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Biomedical subjects

D N Orth

Publications and source records attributed to D N Orth.

At least 109 records · Page 6Linked to original sources
PubMed1983

Human plasma epidermal growth factor/beta-urogastrone is associated with blood platelets.

Human epidermal growth factor (hEGF) has previously been isolated from urine and probably is identical to human beta-urogastrone (hUG). Immunoreactive hEGF/UG has been found in the plasma of normal subjects. In this study, using immunoaffinity chromatography to extract hEGF/UG from plasma, we found that immunoreactive hEGF/UG in blood was associated with blood platelets. It was present in platelet-rich, but not platelet-poor plasma and serum, and was found predominantly in the platelet fraction of whole blood. Sephadex G-50 Fine gel-exclusion chromatography of an extract of outdated blood bank platelets revealed two hEGF/UG components, one of which eluted in the void volume, and the other of which coeluted with purified standard hEGF/UG. The former hEGF/UG component was a high-molecular weight form that was cleaved into hEGF/UG by incubation with either mouse EGF/UG-associated arginine esterase or trypsin. It appeared to be identical to the high-molecular weight hEGF/UG previously reported in human urine, except for its apparently equal activities in radioimmunoassay and radioreceptor assay. The latter hEGF/UG component was immunologically, biologically, and physiochemically indistinguishable from highly purified hEGF/UG from human urine and was immunologically different from purified human platelet-derived growth factor. Platelet-associated hEGF/UG may account for the mitogenic activity of serum in cell lines in which platelet-derived growth factor is not active. Since hEGF/UG appears to be liberated from platelets during coagulation, platelet-associated EGF/UG may be involved in normal vascular and tissue repair and in the pathogenesis of atherosclerotic lesions. The discovery that the EGF/UG in plasma is associated with blood platelets raises important new possibilities for its role in human health and disease.

Blood Platelets↗
PubMed1983

Effect of mouse epidermal growth factor/urogastrone on the functional maturation of rat intestine.

Mouse epidermal growth factor/urogastrone (EGF/UG), administered sc in a dose of 0.1 microgram/g BW twice daily for 3 days, increased intestinal weight per unit length, lactase specific activity, and net calcium transport in normal 2-week-old suckling rats, but had no effect on maltase or sucrase specific activity. In normal 3-week-old weanling rats, the intestinal function of which is essentially fully mature, EGF/UG had no effect. These results suggest that EGF/UG, either secreted endogenously or ingested in breast milk, may have a role in both the morphological and functional maturation of the suckling rat intestine.

Aging↗
PubMed1983

Plasma immunoreactive proopiolipomelanocortin-derived peptides in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism.

Immunoreactive plasma levels of the proopiolipomelanocortin-derived peptides, ACTH, beta-endorphin-lipotropin, and gamma 3MSH, were measured in patients with primary hyperaldosteronism, idiopathic hyperaldosteronism with bilateral adrenal hyperplasia, and dexamethasone-suppressible hyperaldosteronism. Plasma peptide concentrations in patient groups were not different from those in normal controls. Removal of aldosterone-producing adenomas in three patients and of an aldosterone-producing adrenocortical carcinoma in one patient did not affect plasma peptide concentrations. Furthermore, infusion of the opiate antagonist naloxone (0.2 mg/min) in one patient with bilateral adrenal hyperplasia had no effect on either plasma aldosterone or cortisol. These results suggest that the proopiolipomelanocortin-derived peptides are not overproduced in states of hyperaldosteronism.

Adenoma↗
PubMed1983

Effect of synthetic ovine corticotropin-releasing factor: prolonged duration of action and biphasic response of plasma adrenocorticotropin and cortisol.

