Keith Friend

BACKGROUND: Patients with acromegaly are currently treated with surgery, radiation therapy, and drugs to reduce hypersecretion of growth hormone, but the treatments may be ineffective and have adverse effects. Pegvisomant is a genetically engineered growth hormone-receptor antagonist that blocks the action of growth hormone. METHODS: We conducted a 12-week, randomized, double-blind study of three daily doses of pegvisomant (10 mg, 15 mg, and 20 mg) and placebo, given subcutaneously, in 112 patients with acromegaly. RESULTS: The mean (+/-SD) serum concentration of insulin-like growth factor I (IGF-I) decreased from base line by 4.0+/-16.8 percent in the placebo group, 26.7+/-27.9 percent in the group that received 10 mg of pegvisomant per day, 50.1+/-26.7 percent in the group that received 15 mg of pegvisomant per day, and 62.5+/-21.3 percent in the group that received 20 mg of pegvisomant per day (P<0.001 for the comparison of each pegvisomant group with placebo), and the concentrations became normal in 10 percent, 54 percent, 81 percent, and 89 percent of patients, respectively (P<0.001 for each comparison with placebo). Among patients treated with 15 mg or 20 mg of pegvisomant per day, there were significant decreases in ring size, soft-tissue swelling, the degree of excessive perspiration, and fatigue. The score fortotal symptoms and signs of acromegaly decreased significantly in all groups receiving pegvisomant (P< or =0.05). The incidence of adverse effects was similar in all groups. CONCLUSIONS: On the basis of these preliminary results, treatment of patients who have acromegaly with a growth hormone-receptor antagonist results in a reduction in serum IGF-I concentrations and in clinical improvement.

Several decades of basic and clinical research have demonstrated that there is an association between the insulin-like growth factors (IGFs) and neoplasia. We begin with a brief discussion of the function and regulation of expression of the IGFs, their receptors and the IGF-binding proteins (IGFBPs). A number of investigational interventional strategies targeting the GH or IGFs are then reviewed. Finally, we have assembled the available scientific knowledge about this relationship for each of the major tumor types. The tumors have been grouped together by organ system and for each of the major tumors, various key elements of the relationship between IGFs and tumor growth are discussed. Specifically these include the presence or absence of autocrine IGF-I and IGF-II production; presence or absence of IGF-I and IGF-II receptor expression; the expression and functions of the IGFBPs; in vitro and in vivo experiments involving therapeutic interventions; and available results from clinical trials evaluating the effect of GH/IGF axis down-regulation in various malignancies. (Endocrine Reviews 21: 215-244, 2000) I. Introduction II. Overview: IGF Physiology and Gene Regulation A. IGF-I gene expression B. IGF-II gene expression C. IGF-I receptor gene expression D. IGF-II receptor gene expression III.

Background and Purpose- This ARISTOPHANES study (Anticoagulants for Reduction in Stroke: Observational Pooled Analysis on Health Outcomes and Experience of Patients) used multiple data sources to compare stroke/systemic embolism (SE) and major bleeding (MB) among a large number of nonvalvular atrial fibrillation patients on non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin. Methods- A retrospective observational study of nonvalvular atrial fibrillation patients initiating apixaban, dabigatran, rivaroxaban, or warfarin from January 1, 2013, to September 30, 2015, was conducted pooling Centers for Medicare and Medicaid Services Medicare data and 4 US commercial claims databases. After 1:1 NOAC-warfarin and NOAC-NOAC propensity score matching in each database, the resulting patient records were pooled. Cox models were used to evaluate the risk of stroke/SE and MB across matched cohorts. Results- A total of 285 292 patients were included in the 6 matched cohorts: 57 929 apixaban-warfarin, 26 838 dabigatran-warfarin, 83 007 rivaroxaban-warfarin, 27 096 apixaban-dabigatran, 62 619 apixaban-rivaroxaban, and 27 538 dabigatran-rivaroxaban patient pairs. Apixaban (hazard ratio [HR], 0.61; 95% CI, 0.54-0.69), dabigatran (HR, 0.80; 95% CI, 0.68-0.94), and rivaroxaban (HR, 0.75; 95% CI, 0.69-0.82) were associated with lower rates of stroke/SE compared with warfarin. Apixaban (HR, 0.58; 95% CI, 0.54-0.62) and dabigatran (HR, 0.73; 95% CI, 0.66-0.81) had lower rates of MB, and rivaroxaban (HR, 1.07; 95% CI, 1.02-1.13) had a higher rate of MB compared with warfarin. Differences exist in rates of stroke/SE and MB across NOACs. Conclusions- In this largest observational study to date on NOACs and warfarin, the NOACs had lower rates of stroke/SE and variable comparative rates of MB versus warfarin. The findings from this study may help inform the discussion on benefit and risk in the shared decision-making process for stroke prevention between healthcare providers and nonvalvular atrial fibrillation patients. Clinical Trial Registration- URL: https://www.clinicaltrials.gov/ . Unique identifier: NCT03087487.

To determine if the mode of 17 beta-estradiol (E2) administration affects growth hormone (GH) concentrations, eight postmenopausal women were studied under the following conditions: (1) control (no E2), (2) oral E2 (Estrace, 1 mg every 12 h for 2 weeks) and (3) transdermal E2 (Estraderm patch, 0.1 mg, two patches changed daily for 2 weeks). Blood was collected every 5 min for 24 h and assayed for serum GH concentrations using a sensitive chemiluminescence assay. Serum E2 levels were comparable during both E2 treatment regimens when measured with a specific chemiluminescence assay. The 24-h integrated GH concentrations (IGHC, min . micrograms/L) increased in all eight subjects from (mean +/- SE) 494 +/- 102 during control to 860 +/- 111 (P < 0.05) and 832 +/- 149 (P < 0.05) during oral and transdermal E2, respectively. Both E2 treatments significantly increased GH pulse height, individual pulse area, incremental pulse amplitude, interpeak valley concentration, and interpeak valley nadir (as measured by Cluster algorithm) when compared with control. No significant differences were observed in the number of GH pulses per 24 h. Insulin-like growth factor-I (IGF-I, micrograms/L) concentrations decreased from 165 +/- 19 (control) to 109 +/- 11 (oral E2, P < 0.05) and 122 +/- 15 (transdermal E2, P < 0.05). No statistically significant differences in attributes of pulsatile GH release or IGF-I concentrations were observed between the oral and transdermal E2 treatments. We conclude that both oral and transdermal E2 treatment increase serum GH concentrations in postmenopausal women. This increase is manifested by larger GH pulses and higher basal (interpulse) GH levels, not by changes in pulse frequency. Both routes of E2 administration decrease serum IGF-I concentrations, which may attenuate IGF-I negative feedback on pituitary somatotrophs and hypothalamic somatostatin secretion, resulting in enhanced pulsatile GH release.