Search PubMed⌕ Search

Biomedical subjects

G R Merriam

Publications and source records attributed to G R Merriam.

At least 91 records · Page 5Linked to original sources
PubMed1986

Are catechol oestrogens obligatory mediators of oestrogen action in the central nervous system? II. Potencies of natural and synthetic oestrogens for induction of gonadotrophin release and female sexual behaviour in the rat.

The role of catechol oestrogen formation in the mechanism by which circulating oestrogens facilitate gonadotrophin release and female sexual behaviour was explored in adult female rats. The effects of oestradiol-17 beta were compared with those of a group of oestrogens with either a reduced affinity for oestrogen receptors (oestradiol-17 alpha) or a reduced ability to act as substrates for catechol oestrogen formation (2-fluoro-oestradiol, 4-fluoro-oestradiol and moxestrol (11 beta-methoxy-17 alpha-ethynyloestradiol]. Rats were ovariectomized on the evening of dioestrus day 1 of the 4-day oestrous cycle and implanted s.c. 12 h later with infusion pumps containing either one of the test oestrogens or vehicle alone. Infusion rates for oestradiol-17 beta, moxestrol, 2-fluoro-oestradiol and 4-fluoro-oestradiol were adjusted to give concentrations of nuclear oestrogen receptors in the brain and pituitary gland within the range of those found in intact female rats during pro-oestrus. Oestradiol-17 alpha was infused at the same and at a tenfold higher rate than that of oestradiol-17 beta; neither of these treatments with oestradiol-17 alpha significantly increased brain or pituitary gland nuclear oestrogen receptor levels. On the day after the pump was implanted, samples of tail vein blood were withdrawn at 12.00, 14.00, 16.00 and 18.00 h for LH assay. All animals were then injected s.c. with 1 mg progesterone in propylene glycol, and tested for feminine sexual behaviour 5 h later. Oestradiol-17 beta, moxestrol, 2-fluoro-oestradiol and 4-fluoro-oestradiol all elicited pronounced LH surges and facilitated progesterone-triggered proceptive and lordosis behaviours.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1986

Accelerated heavy particles and the lens II. Cytopathological changes.

To assess more fully the risk to normal tissue exposed to accelerated heavy particles in the space program and during radiotherapy on earth, the cytopathological effects of a variety of doses of accelerated (570 MeV/amu) Argon (40Ar) ions on the rat lens were investigated. Time-course analyses of lenses exposed to a 1 Gy (100 rad)-dose revealed that the effects of the particles on mitotic index, nuclear fragmentation, and meridional row (MR) cytoarchitecture were qualitatively similar to those caused by 185 kVp x-rays. The effects of dose on the lens epithelium was also examined at 67 wk post-irradiation. The mitotic index returned to normal levels by that time; however, the biological effectiveness (RBE) of 40Ar relative to x-rays, in causing MR disorganization, increased with decreasing dose and closely resembled the RBE for cataractogenesis. The RBE data are consonant with the view that radiation cataracts are the result of damage to the lens epithelial population, which is later expressed as aberrant differentiation during fibergenesis.

Animals↗
PubMed1985

Evidence that synthetic 31-amino acid inhibin-like peptide lacks inhibin activity.

We studied the biological activity of a recently characterized 31-amino acid inhibin-like peptide (ILP) using a synthetic preparation. While the material yielded a single component on chromatography, amino acid sequence analysis suggested that only 30% of the molecules possess the complete structure. Bioactivity was tested in vitro using whole pituitaries from 25 day-old male Sprague-Dawley rats. Pituitaries were incubated with 500 ng/ml of the ILP preparation or vehicle alone for 60 min, followed by a 3 h exposure to 2 ng/ml of luteinizing hormone releasing hormone (LHRH) or its diluent. In the ILP-incubated pituitary media, no significant suppression of basal FSH and LH release or stimulated FSH release was observed, while a significant increase in stimulated LH release was seen (p less than 0.05). An in vivo bioassay study was performed on 38 day-old male Sprague-Dawley rats. Test animals were injected with 0.1, 1, 10 or 20 mcg of ILP immediately after castration, and 10 and 24 h later. Control animals received bovine serum albumin or vehicle alone. There were no statistically significant differences in serum LH or FSH concentrations taken at 30 h after castration between the ILP-treated rats and controls. Possible reasons for our inability to demonstrate inhibin bioactivity (selective FSH suppression) with this ILP preparation include: Only about 30% of the peptides had the complete amino acid sequence. Other peptides with deletions might have acted as antagonists, thus obscuring the inhibin bioactivity. The 31-amino acid ILP may not be the authentic inhibin molecule. We suggest that further studies are needed to determine the true identity of inhibin.

