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Biomedical subjects

G R Merriam

Publications and source records attributed to G R Merriam.

At least 73 records · Page 4Linked to original sources
PubMed1988

Micronucleation in the lens epithelium following in vivo exposure to physical and chemical mutagens.

Rats were exposed to cataractogenic doses of known physical and chemical genotoxic agents in order to study the efficacy of using micronuclei to monitor mutagenicity in the lens epithelium. The total numbers of micronuclei were counted in lens epithelia from rats exposed to graded doses of either 250 kVp X-rays or the anti-leukemic drug, 1,4 dimethanesulfonoxybutane (Myleran (R)). The results indicate a dose-dependent incidence of micronucleation in the lens epithelium following exposure. The findings are consistent with the hypothesis that the cataractogenicity of certain agents may be related to their effect on the genome of lens epithelial cells.

Alkylating Agents↗
PubMed1988

Reconstruction of the lids of a child with microblepharon and multiple congenital anomalies.

The initial stages in the rehabilitation of a male child with severe microblepharon, corneal opacities, bilateral facial clefts, bilateral complete cleft lip and palate, and unilateral syndactyly are described. Review of the literature suggests that severe microblepharon is associated with other craniofacial anomalies, and often the child is stillborn or retarded. Surviving children have been abandoned because of their appearance. The child described in this case appears to be unique because his intelligence is normal, and, to our knowledge, this is the first reported case of penetrating keratoplasty after reconstruction of functional eyelids. The principal problems after corneal grafting appear to have been chronic partial exposure due to inadequate lid length and a poor Bell's reflex and the persistence of a rim of vascularized fibrous tissue around the corneal graft. Future reconstructive surgery is outlined.

Cleft Lip↗
PubMed1988

The effect of accelerated argon ions on the retina.

It has been postulated that high energy heavy ions cause a unique form of damage in living tissue, which results from the high linear energy transfer of accelerated single particles. We have searched for these single-particle effects, so-called "microlesions," in composite electron micrographs of retinas of rats which had been irradiated with a dose of 1 Gy of 570 MeV/amu argon ions. The calculated rate of energy deposition of the radiation in the retina was about 100 keV/micron and the influence was four particles per 100 micron 2. Different areas of the irradiated retinas which combined would have been expected to be traversed by approximately 2400 particles were examined. We were unable to detect ultrastructural changes in the irradiated retinas distinct from those of controls. The spatial cellular densities of pigment epithelial and photoreceptor cells remained within the normal range when examined at 24 h and at 6 months after irradiation. These findings suggest that the retina is relatively resistant to heavy-ion irradiation and that under the experimental conditions the passage of high energy argon ions does not cause retinal microlesions that can be detected by ultrastructural analysis.

Animals↗
PubMed1987

The progesterone antagonist RU 486. A potential new contraceptive agent.

Since progesterone supports endometrial nidation of the fertilized ovum, a progesterone antagonist would theoretically block this process and thus have contraceptive potential. We have explored the ability of RU 486, a newly developed competitive progesterone antagonist, to function as a contraceptive agent. A single oral dose of 10 mg per kilogram of body weight given in the midluteal phase consistently induced menses within 72 hours in women with normal cycles and no risk of pregnancy. Bleeding was not prevented by administration of human chorionic gonadotropin in the midluteal phase. This suggested that giving a single dose of RU 486 late in the menstrual cycle might be an effective contraceptive strategy. This concept was tested in monkeys. When given to rhesus females on day 25 of the cycle, a single intramuscular dose of RU 486 (5 mg per kilogram) prevented pregnancy. The vehicle-treated control animals had a 28 percent pregnancy rate (P less than 0.05 by chi-square analysis). No side effects were noted in women or monkeys. These data suggest that a progesterone antagonist such as RU 486 has the potential to be an effective, safe, and convenient contraceptive agent. Further work will be necessary to assess the safety of long-term monthly administration and to define the optimal dose and time of administration in women.

Adult↗
PubMed1987

Metabolism of exogenous 4- and 2-hydroxyestradiol in the human male.

