Journal of Endocrinological Investigation

To clarify the hormonal regulation of pituitary insulin-like growth factor-l (IGF-I) bindings, we examined the continuous effect of growth hormone (GH) on [125I] IGF-I binding sites, using rats bearing transplantable GH-secreting rat pituitary tumor cells. A total of 24 female Wistar-Furth rats (4-week old) was divided into four groups (n=6). The first group rats were control (C). The second group rats were injected subcutaneously with 3×106 GH3 pituitary tumor cells (GH). The third group rats were thyroidectomized (Tx) and the fourth were dual-treated (GHTx). The brain, pituitary gland, liver, and kidney were immediately subjected to quantitative receptor autoradiography after a 4-week treatment period. Using kinetic experiments, GH rats had higher Bmax values of specific [125I] IGF-I binding sites in the anterior pituitary gland and Tx rats had lower Bmax values than control rats. Two-way analysis of variance among the 4 groups was examined. The effects of both GH and Tx treatment on [125l] IGF-I binding Bmax were observed only in the anterior pituitary gland and not in the other tissues examined. There were no differences in the Kd values of the binding sites. These data indicate that continuous GH excess selectively up-regulates the number of pituitary IGF-I binding sites in vivo, and that this may play a role in feedback regulation of the GH-IGF-I axis.

Steroids and thyroid hormone are thought primarily to act via binding to hormonespecific nuclear receptor superfamily members. The nuclear ligand-receptor complexes then initiate transcriptional activity. Actions of steroids and iodothyronines that are nongenomic or extranuclear in mechanism have been recognized recently and new insights into such mechanisms are available. Despite their distinct structures and biologic effects, the two families of hormones have similarities in the mechanisms of their nongenomic actions. That is, both steroids and thyroid hormone appear to interact with specific cell surface G protein-coupled receptors and to activate signal transducing kinases such as those involved in the mitogen-activated protein kinase (MAPK) pathway. Much is known about the ability of certain steroids such as estrogen and mineralocorticoids to increase [Ca2+]i acutely and stimulation of the MAPK cascade by L-T4 appears to depend upon a hormone-induced increase in [Ca2+]i via phosphoinositide pathway activation. At least in the case of iodothyronines, hormone activation of the MAPK pathway modulates the cellular activities of certain cytokines and growth factors. One of the two cell surface estrogen receptors (ERs) may be an expression of the same transcript as that for nuclear ER, whereas the mineralocorticoid and progesteronebinding proteins in the plasma membrane appear to be products of genes different from those of nuclear receptors. Iodothyronine structure-activity relationships at the plasma membrane binding site for thyroid hormone suggest that the cell surface receptor for T4 that also binds 3,5,3′-triiodo-L-T3 is different from the nuclear T3 receptor (TR). There are interfaces of nongenomic and genomic mechanisms for both steroids and thyroid hormone. For example, by nongenomic mechanisms, estrogen and thyroid hormone can promote serine phosphorylation, respectively, of nuclear ER and TR. Transcriptional activity of the nuclear receptor proteins can be altered by such phosphorylation.

The antiprogestin (AP) RU38486 (RU) blocks progesterone (P) and glucocorticoid (G) actions. Administration of 4 mg RU on proestrous morning to cyclic rats dissociates LH and FSH secretion on proestrous afternoon, early estrus and on estrous afternoon. In order to ascertain which action blocked by RU is predominant in the control of periovulatory LH and FSH secretion, a study was made on the effects of: a) 1 or 4 mg of ZK98299 (ZK) (type I P antagonist; Schering), b) 2 or 8 mg of Org31710 (OR) (type II P antago-nist lacking anti-G actions; Organon) or c) 1 or 4 mg of RU (type II P antagonist; Exelgyn) to 4-day cyclic rats on proestrous morning on serum concentrations of LH, FSH, inhibin-α (I), estradiol-17ß (E), progesterone (P) and corticosterone (B) at 18:30 h on proestrus and at 02:00 and 18:30 h on estrus. Controls, receiving 0.2 ml oil, had elevated serum concentrations of all six hormones on proestrous afternoon; at early estrus, only serum concentrations of FSH and P remained elevated, and, on estrous afternoon, all hormones but I and B, that peaked again, had reached their lowest serum levels. All AP treatments except 1 mg ZK had the same effects. On proestrous af-ternoon serum LH concentrations were reduced and serum FSH concentrations were suppressed whereas serum levels of I, E, P and B were unaffected. At early estrus, basal serum concentrations of LH and E increased while FSH secretion was abolished. Serum levels of I, P and B did not differ from controls. AP treatments increased basal LH concentration, hyperstimulated FSH secretion and reduced serum I concentration on the afternoon of estrus. E, P and B serum levels did not differ from controls at this stage. Treatment with 1 mg ZK was less effective in reducing serum FSH on proestrous afternoon and at early estrus, and had no effect on serum concentrations of any hormone on estrous afternoon. These results indicate that blockade of P receptor activation by P is, predominantly, the mechanism of AP action on periovulatory gonadotropin secretion in rats.

