The diabetes syndrome of the BB rat resembles human Type 1 (insulin-dependent) diabetes including the prevalence of autoantibodies to the 64 kDa Beta-cell autoantigen, which has been identified as glutamate decarboxylase. This study aimed at detecting the prevalence and level of glutamate decarboxylase autoantibodies in 120-day-old diabetic and non-diabetic diabetes-prone BB/OK rats compared to those of sex- and age-matched diabetes-resistant LEW.1A rats. The antibodies were detected using semipurified glutamate decarboxylase from rat brain in two immunoassays, a direct and a sandwich enzyme-linked immunosorbent assay. For the last assay autoantibody-containing immunoglobulins of a serum from a patient with the stiff-man syndrome were used to bind specifically the enzyme as autoantigen in plastic wells. The antibody levels measured as optical density at 490 nm (x +/- SD)/prevalence of the diabetic group (120 +/- 29 days of age) of BB/OK rats 0.57 +/- 0.29 (n = 51)/88% as well as those of the nondiabetic group (121 +/- 26 days of age) with 0.51 +/- 0.29 (n = 32)/97% was significantly increased (p < 0.01) compared to those of the diabetes-resistant control group 0.15 +/- 0.06 (n = 29)/0%. Furthermore in a 209 +/- 27-day-old group (n = 21) of non-diabetic but diabetes-prone BB/OK rats the autoantibody levels of 1.21 +/- 0.39 vs 0.51 +/- 0.26 were further significantly enhanced (p < 0.01). These results were confirmed by a sandwich assay.(ABSTRACT TRUNCATED AT 250 WORDS)

Two new markers of bone resorption, the collagen cross-linking amino acids pyridinoline (PYD) and deoxypyridinoline (DPD), were measured in 24-h urine collections from 88 healthy children (45 females, 43 males; age 4 to 18 years) and 17 adults. Normal values for pediatric use were established for these parameters. Related to daily excretion of creatinine PYD and DPD were about 3 to 6 fold higher in the pediatric groups than in adults. The collagen cross-links showed a highly significant correlation to the urinary excretion of hydroxyproline (OHP): r = 0.65 for PYD and r = 0.60 for DPD (p < 0.001). Both collagen cross-links and OHP excretion related to creatinine were significantly correlated to growth velocity (r = 0.67, 0.62 and 0.51 for PYD, DPD and OHP respectively; p < 0.001 in each case). PYD and DPD may be useful for the monitoring of growth in children.

We report about a male patient, who underwent bilateral total adrenalectomy due to ACTH-dependent Cushing's syndrome without pituitary adenoma in his 11th year of life. Symptoms of Cushing's disease were absent during the follow-up period. Height and body weight followed the percentiles 25 and 50 respectively. An endogenous cortisol production was not detected and steroid substitution became necessary. Five years after the surgery, he showed normal cortisol levels, but there was no cortisol increase under ACTH-loading. Nine and 12 years (1993) after surgery, we found normal, physiological levels of cortisol suggestive of normal functioning adrenal glands (day profile of cortisol, Liddle-Test, ACTH-Test, CRH-Test, cortisol excretion in 24-h-urine). Moreover, baseline ACTH and its rise under CRH stimulation were normal. Scintigraphy revealed normal-sized adrenal tissue in orthotopic position on both sides. Steroid supplementation was discontinued. Presently the patient is healthy, active and under no steroid therapy. No evidence of residual or relapsing Cushing's disease or Nelson's syndrome has been found up to this point.