The metabolic fate of the isomeric catecholestrogens 4-hydroxyestradiol (4-OHE2) and 2-hydroxyestradiol (2-OHE2) was studied to elucidate possible differences in their metabolism as an explanation for their different bioactivities. Healthy young men (n = 3 each) were infused (90 min) with 4-OHE2 (60 micrograms/h) or 2-OHE2 (100 micrograms/h). The main metabolites were determined in plasma and urine before, during and after infusion. Unconjugated and conjugated steroids, the latter after hot acid hydrolysis, were subjected to chromatography on LH-20 columns and measured by specific RIAs. During the infusion 4-OHE2 reached significant plasma concentrations whereas 2-OHE2 was so rapidly metabolised that its plasma levels remained virtually undetectable in spite of a higher infusion rate. The metabolism of 4-OHE2 was dominated by direct conjugation, that of 2-OHE2 by methyl ether formation. These findings were corroborated by the urinary excretion rates: during the infusion and the first hours afterwards, 4-OHE2 was mainly excreted as 4-OHE2 and 4-hydroxyestrone, while 2-OHE2 was predominantly excreted as 2-hydroxyestradiol 2-methyl ether and 2-hydroxyestrone 2-methyl ether.

Adult↗
PubMed1987

Effect of continuous somatostatin and growth hormone-releasing hormone (GHRH) infusions on the subsequent growth hormone (GH) response to GHRH. Evidence for somatotroph desensitization independent of GH pool depletion.

Continuous infusions of growth hormone-releasing hormone (GHRH) attenuate the subsequent growth hormone (GH) response to GHRH. To test whether this phenomenon can occur in the absence of GH pool depletion, we examined the effects of continuous infusions of 10 nM GHRH and of 10 nM somatostatin (SRIH), separately or in combination, on dispersed, perifused rat anterior pituitary cells. Columns of these cells were given either GHRH alone for 5 h, GHRH and SRIH together for 3 h followed by GHRH alone, or SRIH alone for 3 h followed by GHRH or medium. SRIH blunted both basal GH release and the GH response to GHRH, without affecting the subsequent GH responses to GHRH. The GHRH infusions attenuated the subsequent GH response to GHRH, even when GH release was initially prevented by the concurrent infusion of SRIH. Furthermore, the degree of attenuation was similar in the presence or absence of SRIH, suggesting that pool depletion plays little role in the desensitization process under these experimental conditions. The results are consistent with the hypothesis that a short-term infusion of GHRH leads to attenuation of the GH response in rat anterior pituitary cells primarily through receptor effects rather than through GH pool depletion.

Animals↗
PubMed1987

Effects of sex and age on the 24-hour profile of growth hormone secretion in man: importance of endogenous estradiol concentrations.

We undertook a study of the separate and combined effects of age and sex on the pulsatile pattern of GH secretion. The 24-h secretory profile of GH was generated by 20-min sampling in 10 young women (aged 18-33 yr), 10 young men (aged 18-33 yr), 8 postmenopausal women (aged greater than 55 yr), and 8 older men (aged greater than 55 yr). A computer-assisted pulse analysis program was used to assess both total GH secretion, as reflected in the 24-h integrated GH concentration (IGHC), and pulsatile secretion, as denoted by pulse frequency, duration, amplitude, and the fraction of GH secreted in pulses during the 24-h period (FGHP). IGHC was significantly greater in women than in men (P less than 0.025) and greater in the young than in the old (P less than 0.003). The mean pulse amplitude, duration, and FGHP were each greater in the young (P less than 0.006, P less than 0.03, and P less than 0.0001, respectively), but not significantly different between the sexes. The mean pulse frequency was not affected by sex or age. The serum concentration of free estradiol, but not free testosterone, correlated with IGHC (r = 0.46; P less than 0.005), pulse amplitude (r = 0.53; P less than 0.001), and FGHP (r = 0.59; P less than 0.0002). After correcting for the effects of estradiol, neither sex nor age influenced IGHC or mean pulse amplitude, while the effect of age on FGHP was reduced from 81% to 29%. Of the indices of GH secretion, FGHP had the strongest correlation (r = 0.43; P less than 0.006) with somatomedin-C. Somatomedin-C declined significantly with age in both sexes. Our results indicate that sex and age have independent and interrelated effects on GH secretion. These effects can be largely accounted for by corresponding variations in endogenous estradiol levels. These observations suggest an amplifying action of estradiol on the neuroendocrine regulation of pulsatile GH release.

