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Biomedical subjects

G R Merriam

Publications and source records attributed to G R Merriam.

At least 109 records · Page 6Linked to original sources
PubMed1983

Catechol estrogens and the control of gonadotropin and prolactin secretion in man.

The catechol estrogens, the 2- or 4-hydroxylated metabolites of estrone and estradiol, have pharmacologic properties of both estrogens and catecholamines and are formed from estrogens in peripheral tissues and in the brain. This has led to speculation that they may mediate some of the feedback effects of estrogens upon gonadotropins and prolactin (PRL). Studies testing these hypotheses are still few and have not been conclusive. There have been reports that the catechol estrogen 2-hydroxyestrone (2-OHE1) might act as a partial estrogen antagonist, stimulating gonadotropin secretion; and that it might have dopamine-like effects, suppressing the secretion of PRL. In studies testing the chronic and acute effects of catechol estrogens on LH, FSH, and PRL in men and women, we found that they behaved as estrogens, suppressing gonadotropins when given in doses high enough to compensate for their rapid clearance and degradation. We found no evidence that they suppress PRL secretion. The weight of available evidence suggests that these effects are mediated by estrogen receptor interactions; and that the formation of catechol estrogens is not an obligatory step in the feedback effects of estrogens, although it may have a modulatory role. Plasma levels of catechol estrogens are too low for them to exert circulating neuroendocrine effects.

Animals↗
PubMed1983

Radioimmunoassay and metabolic clearance rate of catecholestrogens, 2-hydroxyestrone and 2-hydroxyestradiol in man.

Plasma levels of 2-hydroxyestrone (2-OHE1) and 2-hydroxyestradiol (2-OHE2) were determined by a new radioimmunoassay which employed a short Sephadex LH-20 column chromatography for the purification of samples and the antiserum to 2-hydroxyestrone-17-(O-carboxymethyl)oxime-BSA conjugate for assay. The plasma value was below the detection limit for the assay (approximately 15 pg/ml) in men and non-pregnant women, but rose 20-200 pg/ml during pregnancy in 2-OHE1 and around 15 pg/ml in the 3rd trimester of pregnancy in 2-OHE2. There was no significant difference of plasma 2-OHE1 level between normal pregnancy and toxemic pregnancy with hypertension, in the 3rd trimester. The plasma level was very low in all of three subjects with the placental dysfunction in toxemic pregnancy. The plasma metabolic clearance rate (MRCp) of 2-OHE1 and 2-OHE2 were determined in normal adults by two methods; infusion of unlabeled 2-OHE1 and 2-OHE2 to equilibrium with radioimmunoassay of their plasma levels, and infusion of [3H]-2-OHE1 and [3H]-2-OHE2 to equilibrium with measurement of chromatographically purified their tritium. The MCRs by the former and latter methods was 40-70 X 10(3) and 15-50 X 10(3) in 2-OHE1, and 18-29 X 10(3) and 12-14 X 10(3) l/day in 2-OHE2, respectively. The major plasma metabolite comigrated with 2-methoxy compounds to each catecholestrogen. The t1/2 of disappearance rate by the method of infusion of unlabeled compounds was approx. 45 s in 2-OHE1 and 90 s in 2-OHE2. When [3H]-2-OHE1 and [3H]-2-OHE2 were incubated with blood samples of adults, 2-methoxy compounds also rapidly formed. From these results it is concluded that the extremely high MCRp of 2-OHE1 and 2-OHE2 make it unlikely these compounds circulate peripherally except in pregnancy in levels sufficient to produce the physiological effects on estrogen receptors or catecholamines.

Adult↗
PubMed1983

Scanning electron microscopic analysis of radiation cataracts in rat lenses. I. X-radiation cataractogenesis as a function of dose.

Cataracts produced in 4-week-old rats following exposure of the eye to various doses of 185 kVp X-rays, were analyzed 45 days after irradiation by scanning electron microscopy (SEM), as well as by conventional light microscopy (LM). The severity and extent of the ultrastructural damage seen at the LM and SEM levels varied as an increasing function of dose and correlated well with the clinical changes which were scored by slitlamp biomicroscopy prior to preparation. In the early-stage low-dose cataracts, damage was generally limited to the equatorial and posterior subcapsular regions. The late-stage high-dose cataracts were associated with clusters of 4 to 10 microns globules at the poles subcapsularly, massive disruption of the equatorial region and the formation of a granular matrix which extended to the posterior pole. Ultrastructural changes were also noted in the superficial cortical region, while the lenticular nucleus and the residium of the cortex remained unchanged.

