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ABSTRACT
In women with endometriosis there is concern that therapeutic use of LH-releasing hormone (LHRH) analogues, to lower ovarian oestrogen production and control endometrial hyperplasia, leads to unwanted oestrogen-deficiency bone loss. We have developed an animal model of this LHRH-mediated oestrogen-deficiency bone loss in the rat, using buserelin. The aim was to use this model to determine whether the progestogen, norethindrone acetate, could counter oestrogen-deficiency bone loss associated with prolonged treatment with the LHRH agonist buserelin. Four groups of animals which had their bones labelled with 45Ca were studied for 4 weeks: group A, control; group B, buserelin treated; group C, norethindrone acetate treated; group D, norethindrone acetate + buserelin treated. Buserelin was given daily (19·2 pmol/kg body wt); norethindrone was given orally three times / week (1·47 μmol/kg body wt). Bone resorption was monitored by measuring the urinary excretion of hydroxyproline and 45Ca and bone 45Ca content. Buserelin-treated rats developed similarly depressed plasma oestradiol-17β values in the presence and absence of progestogen, and both groups given buserelin had significantly smaller uteri than controls or rats given norethindrone without buserelin. However, norethindrone did not prevent buserelin-mediated increases in bone resorption. At the end of the study total body calcium values (mean ± s.d.) in the four groups were (mg) respectively; 2594 ± 123; 2260 ± 92 (P < 0·001 compared with controls); 2616 ± 221; 2415 ± 130 (P < 0·02 compared with controls). Rats given norethindrone and buserelin in combination had higher values (P < 0·02) than animals given buserelin alone, but significantly less total body calcium than controls (P < 0·02). We conclude that progestogen confers partial, but not complete, protection of the skeleton of buserelin-treated rats from oestrogen-deficiency bone loss.
Journal of Endocrinology (1993) 137, 27–33
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ABSTRACT
Prolonged administration of LHRH agonist suppresses pituitary gonadotrophin secretion, thereby lowering blood oestrogen. This study was undertaken to compare the osteopaenic effects of bilateral ovariectomy and chronic administration of the LHRH agonist, buserelin, in the rat. Four groups of animals which had their skeletons labelled with 45Ca were studied for 4 weeks. Group 1 underwent a sham-ovariectomy, group 2 were surgically ovariectomized, group 3 were given buserelin by daily s.c. injection and group 4 were given a continuous infusion of buserelin by osmotic minipump. Plasma concentrations of oestradiol were measured weekly. Bone resorption was assessed by measuring the urinary excretion of 45Ca and hydroxyproline and determining bone 45Ca content.
Ovariectomy and buserelin treatments lowered blood oestradiol, increased biochemical indices of bone resorption and decreased femur and total body calcium and 45Ca values. The degree of oesteopaenia elicited by ovariectomy and buserelin treatment was similar. Bone responses to s.c. buserelin and to continuous buserelin infusion were alike. We attribute evidence of increases in bone resorption and induction of osteopaenia with buserelin treatment to hypo-oestrogenism.
We have shown for the first time by bone analysis that buserelin induces osteopaenia as effectively as bilateral ovariectomy. This appears to be the first demonstration in the rat that long-term administration of LHRH agonist influences bone. Administration of buserelin provides a new way of inducing oestrogen-deficiency osteopaenia in the rat without removing the ovaries.
Journal of Endocrinology (1989) 121, 293–298
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SUMMARY
The efficiency of the dorso-lateral prostate (d.l.p.) of the rat to concentrate 65Zn was markedly depressed following hypophysectomy, but this glandular function could be maintained in the absence of the pituitary by the administration of suitable doses of chorionic gonadotrophin or testosterone. Removal of the testes in the hypophysectomized rat did not alter appreciably the maintenance effect of testosterone on the d.l.p.
The effects of oestradiol on the efficiency of the d.l.p. to concentrate 65Zn were diverse and involved multiple sites of action. With a dose of 0·1 μg of oestradiol there was stimulation of uptake of 65Zn, and with 1 μg a sudden depression. The latter effect was paralleled by decreased size of the gland and histological evidence of marked cell atrophy. Neither the stimulatory nor depressant effects of oestradiol on 65Zn uptake could be reproduced in hypophysectomized rats maintained on gonadotrophin, indicating that these two actions of oestrogen involved the pituitary axis.
