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Biomedical subjects

A D Rogol

Publications and source records attributed to A D Rogol.

At least 145 records · Page 8Linked to original sources
PubMed1987

Sustained inhibitory actions of a potent antagonist of gonadotropin-releasing hormone in postmenopausal women.

The inhibitory time course and dose-related characteristics of a new potent GnRH antagonist peptide, [N-acetyl-D-pCl-Phe1,2-D-Trp3-D-Lys6-D-Ala10]GnRH, on gonadotropin secretion were studied in nine postmenopausal women. Effective suppression of gonadotropin secretion was correlated with increased circulating concentrations of immunoassayable GnRH antagonist. Inhibition of gonadotropin secretion was achieved by a parenteral dose of 300 micrograms/kg GnRH antagonist. This dose reduced plasma bioactive LH concentrations by 49-59%, immunoactive LH by 41-46%, and immunoactive FSH by 25-40%. Blockade of gonadotropin secretion was sustained for 10-28 h after a single injection of the synthetic decapeptide. This prolonged action was associated with significant plasma protein binding of the GnRH antagonist and mean plasma half-times of disappearance of 1.5 and 21 h for the fast and slow components, respectively. In summary, we have described the biological actions of a potent GnRH antagonist that binds avidly to serum proteins, has a prolonged plasma residence time, and exerts sustained inhibitory effects on bio- and immunoactive LH release in man. The extended duration of action of this compound may reflect in part its significant binding to circulating plasma proteins.

Aged↗
PubMed1987

Operating characteristics of the male hypothalamo-pituitary-gonadal axis: pulsatile release of testosterone and follicle-stimulating hormone and their temporal coupling with luteinizing hormone.

To appraise the physiological pattern(s) of episodic testosterone and FSH release in man, we withdrew blood samples at 10-min intervals for 24-36 h in a total of 15 normal men. We subjected the resulting FSH (15 men) and testosterone (5 men) time series to 3 statistically based and mathematically independent procedures for detecting hormone pulsatility, viz. Cluster analysis, the Detect program, and Fourier transformation. The Cluster technique disclosed discrete testosterone and FSH peaks occurring at mean (+/- SEM) interpulse intervals of 112 +/- 14 and 85 +/- 3.4 min, respectively. These values were not significantly different from the mean LH interpulse interval of 95 +/- 11 min. The average durations of the testosterone and FSH pulsations were 90 +/- 11 and 59 +/- 3 min, respectively. The mean testosterone pulse amplitude reached a maximal value of 910 +/- 92 ng/dL (31.5 +/- 3.2 nmol/L), which represented a mean increase of 242 +/- 26 ng/dL (8.4 +/- 0.9 nmol/L) above the preceding nadir. FSH pulses had a maximum of 7.2 +/- 0.3 IU/L, and an incremental amplitude of 1.3 +/- 0.1 IU/L. An independent pulse detection procedure. Detect, yielded a testosterone pulse frequency of 12.3 +/- 0.8 pulses/day [P = NS vs. Cluster program (13 +/- 1.9 pulses/day)]. The Cluster and Detect estimates of FSH pulse frequency were also similar, viz. 16 +/- 1.9 and 16 +/- 0.6 pulses/day. Further analysis by Fourier transformation revealed significant circadian periodicities for serum testosterone, FSH, and LH, which had mean nyctohemeral amplitudes of 185 ng/dL (6.4 nmol/L), 0.38 IU/L, and 1.3 IU/L, respectively. Cross-correlation analyses disclosed significantly positive uncorrected cross-correlations between LH and testosterone that were maximal at a testosterone lag of 60 min (range, 50-70 min). To eliminate high intrinsic autocorrelations within the testosterone and LH time series, stepwise autoregressive fitting was employed. The resulting partial cross-correlation matrices indicated that LH concentrations at any given instant were significantly positively correlated to testosterone concentrations lagged by 10 and 20 min. Similarly, contemporaneous LH and FSH concentrations were significantly positively correlated (r = 0.40-0.89; P less than 0.001). Moreover, autoregressive modeling disclosed significantly positive partial cross-correlations between LH and FSH at a FSH lag of 10 min. In summary, we have identified significant pulsatile as well as circadian (24-h) patterns of testosterone and FSH release in normal men.(ABSTRACT TRUNCATED AT 400 WORDS)

Activity Cycles↗
PubMed1986

Endocrine impact of pure estradiol replacement in postmenopausal women: alterations in anterior pituitary hormone release and circulating sex steroid hormone concentrations.

