Endocrinology--the way we were: a personal history of somatomedin.

Fifty years ago there was no practical method for measuring growth hormone (GH) activity in human plasma. In an attempt to develop such an assay, it was determined that much of the action of GH in vivo on rat cartilage was mediated by a serum factor that was first known as sulfation factor, and later as somatomedin and insulin-like growth factor. This narrative describes my experience and that of others in this important area of endocrine research.

Growth hormone axis overview--somatomedin hypothesis.

The possibility that the action of growth hormone (GH) on cartilage is mediated by a separate hormonal agent found in serum was suggested by incubation with hypophysectomized rat costal cartilage. The stability of this tissue permitted long incubations and the measurement of the uptake of 35S-sulfate provided a convenient index of growth stimulation. Under the conditions arbitrarily selected, normal rat serum, but not serum from hypophysectomized rats, induced a great stimulation of 35S uptake.

Imbalanced expression of the glucocorticoid receptor isoforms in cultured lymphocytes from a patient with systemic glucocorticoid resistance and chronic lymphocytic leukemia.

The human glucocorticoid receptor (GR) is expressed as two alternatively spliced isoforms, GRalpha and GRbeta. Whereas GRalpha is a hormone-activated transcription factor, GRbeta does not bind glucocorticoids (GCs), is transcriptionally inactive, and is a potential inhibitor of activated GRalpha. Differential expression of GR isoforms may play a role in generalized or tissue-specific GC resistance.

Abnormal serum IGF-II transport in non-islet cell tumor hypoglycemia results from abnormalities of both IGF binding protein-3 and acid labile subunit and leads to elevation of serum free IGF-II.

The syndrome of non-islet cell tumor hypoglycemia (NICTH) is the result of hypersecretion of IGF-II by a tumor although serum IGF-II is seldom elevated. This is attributable to abnormalities of the IGF binding proteins (IGFBPs) present in NICTH which is characterized by a marked decrease in the fraction of IGFBP-3 present in the 150 kD complex with acid labile subunit (ALS) and a 2- to 4-fold increase in IGFBP-2. We studied the impact of these changes in IGFBPs on the concentration of free IGF-II using a neutral C-18 Sep-Pak extraction procedure.

Secretion of a large molecular-weight form of insulin-like growth factor by a primary renal tumor.

A 5-year-old boy with an abdominal mass was found to have a primary renal tumor of poorly identifiable histology. Prior to resection of the tumor, the patient exhibited several episodes of biochemical hypoglycemia. The hypoglycemia did not recur after operation.

Non-islet cell tumour induced hypoglycaemia with acromegaloid facial and acral swelling.

The syndrome of non-islet cell tumour hypoglycaemia (NICTH) has been linked with the synthesis and secretion of 'big' IGF-II. We report a patient with a large pelvic clear cell sarcoma who developed recurrent severe hypoglycaemia and in addition presented with severe soft tissue facial swelling, skin tags and nuchal hyperpigmentation. After resection of the tumour serum 'big' IGF-II returned to normal and the acromegaloid skin changes remitted.

A case of hepatoma associated with hypoglycaemia and overproduction of IGF-II (E-21): beneficial effects of treatment with growth hormone and intrahepatic adriamycin.

We describe a case of recurrent hypoglycaemia associated with a hepatoma. During hypoglycaemia serum insulin was undetectable. Plasma insulin-like growth factor II (IGF-II) was not elevated although 71% of plasma IGF-II was present as big IGF-II (molecular weight 11 kDa) which probably represents a non-glycated form of pro-IGF-II.

Immunoreactive growth hormone receptor/binding protein is present on fibroblasts and in serum of Laron-type dwarfs.

Laron-type dwarfism is an autosomal recessive disorder characterised by extreme growth retardation and growth hormone (GH) resistance and has been shown in some cases to be associated with mutations in the GH receptor gene. Limited data suggest that in this condition specific liver GH binding is absent. In the majority of reported cases specific GH binding is also absent in serum.

Serum "big insulin-like growth factor II" from patients with tumor hypoglycemia lacks normal E-domain O-linked glycosylation, a possible determinant of normal propeptide processing.

The insulin-like growth factor II (IGF-II) gene is overexpressed in many mesenchymal tumors and can lead to non-islet-cell tumor hypoglycemia (NICTH). ProIGF-II consists of the 67 aa of IGF-II with a carboxyl 89-aa extension, the E domain. A derivative of proIGF-II containing only the first 21 aa of the E domain [proIGF-II-(E1-21)] has been isolated by others from normal serum and has O-linked glycosylation.

Pituitary gigantism.