Animals↗
PubMed1985

Effects of growth hormone-releasing factor on growth hormone secretion in acromegaly.

Twenty-nine patients with acromegaly (8 untreated and 21 previously treated in various ways) and 16 normal men were given iv bolus doses of human pancreatic tumor GH-releasing factor (hpGRF-40). Twenty-five of the 29 patients responded to hpGRF-40 with elevations of plasma GH. The magnitude of the responses varied widely. Responses of untreated patients were generally similar to those of the normal subjects. Previously treated patients had a significantly lower response than normal individuals [change in GH, 7.5 +/- 1.8 vs. 42.0 +/- 11.0 ng/ml (mean +/- SEM); P less than 0.01], and 4 patients who had received radiation therapy failed to respond to hpGRF-40. There was no significant correlation between the magnitude of the response and patients' age, sex, baseline GH levels, GH responsiveness of TRH, or GH suppression after oral glucose administration. Patients studied both pre- and postoperatively were responsive to hpGRF-40 at all times tested, but the magnitude of the response decreased after successful surgical removal of the adenoma. Thus, most patients with treated or untreated acromegaly respond to hpGRF-40, but their responses do not clearly distinguish them from normal subjects. GH-releasing hormone testing is unlikely to replace other endocrine tests available for the diagnosis and evaluation of acromegaly.

Acromegaly↗
PubMed1985

Growth hormone responses to continuous infusions of growth hormone-releasing hormone.

The pattern of GH secretion during a continuous 4-h iv infusion of 1 microgram/kg.h GH-releasing hormone (1-44)-NH2 (GHRH-44) or saline was examined in 15 adult men. There was prompt release of GH beginning within 20 min of starting the GHRH-44 infusions, reaching peak GH levels of 43 +/- 11 (+/- SE) ng/ml within 60-90 min. This is similar to the peak GH level reached in men after a single 1 microgram/kg GHRH iv bolus dose (34 +/- 8 ng/ml). GH levels then fell progressively, but did not return to baseline during the GHRH infusions. After GHRH infusions, the response (delta) to a 1 microgram/kg GHRH bolus dose was markedly attenuated (delta GH, 2.7 +/- 0.9 ng/ml) compared to the response (delta GH, 23 +/- 3 ng/ml) after saline infusion. Dispersed rat pituicytes perifused with medium containing 10 nM GHRH-44 responded with an initial rapid rise in GH secretion, followed by a progressive decline, and after 150 min of continuous GHRH exposure, the response to pulses of an equal or higher (100 nM) GHRH concentration was blunted. These results indicate that the peak response to GHRH infusions is similar to that of maximally effective bolus doses; during infusions, the GH response is not sustained; and immediately after GHRH infusions, the response to previously effective bolus doses is reduced. These phenomena could reflect either receptor-mediated desensitization, the depletion of rapidly releasable GH stores, or both. A counterregulatory rise in hypothalamic somatostatin secretion is not necessary to produce these effects, since the same phenomenon occurs in vitro and in vivo.

Adult↗
PubMed1985

Effects of pulsatile administration of growth hormone (GH)-releasing hormone on short term linear growth in children with GH deficiency.