Thirteen healthy postmenopausal volunteers were studied under basal conditions and at intervals (days 1, 5, 10, and 30) after intravaginal placement of a polysiloxane ring impregnated with 400 mg of estradiol. Mean serum estradiol concentrations rose 26-fold with a twofold increase in serum estrone concentrations. Serum delta 4-androstenedione, dehydroepiandrosterone sulfate, and total testosterone did not change, but absolute and percent free testosterone concentrations declined significantly by day 5. Concurrently, serum concentrations of immunoactive follicle-stimulating hormone declined progressively, while serum luteinizing hormone and free alpha-subunit concentrations exhibited a biphasic pattern of suppression. Serum levels of prolactin increased monophasically and those of growth hormone, somatomedin C, and thyroid-stimulating hormone did not change.

Estradiol↗
PubMed1986

Prokaryotic adenylate cyclase toxin stimulates anterior pituitary cells in culture.

Bordetella pertussis synthesizes a variety of virulence factors including a calmodulin-dependent adenylate cyclase (AC) toxin. Treatment of anterior pituitary cells with this AC toxin resulted in an increase in cellular cAMP levels that was associated with accelerated exocytosis of growth hormone (GH), prolactin, adrenocorticotropic hormone (ACTH), and luteinizing hormone (LH). The kinetics of release of these hormones, however, were markedly different; GH and prolactin were rapidly released, while LH and ACTH secretion was more gradually elevated. Neither dopamine agonists nor somatostatin changed the ability of AC toxin to generate cAMP (up to 2 h). Low concentrations of AC toxin amplified the secretory response to hypophysiotrophic hormones. We conclude that bacterial AC toxin can rapidly elevate cAMP levels in anterior pituitary cells and that it is this response that explains the subsequent acceleration of hormone release.

Adenylate Cyclase Toxin↗
PubMed1986

Clinical studies with GHRH in man.

GHRH was isolated from two GHRH-secreting pancreatic tumors which resulted in clinical acromegaly. Over 98% of acromegalic patients have a pituitary adenoma; however, acromegaly may occasionally result from ectopic or eutopic GHRH secretion. Administration of GHRH to normal adults stimulates growth hormone (GH) secretion; it may also stimulate GH release in some adults with GH deficiency in childhood and in a majority of GH-deficient children. Continuous infusion of GHRH to normal men stimulates GH secretion which augments naturally occurring GH pulses. GHRH is effective when administered subcutaneously and intranasally, but requires 30- and 300-fold higher doses, respectively. Intermittent subcutaneous GHRH therapy promotes acceleration of linear growth in GH-deficient children and appears promising as a treatment for these children.

Acromegaly↗
PubMed1986

Metabolic clearance of biologically active luteinizing hormone in man.

The plasma metabolic clearance of biologically active luteinizing hormone (bioactive LH) was studied using the rat interstitial cell testosterone (RICT) bioassay in six hypogonadotropic men after single bolus injection of highly purified human LH and during continuous steady-state infusions of three graded doses of LH. The LH bolus disappearance curves provided estimates of metabolic clearance rates (MCR) of 24.1 +/- 4.7 (+/- SD) ml/min for bioactive LH vs. 56.2 +/- 12 ml/min for immunoactive LH in the same men (P = 0.03). A lower MCR of bioactive LH compared with immunoactive LH was also observed during continuous infusions of physiological doses of LH; for example, the mean steady-state MCRs for bioactive and immunoactive LH were, respectively, 26.1 +/- 3.1 and 34.2 +/- 3.2 ml/min (P = 0.02). Moreover, the stepped-dose infusion regimens permitted us to demonstrate that increasing doses of pure human LH resulted in progressive and parallel decreases in the apparent MCRs of both bioactive and immunoactive LH. Based on the respective steady-state MCRs calculated at physiological plasma concentrations of immunoactive and bioactive LH, we estimate a mean endogenous production rate for bioactive hormone of 1,937 IU/24 h, and for immunoactive LH of 589 IU/24 h in normal men. These results indicate that previous estimates of LH production rates from immunoassay data alone markedly underestimate the quantity of biologically active hormone secreted in man.