The three isozymes catalyzing deiodination of thyroid hormones and iodothyronines derived thereof exert a major role in tissue- and development-specific expression of thyroid hormone action in target tissues by activating the prohormone T4 to thyromimetically active T3 or by inactivating the prohormone T4 or active T3 in non-target tissues at inappropriate time points. These three isozymes, in cooperation with the enzymes responsible for non-deiodinative degradation of iodothyronines, thus act as "guardians of the gate" to nuclear thyroid hormone receptors and other cellular target sites for thyroid hormone action. Strict and distinct hormonal, nutritional and nerval regulation of expression of the deiodinase isozymes warrants a closely coordinated control of thyroid hormone action, which directs growth, differentiation, and basal metabolic functions in the developing and the adult organism both in the periphery and in the central nervous system. The integrative action of this essential homeostatic and dynamic ancient hormone system in higher vertebrates is under the influence of two essential trace elements, iodine and selenium, which both are inadequately available for man and life stock in great parts of the world. As soon as, and only if, iodine supplementation is achieved, attempts to establish adequate selenium supply for thyroid hormone synthesis, activation, metabolism and action should be made, but not the other way around. In this review, the physiological, biochemical and pharmacological properties of the three deiodinase isozymes are discussed in detail, with special attention to the role of selenium in regulation of type I 5'-deiodinase expression. The contribution of each deiodinase izozyme to the activation and inactivation of thyroid hormones in specific tissues is reviewed.

The response of the adrenal cortex to a stressor consisting of information about a surgery to be performed the following day was studied in 34 patients by monitoring changes in salivary cortisol. From those, 18 patients were subjected to an individually selected 1 h music program, applied immediately following receipt of the information, and the remaining 16 patients formed a reference group. Another 10 patients, not awaiting surgery, served as controls. Saliva was sampled before the stressor and 5 more samples were collected at 15 min intervals. The stressor produced a 50% rise in salivary cortisol within 15 min. In patients not exposed to music, cortisol levels gradually decreased but after one hour they were markedly higher than the initial level. Listening to music resulted in a marked reduction in salivary cortisol level and after one hour the relative decrease was similar to that observed in control (non-surgical) patients.

The influence of thyroid state on left ventricular systolic function was studied in 11 patients (5 men, 6 women, aged 20-55 years) without cardiac disease, who had undergone total thyroidectomy and radioiodine treatment for thyroid cancer before. Pulsed-wave Doppler echocardiographic measuring of aortic blood flow and two-dimensional/time-motion (2D/M-mode) echocardiography were performed on two occasions once while the patients were mildly hyperthyroid on thyroxine replacement therapy and once when they were hypothyroid. During hypothyroidism left ventricular end-diastolic diameter decreased from 48 +/- 5 mm to 46 +/- 5 mm (p < 0.05). The diameter of the aortic ring, the left ventricular end-systolic diameter, the thickness of the interventricular septum and posterior wall, and fractional shortening did not differ significantly between the two studies. The following parameter of aortic blood flow changed significantly when passing from the hyperthyroid to the hypothyroid state: peak velocity (0.86 +/- 0.15 m/s versus 0.72 +/- 0.15 m/s, p < 0.01); mean velocity (0.49 +/- 0.08 m/s versus 0.44 +/- 0.08 m/s, p < 0.01); time- velocity integral (14.1 +/- 3.0 cm versus 12.3 +/- 3.1 cm, p < 0.05); stroke volume (43.0 +/- 9.7 ml versus 35.2 +/- 8.2 ml, p < 0.05); and preejection period (124 +/- 23 ms versus 147 +/- 21 ms, p < 0.01). Peak acceleration, mean acceleration, acceleration time and left ventricular ejection time did not change when the thyroid state was altered. It is concluded that left ventricular contractile function was not affected by acute hypothyroidism.(ABSTRACT TRUNCATED AT 250 WORDS)

The case of a 53 year old female patient with metastasized androgen producing adrenocortical carcinoma is presented. After initial adrenalectomy a local relapse had been treated by surgery and external irradiation. Solitary liver metastases had been resected repeatedly. Subsequently multiple liver metastases required systemic chemotherapy. Treatment with o,p'-DDD (initially 12 g/d, long term treatment 1.5-3 g/d) has resulted in a complete remission for nearly 4 years. Gastrointestinal side effects occurred initially but subsided with dose reduction of o,p'-DDD.

