Biomedical subjects
R W Whitcomb
Publications and source records attributed to R W Whitcomb.
Hepatic dysfunction associated with troglitazone.
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Troglitazone monotherapy improves glycemic control in patients with type 2 diabetes mellitus: a randomized, controlled study. The Troglitazone Study Group.
To assess the effects of troglitazone monotherapy on glycemic control in patients with type 2 diabetes mellitus, we carried out a 6-month, randomized, double-blind, placebo-controlled study in 24 hospital and outpatient clinics in the United States and Canada. Troglitazone 100, 200, 400, or 600 mg or placebo once daily with breakfast was administered to 402 patients with type 2 diabetes with fasting serum glucose (FSG) > 140 mg/dL, glycosylated hemoglobin (HbA1c) > 6.5%, and fasting C-peptide > or = 1.5 ng/mL. Prior oral hypoglycemic therapy was withdrawn in patients who received it before the study. FSG, HbA1c, C-peptide, and serum insulin were evaluated at baseline and the end of the study. Analysis was performed on two subsets of patients based on prestudy therapy: Patients treated with diet and exercise only before the study (22% of patients), and those who had been receiving sulfonylurea therapy (78% of patients). Patients treated with 400 and 600 mg troglitazone had significant decreases from baseline in mean FSG and HbA1c at month 6 compared with placebo-treated patients (FSG: -51 and -60 mg/dL, respectively; HbA1c: -0.7 and -1.1%, respectively). In the diet-only subset, 600 mg troglitazone therapy resulted in a significant (P < 0.05) reduction in HbA1c (-1.35%) and a significant reduction in FSG (-42 mg/dL) compared with placebo. Patients previously treated with sulfonylurea therapy had significant (P < 0.05) decreases in mean FSG with 200-600 mg troglitazone therapy compared with placebo (-48, -61, and -66 mg/dL, respectively). Significant (P < 0.05) decreases in mean HbA1c occurred with 400 and 600 mg troglitazone therapy at month 6 (-0.8 and -1.2%, respectively) compared with placebo in this same subset. Significant (P < 0.05) decreases in triglycerides and free fatty acids occurred with troglitazone 400 and 600 mg, and increased high-density lipoprotein occurred with 600 mg troglitazone. We conclude that troglitazone monotherapy significantly improves HbA1c and fasting serum glucose, while lowering insulin and C-peptide in patients with type 2 diabetes. Troglitazone 600 mg monotherapy is efficacious for patients who are newly diagnosed and have never received pharmacological intervention for diabetes.
Troglitazone use in insulin-treated type 2 diabetic patients. The Troglitazone Insulin Study Group.
OBJECTIVE: To determine the ability of troglitazone to reduce requirements for injected insulin while maintaining blood glucose levels in insulin-treated patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: This 26-week double-blind study with open-label extension included patients who had failed previous oral antidiabetic medication and took > or =30 but <150 U of insulin daily The 222 patients in the double-blind study received 200 or 400 mg troglitazone once daily or matching placebo. The primary end point was the proportion of patients meeting the target of > or =50% reduction in injected insulin and either a 15% reduction in fasting blood glucose or a blood glucose <7.8 mmol/l. Insulin dose was reduced 25% based on a study-specific algorithm whenever fasting blood glucose was reduced 5% from baseline. Also of interest were changes in insulin dose and HbA1c. The open-label extension included 173 patients. They received 200 mg of troglitazone with optional titration to 400 mg, and insulin dose was adjusted based on investigators' standards of care. Open-label measures were change in insulin dose, HbA1c, and fasting serum glucose (FSG). RESULTS: In the double-blind phase, 22 and 27% of the 200- and 400-mg troglitazone groups, respectively, reached target, compared with placebo (7%) (P < 0.01). Insulin dose reductions of 13 +/- 3, 30 +/- 3, and 41 +/- 3 U were observed for placebo, 200-, and 400-mg troglitazone groups, respectively HbA1c decreased 0.09 +/- 0.14% for placebo, 0.13 +/- 0.14% for 200 mg, and 0.41 +/- 0.14% for 400 mg (P < 0.05) troglitazone. In the open-label extension, troglitazone treatment resulted in >50% reduction from baseline in daily insulin dose and decreases in HbA1c of 1% and in FSG of >17%. CONCLUSIONS: Troglitazone decreases daily injected insulin dose requirements and improves glycemic control in insulin-treated patients with type 2 diabetes.