To assess the efficacy of GH-releasing hormone (GHRH) in the treatment of GH deficiency, we measured the effects of pulsatile iv GHRH administration on GH secretion, plasma levels of somatomedin-C (SmC), and short term linear growth (as determined by lower leg measurements) in seven GH-deficient children in a placebo-controlled study. Either GHRH, at a dose of 1 microgram/kg (seven patients), or 0.9% saline (NS; four of these patients) was given iv every 3 h for 9-12 days; all patients also received GH for a similar period. Lower leg length was measured every 3 weeks before and after each treatment. GHRH was more effective than placebo in accelerating linear growth (P less than 0.05). The responses, however, were heterogeneous; four of the children responded with accelerated growth, and three did not. Two of the children who failed to grow had no increase in plasma GH or SmC during GHRH administration, and one had an attenuated GH response. The four children who grew had induction of pulsatile GH secretion [mean peak GH, 10.4 +/- 1.3 (+/- SEM) ng/ml after GHRH vs. 1.5 +/- 0.5 ng/ml after NS; P less than 0.05] and elevation in SmC levels (maximum, 0.5 +/- 0.1 U/ml during GHRH vs. 0.19 +/- 0.05 during NS; P less than 0.01). The lower leg growth velocity during GHRH treatment (2.8 +/- 0.2 mm/3 weeks) was greater than their own basal rate (0.6 +/- 0.2 mm/3 weeks; P less than 0.01) or their growth during placebo treatment (0.4 +/- 0.2 mm/3 weeks; P less than 0.01). Thus, repeated administration of GHRH stimulated increases in GH and SmC in some but not all GH-deficient children. The growth response appears to be related to the magnitude of the GHRH-stimulated rise in GH levels. GHRH increases short term linear growth in some children with GH deficiency and holds promise as an alternative to GH as a form of therapy in these patients.

Adolescent↗
PubMed1985

Successful treatment of Cushing's syndrome with the glucocorticoid antagonist RU 486.

A patient with Cushing's syndrome due to ectopic ACTH secretion was treated successfully with the new glucocorticoid antagonist RU 486 [17 beta-hydroxy-11 beta-(4-dimethylamino phenyl) 17 alpha-(1-propynyl)estra-4,9-dien-3-one]. This compound is a 19-nor steroid with substitutions at positions C11 and C17 which antagonizes cortisol action competitively at the receptor level. Oral RU 486 was given in increasing doses of 5, 10, 15, and 20 mg/kg . day for a 9-week period. Treatment efficacy was monitored by assessment of clinical status and by measuring several glucocorticoid-sensitive variables, including fasting blood sugar, blood sugar 120 min after oral glucose administration, and plasma concentrations of TSH, corticosteroid-binding globulin, LH, testosterone-estradiol-binding globulin, and total and free testosterone. With therapy, the somatic features of Cushing's syndrome (buffalo hump, central obesity, and moon facies) ameliorated, mean arterial blood pressure normalized, suicidal depression resolved, and libido returned. All biochemical glucocorticoid-sensitive parameters normalized. No side-effects of drug toxicity were observed. We conclude that RU 486 may provide a safe, well tolerated, and effective medical treatment for hypercortisolism.

Adrenocorticotropic Hormone↗
PubMed1984

Performance of LH pulse-detection algorithms at rapid rates of venous sampling in humans.

To assess the influence of the sampling rate on the quantitative characterization of pulsatile luteinizing hormone (LH) release, we withdrew blood at 4-min intervals for 8 h in five men and at 1-min intervals for 2 h in six other men. For comparative purposes, significant LH pulses were enumerated by three independent, computerized pulse-detection algorithms currently available. Our results indicate that, although the absolute number of LH pulses detected was influenced by the particular algorithm used and the estimate of intra-assay variance, all three analyses yielded increased pulse-frequency estimates at more intensive rates of venous sampling. Moreover, using a fourth, modified pulse-detection algorithm intended to maximize recognition of true-positive LH pulses while minimizing both false-positive and false-negative pulses, we observed that venous sampling at 4- and 1-min intervals exposed 4- and 12-fold more LH pulses, respectively, than could be discerned at conventional sampling rates. At rapid rates of venous sampling, the pattern of LH pulses comprised high-frequency, low-amplitude LH pulsations superimposed on lower-frequency LH peaks. This pattern suggests that the pituitary gland is responsive to high rates of intermittent neural stimulation. Moreover, these observed profiles are consistent with rapid initial rates of LH disappearance and/or distribution that we could demonstrate after intravenous bolus injections of purified LH in hypogonadotropic volunteers. In conclusion, we have compared results from three different pulse-detection algorithms at various rates of venous sampling and demonstrated a critical influence of sampling rate on apparent LH pulse frequency in humans.

Adult↗
PubMed1984

Potency and specificity of a growth hormone-releasing factor in a primate and in vitro.