Animals↗
PubMed1983

Effects of a growth hormone releasing factor in man.

The effects of the 44-amino acid growth hormone releasing factor (GRF-44) were tested in normal adult men and women. At a dose of 1 microgram/kg, intravenous boluses of GRF-44 stimulated prompt elevations of plasma GH, which in 5 men reached maximum levels of 34 +/- 28 (S.D.) ng/ml, and in 3 women in the mid-follicular phase, 53 +/- 10 ng/ml. The action of GRF was highly selective; there were no changes in plasma PRL, LH, FSH, TSH, or cortisol at this dose level. Side effects, mostly flushing and a sense of warmth of the face and chest, were mild and occurred only in a minority of subjects.

Adult↗
PubMed1982

Algorithms for the study of episodic hormone secretion.

There is no generally accepted procedure for identifying ultradian pulsations in hormonal time series. We suggest an approach based on removing long-term trends, such as diurnal rhythms, from the series of observations; identifying peaks in the residual series; and resolving each peak, if appropriate, into overlapping secretory episodes. The first step uses a robust smoothing technique to generate a smoothed series that omits peaks or trends with time constants less than 6--12 h. The smoothed series is subtracted from the original, and in the second step their difference, the residual series, is examined for the presence of peaks. The standard deviation of the assay is calculated at each point, and the residuals are rescaled in terms of this unit. Peaks are identified as individual subseries elevated above the base line of duration n, all the points in which have magnitude at least G(n), where the values of G are cut-off criteria based on the width of the peak. Thus the algorithm selects both narrow high peaks and broader peaks that may be lower. The user selects the G(n) for each hormone based on theoretical considerations or a set of calibration data series. Points that meet these criteria are identified as belonging to peaks and flagged. To assure that the smoothing process is not influenced by runs of closely spaced peaks, these flagged points are then assigned a reduced weight, and the smoothing is repeated; the revised residuals are then reexamined. After these two steps are iterated until there are no further changes, each peak is examined once more to determine whether it can be resolved into more than one overlapping peak. Finally, the process collects statistics on the average frequency and amplitude of the peaks. We have developed computer programs to carry out these algorithms.

Adult↗
PubMed1982

Radiation cataractogenesis in the amphibian lens.

This report describes a reproducible and characteristic sequelae for radiation cataractogenesis in the amphibian. The development of lens opacification was investigated as a function of dose and time after X-irradiation of the eye of postmetamorphic bullfrogs. It was found that the development of radiation cataracts in frogs is both age and dose dependent. It was also determined that, far from being radiation resistant, frog lenses are sensitive to doses that are moderately cataractogenic for mammals.

Age Factors↗
PubMed1982

Radioimmunoassay and metabolism of the catechol estrogen 2-hydroxyestradiol.

Plasma levels of 2-hydroxyestradiol (2-OHE2) were measured using a new RIA procedure. Values were below the detection limit of the assay (less than 10 pg/ml), except in the third trimester of pregnancy, when they rose to approximately 15 pg/ml. The infusion of 130 microgram/h purified 2-OHE2 elevated its plasma concentration to 155 pg/ml, consistent with a plasma MCR (MCRp) of approximately 20,000 liters/day. The infusion of [3H] 2-OHE2 to equilibrium and chromatographic separation of the extracted plasma metabolites yielded an MCRp of about 13,000 liters/day; the major plasma metabolite comigrated with 2-methoxyestradiol, and [3H] xi-methoxyestrone was also formed. The MCRp, of 2-OHE2 is approximately half that of 2-hydroxyestrone (2-OHE1), but much higher than those of other steroids. As is true for 2-OHE1, the clearance of 2-OHE2 must occur primarily in the blood compartment. Together, the measured MCRp values and estrogen receptor affinities of 2-OHE2 and 2-OHE1 predict a relative potency for effects upon gonadotropin secretion which is close to that observed in vivo.

2-Methoxyestradiol↗
PubMed1981

Metabolic clearance rate and uterotropic activity of 2-hydroxyestrone in rats.

