing's disease: transient secondary adrenal insufficiency after selective rem oval of pituitary microadenomas; evidence fora pituitary origin. J. Clin. Endocrinol. Metab. 54: 413, 1982.

Our study shows that patients treated by bilateral adrenalectomy for Cushing's disease without pituitary-directed therapy can later have GH responses to GHRH. This suggests that the defective GH responsiveness to GHRH found during the hypercortisolism of Cushing's disease is reversible and does not lend weight to the concept of a primary CNS aetiology for Cushing's disease. However, we cannot exclude the possibility of a persistent subtle abnormality of GH secretion emerging if a much larger group of patients was studied.

9. Beacom R., Atkinson A.B., Kennedy A.L., Sheridan B., Hadden D.R., Merrett JD., Mcllrath E. Studies of hypothalamic pituitary structure and functi on in patients previously treated with bilateral adrenalectomy alone for Cushing's disease. Clin. Endocrinol. (Oxf.) 25: 107, 1986. 10. Demura R. Demura H. Nunokawa T. Bara H. Miura

ACKNOWLEDGMENTS

K.

HW and JMcK were in receipt of Royal Victoria Research Fellowship grpnts. The awhors would like to thank Si ster R Humphries and the nursing staff qf the Metabolie Unit for their assistance; Sanofi, Wythenshawe, for their gift of GRF (1-44); Mr C Patterson, Department of Medical Statistics, The Queen's University of Beilast, lor his statistical advice; and Miss May Weller lor preparation 01 the manuscript.

Response of plasma ACTH, GH, LH and 11-hydroxycorticosteroids to various stimuli in patients with Cushing's syndrome. J. Clin. Endocrinol. Metab. 34: 852, 1972. 11. Suda T., Demura H., Demura R., Jibiki K., Tozawa F., Shizume K. Anterior pituitary hormones in plasma and pituitaries from patients with Cushing's disease. J. Clin. Endocrinol. Metab. 51: 1048, 1980.

REFERENCES 1. James V.H., Landon J., Wynn V., Greenwood F.C. A fundamental defect of adrenocortical control in Cushing's disease. J. Endocrin~.40: 15,1968.

12. Kuwayama A., Kageyama N., Nakane T., Watanabe M., Kanie N. Anterior pituitary function after transphenoidal selective adenomectomy in patien.ts with Cushing's disease. J. Clin. Endocrinol. Metab. 53: 165, 1981.

2. Krieger D.T., Glick S.M. Growth hormone and cortisol responsiveness in Cushing's syndrome. Relation to a possible central nervous system etiology. Am. J. Med. 52: 25, 1972.

13. Smals A.E., Pieters G.F., Smals A.G., Benraad T.J., Kloppenborg p.w. Human pancreatic growth hormone releasing hormone fails to stimulate human growth hormone both in Cushing's disease and in Cushing's syndrome due to 'adrenocortical adenoma. Clin. Endocrinol. (Oxf.) 24: 401, 1986.

3. Krieger D.T., Glick S.M. Sieep EEG states and plasma growth hormone concentrations in states of endogenous and exogenous hypercortisolaemia or ACTH elevation. J. CI in. Endocrinol. Metab. 39: 986, 1974. 4. Krieger D.T., Gewirtz G.P. Recovery of hypothalamic-pituitary adrenal function, growth hormone responsiveness and sleep EEG pattern in a patient following removal of an adrenal cortical adenoma. J. Clin. Endocrinol. Metab. 38: 1075, 1974.

14. Bell P.M., Atkinson A.B., Hadden D.R., Kennedy L., Leslie H., Merrett JD., Sheridan B. Bromocriptine reduces growth hormone in acromegaly. Arch. Intern. Med. 146: 1145, 1986. 15. Nakagawa K., Ishizuka T., Obara T., Matsubara M., Akikawa K. Dichotomic action of glucocorticoids on growth hormone secretion. Acta Endocrinol. (Copenh.) 116: 165, 1987.

5. Krieger D.T., Howanitz P.J., Frantz A.G. Absence of nocturnai elevation of plasma prolactin concentrations in Cushing's disease. J. Clin. Endocnnol. Metab. 42: 260, 1976. 6. Krieger D.T. The central nervous system and Cushing's disease. Med. Clin. North Am. 62: 261, 1978.

16. Jordan V., Dieguez C., Lafaffian 1., Rodriguez-Arnao MD., Gomez-Pan A., Hall R., Scanlon M.F. Influence of dopaminergic, adrenergic and cholinergic blockade and TRH administration onGH responses to GRF 1-29. Clin. Endocrinol. (Oxf.) 24: 291, 1986.

7. Krieger D.T. Physiopathology of Cushing's disease. Endocr. Rev. 4: 22, 1983.

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The growth hormone response to growth hormone releasing hormone in patients previously treated with bilateral adrenalectomy alone for Cushing's disease.

Human growth hormone releasing hormone (GHRH) fails to stimulate human growth hormone (GH) in hypercortisolism. In order to study whether the responsi...
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