The potency and specificity of the 44-amino acid human pancreatic tumor GRF were tested in six adult female rhesus monkeys and in a perifusion system containing a suspension of rat pituicytes. In vivo, plasma GH levels were elevated in a dose-dependent fashion, with an ED50 of approximately 5 micrograms/kg, a value of the same order of magnitude as other hypothalamic releasing hormones. The magnitude of the GH response after GRF treatment was similar to that observed during insulin-induced hypoglycemia, with peak plasma GH concentrations occurring 5-15 min after GRF administration. High doses of GRF slightly stimulated PRL release, but had no effect on arterial blood pressure, heart rate, or plasma cortisol or glucose concentrations. In vitro, GRF released GH in a dose-dependent manner, but no PRL was released even at the highest GRF concentrations employed (100 nM). It thus appears that stimulation of PRL in vivo may be an indirect effect of GRF. Alternatively, there may be species differences in responsiveness to GRF.

Animals↗
PubMed1984

Gonadotropin and prolactin pulsations in hyperprolactinemic women before and during bromocriptine therapy.

Pulsatile gonadotropin secretion and its relationship to PRL and estradiol (E2) secretion were investigated in 20 hyperprolactinemic amenorrheic women by obtaining serial blood samples for 6- to 24-h periods. Thirteen patients were restudied in the early follicular phase of the menstrual cycle (days 3-5) after ovulatory periods were established during bromocriptine therapy. In the hyperprolactinemic women, the number of LH peaks ranged from 0-12/24 h, and LH peak amplitude ranged from 0-1.7 mIU/ml. Serum E2 correlated with mean LH concentrations (P less than 0.001) and LH pulse frequency (P less than 0.05), but not with LH pulse amplitude. FSH pulsations were identified in 3 of the 20 women. There was no correlation between mean FSH concentrations and either serum E2 or PRL. There was a significant correlation between LH and FSH concentrations (P less than 0.001). During bromocriptine therapy, with comparable E2 concentrations, 5 of the 6 patients studied with blood sampling every 20 min for 24 h had a significant decrease (P less than 0.01) in the number of LH peaks per 24 h, with no change in LH peak amplitude. Mean FSH concentrations were unchanged in bromocriptine-treated patients; however, there was a significant (P less than 0.02) decrease in FSH levels during sleep. Serum PRL was normal in all bromocriptine-treated patients, but normal PRL secretory patterns were not reestablished, and there was no correlation between LH pulsations and serum PRL concentrations. We conclude that 1) hyperprolactinemic women have a heterogeneous pattern of pulsatile gonadotropin secretion; 2) serum E2 correlates with LH pulse frequency but not pulse amplitude; 3) LH pulsations and PRL pulsations are asynchronous in hyperprolactinemic women before and during bromocriptine therapy; and 4) normal PRL secretory patterns are not required for ovulatory function in hyperprolactinemic women treated with bromocriptine.

Adenoma↗
PubMed1984

Intensified rates of venous sampling unmask the presence of spontaneous, high-frequency pulsations of luteinizing hormone in man.

To test the validity of venous sampling rates that are generally used to characterize pulsatile LH release in man (e.g. sampling every 15-20 min), we characterized apparent LH pulse frequency in blood withdrawn variously at 20- or 4-min intervals in 19 men, at 2-min intervals in 14 men, and at 1-min intervals in 6 men. In an effort to minimize detection bias, significant LH pulses were evaluated objectively using a computerized pulse-detection algorithm, which tended to maximize recognition of true-positive LH pulses, and minimize false-positive and false-negative pulses. Under these conditions, intensified rates of venous sampling at 4-, 2-, and 1-min intervals exposed approximately 3.6, 4.9, and 13.7-fold more LH pulses, respectively, than could be discerned at a 20-min sampling frequency. In addition, more rapid rates of venous sampling disclosed a previously unobserved pattern of LH pulses, in which higher frequency, lower amplitude LH pulsations were interposed among low frequency, high amplitude LH peaks. Quantitatively, LH pulses unmasked by intensified rates of venous sampling exhibited significantly lower pulse amplitudes, expressed either as a fractional (%) or absolute (mIU/ml) increment, than pulses identified at 20-min intervals. In conclusion, we demonstrated that intensified rates of venous sampling unmask a significant number of otherwise unrecognized LH pulses in the circulation of normal men. Moreover, because generally employed sampling rates overlooked these more rapid physiological fluctuations in LH concentrations, patterns of both high and low frequency LH pulsations must now be characterized in various states of health and disease using more rapid sampling paradigms.