2-Hydroxyestrone (2-OHE1) has much lower uterotropic potency than might be predicted from its uterine estrogen receptor affinity. 2-OHE1 displaces saturably bound [3H]estradiol from rat uterine cytosol with a competitive inhibition constant of 8.6 nM, while the dissociation constant for 17 beta-estradiol (E2) is 0.42 nM. From this ratio of binding affinities, one would expect some agonist or antagonist activity of 2-OHE1 to be apparent at doses roughly 20-50 times the minimum effective dose of E2. Instead, at doses of 2-OHE1 1000 times an effective dose of E2, no uterotropic effect was observed. When 2-OHE1 was injected together with E2 at dose ratios of 500:1, there was no antagonism of the effect of E2. To examine this discrepancy, the plasma MCRs (MCRpS) of E2 and 2-OHE1 were determined by continuous infusion techniques. Plasma concentrations of 2-OHE1 and E2 during control and infusion periods were measured by RIAs. The MCRp of 2-OHE1 averaged 50,000 ml/h, more than 100 times that of E2 (approximately 400 ml/h). The extraordinarily high MCRp of 2-OHE1 may explain the failure to observe any biological effects of this catechol estrogen, even at high doses. This rapid metabolism, presumably occurring in the blood compartment, should be considered in handling blood samples for RIA and in devising studies of the actions of catechol estrogens.

Animals↗
PubMed1981

Effects of catechol estrogen infusions upon gonadotropin and prolactin concentrations in men.

To study the effects of catechol estrogens upon gonadotropin secretion, 2-hydroxyestrone (2-OHE1) and 2-hydroxyestradiol (2-OHE2) were administered iv to young adult men in a range of doses for 4 days. Blood samples were obtained for plasma LH, FSH, and PRL at 20-min intervals for 6 h before and at the end of the infusion period. 2-OHE1 had no effect upon gonadotropins or PRL in doses up to 1.6 mg/day; at 3.2 and 6.6 mg/day, it produced a slight suppression of LH and FSH, with no change in PRL. 2-OHE2 was generally ineffective at 100 micrograms/day, but doses from 200-800 micrograms/day suppressed gonadotropins, without changes in PRL. These infusions elevated 2-OHE1 and 2-OHE2 plasma levels to values comparable to those measured in late pregnancy. There were no associated effects upon blood pressure and only minimal changes in urinary catecholamine excretion. No effects that could be interpreted as antiestrogenic were observed. These results are consistent with the hypothesis that circulating catechol estrogens behave as weak estrogens in men.

Adult↗
PubMed1981

Stimulation of release of luteinizing hormone from cultured pituitary cells by 2- and 4-hydroxylated oestrogens.

We have examined the effect of the catechol oestrogens 2-hydroxyoestradiol (2-OHE2), 4-hydroxyoestradiol (4-OHE2) and 2-hydroxyoestrone (2-OHE1) and their corresponding primary oestrogens on secretion of LH and FSH by enzymatically dispersed rat anterior pituitary cells in monolayer culture. Basal LH levels in the medium were significantly higher than in control wells when cells were exposed to 10(-8) M-oestradiol-17 beta for 40 h: oestrone and all three catechol oestrogens (in the same doses) also stimulated basal LH concentrations to levels quantitatively similar to those seem after oestradiol treatment. The same effects were observed when steroids were given at 10(-9) mol/l. Oestradiol, 2-OHE2, and 4-OHE2 but not 2-OHE1 increased pituitary responsiveness to LH releasing hormone (LH-RH) (given in a range of doses from 10(-11) to 10(-6) mol/l). The responses of cells treated with 2-OHE2 and 4-OHE2 were similar, though less than the response seen after treatment with oestradiol. This contrasts with the very different oestrogenic effects of 2- and 4-OHE2 previously observed in vivo. Neither oestradiol nor the catechol oestrogens had any effect on basal or LH-RH-stimulated FSH release.

Animals↗
PubMed1981

Cataractogenesis in the X-irradiated rabbit eye.

Studies were conducted on the development of cataract in the eyes of young (5-6 week old) New Zealand White rabbits exposed to 20 Gy of X-rays (1 Gy = 100 rads). The findings indicated that the opacities appear initially during the first week post-irradiation and follow a progression typical of cataract development in older rabbits and other species. However, advanced cataractous changes, as indicated by lens intumescence, occur concomitantly with complete opacification. They develop rapidly within a two day period between 2.5 to 3 months post-irradiation.

Animals↗
PubMed1980

Hypophysectomy exerts a radioprotective effect on frog lens.

Exposure to X-rays usually causes cataracts in frogs. These cataracts are always preceded by misalignment of the structures called meridional rows (MR). When cell division is completely halted by hypophysectomy, however, irradiation no longer disturbs the orientation of the MR. Since the MR are the structures formed as lens epithelial cells differentiate into lens fibres it is reasonable to propose that radiocataractogenesis depends upon a mitosis-driven formation of pathological fibres from epithelial cells that have been rendered abnormal by exposure to X-rays.

Animals↗