William H. Daughaday

Synthesis and Secretion of Insulin-like Growth Factor II by a Leiomyosarcoma with Associated Hypoglycemia

We describe a case of recurrent hypoglycemia apparently caused by secretion of insulin-like growth factor II (IGF-II) by a leiomyosarcoma. A 67-year-old woman presented with recurrent severe hypoglycemia and a large mass in the thorax. During hypoglycemia, plasma cortisol was elevated, but insulin and growth hormone levels were low. After resection of a large leiomyosarcoma, the hypoglycemia resolved. After an eight-year remission, both the tumor and symptomatic hypoglycemia recurred. During a second operation a second large tumor was removed, with relief of the patients hypoglycemia. The tumor contained high concentrations of IGF-II mRNA and 2100 ng of IGF-II immunoreactive peptide per gram. Filtration through a BioGel P-60 gel column established that 77 percent of the IGF-II was present as a larger molecule, demonstrating incomplete processing of the pro-IGF-II peptides. A similar fraction of high-molecular-weight IGF-II was present in the serum, indicating that the tumor was the chief source of IGF-II. The high-molecular-weight IGF-II found in both the tumor and serum was fully reactive with the IGF-II receptor. Radioimmunoassay showed that the concentrations of insulin-like growth factor I (IGF-I) in tumor and serum were low, suggesting feedback inhibition of growth hormone secretion by IGF-II. Eight months after reoperation, plasma concentrations of IGF-I and IGF-II were normal, and high-molecular-weight IGF-II was virtually undetectable. We conclude that the most likely cause of this patients recurrent hypoglycemia was IGF-II produced by the leiomyosarcoma.

The natural history of retinopathy in insulin-dependent juvenile-onset diabetes

We determined the cross-sectional natural history of retinopathy by prospective study of 461 insulin-dependent juvenile-onset diabetics. In so doing, we compared the sensitivity of ophthalmoscopy, photography, and fluorescein angiography in detecting retinopathy. Photography was far more reliable than ophthalmoscopy in detecting early retinopathy and equivalent to angiography. Retinopathy was not present at diagnosis of diabetes. After a lag period, the prevalence of retinopathy rose in sigmoidal fashion, reaching 50% at just over seven years duration, and asymptotically approaching 90% at 17--50 years. Proliferative retinopathy was first seen at 13 years duration, and its prevalence rose to 26% at 26--50 years. From the natural history we computed the dimensions of a proposed clinical trial to test the effect of tight metabolic control in prevention of retinopathy.

Human Placental Lactogen: Studies of Its Acute Metabolic Effects and Disposition in Normal Man

The acute metabolic effects and disposition of human placental lactogen (HPL) have been studied in 15 men and 8 women during continuous intravenous infusions. The mean plasma half-life, metabolic pool size, and turnover rate of HPL are comparable to the values previously reported for human growth hormone (HGH). From the data presented, we calculate that the placenta secretes approximately 290 mg HPL daily at term. After 12-hour infusions of HPL in physiologic amounts, impairment of glucose tolerance despite increased plasma insulin responses to glucose was observed in 7 of 8 subjects tested. However, HPL, unlike HGH, did not produce significant changes in blood glucose, plasma insulin, or plasma free fatty acid concentrations in fasting subjects before glucose administration or in carbohydrate tolerance or plasma insulin responses to glucose during 5-hour infusions. These findings are compatible with the thesis that HPL is a physiologic antagonist to insulin during pregnancy.

Levodopa Suppression of Prolactin in Nonpuerperal Galactorrhea

Abstract Nonpuerperal lactation may be the result of pituitary tumors or functional pituitary disorders. Elevations of serum prolactin measured by radioimmunoassay were found in three patients with...

Thyroid Hormone Inhibition of the Prolactin Response to Thyrotropin-Releasing Hormone

A B S T R A C T The influence of serum triiodothvronine (T3) and thyroxine (T4) concentrations on the release of prolactin in man was studied by determining the prolactin response to synthetic thyrotropin-releasing hormone (TRH) in hypothyroid and hyperthyroid patients before and after correction of their serum thyroid hormone abnormalities. The maximum increment in serum prolactin above the basal level (maximum A prolactin) was used as the index of response to TRH. In 12 patients with primary hypothyroidism, the maximum A prolactin in response to TRH fell from 100.5± 29.1 ng/ml (mean +SEM) before treatment to 36.1±6.0 ng/ml (P< 0.01) during the 4th Nk of treatment with 30 jug T3 + 120 jug T4 daily. The mean serum T3 level increased from 57±8 to 138+10 ngl100 nml! and the mean serum T4 level increased from 3.0±0.4 to 7.2±0.4 Ag/lOO ml during this treatment. In eight normal subjects the maximum Aprolactin in response to TRH was not significantly different during the 4th wk of treatment with 30 Ag T3 + 120 /g T4 daily from the response before treatment. In 10 patients with hvperthyroidism, the maximum Aprolactin in response to TRH increased from 14.2±2.9 ng/ml before treatment to 46.9±6.7 nig/ml (P < 0.001) during antithyroid treatment. The mean serum T3 level fell from 313±47 to 90±8 ng/100 ml, and the mean serum T4 level fell from 20.8±2.5 to 6.8+ 0.6 Ig/100 ml during this treatment. These results show that changes from normal serum levels of T3 and T4 are associated with changes in prolactin responses to TRH; subnormal serum levels of T3 and T4 increase TRH-induced prolactin release,

Diagnostic Value of Thyrotrophin-Releasing Hormone in Pituitary and Hypothalamic Diseases: Assessment of Thyrotrophin and Prolactin Secretion in 100 Patients

Abstract The clinical utility of synthetic thyrotrophin-releasing hormone (TRH) in assessing thyrotrophin (TSH) and prolactin secretion was evaluated in 100 patients with pituitary and hypothalamic...