Pituitary gigantism is a rare condition whose association with McCune-Albright syndrome suggests that mutations in alpha-subunit of a Gs protein are an important cause of this condition. In addition to somatotroph adenoma, it is now recognized that somatotroph hyperplasia can also result from increased levels of growth hormone-releasing hormone. Transgenic rats with hypersomatotrophism are prone to renal and hepatic pathology.

Heterogeneity of serum peptides with immunoactivity detected by a radioimmunoassay for proinsulin-like growth factor-II E domain: description of a free E domain peptide in serum.

We have reported that normal human sera contain immunoactivity (IA) detected by a RIA directed against the first 21 amino acids of the E domain of proinsulin-like growth factor-II (pro-IGF-II). Marked elevations of E-21 IA were found in the serum of patients with nonislet cell hypoglycemia (NICTH) and patients with renal failure receiving chronic hemodialysis. In this paper we describe some of the properties of the E-21 IA of normal and abnormal sera.

Measurement of derivatives of proinsulin-like growth factor-II in serum by a radioimmunoassay directed against the E-domain in normal subjects and patients with nonislet cell tumor hypoglycemia.

We describe a modified RIA using a rabbit polyclonal antiserum directed against the first 21 amino acids of the E-domain (E-21) of proinsulin-like growth factor-II (pro-IGF-II). For standardization, we purified big IGF-II from patients with nonislet cell tumor hypoglycemia (NICTH). Under the conditions of our assay there was no significant interference from IGF-binding proteins.

Retinoic acid regulates insulin-like growth factor II expression in a neuroblastoma cell line.

Insulin-like growth factors (IGF-I and IGF-II) are mitogenic polypeptides that play an important role in normal growth and development. IGF-II has been shown to stimulate the growth of neuroblastoma tumors in an autocrine and paracrine fashion. Critical in determining the role of IGF-II in tumorigenesis is the necessity to delineate factors affecting the transcription of IGF-II in normal and tumor tissues.

Impaired formation of the ternary insulin-like growth factor-binding protein complex in patients with hypoglycemia due to nonislet cell tumors.

In some subjects with hypoglycemia associated with tumors of mesenchymal origin, high insulin-like growth factor-II (IGF-II) levels have been described in serum and in the tumors. Tumor IGF-II of 10-15 kDa circulates in a 60-kDa complex, in contrast to the ternary 150-kDa complex in which serum IGFs normally circulate together with the IGF-binding subunit (IGFBP-3) and the acid-labile subunit (alpha-subunit). This study examines the molecular distribution and complex-forming activity of the components of the ternary complex in the serum of subjects with mesenchymal tumor hypoglycemia.

Tumor secretion of growth factors.

An increasing number of polypeptide growth factors have been identified that regulate not only cell proliferation but also an extraordinary range of cell activities, including matrix protein deposition and resolution, the maintenance of cell viability, cell differentiation, inflammation, and tissue repair. Normal cells appear to require growth factors for proliferation and for maintenance of viability. Cells that secrete a polypeptide growth factor have an advantage in growth.

Endogenous insulin-like growth factor (IGF) binding proteins cause IGF-1 resistance in cultured fibroblasts from a patient with short stature.

The ED50 of insulin-like growth factor (IGF)-I-stimulated alpha-aminoisobutyric acid (AIB) uptake (mean +/- SD) in cultured fibroblasts from a child with short stature that we have reported (1.40 +/- 0.24 nM), is significantly higher than the ED50 of IGF-I-stimulated AIB uptake in fibroblasts from 11 normal subjects (0.

Clinical aspects of GH binding proteins.

The high affinity specific binding of 125I-hGH in human serum is attributable to the GH binding protein, which is derived from the extracellular domain of the receptor. Most measurements have been made by gel filtration methods and expressed with a normal human reference serum (RSGHB). The RSGHB is virtually unmeasurable in the cord sera of premature infants and is higher in cord serum of term infants.

Growth hormone-binding protein: II. Studies in pygmies and normal statured subjects.

The serum concentrations of a specific GH-binding protein, derived from the GH receptor, were assayed in sera from 62 African pygmies and 101 normal statured controls. Samples were assayed in the absence and presence of excess GH using 2 separatory procedures. Interassay variability for samples was corrected by a standard reference pool of sera from adults assayed with all unknown samples.

Whole body nitrogen kinetics and their relationship to growth in short children treated with recombinant human growth hormone.

We studied the effects of growth hormone on retention of 15N-labeled amino acids in 34 short, prepubertal, growth hormone-sufficient children and three growth hormone-deficient subjects. All 34 non-growth hormone-deficient children had apparently normal circulating growth hormone molecules and no mutations were detected in the growth hormone or IGF-I genes of any subjects. Fibroblasts from 34 children responded normally when challenged with recombinant human IGF-I.