The duration of the response to synthetic ovine corticotropin-releasing factor (CRF) was studied in 13 healthy male volunteer subjects. Placebo or CRF (0.3, 3, or 30 micrograms/kg BW) was administered as an iv bolus or, in the case of the largest dose, a 30-sec infusion in single blind fashion in the late afternoon. Basal plasma immunoreactive ACTH (IR-ACTH) and IR-cortisol were 10.8 +/- 7.7 pg/ml and 5.0 +/- 1.8 micrograms/dl (mean +/- SD), respectively. IR-ACTH rose rapidly after CRF, reached an initial peak at 15 min, fell rapidly until 1.5 h after CRF, and then either fell more slowly (after the lowest dose) or rose to a second major peak at 2-3 h before falling back to baseline. After 0.3, 3, and 30 micrograms/kg CRF, IR-ACTH remained elevated for 4, 7, and 8 h, respectively. The effect on plasma IR-cortisol was similar, but more prolonged. The magnitude of both peaks of IR-ACTH, the duration of the response, and the area under the curve all appeared dose dependent. The same was true for IR-cortisol, except that the first peak height was similar after all three doses. The duration of CRF's action is probably due to its long circulating half-life. The biphasic response curve may reflect initial secretion of a readily releasable pool of ACTH, followed by later secretion of a second pool of newly synthesized and/or matured peptide. The next morning's normal circadian rise in both IR-ACTH and IR-cortisol was delayed and diminished after 3 micrograms/kg CRF; there was no increase in IR-ACTH after 30 micrograms/kg CRF, and the IR-cortisol level was diminished. Inhibition of the normal circadian rise may reflect inhibition of ACTH secretion by the sustained high plasma cortisol levels.

Adrenocorticotropic Hormone↗
PubMed1983

A pituitary parasellar tumor with extracranial metastases and high, partially suppressible levels of adrenocorticotropin and related peptides.

We report the history, laboratory findings, and studies performed on a 27-yr-old patient with a metastatic parasellar adenoma of the pituitary and Cushing's syndrome. She developed intense hyperpigmentation and extraordinarily high ACTH levels after bilateral adrenalectomy in 1974. With the exception of marked hyperpigmentation, she did well on glucocorticoid replacement therapy until August 1979, when multiple hepatic nodules were observed during a cholecystectomy. Histological studies and immunoperoxidase staining indicated that these lesions were pituitary tumor metastases. What were presumed to be metastatic lesions also developed in lungs and bone. This combination of liver, bone, and lung metastases from primary pituitary tumors has not previously been reported. Immunoreactive plasma ACTH concentrations were as high as 230,000 pg/ml. Similarly, high levels of plasma immunoreactive beta MSH and immunoreactive beta-endorphin were found. High doses of glucocorticoids reduced the concentration of ACTH to one seventh to one tenth the basal level. The sensitivity of plasma ACTH to exogenous steroid administration strongly suggests that an intact intracellular mechanism for negative feedback control of ACTH secretion persisted within the tumor cells. The rapid rise in ACTH and related peptides and the development of metastases after adrenalectomy suggest that both the secretory capacity and the oncogenic potential of the parasellar tumor were chronically inhibited by glucocorticoid hormones.

Adenoma↗
PubMed1983

Plasma distribution, disappearance half-time, metabolic clearance rate, and degradation of synthetic ovine corticotropin-releasing factor in man.

The plasma distribution, disappearance half-time, MCR, and degradation of corticotropin-releasing factor (CRF) were studied in normal men who received a pulse injection of synthetic ovine CRF (oCRF). Graded iv doses of oCRF produced a linear increase in plasma immunoreactive oCRF (IR-oCRF). The calculated total plasma content of IR-oCRF 2 min after injection represented 41.7 +/- 2.5% (mean +/- SE) of the injected dose. The disappearance of IR-oCRF from plasma was characterized by a biexponential decay curve, with initial distribution and subsequent metabolic t 1/2 values of 6.1 +/- 0.5 and 55 +/- 3.8 min (mean +/- SE), respectively. In two subjects who were studied for 14-16 h after being given the largest dose of oCRF, there was third phase of disappearance, with a t 1/2 of 198 +/- 54 min. The MCR of IR-oCRF was 2.4 +/- 0.2 ml/min . kg (146 +/- 12 l/m2 . day) and was relatively constant over a 3000-fold dose range. The volume of distribution of IR-oCRF was 6.2 +/- 0.6 liters. The plasma IR-oCRF component, examined at increasing intervals after injection, was indistinguishable from the injected oCRF in that its apparent molecular size had not been altered, nor had its biological activity been attenuated. The continued circulation of apparently intact, biologically active oCRF for at least 90 min after injection was associated with sustained release of ACTH into the plasma. Thus, the clearance of oCRF from circulating human plasma is prolonged and appears to be responsible for the sustained release of ACTH that occurs after injection of this hormone-releasing factor.

Adrenocorticotropic Hormone↗
PubMed1982

The response of plasma immunoreactive adrenocorticotropin, beta-endorphin/beta-lipotropin, gamma-lipotropin and cortisol to experimentally induced pain in normal subjects.

