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The present work concerns the luteolytic effects of prostaglandin (PG) F2α and its analogue, 16-aryloxy PGF2α, upon isolated luteal cells. Varying doses of these two prostaglandins were incubated with cells in the presence or absence of an optimum stimulatory dose of LH (1 μg/ml). The total contents of progesterone and 20α-dihydroprogesterone in flasks were determined after the incubation periods by radioimmunoassay. Both prostaglandins inhibited basal synthesis of progesterone and 20α-dihydroprogesterone, maximum inhibition occurring at concentrations of either PG of between 250 and 500 ng/ml. In this dose range both prostaglandins were found to abolish LH-stimulated progestogen synthesis completely. These effects were discernible within 5 min of incubation. The studies demonstrated that the onset of PG-induced luteolysis in vitro is characterized by an inhibition of the biosynthesis of both progesterone and its weakly progestogenic metabolite, 20α-dihydroprogesterone; induction of 20α-hydroxysteroid dehydrogenase activity by either PG was not found in incubations extending up to 60 min. In contrast to their relative potencies in vivo, PGF2α and 16-aryloxy PGF2α were essentially equipotent in this in-vitro system.
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Many cells are able to regulate their sensitivity to hormones. In order to investigate the mechanism(s) by which rat luteal cells regulate their sensitivity to LH, we have developed and characterized a cell culture model. Cultures of dispersed rat luteal cells were exposed to graded doses of bovine LH, an analogue of LH releasing hormone (LH-RH) ([d-Trp6]-LHRH), and prostaglandin F2α (PGF2α) for 3 h. The media containing these hormones were then replaced with fresh hormone-free medium and the cells cultured for 24 h. In order to test the sensitivity of these cultures after 24 h, the medium was discarded and replaced by medium alone, or medium containing a standard dose of bovine LH for 1 h. The amount of cyclic AMP accumulated during this hour was used as an index of the sensitivity of the cells to LH.
Control cultures became 'supersensitive' to LH with augmented production of cyclic AMP during culture but LH-receptor binding activity was not increased. During the first 2 h of culture, LH (100 ng/ml) increased accumulation of cyclic AMP by fourfold, but after 5 h of culture, stimulation of cyclic AMP accumulation by the same dose of LH was increased 32-fold, 299-fold at 13 h and 359-fold at 21 h of culture. The increase in LH-responsive accumulation of cyclic AMP with culture was severely impaired by early exposure of cells to LH, LH-RH analogue or PGF2α during the first 2 h of culture. Also, both LH-RH analogue and PGF2α acutely inhibited LH-stimulated accumulation of cyclic AMP. Inhibition of culture-induced sensitization of LH responsiveness was not altered by the addition of 3-isobutyl-l-methylxanthine. Scatchard analysis of LH binding sites indicated that pretreatment of luteal cells with LH (or human chorionic gonadotrophin at an equivalent dose) reduced the number of free LH receptors when measured after 24 h of culture, but total receptor binding activity was not changed. However, a similar effect was not seen with cells treated with PGF2α or LH-RH analogue.
It is suggested that 'culture-induced' supersensitivity may represent either recovery of preisolation sensitivity or result from the loss of an endogenous factor(s) which retards the coupling of the LH receptor and adenylate cyclase. Although PGF2α and LH-RH analogue have been shown to directly prevent the occupied LH receptor from activation of adenylate cyclase, the present observations have indicated that this inhibitory process was continued even when these agents were removed from the culture medium.
Search for other papers by J. I. MORGAN in
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Department of Biological Sciences, University of Aston in Birmingham, Gosta Green, Birmingham, B4 7ET
(Received 17 April 1975)
Within a population of rat thymic lymphocytes there exists a group of cells which may be induced to enter prematurely the DNA synthetic phase and subsequently to enter mitosis (Whitfield, Rixon, MacManus & Balk, 1972). This response can be elicited in vivo by injections of calcium or magnesium chloride (Smith, Gurson, Riddell & Perris, 1975). Similarly, in isolated suspension cultures of thymic lymphocytes an increase in the calcium or magnesium concentration also evokes this response (Morgan & Perris, 1974).
