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Context: Although considerable data exist on the use of long-acting somatostatin analogs to treat acromegaly, their reported efficacy differs substantially among trials., Objective: We conducted a meta-analysis to derive definitive estimates of their efficacy for biochemical control and tumor shrinkage., Data Sources: A search of literature was conducted through 2003, primarily via PubMed., Study Selection: Inclusion criteria, met in 44 trials, included at least 3 months of secondary octreotide long-acting release (LAR) or lanreotide slow release (SR) therapy or of primary octreotide LAR, lanreotide SR, or sc octreotide therapy and clearly reported data on biochemical efficacy and/or tumor shrinkage. Fifty other trials screened did not meet analysis inclusion criteria., Data Extraction: Data were extracted by three independent observers., Data Synthesis: Among subjects not selected for somatostatin analog responsiveness before study entry, both GH efficacy criteria and IGF-I normalization were met in a greater proportion of those treated with octreotide LAR vs. lanreotide SR (GH: B = 0.2310, P = 0.016; IGF-I: B = 0.2325, P = 0.007). Prestudy selection for somatostatin analog responsiveness was not a significant predictor of meeting GH efficacy criteria (B = 0.0992; P = 0.12). Preselection was a positive predictor of IGF-I normalization rate (B = 0.1213; P = 0.04), which was greater among preselected than unselected subjects (B = 0.1472; P = 0.0475). IGF-I normalization occurred in a greater proportion of secondary octreotide LAR- vs. primary octreotide-treated subjects (B = 0.2056; P = 0.009). The odds of tumor shrinkage more than 10% were lower in the unselected vs. preselected subjects. However, the effect of drug type was an important predictor of shrinkage; such that regardless of preselection or not, the odds of shrinkage with lanreotide SR were lower than with octreotide LAR (P = 0.003). Shrinkage greater than 10% occurred in a higher percentage of primary octreotide LAR-treated vs. primary octreotide sc-treated subjects (odds ratio = 9.4; P < 0.0001). The overall rate of tumor increase was 1.4%., Conclusions: In this meta-analysis, we have shown that the efficacy of octreotide LAR is greater than lanreotide SR among subjects unselected for prior somatostatin analog responsiveness. Preselection is a significant positive predictor of IGF-I normalization and is associated with increased odds of tumor shrinkage, which is also greatest with octreotide LAR. Biochemical efficacy is similar, but tumor shrinkage is greater when these drugs are given as primary vs. secondary therapy.

Serum testosterone levels were monitored in female subjects who received therapy with human gonadotropins of urinary origin (menotropins) and human chorionic gonadotropin (hCG). Serum testosterone levels were not elevated in those subjects who did not experience side effects with therapy (Group A); among the other 7 subjects (Group B) with either moderate or severe ovarian hyperstimulation, serum testoterone levels rose distinctly (range 1.4 minus 9.0 ng/ml). Total menotropin dosage and serum estradiol-17beta levels were higher in Group B than in Group A. Ovarian hyperstimulation and elevation of serum testosterone were not restricted to patients with the syndrome of polycystic ovaries.

We examined the effect of hyperglycemia per se on net splanchnic glucose balance. In 2 groups of normal postabsorptive men who had undergone hepatic vein catheterization, somatostatin was administered to block endogenous insulin and glucagon secretion. Exogenous glucose was infused in both groups to maintain euglycemia for 2 h in one group (n = 7) and to induce hyperglycemia of 220-240 mg/dl after 30 minutes of euglycemia in the second group (n = 4). In both groups the induction of insulinopenia and glucagonopenia with euglycemia maintained resulted in an initial 75% fall in net splanchnic glucose production (NSGP). In the group in which euglycemia was maintained NSGP returned to basal rates (157 +/- 31 mg/min) within 2 h. However, in the group in which hyperglycemia was induced, NSGP did not return to basal rates but remained suppressed (28 +/- 4 mg/min) for the duration of the study. These data in normal man indicate that hyperglycemia per se with insulin and glucagon acutely withdrawn can suppress splanchnic glucose production but does not induce net splanchnic glucose storage.

We record further studies over the past 2 yr on a unique female subject with isolated follicle-stimulating hormone (hFSH) deficiency, who developed human anti-gFSH antibodies after treatment with exogenous urinary gonadotropins. Administration of LRH resulted in a significant rise in serum hLH, but hFSH levels remained undetectable, "alpha Subunit" (the common alpha chain of the glycoprotein hormones) was detectable in basal samples obtained from our patient, and rose sharply after LRH. This is concordant with the hypothesis that the defect in our subject may be in the synthesis of the beta chain of hFSH, but it does not exclude other possibilities. The concentration of hFSH antibodies in the patient's serum has been monitored and her response to a further course of exogenous gonadotropins is recorded. The anti serum exhibits specificity for the hFSH molecule; the alpha and the beta chains of hFSH are virtually inert in competing with tracer 125-I-hFSH for binding to the antibody.