Larger doses of oestradiol administered to hypophysectomized and hypophysectomized-castrated rats maintained on testosterone also exerted an inhibitory effect on the efficiency of the d.l.p. to concentrate 65Zn. There was maximal antagonism with an androgen: oestrogen ratio of 5:1, and as the proportion of oestrogen was increased there was a rebound rise in efficiency of the d.l.p. to take up 65Zn. The depression of 65Zn uptake by this peripheral-type of antagonism was not accompanied by depression in glandular weight. Even more striking was the observation that, in the face of this lowered glandular function, there was no evidence of any depression histologically or cytologically.
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SUMMARY
The data presented in this paper illustrate a distinct yearly cycle of activity in the capacity of the dorso-lateral prostate (d.l.p.) of the male laboratory rat to concentrate injected 65Zn. From 60 to 85% more 65Zn was taken up per mg of glandular tissue in the months of February-March and June-July than at other times of year. Studies of the corresponding weights of the d.l.p. showed trends towards lower glandular weights in January and in April; the maximum difference noted between high and low glandular weights was, however, only 28%. That this increased uptake of 65Zn by the d.l.p. in February-March and June-July was a strong inherent feature was illustrated by the fact that rats of various ages, from 8 weeks to 1½ years, showed this increased glandular activity at these times of year. Of all the animals tested only the immature rat of 5 weeks of age and the exhausted breeder did not manifest this seasonal activity.
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SUMMARY
Eleven days following hypophysectomy the capacity of the rat testis to take up administered 65Zn is markedly depressed below values noted in intact controls, even though microscopically there is only a slight diminution in the number of germinal epithelial and interstitial elements. Interstitial cell-stimulating hormone (ICSH) in doses of 5 μg./day administered from the 5th to the 10th day after operation completely prevented the fall in total 65Zn uptake of the testis following removal of the pituitary. Follicle stimulating hormone (FSH) was less effective than ICSH in this regard. The possibility of the FSH effect being due to contamination with ICSH is considered. Growth hormone and prolactin in doses of 200 μg./day administered from the 5th to 10th day after operation were ineffective in preventing the fall in 65Zn uptake of the testis following hypophysectomy.
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SUMMARY
The effects of the β-adrenergic receptor blocking agent, dl-propranolol, and of the antithyroid drug, carbimazole, upon some manifestations of thyroxine (T4)-induced changes in peripheral metabolism were studied in rats. Propranolol lowered the heart rate, but did not alter the following changes induced by T4: increment in heart rate, increase in heart or kidney weight, increase in urinary hydroxyproline, decrease in body weight gain or increase in serum T4. Carbimazole administration lowered serum T4 and reduced weight gain, but had no effect upon heart rate or hydroxyproline excretion.
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ABSTRACT
The cyclic AMP response to bovine TSH was characterized in a strain of rat thyroid follicular cells (FRTL-5) maintained in continuous culture. Significant stimulation of intracellular cyclic AMP was attained at a TSH dose of 5 μu./ml. Cyclic AMP accumulation continued to increase, at higher TSH doses, with no evidence for attainment of a maximum level at the highest dose tested (5 mu./ml). The precision of TSH measurement was better than 10% over the range 50–5000 μu./ml, comparing favourably with that observed with analogous assays based on human cells, tissue slices or membrane preparations. Using sequential subcultures of FRTL-5 cells, the between-assay variation in response to a single dose of a standard preparation of bovine TSH (53/11; 370 μu./ml) was of the order of 20% which compared favourably with the between-assay variation observed with different cultures of human thyroid cells. Prolongation of the incubation of FRTL-5 cells with TSH to 3 h revealed a progressive increase in the extracellular accumulation of cyclic AMP. Addition of TSH to resting FRTL-5 cells resulted in a stimulation of inorganic iodide uptake with pronounced bell-shaped dose–response characteristics. Thus a maximum uptake was observed at a TSH dose of 100 μu./ml with a significant reduction at higher doses. Acute stimulation of cells with TSH (100 μu./ml) resulted in a rapid and marked alteration in cell morphology, with evidence of cellular retraction and surface ruffling.
J. Endocr. (1984) 101, 269–276
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An enriched fraction of zona reticularis cells was obtained by unit gravity sedimentation of decapsulated adrenal glands from female rats. From light microscopic and ultrastructural studies of the whole gland and the isolated cell fractions, the zona reticularis cells of the adrenal gland can be classified mainly on the bases of size, position and mitochondrial morphology. This cell population consists of two types of cell, the 'true' zona reticularis cells (Type I, modal diameter 9 μm), which usually constitute 90% of the isolated reticularis fraction and 80% of the intact reticularis tissue, and cells (Type II, modal diameter 13 μm) with fasciculata-like properties (rich in lipid and spherical mitochondria with vesicular cristae). Staining of the cell preparation for 3β-hydroxysteroid dehydrogenase activity also demonstrates the existence of two types of cell in the zona reticularis.