The mitogenic action of calcium is not evident in female rats, which can be attributed to the presence of oestrogen (Smith et al. 1975). This can be simulated in the culture system by addition of 0·1 μg oestradiol/ml to the cell suspension (Morgan & Perris, 1974). Under these conditions the ability of raised
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Elevated insulin-like growth factor binding protein (IGFBP) levels, including IGFBP-1, occur in renal failure, and may contribute towards reduced IGF bioactivity in uraemia. The reduced IGF bioactivity may, in turn, contribute towards the disturbances in protein metabolism present in renal failure. In this study, the relationships between intra- and extracellular amino acid (AA) levels and IGF-I and/or IGFBP-1 levels were studied in 30 adult patients (aged 24-70 years) on haemodialysis who had no clinical signs of malnutrition. Blood samples (n = 30) and muscle biopsies (n = 13) were collected for determination of free AA in erythrocytes (RBC), plasma and muscle by reverse-phase HPLC while IGFBP-1, IGF-I and insulin plasma levels were determined by radioimmunoassay The patients on haemodialysis had elevated glutamate concentrations in RBC and plasma compared with healthy controls (524 +/- 26 vs 448 +/- 17 mumol/l, P < 0.05 and 45 +/- 4 vs 32 +/- 4 mumol/l, P < 0.01 respectively), although glutamate levels in muscle were within the normal range. The mean IGF-I level was slightly increased (s.d. score +0.74 +/- 0.30) but insulin levels were within the normal range. IGFBP-1 levels, which were inversely correlated to insulin (r = -0.40, P < 0.02), were elevated threefold compared with controls. No plasma AA level displayed a significant correlation with IGF-I, IGFBP-1 or insulin levels. However, glutamate concentrations in RBC were positively correlated to IGFBP-1 (r = 0.51, P < 0.01) and inversely correlated to IGF-I (r = -0.46. P < 0.01), although unrelated to insulin. Muscle glutamate, which was inversely related to RBC glutamate, displayed an opposite pattern with an inverse relation to IGFBP-1 levels (r = - 0.73, P < 0.01) and a positive correlation to IGF-I levels (r = 0.64, P < 0.02). Glutamate was the only AA to display an inverse correlation between RBC and muscle (r = -0.65, P < 0.02, n = 12). These findings lead us to propose that, in uraemia, the elevated IGFBP-I levels, which reduce the bioavailability of IGFs, are linked to glutamate uptake in muscle, resulting in accumulation of RBC glutamate. Whether there is a causal relationship or the correlation is due to some common regulator is not clarified in the present study.
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IGF-I has important roles in regulating growth and metabolism. Circulating IGF-I is bound to specific binding proteins (IGFBP-1 to -6), with hepatocytes containing IGF-I, IGFBP-1 and -2 mRNA. Although many hepatic proteins are regionally expressed in the liver acinus, no studies have reported zonation of IGF protein expression. In this study we investigated the pattern of hepatic mRNA for the IGF proteins, vs the previously reported pepriportal gradient of phosphoenolpyruvate carboxykinase (PEPCK) expression. In situ hybridisation was used to analyse IGF-I, IGFBP-1, -2 and PEPCK mRNA in female Sprague-Dawley rats fed diets containing low (6%), normal (21%) or high (35%) protein. We report for the first time that IGFBP-1 and -2 and IGF-I are differentially expressed in the liver acinus. In the normal- and high-protein groups, levels of IGFBP-1 mRNA were higher in the perivenous region, i.e. the opposite gradient to PEPCK, with a higher gradient of IGFBP-1 expression in the high-protein group. In contrast, IGFBP-2 had a similar pattern to PEPCK, and a periportal gradient of IGF-I mRNA was also seen in the low-protein group. Using computerised image analysis, levels of IGFBP-1 and -2 mRNA were elevated 2- and 10-fold respectively, in the low- vs normal-protein groups. The level of IGF-I mRNA was reduced to 65% of normal, with circulating IGF-I levels at 30% and insulin levels 39% of normal. These results demonstrate that hepatocytes are a heterogeneous population with respect to regulation of IGF proteins, having specific expression patterns dependent on the position of the hepatocyte within the liver acinus.
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Search for other papers by S.-K. Lam in
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ABSTRACT
Passive immunization of immature chickens with sheep somatostatin (SRIF) antiserum promptly increased the basal plasma GH concentration and augmented TRH-induced GH secretion. Although exogenous SRIF had no inhibitory effect on the basal GH concentration in untreated birds or birds pretreated with non-immune sheep serum, it suppressed the stimulatory effect of SRIF immunoneutralization on GH secretion. These results suggest that SRIF is physiologically involved in the control of GH secretion in birds, in which it appears to inhibit GH release tonically.
