Is there a therapeutic role for octreotide in patients with ectopic Cushing's syndrome?

Cushing's syndrome (CS) due to ectopic ACTH secretion (EAS) has a high morbidity and mortality, because of the underlying tumor and the sequelae of severe hypercortisolemia. Therefore, rapid treatment of ectopic CS is mandatory. Scintigraphy shows that up to 80% of ectopic ACTH-producing tumors have somatostatin receptors. While this suggests that somatostatin analogs may reduce ACTH production and treat patients with EAS, the therapeutic role of these agents is still evolving. Here we demonstrate the spectrum of responses to octreotide therapy in 3 patients with EAS. Diagnostic imaging with the 111In-pentetreotide scan did not predict the therapeutic response to octreotide. Two patients with positive somatostatin receptor scintigraphy failed to respond to octreotide, while one with a negative scan reached eucortisolemia on a maintenance dose of 75 microg octreotide twice daily or octreotide LAR 30 mg per month. We conclude that octreotide is not a first line agent to control hypercortisolemia but may be a useful agent when other inhibitors of steroidogenesis fail or parenteral administration is required. Before therapy an octreotide challenge test may predict therapeutic response. Cortisol levels should be monitored regularly on somatostatin analog therapy, because of its unpredictable long-term pharmacodynamic profile.

Rapid improvement of osteoporosis following parathyroidectomy in a premenopausal woman with acute primary hyperparathyroidism.

We describe a premenopausal white woman with symptomatic acute primary hyperparathyroidism and marked osteoporosis. After undergoing a parathyroidectomy, the patient experienced not only rapid symptomatic relief, but also marked improvement in bone mineral density, which increased by 25% in the hip and by 22% in the lumbar spine 1 year after the surgery. Acute primary hyperparathyroidism should be considered in any patient with severe symptomatic hypercalcemia. Appropriate treatment with early parathyroidectomy can result in significant and rapid improvement in bone mineral density.

Hypercalcemia in an AIDS patient treated with growth hormone.

METHOD: Recombinant human growth hormone (rhGH) is a newly approved treatment for weight loss and wasting in patients with AIDS. We report a male patient with advanced AIDS who developed hypercalcemia 2 weeks after institution of rhGH therapy. RESULTS: Parathyroid hormone, parathyroid hormone-related peptide and 1,25-dihydroxyvitamin D levels were suppressed, suggesting that hypercalcemia was mediated through alternative mechanisms. The hypercalcemia responded to discontinuation of rhGH and a single dose of intravenous pamidronate disodium and has not recurred in 8 months of follow-up. CONCLUSION: We believe this to be the first reported case of rhGH-induced hypercalcemia in an HIV-infected patient.

Assessment of hypothalamic-pituitary-adrenal (HPA) axis dysfunction: comparison of ACTH stimulation, insulin-hypoglycemia and metyrapone.

The response to ACTH stimulation, insulin-hypoglycemia and metyrapone in patients with suspected HPA axis dysfunction due to corticosteroid therapy (Group I, n = 10), or pituitary surgery (Group II, n = 7) and in a control population (Group III, n = 8) was studied. Group I patients had been maintained on a stable low dose of prednisone 5.0-7.5 mg/day for 1 month-16 yr (mean = 31 mos) prior to testing. Basal 08:00 h cortisol levels in this group were not different from control values. However, the mean responses to all three testing procedures were suppressed (Group I vs III, ACTH p less than 0.001, insulin p less than 0.01, metyrapone p less than 0.05). Group II patients had undergone surgery 1-26 months (mean = 10 mo) prior to testing and had been maintained subsequently on a stable dose of prednisone 5.0-7.5 mg/day. In this group basal mean 08:00 h cortisol and the cortisol response to ACTH and insulin-hypoglycemia were not significantly different from control values while the response to metyrapone was suppressed (Group II vs III p less than 0.02). Basal serum DHEA-S levels were suppressed in both Groups I and II when compared to Group III (p less than 0.001). Discordant responses to the three testing procedures were noted in 6 patients with suspected HPA dysfunction with abnormal test results in 1/6 using cortrosyn, 3/6 using insulin-hypoglycemia and 4/6 using metyrapone.(ABSTRACT TRUNCATED AT 250 WORDS)

Antibody seronegative human T-lymphotropic virus type III (HTLV-III)-infected patients with acquired immunodeficiency syndrome or related disorders.

The human T-lymphotropic virus type III (HTLV-III) is the primary cause of the acquired immunodeficiency syndrome (AIDS) and related disorders (ARC). Prior studies have reported that nearly all symptomatic patients with AIDS or ARC manifest antibody to HTLV-III. This observation has engendered efforts to screen for HTLV-III, especially prior to blood donation, with assays for antibody to HTLV-III. We report the first two cases, one with AIDS and one with ARC, that are HTLV-III virus positive but antibody negative. Accurate diagnosis of HTLV-III infection in some cases may require direct virus culture or tests for antigen. In addition, lack of HTLV-III antibody may indicate an atypical clinical course of AIDS.