Adult↗
PubMed1986

Pituitary self-priming actions of gonadotropin-releasing hormone. Kinetics of estradiol's potentiating effects on gonadotropin-releasing hormone-facilitated luteinizing hormone and follicle-stimulating hormone release in healthy postmenopausal women.

We examined the kinetically distinct characteristics of estradiol's effects upon pituitary luteinizing hormone (LH) and follicle-stimulating hormone (FSH) release in response to pulses of exogenous gonadotropin-releasing hormone (GnRH) in healthy postmenopausal individuals. The putative self-priming actions of GnRH on LH and FSH release were tested by intravenous injections of equal paired doses of GnRH (10 micrograms) before and after 1, 5, 10, and 30 d of pure estradiol-17 beta delivery via an intravaginal silastic ring. Self-priming actions of GnRH, as defined by heightened gonadotropin release in response to the second pulse of GnRH compared with the first, were completely absent in the hypoestrogenemic state. However, estradiol administration unmasked GnRH self-priming in a time-dependent fashion, with maximal expression after 5 and 10 d of steroid replacement, followed by attenuation by 30 d. Since estradiol's modulation of GnRH action was expressed differentially on LH and FSH release, we suggest that such facilitation of GnRH-stimulated pituitary LH and FSH release may provide an additional mechanism for dissociated secretion of gonadotropic hormones in health or disease.

Drug Interactions↗
PubMed1986

Appraising endocrine pulse signals at low circulating hormone concentrations: use of regional coefficients of variation in the experimental series to analyze pulsatile luteinizing hormone release.

We have developed a regional dual-threshold method for detecting endocrine pulses at variably low hormone concentrations such as those that occur in the pediatric age group. This algorithm uses the local intra-series coefficient of variation to test for a significant increase and decrease (peak or pulse) in the experimental series. The method is unique in combining the following considerations: 1) use of internal measurement error present in the actual sample replicates (rather than that estimated from external standards); 2) an ability to accommodate a wide range of nonuniformity in intraassay coefficients of variation; 3) utilization of both upstroke and downstroke threshold criteria; and 4) adaptability to specify a physiologically relevant proximity of the postpeak nadir to the center of the peak. We have validated the behavior of this method in relation to false-positive rates for various program parameters and have illustrated the application of this new regional dual-threshold method to luteinizing hormone pulse detection in pubertal boys who have relative hypogonadotropism, which renders reliable luteinizing hormone pulse detection particularly difficult.

Adolescent↗
PubMed1986

Serum insulin-like growth factors I and II concentrations and growth hormone and insulin responses to arginine infusion in children with protein-energy malnutrition before and after nutritional rehabilitation.

Serum insulin, growth hormone (GH), insulin-like growth factors (IGFs) I and II, cortisol, and albumin concentrations were measured in 15 children with kwashiorkor, 15 with marasmic-kwashiorkor, and 21 with marasmus, before and in the survivors, after nutritional rehabilitation, as well as in 10 underweight and eight normal Egyptian children. We also evaluated arginine-induced insulin and GH secretion. IGF-I concentrations were reduced in the three severely malnourished groups (0.07 +/- 0.03, 0.05 +/- 0.03, and 0.09 +/- 0.09 U/ml, respectively) but returned to normal after refeeding. IGF-II concentrations were low in the kwashiorkor (175 +/- 79 ng/ml), marasmic-kwashiorkor (111 +/- 57 ng/ml), and marasmic children (128 +/- 70.9 ng/ml) and returned to normal after nutritional rehabilitation. Basal GH levels were high in the three severely malnourished groups (21.9, 28.8, and 16.6 ng/ml, respectively) and returned to normal after refeeding (8.1, 6.5, and 6.0 ng/ml, respectively). GH responses to arginine were depressed in the three malnourished groups and improved significantly in marasmic-kwashiorkor and marasmic children after nutritional rehabilitation. Insulin responses to arginine were impaired in kwashiorkor, and marasmic-kwashiorkor children and improved significantly after refeeding. IGF-I levels correlated significantly with percent of expected weight (r = 0.52, p less than 0.001), percent of expected height (r = 0.42, p less than 0.001), and weight/(height)2 index (r = 0.34, p less than 0.01). IGF-I levels correlated positively with insulin levels (r = 0.421, p less than 0.001) and negatively with cortisol concentrations (r = -0.400, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Anthropometry↗
PubMed1986

Partial insulin resistance in the mouse BC3H-1 cell line: absent hexose-independent actions of insulin.