Inflammatory bowel disease (Crohn's disease and ulcerative colitis) is associated with decreased bone mineral density and increased risk of osteoporosis. However, the pathogenesis of this bone loss is not yet fully understood. In the present study we measured lumbar bone mineral density (by dual photon absorptiometry), serum levels of parathyroid hormone (PTH) and vitamin D metabolites, and serum markers of bone turnover (alkaline phosphatase and osteocalcin) in 15 patients with Crohn's disease and in 4 patients with ulcerative colitis. The median duration of the disease was 4 years and the median lifetime steroid dose was 10g of prednisone. We compared our results to a control group of 19 normal persons, who were matched for age and sex to the patients. We found that lumbar bone density was reduced by 11% in patients compared with control persons (Z-score -0.6 +/- 0.6 versus -0.1 +/- 0.8; p < 0.05). In patients, the serum levels of PTH, 25-hydroxyvitamin D3, and calcitriol (1,25(OH)2D3) were significantly reduced compared with control persons. Serum alkaline phosphatase activity (AP) was significantly higher in the patients and was inversely related to lumbar bone density. Osteocalcin values were not different between patients and control persons. There was also no difference in serum levels of calcium between the two groups, whereas phosphorus levels were higher in patients. We conclude that malabsorption of calcium was not a primary cause of bone loss in our patients, because we did not find secondary hyperparathyroidism. Accordingly, we did not find a severe vitamin D deficiency, since 25-hydroxyvitamin D3 levels were within the normal range.(ABSTRACT TRUNCATED AT 250 WORDS)

Time-resolved fluoroimmunoassay (TR-FIA), which has recently been developed as a non-isotopic immunoassay, was intended for assay of gonadotropins (LH and FSH). Ovine LH or FSH was labeled with N1-(p-isothiocyanatobenzyl)-diethylenetriamine-N1, N2, N3, N3-tetraacetic acid Eu-chelate (DTTA), and competitive binding assay was performed using a 96-weel titer plate previously coated with a second antibody, followed by measurement using time-resolved fluorometry. TR-FIA for standard ovine LH (NIDDK, LH-I-3) or FSH (NIDDK, FSH-I-1) had a sensitivity of about 25 pg/50 microliters sample. The assay system was applied to heterologous assay of porcine gonadotropins. Linearity was obtained by the dilution test using medium from primary culture of porcine anterior pituitary cells. Intra- and inter-assay coefficients of variation of LH and FSH determination in 31 different porcine samples were satisfactorily low, between 3.5 and 8.1% (intra-assay) and between 1.7 and 13.1% (inter-assay). Correlation coefficients between radioimmunoassay and TR-FIA were calculated to be 0.945 for LH and 0.978 for FSH. Stimulation of LH and FSH release with GnRH was observed by TR-FIA. This non-isotopic TR-FIA thus provides as good sensitivity, reproducibility and accuracy as conventional RIAs.

The evolution of specific nuclear transcriptional regulators has endowed tissues of the reproductive system with responsiveness to small hydrophobic compounds such as steroids. Steroids are widely distributed in Nature and their distribution in prokaryotes and eukaryotes has given rise to the concept that their hormonal role came about by target organ specialization and not by the evolution of steroids themselves. Specific nuclear receptors for progesterone in the uterus are prominent during the establishment and maintenance of pregnancy. Anti-progesterone antagonists which interfere with receptor-mediated DNA activation abrogate pregnancy and thus emphasize the functional importance of the pathways by which the effects of progesterone as an extracellular signal are transduced. Comparative studies show that progesterone itself can be ovarian or placental in origin. This seems to reflect the evolution of different mechanisms of endocrine function rather than any obvious selective advantage being associated with the source of hormone secretion. For this reason, the question of whether the endocrine function of the placenta is obligatory for the adoption of viviparity in mammals is far from certain, and should be considered as an evolutionary option rather than a sine qua non. Of growing importance is the idea that the interaction between trophoblast and endometrial cells controls the degree of invasiveness at implantation and immunoreactivity.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence has accumulated for the existence of local tissue renin-angiotensin systems in the reproductive tissues. In the ovary the local renin-angiotensin system (RAS) has been shown to influence ovulation and steroidogenesis. In this review we focus on aspects of a local RAS in the uteroplacental unit. High renin concentrations have been found in all tissues of the uteroplacental unit. The presence of renin mRNA in the endometrium, choriodecidua and the fetal part of the placenta indicates local renin synthesis. Angiotensin (Ang) II, formed by the enzymatic action of tissue renin and Ang I converting enzyme, acts by interaction with its receptors. These receptors have been demonstrated in high densities in the placenta and uterus, indicating an autocrine or paracrine action of Ang II. Several probable effects of the uteroplacental RAS can be defined. It is very likely that the uteroplacental RAS plays an important role during implantation and placentation by stimulation of decidualization and angiogenesis. Furthermore, Ang II may regulate synthesis and secretion of other hormones formed locally in the uteroplacental unit. During labour the action of Ang II may be important for contraction of the uterine musculature, Ang II is also involved in the complex regulation of the uteroplacental blood flow. Species difference in the expression of the uteroplacental RAS exists, and one may speculate that the physiological and pathophysiological roles vary between species.

