0021-972X/79/4805-0874$02.00/0 Journal of Clinical Endocrinology and Metabolism Copyright © 1979 by The Endocrine Society
Vol. 48, No. 5 Printed in U.S.A.
Plasma Cortisol Response to Thyrotropin-Releasing Hormone and Luteinizing Hormone-Releasing Hormone in Cushing's Disease GERLACH F. F. M. PIETERS,* ANTHONY G. H. SMALS, THEO J. BENRAAD, AND PETER W. C. KLOPPENBORG Department of Medicine, Division of Endocrinology, University of Nijmegen, Nijmegen, The Netherlands
ABSTRACT. In 3 of 6 patients with pituitary-dependent Cushing's disease, a paradoxical increase of plasma cortisol was observed both after LRH (Amax, 13.9 ± 3.7 jug/100 ml; 113 ± 52%) and TRH (Amax, 8.0 ± 2.9 jug/100 ml; 53 ± 18%) administration, the maximum values being achieved 30-60 min after the iv bolus injection. In the remaining 3 patients and in 15 control subjects, plasma cortisol levels did not rise in response to either LRH or
TRH administration but rather showed a slight to distinct decrease during the study period. The paradoxical cortisol response in half of the patients with Cushing's disease may be the consequence of loss of specificity of the pituitary receptor or alteration in the hypothalamo-pituitary pathways. (J Clin Endocrinol Metab 48: 874, 1979)
A
PARADOXICAL increase of plasma cortisol and/ or ACTH in response to TRH recently has been reported by Krieger et al. in patients with Cushing's disease or Nelson's syndrome (1, 2), but the data have not been confirmed by others (3, 4). Connell et al. (3) and Matsukura et al. (4) did not observe an increase of ACTH and/or cortisol after TRH administration in treated and untreated patients with Cushing's disease. The latter author, however, reported a paradoxical increase of ACTH and cortisol after iv injection of LRH in one patient with Cushing's disease due to a pituitary adenoma (4). In view of these contradictory data, it seemed worthwhile to study systematically the effect of both releasing hormones on adrenocortical function in patients with Cushing's disease. Materials and Methods
Six women with pituitary-dependent Cushing's disease (mean age ± SD, 39.3 ± 13.4 yr) were given both 200 /ig TRH (TRF, Roche) and 100 jig LRH (LHRH, Hoechst) iv as a bolus injection on two separate occasions with an interval of at least 2 days. Fifteen healthy subjects (mean age ± SD, 26.3 ± 12.4 yr) received 200 jug TRH and 15 other healthy controls (27.6 ± 6.9 yr) received 100 jug LRH. Informed consent was obtained from all patients and controls. All tests were performed with the patients and control subjects fasting and at bedrest. Blood samples for the cortisol assay were collected at —30, 0, 10, 20, 30, 60, and 120 min after TRH or LRH administration using an Received October 11,1978. * To whom requests for reprints should be addressed.
indwelling iv canula kept open with minute amounts of a diluted (10%) solution of heparin. Plasma cortisol levels were measured by a specific RIA using an antibody raised against cortisol-21-hemisuccinate coupled to bovine serum albumin, as described previously (5). The intraassay variation was 5%. All samples from the same subject were measured in the same assay. Statistical analysis was performed by using Student's paired t test. Unless otherwise stated, the means ± SD are given.
Results The results are given in Fig. 1. All control subjects showed a gradual decrease of plasma cortisol levels after administration of both releasing hormones; the maximum decreases were achieved 120 min after TRH (40 ± 19%) and 60 min after LRH (28 ± 26%) administration. In the LRH experiment, the decrease was already statistically significant 30 min after the bolus injection (P < 0.01), and was statistically significant in the TRH study after 60 min (P < 0.01). Remarkably, after LRH administration the decrease was followed by a slight but not significant increase at 120 min. In three of the six patients with Cushing's disease, a paradoxical increase of plasma cortisol was observed after LRH administration (Amax, 13.9 ± 3.7 /ig/100 ml; 113 ± 52%); the maximum values were achieved 60 min after the bolus injection. The cortisol levels were still supranormal at 120 min. After TRH administration, the maximum increase in these three patients was slightly lower (Amax, 8.0 ± 2.9 /ig/100 ml; 53 ± 18%). Two of these three patients who showed a paradoxical cortisol increase had roentgeno-
874
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 14:42 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS LHRH 100>ag i.v.
LHRH 100jag i.v.
I 30-
20-
E 8 10H
-30 0 30 60
120
TRH 200 jig
-30 0 30 60
120
TRH200 ng i.v.
I.V.
1
I 30CL
20-
10-
J
•A (/
\
"»
Vol. 48, No. 5 Printed in U.S.A.
