Medical Management of Acromegaly Due to Ectopic Production of Growth Hormone-Releasing Hormone by a Carcinoid Tumor*

Abstract

A 59-yr-old woman with a disseminated carcinoid tumor was evaluated for acromegaly. She had previously undergone a hypophysectomy for acromegaly and an enlarged pituitary, with a reduction in her serum GH levels from 100 to 4 micrograms/L. Recurrence of acromegalic symptoms 2 yr later was accompanied by elevated serum GH (16 micrograms/L) and insulin-like growth factor I (IGF-I; 528 micrograms/L) and plasma GHRH levels (12 micrograms/L; normal, less than 30 ng/L). Computed tomographic scan did not reveal pituitary enlargement. Metastatic carcinoid tissue in bone removed at biopsy contained GHRH (100 pg/mg tissue). High performance liquid chromatography of plasma GHRH revealed predominantly GHRH-(3-40)-OH, a biologically inactive GHRH metabolite, along with mature GHRH forms, while carcinoid tissue contained both GHRH-(1-40)-OH and GHRH-(1-44)-NH2. Treatment with pergolide initially resulted in reduction in serum GH and IGF-I levels and amelioration of symptoms of acromegaly. However, after 14 months of pergolide therapy, serum GH levels increased despite administration of up to 1000 micrograms pergolide/day. Plasma GHRH levels remained elevated throughout the treatment period. Subsequent treatment with SMS 201-995, a long-acting somatostatin analog, for over 1 yr resulted in sustained reductions of ectopic GHRH secretion, GH hypersecretion, and IGF-I levels. Plasma GHRH levels correlated with simultaneously measured serum GH levels in response to acute SMS 201-995 administration. SMS 201-995 was an effective medical treatment for acromegaly caused by ectopic GHRH production in this patient.

Dipeptidylpeptidase IV and trypsin-like enzymatic degradation of human growth hormone-releasing hormone in plasma.

“…Although our initial study (1) was performed using synthetic GRH(1-44)-NH2, recent characterization of plasma from a patient with ectopic GRH secretion associated with a carcinoid tumor revealed that the majority of GRH immunoreactivity was in the form of GRH(3-40)-OH (3). In the present report we also provide evidence for similar metabolism in another model of GRH hypersecretion, the transgenic hGRH pig.…”

“…The action of these enzymes, however, emphasizes the importance of the development of resistant analogues for potential therapeutic and animal science use. Indeed, we have recently characterized the plasma GRH immunoreactivity in a patient with acromegaly due to an ectopic GRH-producing tumor (3). Plasma IR-GRH levels before treatment were nearly 10 ng/ml, but after HPLC separation, intact, native GRH forms were shown to make up only 5-10% of the total circulating GRH immunoreactivity.…”

Pathophysiology and clinical aspects of the ectopic GH‐releasing hormone syndrome

“…Octreotride therapy was usually given to patients with disseminated GHRH-secreting tumours that could not be removed completely by surgery. Normalization of GH and IGF-I levels was achieved in most of the treated patients (Ch'ng et al, 1985;von Werder et al, 1986von Werder et al, , 1987Barkan et al, 1988;Melmed et al, 1988;Bertherat et al, 1994;Lefebvre et al, 1995), whereas slight (Moller et al, 1989; or no improvement (Southgate et al, 1988;Ezzat et al, 1994) was reported in the others. An undetectable plasma GHRH level was never achieved in any patient, although significant decreases in the circulating peptide were reported (Fig.…”

“…In fact, therapy aimed only at controlling GH hypersecretion is invariably unsuccessful. Pituitary surgery, usually performed because of misdiagnosis, was reported in eight patients (uz Zafar et al, 1979;Thorner et al, 1982;von Werder et al, 1984;Schulte et al, 1985;Barkan et al, 1986;Melmed et al, 1988;Ezzat et al, 1994Genka et al, 1995 and in all cases residual GH hypersecretion persisted after surgery. Dopaminergic drugs, which are completely ineffective on the underlying neoplasm, have been used in eight patients (Losa et al, 1993): only two showed some clinical and biochemical amelioration of acromegaly.…”

“…Another patient with a metastatic bronchial carcinoid initially had a 50% size reduction of hepatic metastases in response to intra-arterial cycles of fluorouracyl and streptozotocin, but subsequently no additional effect on tumour growth was reported (Bertherat et al, 1994). The patients in whom no discernible effect of chemotherapy could be demonstrated had a metastatic bronchial carcinoid (Barkan et al, 1986;Melmed et al, 1988), a metastatic pancreatic islet cell tumour (Wilson et al, 1984) and an adenoid cystic carcinoma (Southgate et al, 1988).…”