Adolescent↗
PubMed1987

The spectrum of abnormal patterns of gonadotropin-releasing hormone secretion in men with idiopathic hypogonadotropic hypogonadism: clinical and laboratory correlations.

Several lines of evidence indicate that hypothalamic-pituitary-gonadal activity varies among men with idiopathic hypogonadotropic hypogonadism (IHH). To test the hypothesis that a spectrum of abnormalities of GnRH secretion underlies the syndrome of IHH, we characterized the patterns of GnRH-induced gonadotropin secretion during periods of frequent sampling in 50 consecutive men with IHH and contrasted them with those in 20 normal men. The largest group of IHH patients (n = 42) had no detectable LH or FSH pulsations and could be categorized into 2 subsets according to the presence or absence of evidence of spontaneous puberty. The most severely affected subset (n = 32), who recalled no history of puberty, had testes with a mean volume of 3.3 +/- 0.5 (+/- SEM) ml, with a prepubertal appearance on biopsy, and often were anosmic (n = 17). The second subset of apulsatile IHH men (n = 10) had histories of partial or complete spontaneous sexual development with subsequent isolated loss of sexual function, testes with a mean volume of 13.3 +/- 1.9 ml (P less than 0.01 compared to the first subset), a pubertal or adult appearance of the testes on biopsy, and an intact sense of smell. In a second group of IHH patients (n = 3), LH was secreted predominantly in a nighttime pattern similar to that of normal children during early puberty. These men were aged 18-24 yr, had a mean testicular volume of 10.5 +/- 2.3 ml, pubertal changes on testicular biopsy, and an intact sense of smell. A third group of IHH men (n = 4) had LH pulses of abnormally low amplitude. Only one patient in this group had a history of spontaneous sexual development. The mean testicular volume of these patients was 5.6 +/- 1.9 ml, and the testes appeared prepubertal (n = 3) or pubertal (n = 1) on biopsy. In addition to these groups, another patient had apparent LH pulsations and nearly normal amplitude, but the LH was bioinactive and appeared to consist chiefly of alpha-subunit. Testing of other anterior pituitary hormone functions did not distinguish IHH men from normal men. However, those IHH patients with some evidence of endogenous GnRH secretion had higher basal and stimulated serum PRL levels than IHH men without such evidence (P less than 0.05), suggesting an influence of GnRH on PRL secretion.

Adolescent↗
PubMed1987

Chronic sex steroid exposure increases mean plasma growth hormone concentration and pulse amplitude in men with isolated hypogonadotropic hypogonadism.

Sex steroid administration can increase the GH response to provocative stimuli, but the relationship of sex steroids to spontaneous GH secretion is still controversial. We sought to characterize the effect of sex steroids on the plasma GH concentration by examining the 24-h pattern of episodic GH secretion in nine previously untreated adult men with isolated hypogonadotropic hypogonadism before and during long term testosterone, gonadotropin, or pulsatile GnRH treatment. After chronic sex steroid exposure, the mean 24-h plasma GH level, mean GH pulse amplitude, and mean area under the curve of pulses were significantly increased compared to pretreatment values [3.2 +/- 1.8 ( +/- SD) vs. 1.8 +/- 1.2 ng/mL (P less than 0.01); 11.4 +/- 7.2 vs. 5.5 +/- 4.4 ng/mL (P less than 0.05); and 720 +/- 547 vs. 316 +/- 371 ng/mL X 20 min (P less than 0.05), respectively], while mean 24-h pre- and posttreatment GH pulse frequencies were indistinguishable (5.7 +/- 2.1 posttreatment vs. 5.0 +/- 3.2 pretreatment; P = NS). The mean posttreatment plasma somatomedin-C level also rose significantly during treatment (1.89 +/- 0.65 vs. 1.28 +/- 0.48 U/mL; P less than 0.01). We conclude that the increase in the mean plasma GH level during chronic sex steroid exposure is due mainly to augmentation of GH pulse amplitude, and that sex steroids probably increase spontaneous GH secretion.