J. Endocr. (1986) 111, 91–97
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Abstract
It has previously been shown that the serum levels of insulin-like growth factor-I (IGF-I), IGF-binding protein-1 (IGFBP-1), and insulin are influenced by genetic effects to various degrees. From a clinical and preventive point of view, however, it is important to identify potentially modifiable non-genetic factors influencing the levels of these measures. Because monozygotic twin pairs share the same genetic background, differences in phenotypic levels within monozygotic twin pairs are believed to be due to non-genetic influences. Accordingly, the associations between intrapair differences in one phenotype and intrapair differences in another phenotype are also due to non-genetic influences. The present sample of 97 pairs of monozygotic twins from the population-based Swedish Adoption/Twin Study of Aging (SATSA) provided the opportunity to assess non-genetic influences on the levels of IGF-I, IGFBP-1, and insulin. Several metabolic measures were found to account for the variation of IGF-I, IGFBP-1, and insulin after controlling for the genetic influences. IGFBP-1 and glucose were significant predictors for the levels of IGF-I. IGFBP-1 and glucose together explained about one quarter of the non-genetic variation of IGF-I. However, when IGFBP-1 was dropped from the regression model, insulin was the only independent predictor of IGF-I, and explained about 19% of the non-genetic variation for IGF-I. For IGFBP-1, insulin and IGF-I were the significant non-genetic predictors. Insulin and IGF-I explained about 28 and 8% respectively of the non-genetic variation for IGFBP-1, while for insulin, IGF-I, triglycerides, body height, glucose, and body mass index (BMI) explained approximately 20, 12, 6, 5 and 5% respectively of the non-genetic variation.
Journal of Endocrinology (1997) 153, 251–257
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ABSTRACT
Young cockerels (6–8 weeks old) were injected with serum from sheep immunized against somatostatin-14 (anti-SRIF) or normal sheep serum (NSS). Blood samples were withdrawn periodically for the determination of plasma corticosterone concentration by radioimmunoassay. With frequent (every 10 min) sampling, NSS-treated control animals exhibited increased plasma corticosterone levels, presumably as a stress response to the experimental manipulation. Anti-SRIF stimulated a much greater increase in plasma corticosterone concentrations and a peak response was observed within 10 to 20 min, when the plasma corticosterone level reached more than twice that of the corresponding control value. With less frequent sampling, plasma corticosterone increased with anti-SRIF administration to as much as nine times the corresponding control value, and the peak response occurred much later. Under pentobarbitone anaesthesia, which itself increased basal corticosterone concentrations, anti-SRIF treatment promoted further increases in plasma corticosterone levels although to a smaller magnitude compared with conscious birds. The results suggest that endogenous somatostatin may play a role in the regulation of adrenocortical function in the domestic fowl. The mechanism of response may involve a central component.
J. Endocr. (1988) 116, 179–183
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ABSTRACT
The influence of somatostatin on thyroid function has been examined in immature domestic fowl passively immunized with somatostatin antiserum. Plasma thyroxine (T4) and tri-iodothyronine (T3) concentrations were markedly increased within 10 min of antisomatostatin administration and remained raised for at least 5 h. The increases in the T3 and T4 concentrations following somatostatin immunoneutralization were directly related to the volume of antisera administered. The increase in the T3 concentration exceeded the increase in the T4 concentration, resulting in a T3: T4 ratio greater than unity. While the raised T4 concentration began to decline 30 min after antisomatostatin administration, raised T3 concentrations were sustained for at least 2 h, and further increased the plasma T3: T4 ratio.
These results demonstrate that somatostatin immunoneutralization stimulates thyroid function in fowl. The magnitude and rapidity of the thyroidal responses to somatostatin immunoneutralization suggests that they occur independently of the hypothalamic-pituitary-thyroid axis. Somatostatin appears to exert a tonic inhibitory control on avian thyroid function, possibly by effects mediated at the thyroid gland to inhibit T4 release and by peripheral effects to suppress the conversion of T4 and T3.
J. Endocr. (1986) 110, 127–132
