Acromegaly from ectopic growth hormone-releasing hormone secretion by a malignant carcinoid tumor.Successful treatment with long-acting somatostatin analogue SMS 201–995

Abstract

A 26-year-old man with acromegaly secondary to ectopic growth hormone-releasing hormone (GHRH) secretion by a metastatic carcinoid tumor is the subject of this study. He previously failed to respond to conventional therapeutic modalities (partial hypophysectomy, pituitary irradiation, highdose bromo-criptine and a combination of streptomtwin and 5-fluorouracil) and was treated with long-acting so-matostatin analogue SMS 201-995 (Sandoz, East Hanover, NJ). Growth hormone and somatomedin C concentrations became normal, and GHRH-LI (GHRH-like immunoreactivity) was suppressed by more than 60%. The growth hormone response to exogenous GHRH 1-40 was stopped and growth hormone rise to thyrotropin-releasing hormone (TRH) was significantly attenuated. A significant shrinkage of the pituitary gland was observed. Similarly, the size of the metastatic carcinoid lesions decreased dramatically and was accompanied by a normalization of liver function. After almost 2 years of SMS 201-995 therapy, the patient was well and had no clinical signs of acromegaly. Thus, SMS 201-995 appears to be a remarkably effective agent for treatment of acromegaly secondary to ectopic GHRH secretion. Cuncer 61:221-226, 1988. HE CLINICAL AND BIOCHEMICAL syndrome of acro-T megaly usually stems from hypersecretion of growth hormone (GH) by benign pituitary somatotroph adenomas. This disease also rarely may result from ec-topic secretion of growth hormone-releasing hormone (GHRH) by malignant islet cell or carcinoid tumors.'d In these cases chronic stimulation by ectopic GHRH leads to the development of pituitary somatotroph hy-perplasia and GH hypersecretion. Removal of ectopic GHRH-producing tumors is followed by normalization of pituitary GH secretion and cure of acromegaly.' Unfortunately , by the time of diagnosis, most of the GHRH-producing tumors are already metastatic and not suitable for surgical resection. Standard chemother-From the *Endocrinology Section, VA Medical Center and the University of Michigan, Ann Arbor, Michigan, and the ?Clayton Founda-apy aimed at the ectopic GHRH-producing tumor is usually ineffe~tive,~-~ and attempts to control excessive GH secretion by "pituitary" approaches (surgery, radiation , or bromocriptine) are also unsuccessful because they cannot overcome the continuous stimulatory drive of ectopic GHRH.'*3*5 Thus, until recently, acromegaly secondary to metastatic GHRH-producing tumors was regarded as an untreatable disease. A long-acting somatostatin analogue, SMS 20 1-995, has a powerful suppressive effect on pituitary somato-trophs7s8 and has been shown to normalize plasma GH and to shrink pituitary tumors in patients with acro-megaly.' Additionally, this drug was found to suppress the hormone secretion by carcinoid" and gastrointesti-tumors. In four patients with unresectable GHRH-producing tumors treated thus far,49S*15*16 SMS 201-995 suppressed both GH and ectopic GHRH secretion. However, the GHRH-producing neoplasms did not shrink. We report the first case of ectopic GHRH-induced acromegaly successfully tr...

Neuroendocrine tumors secreting growth hormone-releasing hormone: Pathophysiological and clinical aspects

“…Somatostatin analogs provide an effective option for medical management of carcinoid patients, especially those with recurrent disease. In fact, somatostatin analog therapy may slow tumor progression in some patients with neuroendocrine tumors [90,92]. Administration of the analog is able to lower circulating GH and IGF-1 levels by suppressing ectopic tumor production of GHRH [93].…”

“…In most of the published studies, medical therapy of acromegaly due to ectopic GHRHsecreting tumors with octreotide or lanreotide over a period of 2.5-36 months did not achieve a significant shrinkage of primary or metastatic neoplastic lesions. On the other hand, Barkan et al [90] observed a significant shrinkage of lung, bone, and liver metastases of a carcinoid of unknown origin under long-term treatment with octreotide at very low doses (100 µg/d) without obtaining, however, any normalization in GHRH plasma levels.…”

Pituitary Apoplexy after Subtotal Thyroidectomy in an Acromegalic Patient with a Large Goiter.

“…The second possibility is that the thyroid goiter might have produced ectopic GHRH. This hormone is reported to be secreted by pancreatic, pulmonary and intestinal endocrine tumors and by sympathetic neuronal tumors (5,6). Some medullary carcinomas of the thyroid may contain immunoreactive GHRHtissue (7,8).…”

Ectopic growth hormone-releasing hormone secretion by a metastatic bronchial carcinoid tumor: a case with a non hypophysial intracranial tumor that shrank during long acting octreotide treatment

“…IGF-1: 984 ng/ml (63-380), GH: 49.8 ng/ ml (<5), PRL: 23.3 ng/ml (5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19)(20), testosterone: 3.6 ng/ml (3)(4)(5)(6)(7)(8)(9)(10)(11)(12), LH: 2.0 mIU/ml (2)(3)(4)(5)(6)(7)(8), FSH: 3.9 mIU/ml (2)(3)(4)(5)(6)(7)(8), mid-molecule PTH: 31.2 pg/ml (£125), gastrin: 29 pg/ml (£90), 5-hydroxyindoleacetic acid: 9 mg/24 h (£6), serum chromogranin A: 20 nmol/l (<4).…”

“…Although experience is still limited (only 19 patients to our knowledge) [5,7,8], somatostatin (SMS) analogs have been used in the treatment of ectopic acromegaly since they may not only control the endocrine hypersecretion but also tumor proliferation. Despite the favorable clinical improvement documented for most of the patients, the significant decrease in GH and insulin-like growth factor 1 (IGF-1) [9][10][11][12] and shrinkage of the previously hyperplastic pituitary gland [7,12], the response of the GHRH-producing tumor and its metastases is less predictable and tumor size can increase despite suppression of the GH axis [5][6][7][8][9].…”