Histological characterization of a lingual mass using thyroglobulin immunoperoxidase staining.

We report a patient with a lingual mass clinically diagnosed as lingual thyroid. Due to marked distortion of the normal thyroidal architecture from prior 131I therapy, pathological examination of the mass was consistent with a mixed salivary gland tumor. Immunoperoxidase staining for thyroglobulin was utilized to correctly characterize the lingual mass as ectopic thyroid.

A unique growth factor in patients with acromegaloidism.

Acromegaloidism is a syndrome characterized by features of acromegaly without biochemical evidence of excessive GH or somatomedin production. We searched for a growth factor in the serum of patients with this syndrome. Growth-promoting activity was measured by determining the stimulatory effect of whole and fractionated serum on colony formation by human erythroid progenitors in vitro. Sera from five subjects with acromegaloidism gave a mean (+/- SEM) stimulated colony growth of 211 +/- 4.0 colonies, in contrast to normal sera which yielded a mean colony growth of 100 +/- 11.0 (n = 9; P less than 0.001). When serum was chromatographed on a Sephadex G-200 column, the maximal stimulation of colony growth was found in the fractions coinciding with the descending slope of the second protein peak. Based on gel filtration chromatography, the estimated molecular weight was 70,000 daltons. Epidermal growth factor, nerve growth factor, fibroblast growth factor, and platelet-derived growth factor resulted in no substantial stimulation of colony growth under the conditions used. Although the erythroid progenitor cells of a Laron dwarf were unresponsive to 200 ng/ml human GH, they were clearly stimulated by serum from a patient with acromegaloidism. The present study describes the presence of a heretofore unidentified growth factor in the serum of subjects with acromegaloidism. This factor also stimulated the erythroid precursor cells of a Laron dwarf whose cells were unresponsive to GH. The physiological role of this growth factor in normal man as well as its pathogenic role in subjects with acromegaloidism remain to be established.

Circular Dichroism Studies of Cyanate-Induced Conformational Changes in Hemoglobins A and S.

Circular dichroism and difference spectroscopy have been used to study dilute aqueous solutions of oxygenated, deoxygenated, and carbamoylated deoxygenated hemoglobins A and S (HbA and HbS, respectively). The spectra of HbA and HbS, in comparable state of oxygenation or carbamoylation, are identical, strongly implying identical conformations about the heme groups of the respective proteins. The spectra of the oxygenated forms change little upon addition of KCNO, which is known to carbamoylate the NH2 terminals of the individual chains (Cerami and Manning, 1971). The spectra of the deoxygenated forms, on the other hand, are markedly altered. The decreased magnitude of the 430-nm extremum with increased cyanate concentration can be used to calculate an addition curve which becomes asymptotic at a cyanate:heme molar ratio of approximately 10(3). This conformational change occurs in the absence of O2 and has been predicted (Njikam et al.,1973); it can also be demonstrated by difference spectroscopy techniques, whereby a comparable addition curve can be constructed from changes in the 555-nm absorption, while the 541-nm absorption remains invariant. The change described corresponds to the formation of a new conformation, corresponding to carbamoyldeoxyhemoglobin, carrying one carbamoyl group per chain. In the presence of a small quantity of oxygen, however, the above reported changes in CD are accompanied by a concomitant rise in the 415-nm peak-corresponding to the formation of oxyhemoglobin-while those in the difference spectra reflect not only a change in the 555-nm band but also a parallel one at 541 nm, confirming the formation of oxyhemoglobin. Thus the conformation achieved upon carbamoylation of deoxyhemoglobin has the higher oxygen affinity predicted by Nigen et al. (1974) for carbamoyldeoxyhemoglobin. Cyanate has been used (Cerami and Manning, 1971) as an antisickling reagent in vivo and in vitro, but, although it has been shown that it binds covalently to the NH2-terminal residues of hemoglobin (Lee and Manning, 1973), its effect on hemoglobin conformation has not been previously shown nor has its mechanism of action been fully clarified. The results presented here show that the effect of cyanate on hemoglobin is the formation of a new conformation with heightened oxygen affinity. Since oxyHbS does not aggregate while deoxyHbS does, in a temperature-dependent fashion, the formation of carbamoyldeoxyHbS interferes with such aggregation in vitro in deoxygenated samples. In vivo, where there are generally low residual concentrations of O2, the formation of oxyHb is favored by the higher O2 affinity of carbamoyldeoxyHbS, and aggregation with concomitant red cell sickling is therefore disfavored.