Troglitazone in combination with sulfonylurea restores glycemic control in patients with type 2 diabetes. The Troglitazone Study Group.
OBJECTIVE: To determine if the combination of troglitazone (a peroxisome proliferator-activated receptor-gamma activator) and sulfonylurea will provide efficacy not attainable by either medication alone. RESEARCH DESIGN AND METHODS: There were 552 patients inadequately controlled on maximum doses of sulfonylurea who participated in a 52-week randomized active-controlled multicenter study. Patients were randomized to micronized glyburide 12 mg q.d. (G12); troglitazone monotherapy 200, 400, or 600 mg q.d. (T200, T400, T600); or combined troglitazone and glyburide q.d. (T200/G12, T400/G12, T600/G12). Efficacy measures included HbA1c, fasting serum glucose (FSG), insulin, and C-peptide. Effects on lipids and safety were also assessed. RESULTS: Patients on T600/G12 had significantly lower mean (+/- SEM) FSG (9.3 +/- 0.4 mmol/l; 167.4 +/- 6.6 mg/dl) compared with control subjects (13.7 +/- 0.4 mmol/l; 246.5 +/- 6.8 mg/dl; P < 0.0001) and significantly lower mean HbA1c (7.79 +/- 0.2 vs. 10.58 +/- 0.18%, P < 0.0001). Significant dose-related decreases were also seen with T200/G12 and T400/G12. Among patients on T600/G12, 60% achieved HbA1c < or =8%, 42% achieved HbA1c < or =7%, and 40% achieved FSG < or =7.8 mmol/l (140 mg/dl). Fasting insulin and C-peptide decreased with all treatments. Overall, triglycerides and free fatty acids decreased, whereas HDL cholesterol increased. LDL cholesterol increased slightly, with no change in apolipoprotein B. Adverse events were similar across treatments. Hypoglycemia occurred in 3% of T600/G 12 patients compared with <1% on G12 or troglitazone monotherapy CONCLUSIONS: Patients with type 2 diabetes inadequately controlled on sulfonylurea can be effectively managed with a combination of troglitazone and sulfonylurea that is safe, well tolerated, and represents a new approach to achieving the glycemic targets recommended by the American Diabetes Association.
Cardiac and glycemic benefits of troglitazone treatment in NIDDM. The Troglitazone Study Group.
Troglitazone is a thiazolidinedione under development for the treatment of NIDDM and potentially other insulin-resistant disease states. Treatment with troglitazone is associated with an improvement in hyperglycemia, hyperinsulinemia, and insulin-mediated glucose disposal. No significant side effects have been observed in humans. Because of reported cardiac changes in animals treated with drugs of this class, this multicenter 48-week study was conducted to evaluate whether NIDDM patients treated with troglitazone develop any cardiac mass increase or functional impairment. A total of 154 NIDDM patients were randomized to receive troglitazone 800 mg q.d. or glyburide titrated to achieve glycemic control (< or =20 mg b.i.d. or q.d.). Two-dimensional echocardiography and pulsed Doppler were used to measure left ventricular mass index (LVMI), cardiac index (CI), and stroke volume index (SVI). All echocardiograms were performed at each center (baseline, 12, 24, 36, and 48 weeks), recorded on videotape, and forwarded to a blinded central echocardiographic interpreter for analysis. The results showed that LVMI of patients treated with troglitazone was not statistically or clinically different from baseline after 24 or 48 weeks. Statistically significant increases in SVI and CI and a statistically significant decrease in diastolic pressure and estimated peripheral resistance were observed in troglitazone-treated patients. These results were not sex-specific. Glycemic benefits of troglitazone treatment were observed as evidenced by long-term improvement of HbA1c and C-peptide levels. Furthermore, triglycerides were significantly lower, and HDL was significantly higher at weeks 24 and 48. In conclusion, NIDDM patients treated with troglitazone do not show any cardiac mass increase or cardiac function impairment. Conversely, patients on troglitazone benefited from enhanced cardiac output and stroke volume, possibly as a result of decreased peripheral resistance. Treatment with troglitazone appears to have a favorable impact on known cardiovascular risk factors and could potentially lower cardiovascular morbidity in NIDDM patients.
