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K. KOVÁCS

SUMMARY

Homotransplantation of the anterior pituitary gland of rats was made into the anterior chamber of the eye. The centre of the grafts developed ischaemic necrosis, but the peripheral zone remained alive to a depth of about 100 μ. During the next 6 weeks there was no evidence of significant regeneration or atrophy of this live peripheral zone, and mitoses were not observed there. The gradual resorption and scarring of the central necrotic area led to a diminution of the overall size of the graft.

In the surviving tissue nearly all the chromophil cells became completely degranulated during the first week or two. After 6 weeks only very rare shrunken basophil cells remained, although a few acidophil cells could still be identified.

From previous work it is known that such intraocular grafts have very little functional activity. This may possibly be because of the absence of any direct connexion between the graft and the hypothalamus, but the reduction of the total amount of parenchyma may also be an important factor.

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K. Kovács, P. Péczely and Z. Szelényi

ABSTRACT

Steroid binding profiles in chicken feather follicles were studied in vitro. Progesterone and promegestone were bound specifically with high affinity (dissociation constant = 7·79 nmol/l in females and 2·0 nmol/l in males) and with low capacity to the high-speed supernatant fraction (cytosol) of homogenized feather follicles. The number of progestin-binding sites was significantly (P < 0·01) higher in females than in males (1·35 ± 0·07 (mean ± s.d.) vs 0·605 ± 0·15 pmol/mg protein). Significant cross-competition was observed between progestins and glucocorticoids for the binding sites. The heat-activated progestin–receptor complexes bound specifically to DNA-cellulose in vitro. The DNA-cellulose binding was 36·6% of the total specific binding. The presence of progestin-binding sites in the feather follicles implies a direct action of progesterone in this structure, which may be an important factor in the regulation of moulting. The lack of oestrogen binding to the cytosol prepared from the feather follicles suggests different regulation of progestin receptors in different target organs.

J. Endocr. (1986) 109, 187–191

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R. CARROLL, K. KOVÁCS and E. TAPP

SUMMARY

Infarction of the anterior pituitary and adrenal cortex caused by hexadimethrine in experimental animals was found to be variable in incidence and extent. Pretreatment with oestrogen made the lesions more severe and almost of constant occurrence.

The early stages of the lesions were studied in rats from 1 to 6 hr. after the administration of hexadimethrine. The local vasospasm which caused the infarction in the adrenal cortex seemed to pass off in 2 or 3 hr. and to be followed by a failed reflow which produced much haemorrhage. On the other hand, it appears that there was little or no reflow into the dead anterior pituitary during the first 6 hr. Necrotic changes did not develop within that period in animals pretreated with oestrogen but secondary thrombosis occurred in vessels of the marginal zones of the necrotic anterior pituitary after about 12 to 24 hr.

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K. KOVÁCS, MARGIT A. DÁVID and F. A. LÁSZLÓ

SUMMARY

Lesions were made in the pituitary stalk of rats, and the functional capacity of the hypophysial-adrenocortical axis of animals suffering from diabetes insipidus was studied. Eight days after the operation the weight, histological structure and histologically demonstrated lipid content of the adrenals had not changed. Whereas operative stress and unilateral adrenalectomy caused no ascorbic acid depletion in the contralateral adrenals, administration of adrenocorticotrophic hormone induced a significant decrease. The corticosterone content of the adrenal venous blood decreased moderately, whilst in vitro the adrenal slices secreted less corticosterone than normally. Secretion of aldosterone by the adrenals of animals with lesions was not different from that of controls. When large doses of corticosterone were administered adrenal atrophy occurred in both operated and control rats.

It is concluded that the functional capacity of the hypophysial—adrenocortical axis is decreased 8 days after the destruction of the pituitary stalk, although the production of hormones by the adrenal cortex does not cease completely; one must be cautious in assessing the functional state of the adrenal glands since the methods used for their evaluation do not always give comparable results.