Adult↗
PubMed1987

Evidence for Leydig cell dysfunction in infertile men with a selective increase in plasma follicle-stimulating hormone.

Recent studies in acutely castrated males of several species have demonstrated that testosterone (T) alone, given in doses that produce normal plasma T levels, can maintain normal plasma FSH and LH levels. This suggests that a nonsteroidal factor from the seminiferous tubule is not required to regulate FSH release, and raises the possibility that Leydig cell function may not be fully normal in oligo- or azoospermic men with increased plasma FSH levels. To clarify this, we studied T production rates in 11 sexually mature, infertile, but otherwise healthy men who had increased plasma FSH and normal plasma LH, T, and estradiol levels and in 9 normal men. Although individual plasma T and LH levels in the infertile men were within the normal ranges, the mean plasma T level of the infertile men was significantly lower (P less than 0.002), and the mean plasma LH level was significantly higher (P less than 0.002) than values in the normal men. The infertile men also had significantly lower plasma free T concentrations (P less than 0.005), while sex hormone-binding globulin and estradiol levels were similar to those of the normal men. The production rate of T in the infertile men was half that in the normal men (P less than 0.001). We conclude that T production is significantly reduced in infertile men who have a selective increase in plasma FSH. Because of the known role of Leydig cell sex steroids in the negative feedback control of FSH, this finding may explain the elevated plasma FSH concentrations characteristic of men with germ cell loss without the need to postulate a deficiency of a separate seminiferous tubule factor.

Adolescent↗
PubMed1987

Growth hormone-releasing hormone: therapeutic perspectives.

Growth hormone-releasing hormone (GHRH), the hypothalamic peptide which stimulates the release of growth hormone (GH) from the pituitary, has been the center of intense study since its structure was described in 1982. It is in the area of growth hormone deficiency (GHD) that GHRH has its greatest clinical potential. Several studies have addressed the efficacy of GHRH as an alternative therapy in GHD. It appears that GHRH can be equally effective, whether given in a pulsatile manner or as discrete injections several times a day; i.e. the total dose may be more crucial than how it is given. While there are several issues that must be addressed before an optimal GHRH regimen can be devised, the available data would suggest that GHRH may become a safe, effective alternative to GH therapy in some patients with GHD.

Child↗
PubMed1986

Production of monoclonal antibodies against human growth hormone releasing hormone and their use in an enzyme-linked immunosorbent assay (ELISA)

Two murine monoclonal antibodies (mAbs) specific for human growth hormone releasing hormone (GHRH-44-NH2) were produced from a fusion of spleen cells from a BALB/c mouse immunized with GHRH-conjugated BSA with SP 2/0 myeloma cells. The antibodies were of the IgG1 kappa, and IgG2b-kappa isotypes. The binding of both antibodies to GHRH-coated plates was inhibited by a 30-44 amino acid fragment but not by a 1-26 fragment. Thus, both antibodies are directed against the carboxy terminus of the peptide. Furthermore, both antibodies bind to the same epitope on the 30-44 amino acid portion since they cross-inhibit each other's binding to intact GHRH. Using these mAbs, a direct binding GHRH enzyme-linked immunosorbent assay (ELISA) was developed which had a least detectable dose of 30 pg. The availability of these antibodies and their use in ELISA methodology permits consistent and specific detection of GHRH in a non-isotope assay. They should prove of value in screening acromegalic patients for ectopic sources of GHRH secretion and in studies of ontogenic analysis of GHRH production.

Animals↗
PubMed1986

The effects of nuclear magnetic resonance imaging on ocular tissues.