Hypogonadotropic hypogonadism: gonadotropin-releasing hormone therapy.
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Efficacy and local tolerance of a low-dose, 7-day matrix estradiol transdermal system in the treatment of menopausal vasomotor symptoms.
OBJECTIVE: To determine the efficacy and local tolerance of a new matrix transdermal drug-delivery system that delivers 0.02 mg of 17 beta-estradiol (E2) daily for 7 days for the relief of vasomotor symptoms. METHODS: A total of 324 surgically or naturally menopausal women, all with prior hysterectomy and moderate to severe vasomotor symptoms (56-140 hot flushes per week, with episodes of sweating, during a baseline observation period), participated in two independent, 12-week, randomized, double-blind, placebo-controlled studies. After a 4-week, treatment-free period, each woman received a continuous regimen of either one E2 transdermal system, two E2 transdermal systems, or placebo transdermal system(s) applied every week for 12 weeks. Efficacy was measured as reduction in hot flush frequency, determined from subject diaries. To measure local tolerance, skin irritation (erythema and edema) was objectively and systematically evaluated under blue light after removal of the transdermal system(s). Serum E2 and estrone concentrations were determined in one of the studies during baseline and on days 1, 9, 30, 58, 79, and 84. RESULTS: Mean hot flush frequency decreased from 80 hot flushes per week at baseline to approximately 13 hot flushes per week (84% decrease) after 12 weeks of transdermal E2 treatment. Compared with placebo, the decrease in hot flush frequency was significant as early as weeks 2 and 3, and was maintained through the end of the study. Few clinically significant skin reactions occurred, and only nine (3%) of the subjects withdrew because of a skin effect. After initial increase, serum E2 concentrations remained stable throughout the study, achieving values of approximately 20 and 40 pg/mL above baseline for one and two E2 transdermal systems, respectively. CONCLUSION: The E2 transdermal system effectively reduced the frequency of moderate to severe vasomotor symptoms as early as the second week of therapy and was very well tolerated. The decrease in hot flush frequency was similar to that reported for oral and other transdermal estrogens, but at lower serum E2 concentrations. This result may be due to the stable E2 blood level achieved with this transdermal system.
Contour of the GnRH pulse independently modulates gonadotropin secretion in the human male.
GnRH pulse frequency, amplitude, and interpulse interval have all been demonstrated to regulate gonadotropin secretion individually. We tested the hypothesis that the contour of the GnRH pulse also modulates gonadotropin output in 10 men with isolated GnRH deficiency in whom a fixed GnRH dose was administered at a constant physiologic frequency by either instantaneous bolus or by 1-, 5-, or 30-min infusions. LH, FSH and free alpha subunit (FAS) responses were also compared to spontaneous gonadotropin secretion in normal adult men. While the LH and FAS pulses following the instantaneous bolus and 1-min infusion of GnRH were indistinguishable, further increases in the duration of gonadotrope stimulation by GnRH were associated with progressive decreases in all parameters of gonadotropin secretion (mean levels, amplitude, peak levels, AUC). FSH secretion was also decreased following variations in the contour of the GnRH pulse, although overall changes were less dramatic than for LH and FAS. The LH pulses following the bolus GnRH stimulation were indistinguishable from spontaneous LH pulses occurring in normal men whereas those stimulated by the 1-, 5-, and 30-min infusions of GnRH became progressively blunted with the lowest levels of secretion occurring after the longest infusion. In sharp contrast, FAS pulse parameters in the GnRH-deficient subjects greatly exceeded those of normal men regardless of the contour of the GnRH stimulus, whereas mean FSH levels were all modestly (although significantly) higher than those of normal adult men. These results demonstrate that the pituitary is sensitive to subtle changes in the contour of the GnRH stimulus, with a more prolonged duration of GnRH stimulation resulting in a diminished pituitary response. Alterations of the contour of endogenous GnRH secretion may represent an additional mechanism for altering gonadotrope function and provide additional evidence for the differential regulation of LH, FAS, and FSH by GnRH. However, the previously reported elevated levels of FAS secretion in GnRH-deficient men undergoing long-term GnRH replacement are not explained by abnormalities of GnRH contour.