1. We examined the effect of ischaemic pain and sustained isometric muscle contraction on plasma immunoreactive gamma-lipotropin (gamma LPH), beta-endorphin/beta-lipotropin (beta END/beta LPH) and corticotropin (ACTH), which are all synthesized from a common precursor (pro-opiocortin), and plasma cortisol in 10 normal subjects. 2. Experimental pain was produced by inflation to 250 mmHg of a sphygmomanometer cuff, placed above the elbow of the 'dominant' arm, after which the subject squeezed a hand dynamometer, loaded to 12 kg, 20 times at 2 s intervals. Blood was drawn before, after 5 and 10 min of pain, and 30 min after release of the cuff. In a control session, the subjects were asked to squeeze the handgrip alone for 5 min at 30% of their maximum strength, a procedure which elevates the blood pressure without causing pain. 3. One subject had unexplained high (30--71 pmol/l) baseline peptide concentrations. Baseline values for the nine other subjects were: ACTH, 7.3 +/- 1.9 pmol/l (mean +/- SEM); gamma LPH, 18.6 +/- 1.0 pmol/l; beta END/beta LPH, 10.0 +/- 1.1 pmol/l; cortisol, 599 +/- 55 nmol/l. Neither procedure significantly increased the plasma concentration of ACTH or any other peptide, whereas plasma cortisol was significantly increased at both 5 min and 10 min. Plasma ACTH was positively correlated with plasma gamma LPH (r = 0.701; P less than 0.001), beta END/beta LPH (r = 0.970; P less than 0.001) and plasma cortisol (r = 0.758; P less than 0.05). 4. The present study demonstrates that, in normal man, plasma endorphins do not change with experimental ischaemic pain. The rise in plasma cortisol without concomitant rise in ACTH is not explained, but suggests the action of some other agent at the level of the adrenal cortex.

Adrenocorticotropic Hormone↗
PubMed1982

NH2-terminal amino acid sequence and peptide mapping of purified human beta-lipotropin: comparison with previously proposed sequences.

Beta-Lipotropin was purified from human pituitary glands to a purity of greater than 90%. The amino acid compositions of beta-lipotropin and its three cyanogen bromide cleavage peptide fragments were in agreement with the structure proposed by Li and Chung [Li, C.H. & Chung, D. (1981) Int. J. Pept. Protein Res. 17, 131-142]. However, the amino acid sequence of its NH2-terminal 46 amino acid residues established here differs both from the sequence derived from the direct sequence analysis of the peptide reported by Li and Chung and from that predicted on the basis of the nucleotide sequence of the human pro-opiolipomelanocortin gene proposed by Chang et al. [Chang, A.C.Y., Cochet, M. & Cohen, S.W. (1980) Proc. Natl. Acad. Sci. USA 77,4890-4894] but agrees with the structure recently derived by direct sequence analysis by Hsi et al. [Hsi, K.L., Seidah, N.G., Lu, C.L. & Chrétien, M. (1981) Biochem. Biophys. Res. Commun. 103, 1329-1335] and predicted on the basis of nucleotide sequence analysis by Takahashi et al. [Takahashi, H., Teranishi, Y., Nakanishi, S. & Numa, S. (1981) FEBS Lett. 135, 97-102]. These discrepancies, found from residues 9 to 25 of beta-lipotropin, could result from pro-opiolipomelanocortin gene polymorphism, from the existence of multiple genes for pro-opiolipomelanocortin, or, more probably, from minor errors in nucleotide and amino acid sequence analyses.

Amino Acid Sequence↗
PubMed1982

Proopiolipomelanocortin peptides in normal pituitary, pituitary tumor, and plasma of normal and Cushing's horses.

Using RIAs for six regions within proopiolipomelanocortin (proOLMC), gel filtration, and electrophoresis, we studied pituitary peptides in a normal horse and one with Cushing's disease caused by a pars intermedia adenoma. Almost all immunoreactive (IR) ACTH (78%) was 4,500 mol wt (4.5K) ACTH in normal pars distalis, but it was almost 100% corticotropin-like intermediate lobe peptide (CLIP) in normal pars intermedia. alpha MSH and beta MSH were found mainly in pars intermedia: equal concentrations of the beta MSH precursors, beta-lipotropin (beta LPH) and gamma LPH, were found in pars distalis. Most IR-beta-endorphin (IR-beta END) was found as beta END in pars intermedia, but roughly equal concentrations of beta END and its precursor, beta LPH, were found in pars distalis. A 33K molecule containing IR-ACTH, IR-gamma 3MSH, and IR-beta END, presumed to be proOLMC, and a variety of 15-27K presumed biosynthetic intermediates were found in both normal pars distalis and pars intermedia. The pars intermedia adenoma causing Cushing's syndrome contained high IR-peptide concentrations. Several differences in precursors were noted, including the presence of three larger presumed precursors (38.5K, 47K, and 63K) that had both ACTH and beta END immunoreactivities and both deletions and additions of 15-27K intermediates. The Cushing's horse's plasma peptides reflected tumor concentrations; 4.5K ACTH was modestly elevated, but the concentrations of CLIP, alpha MSH, beta MSH, gamma LPH, and beta END were dramatically increased. About 20% of plasma IR-ACTH and 5% of IR-beta MSH and IR-beta END were found as high molecular weight forms. Normal processing of horse proOLMC appears to be similar to that in other species, but may be altered in pars intermedia tumors of horses with Cushing's disease, the plasma of which contains disproportionately increased concentrations of pars intermedia proOLMC peptides.

