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F. A. Antoni and G. Dayanithi


The aim of the present study was to characterize the inhibitory action of atriopeptin on secretagogue-evoked ACTH release in vitro.

Perifused isolated rat anterior pituitary cells were exposed to repeated pulses of 41-residue corticotrophin-releasing factor (CRF-41) or arginine vasopressin (AVP). The net ACTH secretory response to both neurohormones increased progressively with the number of pulses applied, until a maximum hormonal response was reached which was stable for the subsequent period of observation (2–3 h). The maximal secretagogue-evoked hormone release eventually achieved was 4 and 1·7 times greater than the initial response to AVP and CRF-41 respectively. The size of the ACTH response elicited by 50 pmol CRF-41/1 and 500 pmol AVP/1 (CRF/AVP) given together also underwent progressive enhancement. The number of secretagogue pulses required to reach the maximal response to a particular stimulus depended upon the concentration of the secretagogue peptides, higher concentrations favoured a more rapid development of the stable secretory response.

The potency of 103–126 residue atriopeptin to inhibit CRF/AVP-induced ACTH release varied by about 1000-fold depending upon the prior treatment of the cells. In general, cells not previously exposed to secretagogues appeared largely resistant, those under a moderate secretagogue drive were strongly inhibited, and those under intense stimulation were again refractory to inhibition by atriopeptin. In contrast, corticosterone suppressed stimulated ACTH release regardless of the state of the cells.

The data demonstrate that the conditions of cell maintenance are pivotal determinants of the inhibitory effect of atriopeptin on secretagogue-stimulated ACTH release in vitro. The in-vivo correlate of these findings may be that the sensitivity of corticotrophs towards atriopeptin is determined by requirements encoded through the pattern of release of hypothalamic CRF-41 and AVP.

Journal of Endocrinology (1990) 125, 365–373

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JA Sterle, C Boyd, JT Peacock, AT Koenigsfeld, WR Lamberson, DE Gerrard and MC Lucy

Fetal growth is increased when pregnant gilts are treated with recombinant porcine somatotropin. The mechanism for increased fetal growth was examined by measuring the expression of IGF-I and -II and IGF-binding protein-2 (IGFBP-2) mRNA in liver and reproductive tissues of somatotropin- and saline-treated pregnant gilts. Twenty-four pregnant gilts received daily injections of either saline (control; n=12) or 5 mg recombinant porcine somatotropin (n=12) from day 30 to day 43 of gestation. Gilts were slaughtered on day 44 of gestation and liver, ovary, placenta, placental uterus (uterus with adjacent placental tissue) and non-placental uterus (region of the necrotic tip) were collected. The mRNAs for somatotropin receptor, IGFs -I and -II, IGFBP-2 and pregnancy-associated glycoprotein (a marker of trophoblast tissue) were analyzed by Northern blotting or ribonuclease protection assay. Gilts treated with somatotropin had heavier fetuses and placentas. The concentration of mRNA for the components of the IGF system was tissue-dependent. The uterine IGF-I mRNA concentration was greater in non-placental than in placental uterus. The greatest IGF-II mRNA concentration was observed in placenta, and adjacent uterine tissue expressed IGFBP-2 mRNA intensely. In non-placental uterus, IGFBP-2 mRNA was nearly undetectable. Somatotropin-dependent regulation of IGF-I was only observed in liver, where the greatest somatotropin receptor mRNA concentration was found. In the pregnant uterus, somatotropin failed to change the concentration of IGF or IGFBP-2 mRNA. Pregnancy-associated glycoprotein mRNA concentration was decreased by somatotropin. In summary, increased fetal growth in somatotropin-treated pregnant pigs was not associated with changes in IGF or IGFBP-2 mRNA concentration in reproductive tissues. Other mechanisms, therefore, lead to enhanced fetal growth in somatotropin-treated pregnant pigs.