Hypogonadotropic hypogonadism: gonadotropin-releasing hormone therapy.
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Male hypogonadotropic hypogonadism.
Hypogonadotropic hypogonadism in the male is caused by alterations in gonadotropin-releasing hormone secretion or through abnormal pituitary secretion of luteinizing hormone or follicle-stimulating hormone. Recent studies in animal and human models have demonstrated possible pathophysiologic explanations for the occurrence of some GnRH-deficient states. It is critical to ascertain whether such patients represent a variant of normal or have true hypogonadotropic hypogonadism. Recent developments in both diagnostic techniques and hormonal treatment increase the chances of a correct diagnosis and successful treatment outcome.
Hypogonadism caused by a single amino acid substitution in the beta subunit of luteinizing hormone.
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Neuroendocrine control of human reproduction in the male.
The traditional difficulty in studying the neuroendocrine control of reproduction in the human male has been the inability to tease out the hypothalamic from the pituitary component of this neuroendocrine system. The use of multiple models, each with its own strength and weakness, represents an overlapping approach that has permitted further insights to be gained into the hypothalamic control of the neuroendocrine regulation of gonadotropin secretion in the human. Such an insight is an important prerequisite to the understanding of the pathophysiology of various disease states, the unraveling of a control of FSH secretion by GnRH vs other modulators, and the subsequent design of rational therapies for male reproductive disorders.
Priapism in hypogonadal men receiving gonadotropin releasing hormone.
To our knowledge we report the first 2 cases of priapism occurring in hypogonadal men receiving gonadotropin releasing hormone therapy. Hypogonadal patients receiving hormonal therapy should be informed about the possibility of priapism and the importance of early urological consultation.
Normal sequence of the gonadotropin-releasing hormone gene in patients with idiopathic hypogonadotropic hypogonadism.
Idiopathic hypogonadotropic hypogonadism (IHH) results from absent or greatly diminished secretion of GnRH. Defects in the GnRH gene have been identified in an animal model of IHH and have been hypothesized as a possible basis for GnRH deficiency in humans. In this study, we used the polymerase chain reaction to clone and sequence the coding regions, promoter, and 3' untranslated tract of the GnRH genes from both alleles of four unrelated patients with IHH. One of the patients studied is a member of a kindred in which X-linked inheritance has been excluded by father-to-son transmission of the disease. No DNA sequence mutations were found. We conclude that most cases of IHH in humans do not involve mutations in the GnRH gene and are presumably caused by mutations at one or more other genetic loci that are required for normal function of GnRH-producing neurons.
Circulating antagonist of luteinizing hormone in association with infertility in stallions.
Using a LH radioligand receptor assay (RRA) previously validated for use in serum and an equine monoclonal RIA, we have distinguished a subset of subfertile stallions with an elevated RRA/RIA ratio. After purification of the active moiety by anion exchange chromatography and immunoprecipitation with the equine LH (eLH) monoclonal antibody, RRA activity remained in the supernatant. This activity was also recognized by a polyclonal LH antibody (GDN 15) with wide cross-species recognition. This active fraction was further purified by gel filtration chromatography and shown to displace labeled eLH in a dose-dependent fashion in the RRA with an inhibition slope of 2.8 compared with a slope of 1.1 for native eLH. This fraction also inhibited the LH-stimulated steroidogenesis of Leydig cells in vitro in a dose-dependent fashion, but had no effect on basal (minus LH) steroid production. Polyacrylamide gel electrophoresis and electroelution of this material demonstrated RRA activity in a fraction with a mol wt between 45-66 kDa. We conclude that this substance 1) competitively inhibited binding of eLH and hCG to the LH receptor, 2) antagonized LH-stimulated steroidogenesis in vitro, and 3) may represent a LH isoform found in association with infertility in these animals.
Precursors of alpha-inhibin modulate follicle-stimulating hormone receptor binding and biological activity.