We have studied the regulation of glycogen metabolism by insulin in the insulin-sensitive nonfusing muscle cell line BC3H-1. The basal percentage of glycogen synthase I activity was not altered by insulin alone at any concentration, time of exposure, or age of cells tested. The addition of glucose or 2-deoxyglucose to the glucose- and serum-free incubation medium caused a 2-fold increase in glycogen synthase I activity over basal levels, and the effect was enhanced to 3-fold if insulin was added to the medium. Glycogen phosphorylase a activity was not altered by incubation in the presence of insulin, but was lowered by the addition of 2-deoxyglucose. This effect was also enhanced in the presence of insulin. The effect of exogenously added sugar occurred only if a 6-phosphorylatable hexose was used. The effect seen with 2-deoxyglucose was stable to Sephadex G-25 desalting, suggesting that activation of glycogen synthase was the result of a stable (covalent) modification of the enzyme. We were also able to demonstrate the presence of glucose-6-phosphate-activatable glycogen synthase phosphatase activity in the myocytes. The effect of 2-deoxyglucose in the presence or absence of insulin could be completely reversed by including cytochalasin B in the medium, suggesting that both the effect of hexose and the insulin enhancement of its effect were entirely dependent on carrier-mediated hexose uptake. Four insulin-mimetic agents, H2O2 Concanavalin A, Na orthovanadate, and antiinsulin receptor B2 serum, were also tested. Despite different mechanisms of action, each agent qualitatively mimicked insulin in the myocytes. All stimulated hexose transport, glucose incorporation into glycogen, and hexose-dependent activation of glycogen synthase in a manner not additive with insulin, but none increased basal glycogen synthase I activity in the absence of hexose. These results suggest that although insulin is capable of regulating glycogen metabolism both by increasing the uptake of sugar and by altering the activation state of glycogen synthase and phosphorylase, these effects are entirely due to the stimulation of hexose uptake, and hexose-independent actions of insulin are absent in BC3H-1 cells.

3-O-Methylglucose↗
PubMed1986

The effect of androgens on the pulsatile release and the twenty-four-hour mean concentration of growth hormone in peripubertal males.

Oxandrolone (Ox) and testosterone (T) are used as growth-promoting agents in the therapy of boys with constitutional delay of growth and adolescence. Although the mechanism of action of these androgens is not known, it is recognized that T enhances GH release during GH stimulation tests. We studied the effects of T and Ox on the mean concentration of GH, the pattern of GH secretion, and somatomedin-C (SmC) concentrations in boys with short stature and/or delayed sexual development to determine whether their growth-promoting effects might be mediated through endogenous GH release. Ten boys received Ox (0.1 mg/kg . day, orally) for 65 +/- 5 days (mean +/- SD), and five boys received T propionate (7.5 mg, im, for 7 days), followed by T enanthate (100 mg, im, monthly for 3 months). Serum GH was measured in samples obtained at 20-min intervals for 24 h before and 65 +/- 5 days (mean +/- SD) after the initiation of therapy. SmC levels were measured twice during the same 24-h period before and 65 +/- 5 days (mean +/- SD) after initiation of therapy. In the boys treated with T, there were significant increases in the mean concentration of GH (mean increase, 4.3-fold; range, 2-12), in the number of GH pulses 10 ng/ml or greater [1.6 +/- 2.0 vs. 4.8 +/- 1.5/24 h (mean +/- SD)], and in the SmC levels [0.82 +/- 0.46 vs. 2.3 +/- 0.4 mu/ml (mean +/- SD)]. There were, however, no significant changes in the boys treated with Ox. Both Ox and T significantly improved the growth rates; however, T increased the growth rate by 0.95 +/- 0.24 (mean +/- SD) cm/months, and Ox increased the growth rate by 0.24 +/- 0.26 (mean +/- SD) cm/month. These results indicate that T, but not Ox, at the doses tested increases GH secretion in boys with short stature and/or delayed sexual development. This increase in GH secretion may contribute to the increased growth rate in males at puberty.