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L G Rao, J N Wylie, M S Kung Sutherland and T M Murray


We tested the effect of osteoblastic differentiation on the interactive effects of 17β-oestradiol (E2) and 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) on alkaline phosphatase activity. As cell models we utilized the more differentiated human osteosarcoma (SaOS) cells that had been cultured for 6 days in medium containing 10 nm dexamethasone (Dex) (SaOS+Dex cells) and the less differentiated cells cultured in the absence of Dex (SaOS−Dex cells). The cells were challenged with 1,25(OH)2D3 in the presence or absence of Dex for 24 h and then with E2 for an additional 24 h. In SaOS−Dex cells, alkaline phosphatase activity remained constant over the 48-h period and was not significantly affected by E2, 1,25(OH)2D3 or 1,25(OH)2D3+E2 treatment. On the other hand, in SaOS+Dex cells, 1,25(OH)2D3 and E2+1,25(OH)2D3 stimulated alkaline phosphatase activity (ANOVA, F= 154·2, P<0·0001) with the maximal response at 48 h (P<0·01). In SaOS+Dex cells, 1,25(OH)2D3 had dose-dependent stimulatory effects which were strongly enhanced by 10 nm E2 (ANOVA, F=46·0, P<0·001). Studies on dose-dependent effects of E2, in the presence or absence of 100 nm 1,25(OH)2D3, revealed that in the presence of 1,25(OH)2D3, the E2 dose-response curve was biphasic in SaOS+Dex cells (ANOVA, F=3·40, P<0·005), with maximum stimulation at 10 nm E2 (P<0·01). The specificity of E2 was verified using the inactive 17α-oestradiol and the oestrogen antagonist, tamoxifen. These data indicate that E2 and 1,25(OH)2D3 have positive interactive effects on alkaline phosphatase activity in human osteoblasts, and suggest that the expression of this interaction is dependent on the stage of differentiation of the cells.

Journal of Endocrinology (1996) 148, 181–187

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J Trojan, M Theodoropoulou, KH Usadel, GK Stalla and L Schaaf

Enhanced sialylation of thyrotropin (TSH) prolongs its metabolic clearance rate and thus increases the hormone's in vivo bioactivity. This has been shown for hypothyroid rats and for recombinant human TSH, but there are few data on the sialylation of human serum TSH. The aim of this work was to further study sialylated human serum TSH, its precursors bearing terminal galactose residues, and the role of pharmacological doses of thyrotropin-releasing hormone (TRH) on their secretion under different degrees of primary hypothyroidism. We analyzed serum TSH in patients with subclinical (n = 9) and overt primary hypothyroidism (n = 13) compared with euthyroid individuals (n = 12) and human standard pituitary TSH (IRP 80/558). Blood was drawn before and 30 min after intravenous administration of 200 micrograms TRH, and TSH was purified by immunoaffinity concentration. The content of sialylated (sialo-) TSH and isoforms bearing terminal galactose (Gal-TSH, asialo-Gal-TSH) was measured by Ricinus communis (RCA 120) affinity chromatography in combination with enzymatic cleavage of sialic acid residues. TSH immunoreactivity was measured by an automated second generation TSH immunoassay. Pituitary TSH contained 16.5 +/- 0.8% Gal-TSH. In euthyroid individuals the proportion of Gal-TSH was 14.6 +/- 1.9%, whereas TSH in patients with subclinical and overt primary hypothyroidism contained 23.9 +/- 3.5% (P < 0.05 vs euthyroid individuals) and 21.1 +/- 1.7% Gal-TSH respectively. The mean ratio of asialo-Gal TSH was 23.8 +/- 0.6% for pituitary TSH, 35.7 +/- 4.2% in euthyroid individuals, 48.0 +/- 3.3% in patients with subclinical, and 61.5 +/- 3.8% (P < 0.001 vs euthyroid individuals) in patients with overt primary hypothyroidism. For pituitary TSH the calculated proportion of sialo-TSH was 6.5 +/- 0.2%, for euthyroid individuals 20.3 +/- 2.8%, for patients with subclinical hypothyroidism 24.1 +/- 3.0%, and for patients with overt primary hypothyroidism 40.7 +/- 3.0% (P < 0.001 vs euthyroid individuals). The proportions of Gal-TSH, asialo-Gal-TSH, and sialo-TSH did not differ significantly before and after TRH administration in the individuals studied. Our data show that patients with subclinical and overt primary hypothyroidism have a markedly increased proportion of serum TSH isoforms bearing terminal galactose and sialic acid residues, which may represent a mechanism for the further stimulation of thyroid function. Pharmacological doses of TRH cause an increased quantity of TSH to be released, but do not significantly alter the proportion of sialylated or terminally galactosylated TSH isoforms.