Although several forms of monomeric alpha-inhibin have been isolated from follicular fluid, no biological function has yet been ascribed to these posttranslationally processed forms of the alpha-subunit precursor protein. Moreover, previous studies of a FSH receptor binding competitor (FRBC) isolated and characterized from porcine follicular fluid (pFF) suggested certain biochemical similarities between this protein and alpha-inhibin precursors. We, therefore, investigated the hypothesis that alpha-inhibin and/or its precursors might represent autocrine and/or paracrine modulators of FSH action in the ovary, accounting for some of this FRBC activity and thereby exerting some degree of regulation over follicular maturation. Three separate sources of alpha-inhibin proteins were investigated for FRBC activity, including pFF, human FF (hFF), and a 293 cell line into which the full-length human alpha-inhibin cDNA had been stably transfected. Conditioned medium from these transfected cells contained several forms of alpha-inhibin precursors as well as mature alpha-inhibin, but no beta-subunit or intact inhibin. alpha-Inhibin proteins from all three sources, purified by a variety of methods, including immunoaffinity chromatography on an anti-alpha-inhibin column, inhibited FSH binding to both natural tissue FSH receptors as well as recombinant rat FSH receptors expressed in 293 cells. Furthermore, dimeric inhibin and activin, medium from untransfected 293 cells, and non-alpha-inhibin-containing purification fractions were inactive in either assay. In addition, purified recombinant alpha-inhibin proteins were partial in vitro FSH antagonists in a bioassay in which cAMP generation from 293 cells expressing the recombinant FSH receptor is used as an index of FSH biological activity. These same fractions of hFF containing FRBC activity did not bind to LH receptors, thereby demonstrating receptor specificity for this activity. Using sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blotting with alpha-inhibin or FRBC antisera, a 57,000 mol wt protein was identified in FRBC-active fractions from all three sources, suggesting that the active moiety was the full-length alpha-inhibin precursor protein or a large mol wt fragment, but not mature alpha-inhibin. Lastly, all FRBC activity from all three sources was extracted by an alpha-inhibin immunoaffinity column and was recoverable upon elution. These results demonstrate that proteins derived from the alpha-inhibin precursor modulate FSH binding to its receptor as well as its biological activity.(ABSTRACT TRUNCATED AT 400 WORDS)
Altered patterns of pituitary secretion and renal excretion of free alpha-subunit during gonadotropin-releasing hormone agonist-induced pituitary desensitization.
Intact LH and free alpha-subunit (FAS) are differentially regulated during GnRH agonist (GnRHa)-induced pituitary desensitization; circulating levels of FAS rise, while LH levels decline. Increased steady state alpha and decreased LH beta mRNA levels in desensitized rat pituitaries suggest that differential regulation occurs at the level of subunit transcription. We assessed a renal contribution to these changes in serum hormone concentrations by studying LH and FAS levels in serum and urine in 15 pubertal children before and during long term GnRHa administration. Before GnRHa, serum LH and FAS were secreted in concordant pulses, and both responded briskly to exogenous GnRH. During GnRHa-induced pituitary desensitization, mean (+/- SEM) serum and urinary LH levels fell [11 +/- 3 vs. 2 +/- 0.2 IU/L (P less than 0.01) and 39 +/- 15 vs. 5 +/- 1 IU/g creatinine (P less than 0.05), respectively), and the LH response to exogenous GnRH was ablated (117 +/- 20 vs. 1 +/- 0.3 IU/L; P less than 0.01). In contrast, despite suppression of FAS pulsatility, mean serum FAS levels rose during GnRHa treatment (204 +/- 23 vs. 405 +/- 50 ng/L; P less than 0.01), and responsiveness to exogenous GnRH was maintained. Paradoxically, urinary FAS levels fell (3.2 +/- 0.9 vs. 1.7 +/- 0.4 micrograms/g creatinine; P less than 0.05) as did its renal clearance (3.1 +/- 0.5 vs. 1.3 +/- 0.1 mL/min.m2; P less than 0.05). We conclude that during GnRHa-induced pituitary desensitization, the gonadotrope maintains the ability to respond to GnRH with FAS release, and the rise in serum FAS is due in part to its diminished renal clearance.