Adrenocorticotropic Hormone↗
PubMed1982

Bioactive and immunoreactive adrenocorticotropin in normal equine pituitary and in pituitary tumors of horses with Cushing's disease.

Equine Cushing's disease is caused by hypersecretion of ACTH by hyperplasia or adenomas of pars intermedia (PI) cells, in contrast to human Cushing's disease, which is caused by hyperplasia or adenomas of pars distalis (PD) ACTH-secreting cells. We assayed both bioactive and immunoreactive (IR) ACTH in two normal equine pituitary glands and in the PD, PI, and pars nervosa of four such glands, as well as in the PI adenomas of five horses with Cushing's disease. In normal horse pituitaries, as in those of other species, most of the bioactive and IR-ACTH was found in PD, much less in PI, and only traces in pars nervosa. In PI adenomas of horses with Cushing's disease, bioactive ACTH concentrations were similar to those in normal PI, but the total tumor content of bioactive ACTH exceeded that of normal whole pituitary. IR-ACTH concentrations were even higher in PI tumors, suggesting that some of the tumor ACTH was biologically inactive. Plasma IR-ACTH, which, like the PI adenoma tissue, presumably included a major fraction of bioactive ACTH, was greatly elevated in five horses with Cushing's disease and would account for the adrenal hyperplasia and hyperfunction observed in these animals.

Adrenocorticotropic Hormone↗
PubMed1982

Effect of beta-lipotropin on aldosterone production in the isolated rat adrenal cell preparation.

Stimulation of aldosterone and corticosterone production by pituitary peptides structurally or biosynthetically related to ACTH was investigated in suspensions of isolated rat adrenal glomerulosa and fasciculata cells, respectively. Three different preparations of highly purified ovine (Li) or human (Chrétien and Orth) beta-lipotropin (beta LPH) were tested. In contrast to synthetic ACTH-(1-24), which stimulated aldosterone secretion at concentrations of 10(-12)-10(-11) M, beta LPH concentrations of 10(-8)-10(-6) M were required for significant stimulation. Stimulation of corticosterone production by beta LPH preparations generally paralleled their aldosterone-stimulating activity, and most steroidogenic activity could be accounted for by immunoreactive ACTH, as determined in two ACTH RIAs. Synthetic human beta LPH-(37-58), which contains the 47-53 heptapeptide sequence common to beta LPH and ACTH, had aldosterone- and corticosterone-stimulating activities similar to those of equimolar concentrations of beta LPH, whereas synthetic fragments of the COOH-terminal (61-91) portion of beta LPH had no steroidogenic activity. These data indicate that part of the slight steroidogenic activity of purified beta LPH preparations is due to contaminating ACTH, and part is due to the intrinsic ACTH-like activity conferred upon beta LPH by the amino acid sequence shared with ACTH. In contrast to ACTH, the concentrations of beta LPH required to stimulate adrenal steroidogenesis were 10(2)-10(5) times greater than normal plasma levels, indicating that physiological pituitary beta LPH secretion has no direct role in regulating the secretion of aldosterone.

Adrenal Glands↗
PubMed1982

Pituitary microadenomas causing Cushing's disease respond to corticotropin-releasing factor.