Growth hormone-dependent growth failure

Growth failure may be associated with low serum somatomedin concentrations despite normal to increased concentrations of serum growth hormone. We have recognized five patients who responded to GH administration with an increase in serum Sm and an acceleration in skeletal growth, and have characterized the circulating GH in an homologous human GH radioreceptor assay employing the IM-9 lymphocyte as a source of human GH receptor. These five prepubertal children, who had a mean height 7.8 SD below the mean for age, had a mean RIA-GH of 34.2 +/- 3.5 ng/ml in response to stimulation, a basal Sm activity by hypophysectomized rat cartilage bioassay of less than 0.3 IU/ml, and a mean peak Sm of 0.9 +/- 0.1 IU/ml in response to 48 hours of GH therapy. During a one-year trial of GH therapy, four of these children significantly increased their growth velocity as compared to their growth rate before GH therapy. These children had a mean RIA-GH/RRA-GH ratio of 2.f. The fifth patient had a low RIA-GH/RRA-GH ratio and had no increase in growth rate. These studies suggest that growth in certain growth retarded children may be dependent on exogenous GH, even though they are not GH deficient by standard criteria.

Suppression of sleep-related prolactin secretion and enhancement of sleep-related growth hormone secretion.

Methysergide, a clinically-used blocker of serotonin receptors, was administered to 10 normal young men at a dose of 2 mg every 6 h for 48 h. After drug treatment, serum levels of growth hormone during sleep were 41.9% higher than placebo values (less than 0.001). In contrast, drug treatment was associated with a 36.4% decrease in stimulated growth hormone secretion during insulin tolerance testing (P less than 0.01). These opposite effects of methysergide suggest that different mechanisms are responsible for sleep-related and insulin-induced growth hormone secretion. Accordingly, data obtained with pharmacologic stimuli may lead to erroneous inferences regarding physiologic growth hormone control mechanisms. Administration of methysergide profoundly suppressed sleep-related prolactin secretion; overall nocturnal mean prolactin fell by 70.3% from 4.30+/-0.19 to 1.28+/-0.06 ng/ml (P less than 0.0001). It appears that serotonin may be significant modulating neurotransmitter for the control of growth hormone secretion, limiting sleep-related release, and enhancing insulin-induced release. It seems likely from these data that the role of serotonin in the control of prolactin secretion is relatively more important, since serotonin receptor blockade dramatically reduced sleep-related prolactin secretion.

STUDIES ON HUMAN GROWTH HORMONE. II. THE PHYSIOLOGICAL DISPOSITION AND METABOLIC FATE OF HUMAN GROWTH HORMONE IN MAN

The metabolic effects of human growth hormone have received much attention, but little is known regarding the metabolism of the hormone itself in man. Studies of growth hormone metabolism carried out in experimental animals suggest that both bovine growth hormone and human growth hormone have rapid turnovers. Van Dyke, Simpson, Li and Evans (1) and Gemzell, Heijkenskjdld and Str6m (2) injected rats with large doses of bovine growth hormone and determined plasma levels of growth hormone by the tibial cartilage width assay. The half-lives of disappearance were 26 and 40 minutes, respectively, in the two studies, and the volume of distribution of the hormone was roughly equivalent to the extracellular fluid space. Isotopic methods have also been applied to the study of growth hormone metabolism. Sonenberg and co-workers (3) injected rats with radioiodinated bovine growth hormone and, although their work was principally concerned with tissue localization, they published a graph depicting the disappearance of radioactivity from plasma after a single intravenous injection. The half-life of disappearance was approximately 25 minutes. In the experiments of Salmon, Utiger, Parker and Reichlin (4), radioiodinated human growth hormone had a half-life of disappearance from plasma of 17 minutes when injected into rabbits. Only preliminary reports of the disappearance

Current Concepts of Somatomedin and Other Biologically Related Growth Factors

Since the discovery 20 years ago that the growth-promoting effects of somatotropin are mediated through a serum factor(s), research in this area has rapidly expanded. It is the purpose of this review to bring this area of scientific endeavor into perspective. The first part of this review will deal with aspects of total serum somatomedin activity and its biologic actions and measurements in health and disease. The last part of this review will summarize some of the physical and biologic characteristics of the recently purified “somatomedin-like” substances: somatomedin A, B, and C, NSILA-S (nonsuppressible insulin-like activity-soluble in acid ethanol) and MSA (multiplication-stimulating activity).