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J. F. Murray, J. A. Downing, G. Evans, J. K. Findlay and R. J. Scaramuzzi


Epidermal growth factor (EGF) is a potential intra-ovarian modulator of gonadotroph action on differentiated follicular cells. Specific binding sites have been identified in the ovary and functional differentiation in cultured granulosa cells can be modulated by treatment with EGF. The aim of this study was to determine if EGF was capable of altering ovarian function in vivo during the follicular phase of the sheep oestrous cycle. Fourteen cross-bred ewes with ovarian autotransplants were treated with progestagen pessaries for 12 days. Three ewes were infused with murine EGF (mEGF) via the jugular vein (75 μg/kg bodyweight per 12 h) during the 12 h preceding progestagen pessary withdrawal, and received an injection of a prostaglandin analogue at 0 h to induce luteolysis. Over the same time-period, two doses of EGF were administered to other groups of ewes by infusion into the ovarian artery (low: 6 μg/12 h, n = 3 and high: 60 μg/12 h, n = 3). The remaining five ewes were not infused with EGF (controls). Jugular and ovarian venous blood samples were taken at 10-min intervals at two stages during the follicular phase (21–27 h and 38–42 h after pessary withdrawal) and every 2 h from 44 to 76 or 86 h. mEGF, LH, FSH, inhibin, androstenedione, oestradiol-17β and progesterone concentrations in plasma were determined using radioimmunoassays. The secretion rates of androstenedione, oestradiol, progesterone and inhibin by the ovary were calculated.

EGF acted directly on the ovary in a dose-dependent manner. Oestradiol secretion was inhibited following treatment with EGF but androstenedione secretion was unaffected. EGF appears therefore to act within the granulosa cells to inhibit aromatization. Inhibin secretion was also suppressed by treatment with EGF, though it was not possible to determine if this was caused by a direct or indirect action of EGF on granulosa cells. The rate of progesterone secretion increased in ewes receiving systemic (i.e. via the jugular vein) and high-dose intra-arterial infusions of EGF, even though a preovulatory LH surge was not observed in these animals during the entire experimental period. Concomitant increases in both LH and FSH secretion were associated with these effects of EGF on ovarian function.

In conclusion, EGF appears to act directly on the granulosa cells of the follicle to inhibit aromatization and also to inhibit inhibin production. The low levels of oestradiol and inhibin in the presence of high levels of gonadotrophin indicate that atresia may have been induced in medium to large antral follicles. The increase in progesterone secretion following high doses of EGF may be derived from a luteinized follicle. FSH-stimulated functions cease when a follicle luteinizes and progesterone secretion commences. EGF treatment inhibited both oestradiol and inhibin secretion whilst enhancing progesterone which suggests that EGF may also be involved in the induction of functional luteinization. EGF or an EGF-like substance may therefore be an important factor in the induction of functional luteinization, with atresia occurring in antral follicles which are exposed to EGF too early in their development.