Removal of the pituitary from pregnant rats provided early evidence that the placenta was the source of prolactin-like bioactivity. After mid-pregnancy the placenta was able to support progesterone production by the corpus luteum (luteotrophic activity) and continued development of the mammary gland (mammotrophic activity). Three groups of mammals, the rodents, the ruminant artiodactyls and the primates are now known to produce from fetal placenta a remarkable variety of proteins which are related in structure to pituitary prolactin and growth hormone. Prolactin and growth hormone are themselves structurally related and are thought to have arisen from a common ancestral gene by gene duplication and evolutionary divergence. The receptors with which they interact also form a family of homologous proteins. Surprisingly the placental lactogens appear to have arisen more than once in evolution since in primates they are structurally closely related to growth hormone, while in rodents and ruminants they have closer similarity to prolactin. There is suggestive evidence that there may be specific receptors for placental lactogens in some fetal and maternal tissues. In humans a five-gene cluster on chromosome 17 contains two growth hormone (GH) and three placental lactogen (PL) genes. Two human PL genes encode identical proteins that are expressed in the placenta. One of the human GH genes is also placentally expressed. In mice, chromosome 13 carries the genes for mouse prolactin, for placental lactogen-I and -II (PL-I and PL-II) and for two other prolactin-related proteins, the proliferins. Rats also express PL-I and PL-II, together with at least three other placental prolactin-like proteins different from proliferins.(ABSTRACT TRUNCATED AT 250 WORDS)

Chorionic gonadotrophins seem to be unique for primate and equid species. Unlike primates, the equine conceptus does not implant in the maternal uterine endometrium until around day 37 of pregnancy. At this time specialized cells of the trophoblast, organized in the embryonic girdle, invade the endometrium and become established in the endometrial stroma, forming the so-called endometrial cups. This migration of girdle cells is accompanied by their morphological transformation into large decidual-like cells and by the appearance of a gonadotrophic hormone in the mare's blood. There is convincing evidence today that the hormone is of chorionic origin; therefore the term equine Chorionic Gonadotrophin (eCG) seems to be more appropriate than the formerly used term Pregnant Mare Serum Gonadotrophin (PMSG). Secretion of eCG peaks between days 60 and 80 in pregnant mares, to decline gradually until day 130 of gestation, with pronounced inter-individual variation. There appear to be no hormonal regulatory mechanisms controlling eCG synthesis and secretion, suggesting that the size and the morphology of the endometrial cups are the limiting factors. Equine CG is a glycoprotein hormone, composed of noncovalently bound alpha- and beta-subunits. The alpha-subunit consists of 96 amino acids and is identical for eCG and the pituitary hormones eLH, eFSH, and eTSH. The beta-subunit is similar to beta-hCG in that both have a C-terminal extension. It is comprised of 149 amino acids and the peptide primary structure is identical to that of beta-eLH.(ABSTRACT TRUNCATED AT 250 WORDS)