Adult↗
PubMed1984

Dose-response relationships for the effects of growth hormone-releasing factor-(1-44)-NH2 in young adult men and women.

Human GRF-(1-44)-NH2 (GRF-44) was administered iv in graded doses of 0.01-10 micrograms/kg to 35 normal young adult men and 38 women. GRF-44 stimulated the release of GH in a dose-dependent fashion, although the individual responses varied widely. The ED50 values for this effect were 0.4 micrograms/kg in men and 0.2 micrograms/kg in women in the midfollicular phase of the menstrual cycle. Maximal responses in men and women were not significantly different, and a dose of 1 micrograms/kg was sufficient to produce a maximal response. There was, likewise, no difference between responses of women tested in the midfollicular and midluteal phases of the cycle. There were no changes in PRL, LH, FSH, TSH, ACTH, beta-endorphin, or cortisol at doses up to 1 microgram/kg; at 10 micrograms/kg, PRL increased by an average of 7.6 ng/ml in the women. Side effects occurred in approximately 20% of both men and women at 1 microgram/kg and in nearly all subjects given 10 micrograms/kg; these consisted primarily of flushing and a sense of warmth. Thus, a dose of 1 microgram/kg GRF-44 is safe and effective, and would appear to be a reasonable choice for use in studying GH responses in normal subjects of other ages and in patients with disorders of GH secretion.

Adolescent↗
PubMed1984

A comparison of two methods for detecting hormone peaks: the effect of sampling interval on gonadotropin peak frequency.

There is no consensus on the optimum method to identify gonadotropin pulses in serum. We compared two approaches for detecting gonadotropin peaks. The first employed the conventional criterion of an increment from nadir to peak of 3 times the intraassay coefficient of variation (3 CV). The second identified peaks by Student's t test to quadruplicate measurements at each time point. We obtained blood samples every 5 min for 6 h from four women in the follicular phase. We also constructed control or noise series by subdividing single serum pools into consecutively labeled aliquots. Any variations in hormone concentration in the noise series that were identified as peaks were, by definition, false positive peaks. We evaluated the effect of sampling interval on gonadotropin peak detection by omitting data to simulate sampling every 10, 15, or 20 min. The 3 CV approach identified numerous false positive peaks in the noise series and detected as many peaks in the noise series as it did in the patient series. Increasing the sampling frequency from every 20 to every 5 min nearly doubled the apparent peak frequencies in both the patient and the noise series (P less than 0.025). By contrast, the t test method detected far fewer false positive peaks and significantly more peaks in the patient series than in the noise series. Increasing the sampling frequency from every 20 to every 5 min resulted in a 50-75% increase in peak frequency by the t test method. This increase in peak frequency appeared to result from improved detection of small peaks, because samples were obtained nearer the true peaks and nadirs. The resulting increase in the nadir to peak increment made it more likely that a small peak would achieve statistical significance. We conclude that increasingly stringent criteria for pulse detection should be applied as one increase the sampling frequency, and that the t test approach is a more valid method than the 3 CV approach because it yields significantly fewer false positive peaks.

Adolescent↗
PubMed1984

Idiopathic precocious puberty in the chimpanzee: a case report.

A female chimpanzee developed premature sex skin swelling, breast budding, advanced bone age, and moderate estrogen effect of the vaginal cytology. Extensive radiographic and hormonal studies excluded all the known causes of precocious puberty and pseudopuberty, yielding a diagnosis of idiopathic true precocious puberty. To our knowledge this is the first observation of idiopathic true precocious puberty in a chimpanzee.

Animals↗
PubMed1984

Accelerated heavy particles and the lens. I. Cataractogenic potential.

The effect of varying doses of accelerated (570 MeV/ amu ) argon ions on the rat lens is described with detailed observations on the sequence of development of the cataracts, the time-dose relationship, and the analysis of their cataractogenic potential. The relative biological effectiveness (RBE) of the heavy particles for cataract production, compared to low linear energy transfer (LET) radiation (X rays), has been established. These data indicate that, as with neutrons, the RBE increases with decreasing dose and that at a dose of 0.05 Gy an RBE of about 40 was observed.