Corticotropin-releasing factor (CRF) was administered as an iv bolus to two young women with mild Cushing's disease shortly before and one week after successful transsphenoidal microadenomectomy. The dose of CRF (1 microgram/kg body weight) had previously been shown to stimulate increased plasma ACTH and cortisol in normal subjects. In the first patient, prior to surgery, there were brisk increases in ACTH and cortisol that exceeded those observed in normal subjects. ACTH rose by 2 min and reached a peak between 15-30 min. Cortisol increased by 10 min and peaked between 45-60 min. After surgery, at a time when plasma cortisol was maintained at similar levels with exogenous hydrocortisone, there was no plasma ACTH or LH, TSH and prolactin increased after administration of LRH and TRH, and GH increased in response to insulin-induced hypoglycemia. The second patient had higher basal plasma ACTH and cortisol than the first patient. CRF-induced increments in ACTH and cortisol were much less, but the time course was similar and peak levels attained were still higher than those in normal subjects. After surgery, at a time when plasma cortisol was maintained at a much lower level with exogenous hydrocortisone, there was no plasma ACTH or cortisol response. She had mild, transient diabetes insipidus. Basal levels of all other anterior pituitary hormones were normal. These results demonstrate that two microadenomas causing Cushing's disease were responsive to CRF in situ and suggest that CRF may be involved in the etiology and/or the responses to changes in plasma glucocorticoid concentrations observed in patients with Cushing's disease.

Adenoma↗
PubMed1982

A case of ectopic ACTH syndrome: diagnostic difficulties caused by intermittent hormone secretion.

A patient with a thymic carcinoid tumour causing ectopic ACTH syndrome is presented. The case illustrates the rapid development of the clinical and laboratory findings often associated with ectopic secretion of ACTH, including severe proximal myopathy, emotional lability, and hypokalaemic alkalosis. Interpretation of conventional tests of pituitary-adrenal function was complicated by intermittent secretion of ACTH by the tumour. The results of selective venous sampling for ACTH ruled out pituitary ACTH hypersecretion and were suggestive of a thymic source; computerized tomography of the chest localized the tumour. In vivo and in vitro investigations confirmed excessive ACTH production by the tumour, and surgical resection plus radiotherapy has resulted in resolution of the syndrome. The diagnostic problems created by intermittent secretion of ACTH by these tumours and the pre-operative and post-operative medical management of these patients are discussed.

17-Hydroxycorticosteroids↗
PubMed1981

Clinical and laboratory findings and results of therapy in 58 patients with adrenocortical tumors admitted to a single medical center (1951 to 1978).

We reviewed 150 findings in 58 patients (14 males and 44 females) with adrenocortical tumors (26 with adenoma and 32 with carcinoma) admitted to Vanderbilt Hospital during 28 years. In general, our findings agree with those reported by others in multi-institutional series or literature reviews. Adenomas took longer to diagnose than carcinomas. Adenomas usually caused Cushing's syndrome, but two caused virilization and three caused no endocrine syndrome. There was no difference in time required for diagnosis of carcinoma in men or women or in those with Cushing's syndrome, virilization or no endocrine syndrome. Urinary 17-hydroxycorticoid (17-OHCS) levels were similar in those with adenoma and those with carcinoma, but 17-ketosteroid (17-KS) levels were usually less than 20 mg per day in patients with adenoma and greater than 20 mg per day in patients with carcinoma. Adenomas were uniformly independent of endogenous ACTH stimulation, but frequently responded to exogenous ACTH. As with adenomas, no carcinoma demonstrated normal suppression with dexamethasone or normal response to metyrapone, but only one responded to exogenous ACTH. Some patients had no clinical Cushing's syndrome despite high levels of plasma cortisol and urine 17-OHCS. "Nonfunctional" tumors probably merely secreted insufficient steroids to cause signs and symptoms. Patients with adenoma were uniformly cured by surgical tumor resection. Occasional patients with carcinoma enjoyed long survival despite incomplete resection of their tumors, but most patients died of recurrent of metastatic carcinoma within seven years, often within a year of two. Small tumor size and benign histologic features were insufficient to predict benign clinical behavior. The adrenocorticolytic drug, o,p'DDD, offered objective remission for only an occasional patient.

Adenoma↗
PubMed1981

Simultaneous assay of immunoreactive beta-lipotropin, gamma-lipotropin, and beta-endorphin in plasma of normal human subjects, patients with ACTH/lipotropin hypersecretory syndromes, and patients undergoing chronic hemodialysis.