The zona reticularis cell fraction, like the zona fasciculata cell fraction, was capable of producing the subsequent steroids from radioactive pregnenolone: corticosterone, deoxycorticosterone, 18-hydroxydeoxycorticosterone, 11-dehydrocorticosterone, progesterone and androstenedione. However, the pattern of steroid production differed markedly between the zona reticularis and zona fasciculata cells, particularly with respect to the production of deoxycorticosterone and corticosterone (and its correlated steroids, 11-dehydrocorticosterone and 18-hydroxydeoxycorticosterone). When R (the ratio of deoxycorticosterone: corticosterone plus 11-dehydrocorticosterone) for the purest preparation of reticularis cells was compared with R for the corresponding preparation of fasciculata cells, the normalized ratio was found to be 6·4, 16·4 and 20·1 in three experiments. The pattern of production of androstenedione per cell was similar in the reticularis and fasciculata cell fractions. The exact mechanism for the altered pattern of steroid metabolism remains to be elucidated. However, these results establish that the corticosteroids produced by the cells of the zona reticularis may be quantitatively, if not qualitatively, different from those produced by the zona fasciculata cells.
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This study was designed to determine the effect of menopause and hormone replacement therapy (HRT) on plasma cholesteryl ester fatty acid (CEFA) composition and insulin sensitivity and the relationships between these variables in perimenopausal women (aged 40-55 years) including 49 who were premenopausal and 32 who were postmenopausal. Plasma cholesteryl ester proportions of dihomo-gamma-linolenic acid (20:3 n-6) were correlated significantly with insulin sensitivity index (r=-0.319, P=0.005), fasting serum insulin levels (r=0.230, P=0.038), body mass index (r=0.242, P=0.03) and per cent body fat (r=0.329, P=0.003) in perimenopausal women (n=81). Similar associations were observed in premenopausal women. Regression analysis suggested the relationships between 20:3 n-6 proportions and indices of insulin action may be partly mediated by levels of adiposity. In postmenopausal women, 6 months of HRT significantly (P=0.008) increased the ratio of arachidonic acid (20:4 n-6) to linoleic acid (18:2 n-6), which is an indicator of activity in the pathway of 20:4 n-6 synthesis, compared with placebo. These findings suggest that the type of fat in the diet indicated by plasma CEFA composition is linked to adiposity and insulin action. They also suggest that in postmenopausal women, HRT may increase the synthesis of 20:4 n-6, which is the precursor for eicosanoids with important cardiovascular functions.
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The outputs of corticosterone, deoxycorticosterone and androstenedione from dispersed, purified rat adrenal zona reticularis and zona fasciculata cells have been measured by radioimmunoassay.
Preferential production of deoxycorticosterone by zona reticularis cells was demonstrated by their higher basal deoxycorticosterone: corticosterone ratio when compared with zona fasciculata cells.
Adrenocorticotrophin (ACTH) stimulated corticosterone output by all cell pools prepared by unit gravity (1 g) sedimentation, zona fasciculata cells being stimulated 130-fold compared with 20-fold for the zona reticularis cells in relation to their basal corticosterone output.
In every cell pool, ACTH stimulated the output of corticosterone more than it stimulated the output of deoxycorticosterone. In parallel cell preparations, it was shown that ACTH increased the conversion of tracer amounts of radioactive deoxycorticosterone to corticosterone and decreased the conversion of radioactive corticosterone to 11-dehydrocorticosterone. Adrenocorticotrophin did not increase the conversion of radioactive deoxycorticosterone to total 11-oxygenated steroids (corticosterone+ 11-dehydrocorticosterone). It is unlikely therefore that ACTH stimulates 11 β-hydroxylation.
Data indicate that the ratio of deoxycorticosterone to total 11-oxygenated steroids (corticosterone +11-dehydrocorticosterone) is characteristic for each cell type, and that this ratio will be relatively independent of ACTH stimulation or the amount of pregnenolone substrate available.
Basal androstenedione outputs were similar for both types of cell, and ACTH stimulation was very small, being slightly greater for zona fasciculata than for zona reticularis cells.
The contribution of the zona reticularis cells to the basal output of any steroid by the cells of the inner two zones of the adrenal cortex of the rat was relatively small (20% for deoxycorticosterone and 10% for corticosterone) and was even less after stimulation by ACTH. Unless a specific stimulus can be found, therefore, a significant role for the zona reticularis cannot yet be established.
