Treatment of Hemangiopericytoma-Induced Hypoglycemia with Growth Hormone and Corticosteroids

Damiano Gullo, Laura Sciacca, Giuseppina Parrinello, Letizia Tomaselli and Riccardo Vigneri

Cattedra di Endocrinologia Università di Catania I-95123 Catania, Italy

A 56-yr-old man was admitted to our department because of recurrent and severe hypoglycemia. Ten years previously the patient had undergone surgery for an intraabdominal hemangiopericytoma, a mesenchymal tumor. An ileocolectomy with colostomy was performed about twenty months later because of local recurrence of the tumor. He was apparently well thereafter until 2 years before the admission to our department, when he was treated with chemotherapy and radiotherapy because of a small mass in the pelvis evidenced at a computed tomography scan. Two months before admission to our department, he was brought to the emergency room in a state of unconsciousness and with a plasma glucose level of 20 mg/dL (1.1 mM). He was given 20% dextrose iv, and he promptly recovered. The hypoglycemic episodes recurred and became more frequent. Upon admission to our department the patient was first treated with 50% dextrose infusion through a subclavian vein. Nevertheless episodes of hypoglycemia persisted, especially at night, when fasting was longer than 4–5 hr. Increased meal frequency with complex carbohydrates administration plus continuous dextrose infusion were no longer able to control hypoglycemia. The patient had normal-to-low plasma insulin levels and very high levels of insulin-like growth factor (IGF)-II, especially in the isoform 10–17 kDa, around 80% of total measured IGF-II (Fig. 1aGond Table 1Go ). The diagnosis of nonislet cell tumor hypoglycemia (NICTH) was proposed. Evaluation of liver showed metastatic lesions, but because of the size, a palliative surgical attempt was not advised. Therapy with both prednisone (15 mg/day per os) and, after informed consent, biosynthetic GH (2 U/day sc) at bedtime was soon started. Dextrose infusion was gradually reduced and eventually suspended 4 days after beginning continued hormone treatment. No further episode of hypoglycemia occurred in the following 3 days, and he was discharged from the hospital in apparent good condition with instructions for blood glucose self monitoring and glucagon use in the case of severe hypoglycemia.



View larger version (71K):
[in this window]
[in a new window]
 
Figure 1. Western blot analysis of IGF-II of the patient. After acid-ethanol extraction of 300 µL of serum, IGF-II was immunoprecipitated with an anti IGF-II antibody 2H-11 conjugated resin. The samples were solubilized, electrophorezed, and analyzed by an anti-IGF-II antibody (2H-11). Immunoblotting indicates that the serum of the patient shows an abundance and a size-heterogeneity of IGF-II compared with control serum. The molecular weight was between 10–17 kDa, rather than the 7.5 kDa found in two normal control subjects.

 

View this table:
[in this window]
[in a new window]
 
Table 1. Hormonal measurements before and after 1 month therapy with GH, 2 U/day sc, and prednisone, 15 mg/day po (m ± SD of 4 different measurements)

 
In the following month only one episode of hypoglycemia was reported. The patient was admitted again to the hospital for control (Table 1Go). Blood glucose levels were low only sporadically, especially during afternoon and the night. The patient showed a state of relative well-being and no relevant side-effect of GH treatment. The prednisone and GH dose were reduced to 10 mg and 1.5 U/day, respectively. Three months later the patient decided to discontinue GH treatment because of concern of an effect on tumor growth. The patient’s condition rapidly worsened, with increasingly frequent episodes of hypoglycemia, and iv glucose treatment was again required. The patient died 5 months later.

It has been reported that mesenchymal tumors may produce and release an excessive amount of IGF-II as well as the isoform called big IGF-II (1). This high molecular weight IGF-II is considered the causative agent of NICTH because of its insulin-like effect, exherted primarily by stimulating glucose uptake at peripheral tissue level (2). In addition, the increased serum IGF-II inhibits both GH and insulin secretion and, as a consequence, lowers the plasma concentration of insulin and GH-dependent IGF binding proteins (mainly IGFBP-3). This in turn increases the unbound IGF-II fraction and worsens its hypoglycemic effect (3).