Adolescent↗
PubMed1986

Physiological properties of the luteinizing hormone pulse signal: impact of intensive and extended venous sampling paradigms on its characterization in healthy men and women.

The pulsatile nature of the gonadotropin signal is a critical determinant of physiological activation of the gonadal axis. Nonetheless, major uncertainties exist regarding the exact patterns of LH secretion that constitute normal physiological profiles in man. To assess possible bases for the discrepancies in the literature, we sampled blood at 5-min intervals for 24 h in eight normal men and eight normal women in the early follicular phase of the menstrual cycle. The constituent 5-, 10-, 15-, and 20-min immunoactive LH series and the consituent 6-, 12-, or 24-h sampling durations provided ranges of sampling intensities and durations for analysis of significant LH pulses. A technique for minimizing the influence of false positive immunoassay errors on peak detection was used to aid in estimating apparent true positive LH pulse frequency. Nonlinear curve fitting of the relationship between sampling intensity and apparent true positive LH pulse frequency revealed a stable pulse frequency estimate at intensive rates of venous sampling, with values of 19.5 +/- 1.9 (+/- SEM) pulses/24 h (periodicity, 73.8 +/- 6.5 min/pulse) in men and 20.6 +/- 3.6 pulses/24 h (periodicity, 70.0 +/- 10 min/pulse) in women. Further analyses indicated that sampling every 3.1 and 2.0 min for 24 h would be required to capture 90% of the LH pulses in men and women, respectively. Moreover, even with a 5-min sampling rate, the statistical counting errors of the LH pulse frequency estimates varied markedly with sampling duration; for example, in men sampled in 6-, 12-, and 24-hr sessions, the values were, respectively, 49%, 35%, and 24% of the observed pulse frequencies. Similar variations were found in women. Counting errors were 30-50% higher for conventional 20-min sampling rates than for 5-min sampling intervals. Measured interpulse intervals varied widely from 10-330 min (median, 60 min; n = 131 LH pulses) in men and from 10-340 min (median, 65 min; n = 125 LH pulses) in women. In addition, absolute LH pulse amplitudes varied from 1-28 mIU/ml (median, 4.1 mIU/ml) in men and from 1-24 mIU/ml (median, 3.6 mIU/ml) in women. These estimates were associated with a median number of points identified within each pulse of 6.0 in men and 4.0 in women. In summary, the present exhaustive sampling studies demonstrate for the first time stable estimates of physiological LH pulsations in normal men and women, and document broad ranges of normal LH pulse amplitudes and interpulse intervals.(ABSTRACT TRUNCATED AT 400 WORDS)

Adult↗
PubMed1986

Failure to detect the "dawn phenomenon" in nondiabetic subjects with markedly different patterns of nocturnal growth hormone secretion.

Overnight serum insulin and plasma glucose concentrations were measured every 20 min from midnight to 0900 h in 13 nondiabetic subjects. Seven were normal men, and 6 had isolated GH deficiency. The pre-breakfast increase in serum insulin concentrations ("dawn phenomenon") did not occur in either group of individuals, and a progressive decline in serum insulin concentrations occurred particularly in the dawn hours (0600-0900 h). The GH secretory patterns were strikingly different in the two groups, with normal spontaneous GH peaks mostly between 0100-0200 h in the normal subjects vs. virtually flat GH secretion in the isolated GH deficiency group. The absence of the dawn phenomenon in these nondiabetic subjects regardless of their GH secretory pattern suggests that the dawn phenomenon, as described in insulin-dependent diabetic patients, is not an exaggeration of normal circadian rhythmicity in insulin sensitivity.

Adolescent↗
PubMed1986

Role of endogenous opiates in pubertal maturation: opposing actions of naltrexone in prepubertal and late pubertal boys.