Four cases of pseudohyperaldosteronism due to chronic ingestion of liquorice-containing laxatives are described. All patients had hypertension and hypokalemia with suppression of plasma renin activity and aldosterone; the diagnosis was based only on retrospective grounds. In patients with hypokalemia and hypertension a possibility of such a cause must be excluded to avoid unnecessary diagnostic procedures.

Background: Treatment with GH promotes linear growth and decreases body fat in patients with isolated GH deficiency (GHD). However, few studies have analyzed how GH replacement modifies ghrelin levels and the adipokine profile and the relationship of these modifications with the metabolic changes. Aims: To analyze the eventual differences between serum levels of leptin, leptin soluble receptor (sOBR), resistin, adiponectin, interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), otal (TG) and acylated ghrelin (AG) and lipid and glycemic profiles in children with GHD, as well as to determine the effect of GH replacement on these parameters during the first year of therapy. Subjects and methods: Thirty pre-pubertal (Tanner stage I) GHD children and 30 matched controls were enrolled. Children with GHD were studied before and after 6 and 12 months of GH treatment. Weight, height, BMI, fasting glucose, insulin, lipid profile and serum levels of adipokines and ghrelin were studied at every visit. Adipokines, insulin and ghrelin levels were determined by using commercial radio- and enzymoimmunoassays. Results: At baseline children with GHD had significantly higher sO-BR (p<0.01) and adiponectin (p<0.01) levels than controls. Treatment with GH resulted in a decline in leptin (p<0.05) and TG (p<0.001) levels, an increase of homeostasis model assessment index and restored IGF-I levels (p<0.001). Conclusions: These data indicate that GH replacement has a negative effect on leptin levels and may also produce a slight unfavorable effect on carbohydrate metabolism. In addition, the changes observed in the adipokine profile appear to be independent of body mass index.

We aimed to assess adrenal function following treatment of moderate-to-severe and active Graves’ orbitopathy (GO) with intravenous methylprednisolone (IVMP) in weekly pulses in a cumulative dose of 4.5 or 7.5 g. We evaluated the impact of IVMP pulses on adrenal reserve using a low-dose (1 μg) ACTH stimulation test (LDT) for the first time. In this prospective study we evaluated adrenal function in 21 patients with moderate-to-severe and active GO treated with 12 weekly IVMP pulses according to the European Group on Graves’ Orbitopathy (EUGOGO) recommendations. We assessed serum cortisol, plasma adrenocorticotropic hormone (ACTH), and dehydroepiandrosterone sulfate (DHEA-S) levels before the 1st and 12th IVMP pulse. We performed dynamic testing using LDT before the 12th IVMP pulse in all patients. In those who failed LDT, adrenal function was reassessed with LDT and the overnight metyrapone test after 4–7 weeks. Two patients failed to achieve serum cortisol levels ≥ 18.1 μg/dL at 30 and 60 min in LDT and were diagnosed with glucocorticoid-induced adrenal insufficiency (GC-induced AI). They were recommended to take hydrocortisone in situations of acute stress. Both patients were reassessed within 4–7 weeks after treatment cessation and showed an adequate response in LDT and overnight metyrapone test. We observed a statistically significant decrease in DHEA-S levels (p = 0.004) before the 12th IVMP pulse compared to baseline in all patients. For the first time, our research shows that administering IVMP in 12 weekly pulses can result in GC-induced AI. We suggest that patients should undergo careful evaluation for GC-induced AI, including LDT, after therapy with IVMP according to EUGOGO guidelines. Screening for altered adrenal reserve could prevent life-threatening complications, particularly during acute stress situations.

The response of serum 21-deoxycortisol (21-DF), 17-hydroxypregnenolone (17-OHPE), 11-deoxycortisol and Cortisol to iv ACTH, was compared in 14 adult controls and 13 sets of parents of children with adrenal 21-hydroxylase deficiency. The baseline and post stimulation concentrations of hormones were similar in controls and parents, except for those of 21-DF, which were significantly greater in heterozygotes 30 min (p<0.005), 60 min (p<0.0025) and 90 min (p< 0.005) after stimulation with ACTH. When rates of increase were determined, those of 21-DF at 30, 60 and 90 min were significantly higher in the parents. Sixteen of the 26 parents (62%) had a rate of increase of 21-DF from 0 to 60 min greater than the mean plus two standard deviations of the control group. Using this same criteria, 11 of the 13 mothers (85%) of affected children could be identified as heterozygotes. The rate of increase of 21-DF from 0 to 60 min following ACTH provides a method for the detection of some heterozygote carriers of congenital adrenal hyperplasia and may be useful particularly in the identification of female carriers.