We have studied the relative concentrations of the human immunoreactive (IR) peptides gamma-lipotropin (hgammaLPH, [1-58]hbetaLPH), beta-lipotropin (hbetaLPH), and beta-endorphin (hbetaEND, [61-91]hbetaLPH) using gel exclusion chromatography together with a specific radio-immunoassay (RIA) for hgammaLPH and a RIA that (because hbetaEND is the COOH-terminus of the hbetaLPH molecule) measures both hbetaEND and hbetaLPH on an equimolar basis. In normal subjects, basal plasma IR-hgammaLPH was often undetectable (<12.5 fmol/ml), but ranged up to 21 fmol/ml, and IR-hbetaEND/hbetaLPH was 10.8+/-0.7 fmol/ml; previous studies by others suggest that most of the IR-hbetaEND/hbetaLPH was probably hbetaLPH. Both IR-hgammaLPH and IR-hbetaEND/hbetaLPH were significantly elevated (P < 0.001) in patients undergoing chronic hemodialysis (101.5+/-12.7 and 23.8+/-2.0 fmol/ml, respectively). Their IR-hgammaLPH coeluted with standard hgammaLPH as a single peak, and IR-hbetaEND/hbetaLPH coeluted with hbetaLPH; no distinct peak of IR-hbetaEND was observed. In patients with ACTH/LPH hypersecretion due to Addison's disease, Nelson's syndrome, or ectopic ACTH syndrome, IR-hgammaLPH and IR-hbetaEND/hbetaLPH were both elevated, and IR-hbetaEND/hbetaLPH eluted as two peaks, one coeluting with hbetaLPH and the other with hbetaEND. The molar concentrations of all three peptides were significantly correlated with one another. The lower concentrations of endogenous IR-hbetaEND observed may be due in part to its apparent shorter plasma half-life, as estimated in an Addison's patient given a cortisol infusion. The biologic significance of these three peptides in circulating blood is still unknown. The increased levels of hbetaLPH and hgammaLPH in plasma of patients with chronic renal failure suggest that the kidney may be an important organ for their metabolism.

ACTH Syndrome, Ectopic↗
PubMed1981

Human gamma-lipotropin radioimmunoassay: identification of immunoreactive gamma-lipotropin in human plasma and tissue.

Disagreement exists concerning the relative contributions to total plasma immunoreactive human lipotropin (hLPH) made by h beta LPH and its amino-terminal fragment, h gamma LPH [h beta LPH-(1-58)]. Using an antiserum (R1547) which requires the free COOH-terminal Asp58 residue of h gamma LPH for full affinity and reacts only 1% as well with h beta LPH and antisera (R3 and G106) that react with both LPHs, we examined gel chromatography eluate fractions of plasma extracts from one normal subject under basal conditions and another after metyrapone administration, of plasma or plasma extracts from patients with ACTH/LPH hypersecretion of various causes, of an extract two normal pituitary glands, and an extract of an ectopic ACTH/LPH-secreting tumor. Immunoreactive h gamma LPH was always a major, frequently the predominant, and sometimes the only immunoreactive LPH observed. We also observed in plasma or tissue of two patients with ectopic ACTH/LPH syndrome a peptide whose immunoreactivity and apparent molecular size were consistent with those of octadecapeptide human beta MSH, a molecule that is not thought to exist in normal man. These studies demonstrate that h gamma LPH is a major LPH component in plasma and tissues and indicate that the h gamma LPH RIA provides a reliable estimate of the h gamma LPH concentration in plasma without prior chromatography.

ACTH Syndrome, Ectopic↗
PubMed1980

Molecular weight forms of immunoreactive calcitonin in a patient with medullary carcinoma of the thyroid: dynamic studies with calcium, pentagastrin and somatostatin.

We have examined the characteristics of circulating immunoreactive human calcitonin (IR-hCT) by studying its different molecular weight (MW) forms under various secretory conditions in a patient with medullary carcinoma of the thyroid. Plasma IR-hCT (318 mg/l basal) increased 9 and 12 times, respectively, after calcium (0 . 3 mg/kg/min over 10 min i.v.) and pentagastrin (3 . 2 microgram i.v.) administration. Somatostatin infusion (500 microgram/h) caused a 41% decrease in plasma IR-hCT and markedly diminished the responses to both pentagastrin and calcium. Sephadex G50 chromatography separated different IR-hCT forms: hCT itself predominated after stimulation with either calcium or pentagastrin (52% and 62%, respectively), while it was reduced in the basal state (33%) and following somatostatin (11%); reciprocal changes were observed for the higher MW forms. Under denaturing conditions, with or without reducing agent, total plasma IR-hCT was resolved into one major peak co-eluting with 125I-hCT. Thus, the hCT monomer appears to be the major secretory product of the medullary carcinoma of the thyroid studied here. The predominance of higher MW forms in the basal state reflects their slower plasma disappearance rate. These high MW forms are mainly the result of aggregation or non-covalent protein binding of the hCT monomer.

Adult↗