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S Vidal, A Roman, L Moya and K Kovacs

3 beta-Hydroxysteroid dehydrogenase/isomerase (3 beta-HSD) catalyses an essential step in the biosynthesis of steroid hormones and is widely distributed in peripheral steroid target organs. The present report describes for first time the expression of this enzyme in the pituitary of female rats. Immunohistochemistry at the light microscopic level was performed on pro-oestrous and ovariectomized rat pituitaries. Immunoreactive cells were scattered and randomly distributed throughout the anterior lobe, whereas cells located in the posterior lobe and pars intermedia were immunonegative. Differences were observed in cell morphology and in the number of 3 beta-HSD-immunopositive cells between ovariectomized and pro-oestrous female rat pituitaries, suggesting that steroidogenic activity is affected by ovarian endocrine function. Apart from adenohypophyseal immunoreactive cells, 3 beta-HSD immunopositivity was also noted in endothelial cells of almost all pituitary capillaries located in the anterior and posterior lobes.

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M. Feinmesser, S. L. Asa, K. Kovacs and M. J. Low

ABSTRACT

We report the light microscopic, transmission and scanning electron microscopic features of the adrenal cortices in rats bearing a medullary thyroid carcinoma cell line transfected with a corticotrophin-releasing hormone (CRH) cDNA expression vector. The animals had elevated CRH, ACTH and corticosterone blood levels, involuted thymuses and markedly enlarged adrenal glands with prominent lipid-depleted cortices and dilated congested capillaries, similar to those of animals treated with ACTH. Using electron microscopy it was found that the enlarged fasciculata and reticularis zones were composed of large, compact cells with abundant smooth endoplasmic reticulum, prominent Golgi complexes, increased number of large mitochondria with focal loss of cristae and cavitation of the internal compartments, numerous lysosomes and prominent elongated microvilli. In addition, small cytoplasmic fragments were seen within the capillary lumina; these structures resembled microvilli that were apparently detached from adrenocortical cells and entered the blood stream via discontinuous endothelium of dilated capillaries. By scanning electron microscopy it was found that the cells had bulging surfaces with scattered pits and numerous long microvilli pointing in different directions.

This animal model allows analysis of the effects of protracted CRH excess resembling tumoural CRH-dependent Cushing's syndrome in human patients. Our findings call attention to the role of microvilli in adrenocortical secretion. The increased number and size of microvilli has been thought to lead to an increase in the surface area of adrenocortical cells, thereby facilitating hormone discharge. The detachment of microvilli from adrenocortical cells may represent a form of apocrine secretion and may contribute to hypercorticosteronaemia in CRH excess.

Journal of Endocrinology (1992) 135, 271–277

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I. J. Elenkov, K. Kovács, J. Kiss, L. Bertók and E. S. Vizi

ABSTRACT

Stimulation of the immune system or experimental conditions (bacterial lipopolysaccharide (LPS) treatment) provoke a broad spectrum of physiological responses. It was recently shown that one of them is the activation of the hypothalamic-pituitary-adrenal (HPA) axis. The mechanism and the site or sites through which LPS stimulates the HPA axis are not well understood.

To establish whether the effect of bacterial LPS is related in vivo to the presence of hypothalamic hypophysiotrophic peptides (corticotrophin-releasing factor-41, arginine vasopressin, etc.), plasma ACTH and corticosterone levels were monitored in intact and sham-operated rats, and in rats with paraventricular nucleus lesions in order to remove the main source of these neuropeptides. Evidence was obtained that 4 h after treatment, LPS was able to activate the hypophysial-adrenal system in the absence of hypophysiotrophic neuropeptides of paraventricular origin.

It is suggested that, in vivo, LPS could have a direct effect on the pituitary gland or that it acts through an extrapituitary, non-paraventricular pathway to activate the HPA axis.

Journal of Endocrinology (1992) 133, 231–236

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M Kovacs, AV Schally, EJ Lee, R Busto, P Armatis, K Groot and JL Varga