Despite the acute enhancement of gonadotropin output that occurs in the presence of opiate blockade in sexually immature rats and adult men, studies thus far have not demonstrated a role for endogenous opioid peptides during pubertal development in the human. We studied 15 normal boys, 5 sexually developed (Tanner stages IV-V) and 10 sexually infantile, before and after chronic (1-month) administration of a selective micromicron-opiate-receptor antagonist (naltrexone). Gonadotropin secretion was assessed by repetitive venous sampling for 24 h to appraise the pulsatile features of LH release as well as by graded serum LH responses to GnRH. Using an objective pulse detection method, we found that 1) in response to naltrexone, pubertal boys had significantly higher LH pulse frequency (P = 0.044), mean LH concentration (P = 0.0325), and area under the LH vs. time curve (P = 0.0325) compared to those in the basal state; and 2) in sexually immature individuals, naltrexone significantly decreased LH pulse frequency (P = 0.014), mean LH concentration (P = 0.049), and absolute LH peak concentration (P = 0.039) compared to those in the basal state. We suggest that the paradoxical inhibitory response to naltrexone in prepubertal boys represents an agonist-like effect of chronic naltrexone administration. This consideration implies that opiate neural pathways are responsive if not highly sensitive to the agonist effect of opiate substances in the prepubertal male. Accordingly, physiological pubertal progression may be accompanied by decreased sensitivity of the hypothalamic gonadostat to the inhibitory effects of opioid peptides.

Adolescent↗
PubMed1986

Growth hormone releasing factor and somatomedin C production: extrahypothalamic localization and possible functional significance.

Growth hormone-releasing factor (GRF) is found in the highest concentration (albeit lower compared to other hypothalamic regulatory hormones) in the hypothalamus. There is mounting evidence that GRF-like immunoreactivity is found in other sites in the CNS and in the periphery. The role of GRF, other than to stimulate growth hormone secretion by the somatotroph, is unknown. In addition generation of IGF-1 in response to GRF appears to be dependent on an intact pituitary.

Animals↗
PubMed1986

Carbamazepine toxicity: comparison of measurement of drug levels by HPLC and EMIT and model of carbamazepine kinetics.

A 23-month-old boy accidently ingested 2000 mg (148 mg/kg) of carbamazepine. The delayed onset of convulsions coincided with the peak serum level of total parent drug and an active metabolite (carbamazepine 10,11-epoxide). Comparisons of homogeneous enzyme multiplied immunoassay technique (EMIT) and high pressure liquid chromatography (HPLC) revealed that the EMIT slightly over-estimated plasma carbamazepine levels due to immunochemical cross reactivity with the epoxide metabolite. The peak plasma levels of the parent drug plus the active metabolite were more accurately determined by HPLC. These results emphasize the need to understand both the presence of active metabolites and characteristics of the assay being used in managing clinical intoxication with carbamazepine.

Carbamazepine↗
PubMed1986

Hexose-independent activation of glycogen synthase and pyruvate dehydrogenase by insulin is dissociated in the mouse BC3H-1 cell line.

We have studied the effects of insulin on several aspects of cell metabolism in the insulin-sensitive, nonfusing muscle cell line BC3H-1. In the absence of exogenous hexose, insulin did not alter basal glycogen synthase percentage I activity, or attenuate the increase in intracellular cAMP content, the activation of glycogen phosphorylase a, or the decrease in glycogen synthase I brought about by beta-adrenergic receptor activation with epinephrine. In contrast, both insulin and the tumor-promoting phorbol ester, tetradecanoylyl phorbol acetate markedly increased mitochondrial pyruvate dehydrogenase activity in the absence of hexose. Both glycogen synthase phosphatase and glycogen synthase kinase activities were present in BC3H-1 cell extracts and were regulated in the expected manner by glucose 6-phosphate and cAMP, respectively. Since the pattern of partial insulin resistance seen in BC3H-1 myocytes would require that several potentially insulin-sensitive enzymes be insensitive to insulin-generated signals, the most likely explanation for these data is that the myocytes are defective in some mechanism of insulin signaling which is independent of the mechanism for pyruvate dehydrogenase activation.

1-Methyl-3-isobutylxanthine↗