Journal of Endocrinology (1993) 137, 253–264

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Sarah Teillon, German A Calderon and Maribel Rios

-Suarez et al . 2006 ). As liver and portal vein afferents serve as sensors for amino acids, glucose, insulin, and glucagon, their expression of TRKB could facilitate the transmission of metabolic signals to the brain. BDNF was previously reported to enhance

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Shannon M Gifford, Fu-Xian Yi and Ian M Bird

Introduction We have previously established that enhanced vasodilator production by uterine artery endothelial cells (UAEC) involves remapping of cell signaling in a manner that is programmed ( Bird et al. 2000 , 2003 , Di et al

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Saeed Alshahrani and Mauricio Di Fulvio

glucose, enhanced glucose tolerance and β-cell secretory capacity. Further, we discover the presence of a BTD-sensitive mechanism involved in insulin secretion in β-cells lacking NKCC1, thus unmasking a potential new role for NKCC2 in β-cell physiology

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C Fottner, D Engelhardt and MM Weber

Although the effect of insulin-like growth factors (IGFs) in fetal adrenocortical cells has been investigated extensively, the role of the IGF system in the adult human adrenal gland remains unclear. In the present study we investigated the effect of recombinant human IGF-I and IGF-II on cortisol, dehydroepiandrosterone sulfate (DHEA-S) and cAMP synthesis in adult human adrenocortical cells in primary culture. Both IGFs stimulate basal as well as adrenocorticotropin (ACTH)-induced steroid secretion in a time- and dose-dependent fashion. While both IGFs (6.5 nM) induced only a moderate 2-fold increase in basal cortisol output after 48 h, the effect on basal DHEA-S secretion was significantly stronger, with a 2.7- and 3.7-fold stimulation by IGF-I and IGF-II respectively. Similarly, IGF-II enhanced ACTH-induced cortisol and DHEA-S secretion more potently than IGF-I. In dose-response experiments, the maximum stimulation of ACTH-induced DHEA-S secretion was induced by 1.6 nM IGF-I (2-fold increase) or IGF-II (2.9-fold increase), while the maximum response of cortisol secretion was elicited only at 13 nM IGF-I (2-fold increase) or IGF-II (2.5-fold increase). This resulted in a significant shift of the DHEA-S dose-response curves to the left, indicating a relative selective stimulation of androgen biosynthesis by physiologically low concentrations (0.4-3.2 nM) of IGF-II, and less potently by IGF-I. At all doses tested, the steroidogenic effect of IGF-II was significantly stronger than the effect of IGF-I. Although both IGF receptors are present in adult human adrenocortical cells, the steroidogenic effect of IGF-II is mediated through the IGF-I receptor, since [Arg54,55]IGF-II, which only binds to the IGF-I receptor, was equipotent with native IGF-II, whereas [Leu27]IGF-II, which preferentially binds to the type II IGF receptor, did not show any effect. In addition, [des1-3]IGF-I, which exhibits only minimal binding to IGFBPs, was significantly more potent than native IGF-I in stimulating adrenal steroid biosynthesis, and elicited almost the same maximum stimulatory effect as IGF-II and [des1-6]IGF-II. By Western ligand blotting of conditioned medium it was shown that adult human adrenocortical cells secrete various IGF-binding proteins (IGFBPs), which are induced differentially by treatment with ACTH. In conclusion, these results demonstrate that: (1)IGF-II stimulates basal as well as ACTH-induced DHEA-S and cortisol secretion from adult human adrenocortical cells more potently than IGF-I; (2) both IGFs predominantly stimulate androgen biosynthesis; (3) the steroidogenic effect of IGF-I and IGF-II is mediated through interaction with the IGF-I receptor; (4) the different steroidogenic potency of IGF-I and IGF-II might be explained by interaction of these ligands with locally produced IGFBPs. These data indicate that the IGF system plays an important role in the regulation of the differentiated function of adult human adrenocortical cells.

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Julia M Young, Jennifer L Juengel, Kenneth G Dodds, Mhairi Laird, Peter K Dearden, Alan S McNeilly, Kenneth P McNatty and Theresa Wilson

the mutant Booroola ALK6 receptor in the cells synthesising FSH, but that the sensitivity of BB cells to BMPs appears enhanced when compared with WT cells. BMPs may potentially act through the type IA BMP receptor (ALK3), which has been shown to be