GH3 rat pituitary tumor cells produce GH and prolactin (PRL), but lack the GHRH receptor (GHRH-R). We expressed human GHRH-R (hGHRH-R) in GH3 cells using recombinant adenoviral vectors and studied the effects of GHRH antagonists. The mRNA expression of the GHRH-R gene in the cells was demonstrated by RT-PCR. An exposure of the GH3 cells infected with hGHRH-R to 10(-10), 10(-9) and 10(-8) m hGHRH for 1 or 2 h in culture caused a dose-dependent elevation of the intracellular cAMP concentration and the cAMP efflux. Exposure to hGHRH also elicited dose-dependent increases in GH and PRL secretion from these cells. Neither the uninfected nor the antisense hGHRH-R-infected control cells exhibited cAMP, GH and PRL responses to GHRH stimulation. GHRH antagonists JV-1-38 and jv-1-36 applied at 3x10(-8) m for 3 h, together with 10(-9) m GHRH, significantly inhibited the GHRH-stimulated cAMP efflux from the hGHRH-R-infected cells by 36 and 80% respectively. The more potent antagonist JV-1-36 also decreased the intracellular cAMP levels in these cells by 55%. Exposure to JV-1-36 for 1 h nullified the stimulatory effect of GHRH on GH secretion and significantly inhibited it by 64 and 77% after 2 and 3 h respectively. In a superfusion system, GHRH at 10(-10), 10(-9) and 10(-8) m concentrations induced prompt and dose-related high cAMP responses and smaller increases in the spontaneous GH secretion of the hGHRH-R-infected cells. Antagonists JV-1-36 and JV-1-38 applied at 3x10(-8) m for 15 min, together with 10(-9) m GHRH, inhibited the GHRH-stimulated cAMP response by 59 and 35% respectively. This work demonstrates that GHRH antagonists can effectively inhibit the actions of GHRH on the hGHRH-R. Our results support the view that this class of compounds would be active clinically.

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C S Kovacs, C L Chik, B Li, E Karpinski and A K Ho

Abstract

Pituitary adenylate cyclase-activating peptide (PACAP) and vasoactive intestinal peptide (VIP) share 68% homology and function as neurotransmitters or neuroendocrine factors. Although VIP immunoreactivity has been detected in bone cells, the presence of PACAP or PACAP receptors in bone has not been determined. In this study, we investigated the role of PACAP and VIP in regulating cAMP accumulation in the UMR 106 osteoblast-like tumor cell line.

PACAP 27 (10−9 to 3 × 10−7 m), PACAP 38 (10−9 to 3 × 10−7 m) and VIP (10−8 to 10−6 m) stimulated cAMP accumulation up to eightfold. PACAP 27 was slightly more potent than PACAP 38, and both were tenfold more potent than VIP. Both PACAP- and VIP-stimulated cAMP accumulation were potentiated by 4β-phorbol 12-myristate 13-acetate, an activator of protein kinase C. Two PACAP antagonists, PACAP 6–27 (3 × 10−6 m) and PACAP 6–38 (3 × 10−6 m), blocked PACAP- and VIP-stimulated cAMP accumulation. Two VIP antagonists ([Lys1,Pro2,5,Arg3,4,Tyr6]-VIP, and 4 Cl-d-Phe6,Leu17]-VIP) did not reduce the PACAP-or VIP-stimulated cAMP accumulation. Pretreatment with PACAP 27, PACAP 38 or VIP equally blocked PACAP- and VIP-stimulated cAMP accumulation.

These results suggest that PACAP is a more potent stimulator of cAMP accumulation than VIP in UMR 106 cells. PACAP and VIP may share a role in the paracrine or neuroendocrine regulation of bone metabolism.

Journal of Endocrinology (1996) 149, 287–295

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E Pap, K Racz, JK Kovacs, I Varga, E Buzas, B Madarasz, C Foldes, C Szalai, T Watanabe, H Ohtsu, A Ichikawa, A Nagy and A Falus

Histamine is synthesized in cells by histidine decarboxylase (HDC). HDC-deficient knockout (KO) mice lack functional HDC and histamine in the tissues. In the present study we used this in vivo model for studying the role of HDC deficiency in the regulation of male steroid hormone metabolism. In agreement with earlier studies showing the lack of effects of central histamine on the basal secretion of gonadotrope hormones, we found no difference with in situ hybridization in the expression of GnRH in the hypothalamus of wild type and KO mice. The tissue concentrations of testosterone and several androgenic steroids were significantly elevated in the testes but not in the adrenal glands of HDC-KO mice. In contrast, serum estradiol levels failed to show a significant difference between the two groups. The weight of the testes was significantly smaller in both 7-day-old and adult KO mice. The ultrastructure of the adult testis indicated elevated steroid synthesis with more tightly coiled membranous whorls in Leydig cells. The present results suggest that changes in reproductive functions and sex steroid secretion in male HDC-KO mice are not due to altered hypothalamic GnRH expression but are probably related to definite modifications during fetal development of KO mice reinforced later by the lack of the effect of peripheral histamine. This may provide in vivo evidence that peripheral histamine is an important regulatory factor of male gonadal development during embryogenesis and of sex steroid metabolism later in adulthood.