The cultured human choriocarcinoma cell line, JEG-clone 3, secretes substantial quantities of both biologically active hCG and an immunoreactive alpha-subunit (JEG-alpha). This study is concerned with a comparative characterization, using RIA, of the chromatographic properties (via gel exclusion and isoelectric focusing) of JEG-alpha and standard urinary hCG-alpha. Most of the molecules comprising the JEG-alpha fraction have an apparent molecular weight greater than that of hCG-alpha. Both hCG-alpha and JEG-alpha exhibit heterogeneity on electrofocusing. However, JEG-alpha contains a major component with an isoelectric pH (pI) of 4.8; this is a minor component, if present at all, in hCG-alpha. The JEG-alpha pI 4.8 component chromatographs with an apparent molecular weight greater than hCG-alpha, while a minor JEG-alpha pI 7.0 component chromatographs with an apparent molecular weight similar to that of the standard. Heterogeneity is expected in the carbohydrate moieties of the glycoprotein hormone subunits. Results of studies on the incorporation of 14C- and 3H labeled amino acids into JEG-alpha suggest that heterogeneity also exists in the protein moiety of JEG-alpha. An interesting possibility is that the form(s) of JEG-alpha with larger apparent molecular weight represents a precursor of the alpha-subunit used to form hCG.

The rise and subsequent return to basal of glucose production (Ra) during a constant glucagon infusion ("downregulation") has suggested to some workers that glucagon's effects are evanescent. To examine whether glucagon displays persistent biological activity even after downregulation, 6 healthy males received an 8 hour infusion of somatostatin and glucagon, with 3H-3-glucose to measure glucose turnover. Ra rose from 2.8 +/- 0.3 to 4.2 +/- 0.3 mg/kg . min at 90 minutes, returned to basal levels at 150 minutes, and remained at this level for the ensuing 330 minutes. Six additional subjects received an 8 hour somatostatin infusion, with glucagon administered concomitantly for the first 5 hours. Glucagon withdrawal at 5 hours produced an immediate decline in Ra from 1.8 +/- 0.2 to 0.9 +/- 0.2 mg/kg . min. Thus, even after downregulation the maintenance of basal Ra is dependent on circulating glucagon.

Epidermal growth factor (EGF) binds to JEG-3 cells, a tissue culture line of human choriocarcinoma. EGF also stimulates secretion of human chorionic gonadotropin (hCG) and to a lesser extent the secretion of free hCG-alpha.

The heterogeneity of circulating human PRL (hPRL) in sera of patients with hyperprolactinemia was studied by exclusion chromatography on Sephadex G-100. Big hPRL, which elutes between the void volume and the elution position of monomeric small hPRL, is stable upon rechromatography but is almost entirely converted into small hPRL after reduction with 0.5% mercaptoethanol. These results suggest that the existence of circulating big hPRL is dependent upon the formation of interpolypeptide disulfide bonds and does not represent a classical biosynthetic precursor of hPRL.

Metabolic responses to the administration of Angiotensin II, K and ACTH are described in two salt-wasting syndromes: hypoaldosteronism in Jews from Iran, which is characterized by an enzymic block in the conversion of 18-hydroxycorticosterone to aldosteron; and pseudohypoaldosteronism, a disorder in which aldosterone secretion is high in association with renal tubular unresponsiveness to mineralocorticoids. The response of plasma and urinary aldosterone to K and ACTH is qualitatively normal in hypoaldosteronism; however, infusion of Angiotensin II, in a dose that was pressor and elevated aldosterone levels threefold in control subjects, was only pressor in hypoaldosteronism. In pseudohypoaldosteronism, plasma and urinary aldosterone respond to Angiotensin II, K and ACTH, notwithstanding very high basal hormonal levels.

Studies in 8 families of Iranian Jews revealed 12 patients with selective aldosterone deficiency due to a biosynthetic defect. There was a marked range in clinical severity which varied from acute salt-wasting crisis in infancy to an asymptomatic state in adults detectable only by biochemical screening. Manifestations of intermediate degrees of severity included unexplained short stature and postural hypotension. This clinical variability in the manifestations of aldosterone deficiency was not due entirely to quantitative differences in hormone secretion but also to a changing pattern of requirement throughout life in which deficiency during the first year of life had grave consequences while a similar degree of deficiency in the adult was well-tolerated, suggesting that the hormone was no longer essential. Most families came from a relatively isolated community in Isfahan with a high incidence of consanguinity and three were related. Aldosterone deficiency was due to an inborn error involving the terminal portion of the biosynthetic pathway and characterized by marked overproduction of glomerulosa zone 18-hydroxycorticosterone relative to aldosterone. The best diagnostic index was the excretory ratio of the major urinary metabolites of these steroids. This ratio, normally less than 3.0, was frequently greater than 100 in untreated patients with this defect. Plasma aldosterone was not a reliable index of the disorder since some patients achieved normal levels but at the expense of marked elevation in plasma renin activity and overproduction of precursors.

The hormonal response to luteinizing hormone releasing hormone (LHRH) thyrotropin releasing hormone (TRH) and chlorpromazine has been evaluated in eleven female subjects with the syndrome of isolated bihormonal gonadotropin deficiency (IGD). Following LHRH, all subjects had elevations of both LH and FSH, but the gonadotropin responses were attenuated relative to those observed in normal female subjects studied in the early proliferative phase of the cycle. Similarly, peak TSH levels after TRH were significantly less in subjects with IGD relative to normal controls. Basal prolactin levels were low in the patient group. Prolactin levels following TRH increased at least two-fold in control subjects and in the group with IGD. Conversely, chlorpromazine failed to induce elevations of prolactin in eight of nine females with IGD.

A radioimmunoassay is described for the measurement of 17alpha-hydroxyprogesterone in human plasma. We have employed the principle of "immunologic purification." 17-OHP and related steroids are bound to an excess of antiserum. Steroids with a low affinity for the antibody are extracted by ether. The 17-OHP is subsequently freed from antibody by acid hydrolysis and this extract is assayed by radioimmunoassay.