Nuclear magnetic resonance, an imaging technique with great promise for detecting cerebral abnormalities, was studied to determine its possible deleterious effects on the mammalian eye. Young (3.5-week-old) Columbia-Sherman rats were exposed simultaneously to a constant magnetic field of 2.7 tesla and radio frequency pulses of 29 MHz at 800-ms intervals for six hours at field strengths representing the maximum used in a clinical setting. The six-hour exposure is many times greater than the four to six minutes currently employed in most diagnostic protocols. The animals were examined by slit-lamp biomicroscopy and ophthalmoscopy at regular intervals. Autoradiograms of lenses from animals injected with tritiated thymidine prior to exposure did not reveal any disturbances in cell-cycle kinetics. Eyes from rats not previously injected with the isotope were processed for cytopathologic analysis at various intervals. A two-year follow-up has indicated that at both the slit-lamp biomicroscopic and the light microscopic levels, there were no discernable effects on the rat eye.

Animals↗
PubMed1986

Responses of growth hormone (GH) and somatomedin-C to GH-releasing hormone in healthy aging men.

Although controversy exists regarding the effects of aging on GH secretory responses to indirect stimulation, in the only prior study of GH-releasing hormone (GHRH)-mediated GH secretion decreased GH responsivity occurred in healthy men after age 40 yr. We measured serum GH before and up to 180 min after and somatomedin-C (SM-C) levels before and 24 h after single morning bolus iv injections of GHRH-(1-44)-NH2 (1 microgram/kg) in 50 healthy fasted men, aged 21-86 yr, from the Baltimore Longitudinal Study of Aging. Only subjects with a body mass index (BMI; kilograms per m2) between 20.0 and 29.0 were studied. Basal serum GH levels were undetectable (less than 0.7 ng/ml) in all but 2 men. Neither the frequency of GH responses (P greater than 0.8), the magnitude of response (P greater than 0.2), nor the timing (P greater than 0.05) of the peak GH responses to GHRH were significantly altered with age. Although BMI values did not vary significantly with age in our study group, there was a significant negative correlation (r = -0.37; P less than 0.01) of peak GH with BMI. Regression analysis revealed a slight but significant increase in the level of fasting blood sugar with age, but no significant correlation between fasting blood sugar and peak GH levels. Serum levels of SM-C were significantly lower in older men both before (P less than 0.001) and 24 h after (P less than 0.02) GHRH injection. Repeated measures analysis of variance revealed significant (P less than 0.001) responses of SM-C to endogenous GH elevations produced by GHRH at all ages, but no age-dependent alterations in the magnitudes of these responses (P greater than 0.7). Our findings suggest that increasing age in adult men has little effect on the secretory responsiveness of pituitary somatotropes to GHRH. However, the finding of lower serum levels of SM-C with intact SM-C responsivity to endogenous GH is compatible with prior observations of an age-related decrease in the total daily spontaneous secretion of GH.

Adult↗
PubMed1986

Characterization of the physiological pattern of episodic gonadotropin secretion throughout the human menstrual cycle.

To characterize the spectrum of pulsatile gonadotropin secretion during the course of the normal menstrual cycle, we studied normal women during 51 ovulatory cycles. Plasma gonadotropin concentrations were measured at 10-min intervals for 20-24 h during the early, mid-, and late follicular phases and the early, mid-, and late luteal phases. LH data series were analyzed using 2 different computer-assisted algorithms for pulse detection. The LH interpulse interval decreased during the follicular phase (FP) from 94 +/- 4 (+/- SEM) min in the early FP (EFP) to 71 +/- 4 min by the late FP (LFP; P less than 0.001). The estimation of LH pulse frequency in the EFP was significantly affected by slowing of episodic LH secretion during sleep. In the luteal phase (LP), the LH interpulse interval progressively increased from 103 +/- 8 min in the early LP (ELP) to 216 +/- 39 min by the late LP (LLP; P less than 0.001). Sleep-associated slowing of episodic LH secretion also occurred in the ELP. The mean LH pulse amplitude in the EFP (6.5 +/- 0.4 mIU/ml) decreased significantly by the midfollicular phase (MFP; 5.1 +/- 0.8 mIU/ml; P less than 0.05) and increased once again by the LFP (7.2 +/- 1.2 mIU/ml). LH pulse amplitude was highest in the ELP (14.9 +/- 1.7 mIU/ml), decreased by the midluteal phase (MLP) to 12.2 +/- 2.0 mIU/ml, and declined further by the LLP to 7.6 +/- 1.1 mIU/ml (P less than 0.001 vs. ELP). FSH secretion was significantly (P less than 0.05) correlated with LH secretion at time lags of 0-10 min in 82% of the studies. These results indicate the following. 1) In the EFP and ELP, the frequency of gonadotropin pulsations is reduced at night in association with sleep. 2) The frequency of LH secretion increases from the EFP to MFP and LFP. 3) LH pulse amplitude decreases in the MFP, suggesting enhanced negative feedback of estrogen on the hypothalamic-pituitary axis and/or a decrease in GnRH secretion at this stage. 4) A progressive reduction of LH pulse frequency and amplitude occurs during the LP which is correlated with the duration of exposure of the hypothalamic-pituitary axis to progesterone. 5) A close relationship exists between secretion of LH and FSH, suggesting a common stimulatory factor for both gonadotropins.