Animals↗
PubMed1983

Effects of human pancreatic tumour growth hormone releasing factor on growth hormone and somatomedin C levels in patients with idiopathic growth hormone deficiency.

Human pancreatic tumour growth hormone releasing factor (hpGRF-40) 10 micrograms/kg was administered intravenously to 6 normal young men and 12 adult patients who had presented in childhood with growth hormone (GH) deficiency (7 patients had isolated GH deficiency, 4 had multiple anterior pituitary hormone deficiencies, and 1 had Hand-Schüller-Christian [HSC] disease). hpGRF-40 administration increased serum GH concentrations in all normal subjects and in 3 of 7 patients with isolated GH deficiency and in the 1 with HSC disease; however, the mean serum GH concentration in the patients who responded was less than that of the normal subjects. Somatomedin C concentrations were increased 24 h after a single dose of hpGRF-40 in 8 of 10 patients with GH deficiency. All subjects experienced flushing in response to hpGRF-40. A patient with isolated GH deficiency received 0.33 micrograms/kg hpGRF-40 every 3 h for 5 days. Despite the modest increase in GH in response to a subsequent dose of 10 micrograms/kg hpGRF-40, serum somatomedin C levels increased within 12 h from 0.06 to 0.1 U/ml and peaked at 0.36 U/ml at 72 h; in addition the patient with HSC disease, treated with hpGRF-40 daily for 5 days, demonstrated an increase in somatomedin C from 0.4 to 0.58 U/ml. The increase after hpGRF-40 in serum GH levels in this patient and the similar or greater responses in 3 of 7 patients suggest that at least some of these patients may have hypothalamic GH-releasing-hormone deficiency. hpGRF-40 may be useful in distinguishing pituitary disease from hypothalamic disease. After hpGRF-40 administration serum somatomedin C levels may increase without a change in serum immunoreactive GH concentrations. Further studies are needed to determine whether hpGRF-40 is useful in promoting linear growth in children with GH deficiency.

Adult↗
PubMed1983

Primary cortisol resistance: a familial syndrome and an animal model.

Primary cortisol resistance in man is a familial disease. It is characterized by increased plasma cortisol concentrations, high urinary free cortisol excretion, a normal circadian pattern of cortisol secretion, resistance to adrenal suppression by dexamethasone and absence of clinical stigmata of Cushing's syndrome. In its severe form, hypertension and hypokalemic alkalosis are present, owing to increased secretion of the sodium-retaining corticoids, corticosterone and deoxycorticosterone. In subjects with a less severe resistance to cortisol, there are no clinical abnormalities and the disease is revealed only by detailed examination of several parameters of cortisol metabolism. In the whole-cell assay (peripheral mononuclear leukocytes or fibroblasts) the glucocorticoid receptor shows a low affinity for dexamethasone. The receptor may be unsaturable as suggested by decreased receptor concentrations in broken-cell systems. Thus, generalized target-tissue resistance to cortisol, including the pituitary gland and the hypothalamus, is accompanied by a decreased negative feedback of the cortisol-ACTH feedback system resulting in increased ACTH secretion. This causes higher plasma cortisol to compensate for the end-organ resistance and also increases the production of adrenal mineralocorticoids, as by-products. Thus hypertension and hypokalemic alkalosis depends on the degree of the resistance. Cortisol resistance in many New World primate species is characterized by greatly increased plasma cortisol concentrations, decreased cortisol binding globulin capacity and affinity, high levels of plasma and urinary free cortisol, marked resistance of ACTH suppression by dexamethasone, and no physiologic evidence of glucocorticoid hormone excess. Target tissues have normal concentrations of glucocorticoid receptors with decreased affinity for dexamethasone. The New World primates, unlike man, have compensated for this cortisol resistance with intra-adrenal adaptations over the 50 million years of their evolutionary development. These primates also have abnormalities of other steroid hormone-receptor systems such as progesterone, estrogen, androgen and mineralocorticoid. In contrast, the human syndrome appears to be a recent mutation with pathophysiologic consequences.

Adrenal Gland Diseases↗