Plasma Cortisol Response to Thyrotropin-Releasing Hormone and Luteinizing Hormone-Releasing Hormone in Cushing's Disease GERLACH F. F. M. PIETERS,* ANTHONY G. H. SMALS, THEO J. BENRAAD, AND PETER W. C. KLOPPENBORG Department of Medicine, Division of Endocrinology, University of Nijmegen, Nijmegen, The Netherlands
ABSTRACT. In 3 of 6 patients with pituitary-dependent Cushing's disease, a paradoxical increase of plasma cortisol was observed both after LRH (Amax, 13.9 ± 3.7 jug/100 ml; 113 ± 52%) and TRH (Amax, 8.0 ± 2.9 jug/100 ml; 53 ± 18%) administration, the maximum values being achieved 30-60 min after the iv bolus injection. In the remaining 3 patients and in 15 control subjects, plasma cortisol levels did not rise in response to either LRH or
TRH administration but rather showed a slight to distinct decrease during the study period. The paradoxical cortisol response in half of the patients with Cushing's disease may be the consequence of loss of specificity of the pituitary receptor or alteration in the hypothalamo-pituitary pathways. (J Clin Endocrinol Metab 48: 874, 1979)
A
PARADOXICAL increase of plasma cortisol and/ or ACTH in response to TRH recently has been reported by Krieger et al. in patients with Cushing's disease or Nelson's syndrome (1, 2), but the data have not been confirmed by others (3, 4). Connell et al. (3) and Matsukura et al. (4) did not observe an increase of ACTH and/or cortisol after TRH administration in treated and untreated patients with Cushing's disease. The latter author, however, reported a paradoxical increase of ACTH and cortisol after iv injection of LRH in one patient with Cushing's disease due to a pituitary adenoma (4). In view of these contradictory data, it seemed worthwhile to study systematically the effect of both releasing hormones on adrenocortical function in patients with Cushing's disease. Materials and Methods
Six women with pituitary-dependent Cushing's disease (mean age ± SD, 39.3 ± 13.4 yr) were given both 200 /ig TRH (TRF, Roche) and 100 jig LRH (LHRH, Hoechst) iv as a bolus injection on two separate occasions with an interval of at least 2 days. Fifteen healthy subjects (mean age ± SD, 26.3 ± 12.4 yr) received 200 jug TRH and 15 other healthy controls (27.6 ± 6.9 yr) received 100 jug LRH. Informed consent was obtained from all patients and controls. All tests were performed with the patients and control subjects fasting and at bedrest. Blood samples for the cortisol assay were collected at —30, 0, 10, 20, 30, 60, and 120 min after TRH or LRH administration using an Received October 11,1978. * To whom requests for reprints should be addressed.
indwelling iv canula kept open with minute amounts of a diluted (10%) solution of heparin. Plasma cortisol levels were measured by a specific RIA using an antibody raised against cortisol-21-hemisuccinate coupled to bovine serum albumin, as described previously (5). The intraassay variation was 5%. All samples from the same subject were measured in the same assay. Statistical analysis was performed by using Student's paired t test. Unless otherwise stated, the means ± SD are given.
Results The results are given in Fig. 1. All control subjects showed a gradual decrease of plasma cortisol levels after administration of both releasing hormones; the maximum decreases were achieved 120 min after TRH (40 ± 19%) and 60 min after LRH (28 ± 26%) administration. In the LRH experiment, the decrease was already statistically significant 30 min after the bolus injection (P < 0.01), and was statistically significant in the TRH study after 60 min (P < 0.01). Remarkably, after LRH administration the decrease was followed by a slight but not significant increase at 120 min. In three of the six patients with Cushing's disease, a paradoxical increase of plasma cortisol was observed after LRH administration (Amax, 13.9 ± 3.7 /ig/100 ml; 113 ± 52%); the maximum values were achieved 60 min after the bolus injection. The cortisol levels were still supranormal at 120 min. After TRH administration, the maximum increase in these three patients was slightly lower (Amax, 8.0 ± 2.9 /ig/100 ml; 53 ± 18%). Two of these three patients who showed a paradoxical cortisol increase had roentgeno-
874
The Endocrine Society. Downloaded from press.endocrine.org by [${individualUser.displayName}] on 14 November 2015. at 14:42 For personal use only. No other uses without permission. . All rights reserved.
COMMENTS LHRH 100>ag i.v.
LHRH 100jag i.v.
I 30-
20-
E 8 10H
-30 0 30 60
120
TRH 200 jig
-30 0 30 60
120
TRH200 ng i.v.
I.V.
1
I 30CL
20-
10-
J
•A (/
\
"»