Adolescent↗
PubMed1986

Growth hormone (GH) responses to GH-releasing hormone during pubertal development in normal boys and girls: comparison to idiopathic short stature and GH deficiency.

The normal ranges for GH responses to GH-releasing hormone (GHRH) have previously been defined for adult men and women. To determine whether the GHRH responses of normal children differ from those of adults and whether children with GH deficiency (GHD) and children who are growing below the first percentile but are otherwise normal (ISS) have GH responses comparable to those of normal children, we studied 90 normal children, 46 girls and 44 boys, with heights between the 10th and 95th percentiles for age, at different pubertal stages. Their responses were compared to those of 24 children with ISS and 32 children with GHD and to values previously measured in young adult men and women. Girls were grouped by Tanner breast stages and boys by testicular volumes. Plasma somatomedin-C, estradiol or testosterone, and bone age were measured in all children. All received a 1 microgram/kg iv bolus dose of GHRH-(1-44)NH2, and GH responses were measured during a 2-h sampling period. Incremental serum GH responses in girls did not change throughout pubertal development and were similar to those of adult women. The responses in boys at midpuberty were somewhat lower (P less than 0.05) than those in either prepubertal boys or adult men. ISS children had mean GH responses [23 +/- 4 (+/- SE) ng/ml] similar to those of normal children. GHD children had significantly lower mean GH responses (11 +/- 3.7 ng/ml) than normal prepubertal children (35 +/- 4.0 ng/ml; P less than 0.01), but the responses of 17 of the 32 GHD children overlapped with the normal range. GH responses to GHRH were not correlated with bone age, weight, height, SmC levels, or estradiol or testosterone concentrations. These results indicate that GH responses to GHRH testing are relatively constant throughout puberty and young adulthood, that ISS children respond normally to GHRH, and that the GHRH test is not a reliable discriminator between individual normal and GHD children.

Adolescent↗
PubMed1986

Are catechol oestrogens obligatory mediators of oestrogen action in the central nervous system? I. Characterization of pharmacological probes with different receptor binding affinities and catechol oestrogen formation rates.

In an attempt to define pharmacological probes with which to test the role of catechol oestrogen formation in the central nervous system, five oestrogens (oestradiol-17 beta, oestradiol-17 alpha, 4-fluoro-oestradiol, 2-fluoro-oestradiol and moxestrol (11 beta-methoxy-17 alpha-ethynyloestradiol) were studied for binding to oestrogen receptors and conversion to catechol metabolites. Binding to cytosol oestrogen receptors was measured in the hypothalamus-preoptic area-amygdala (HPA), pituitary gland and uterus of ovariectomized rats. Conversion to catechol oestrogens was tested in microsomes from the HPA, pituitary gland and liver, using a catechol-O-methyltransferase-coupled radioenzymatic assay. Oestradiol-17 alpha was the only weak oestrogen receptor ligand. Binding affinities of the other compounds tested were much higher and comparable to those of oestradiol-17 beta. In contrast, oestradiol-17 alpha was rapidly converted to catechol metabolites, while moxestrol was a relatively poor substrate for catechol oestrogen formation. 4-Fluoro-oestradiol could be 2-hydroxylated but not 4-hydroxylated. 2-Fluoro-oestradiol exhibited impaired 2-hydroxylation but normal 4-hydroxylation.

Animals↗