When surgical removal or radiotherapy is not advised, many other strategies may ameliorate a patient’s severe hypoglycemia, including corticosteroid administration (which, in addition to its antihypoglycemic action, may also suppress IGF-II production by the tumor) (4) and subcutaneous glucagon infusion (5). GH treatment has also been tried in such patients (6, 7), with the postulated mechanism of reducing IGF-II availability to tissues by increasing IGFBP-3 levels and the acid labile subunit (ALS) that will form the "ternary complex" containing bound (biologically nonactive) IGF-II. In vitro GH does not appear to have any significant mitogenic effect (8, 9). Increased cancer prevalence in acromegaly is probably a consequence of elevated IGF-1 levels (10). In our patient, however, plasma IGF-1 remained low during hGH treatment at the doses used (Table 1Go).

In this very severe case of NICTH the combined treatment with prednisone and GH proved effective in ameliorating the hypoglycemic syndrome without side-effects. It can therefore be proposed as a cost-effective palliative treatment in these patients.

Footnotes

Address correspondence to: Dr. Damiano Gullo, Divisione Endocrinologia, Ospedale Garibaldi, Piazza S. M. Gesù, I-95123 Catania, Italy.

Received December 1, 1998.

References

  1. WH Daughaday, MA Emanuele, MH Brooks, AL Barbato, M Kapadia, P Rotwein. 1988 Synthesis and secretion of insulin-like growth factor-II by a leiomyosarcoma with associated hypoglycemia. N Engl J Med. 319:1434–1440.[Abstract]
  2. D Le Roith. 1997 Insulin-like growth factors. N Engl J Med. 336:633–640.[Free Full Text]
  3. J Chung, RR Henry. 1996 Mechanism of tumor-induced hypoglycemia with intraabdominal hemangiopericytoma. J Clin Endocrinol Metab. 81:919–925.[Abstract]
  4. RC Baxter, S R Holman, A Corbould, S Stranks, P Jean HO, W Braund. 1995 Regulation of the insulin-like growth factors and their binding proteins by glucocorticoid and growth hormone in nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab. 80:2700–2708.[Abstract]
  5. D Houlbert, JJ Altman, A Lageron, et al. 1985 Continuous subcutaneous infusion of glucagon by portable pump in non beta cell tumor hypoglycemia. Diabete Metab. 11:125–127.[Medline]
  6. JD Teale, WF Blum, V Marks. 1992 Alleviation of non-islet cell tumours by growth hormone therapy is associated with changes in IGF binding protein-3. Ann Clin Biochem. 29:314–323.[Medline]
  7. LE Katz, F Liu, B Baker, et al. 1996 The effect of growth hormone treatment on the insulin-like growth factor axis in a child with nonislet cell tumor hypoglycemia. J Clin Endocrinol Metab. 81:1141–1146.[Abstract]
  8. G Rosselot, R Vasilatos-Younken, RM Leach. 1994 Effect of growth hormone, insulin-like growth factor I, basic fibroblast growth factor, and transforming growth factor ß on cell proliferation and proteoglycan synthesis by avian postembryonic growth plate chondrocytes. J Bon Miner Res. 9:431–439.[Medline]
  9. A Gertler, A Walker, HG Friesen. 1985 Enhancement of human growth hormone-stimulated mitogenesis of Nb2 node lymphoma cells by 12-O-tetradecanoyl-phorbol-13-acetate. Endocrinology. 116:1636–1644.[Abstract]
  10. SM Orme, McNally RJ, RA Cartwright, PE Belchetz. 1998 Mortality and cancer incidence in acromegaly: a retrospective cohort study. United Kingdom Acromegaly Study Group. J Clin Endocrinol Metab. 83:2730–2734.[Abstract/Free Full Text]




This Article
Full Text (PDF)
Submit a related Letter to the Editor
Purchase Article
View Shopping Cart
Alert me when this article is cited
Alert me when eLetters are posted
Alert me if a correction is posted
Citation Map
Services
Email this article to a friend
Similar articles in this journal
Similar articles in PubMed
Alert me to new issues of the journal
Download to citation manager
Request Copyright Permission
Google Scholar
Articles by Gullo, D.
Articles by Vigneri, R.
Articles citing this Article
PubMed
PubMed Citation
Articles by Gullo, D.
Articles by Vigneri, R.


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals