Abstract: This report describes a model of steroid transport in human plasma. The binding affinities of 21 endogenous steroids for both testosterone-binding globulin (TeBG) and corticosteroid-binding globulin (CBG) were determined under equilibrium conditions using a solid phase method at physiological pH and temperature. A computer program was used to solve the complex equilibrium interactions between these steroids and TeBG, CBG, and albumin. In this manner, we calculated the plasma distribution of each steroid into TeBG-bound, CBG-bound, albumin-bound, and unbound fractions in normal men, normal women during both the follicular and luteal phases of the ovarian cycle, and women during the third trimester of a normal pregnancy.

Abstract: Data are discussed which demonstrate that insulin plays an important role in sodium metabolism. The primary action of insulin on sodium balance is exerted on the kidney. Increases in plasma insulin concentration within the physiological range stimulate sodium reabsorption by the distal nephron segments and this effect is independent of changes in circulating metabolites or other hormones. Several clinical situations are reviewed: sodium wasting in poorly controlled diabetics, natriuresis of starvation, anti-natriuresis of refeeding and hypertension of obesity, in which insulin-mediated changes in sodium balance have been shown to play an important pathophysiological role.

Abstract: The steroid hormone, 1,25-dihydroxycholecalciferol (1,25-(OH)2D3) causes the de novo synthesis of a calcium-binding protein (D-CaBP)1,2 This protein is present in highest concentrations in intestine, kidney and shell gland, across which calcium is transported in relatively large amounts, but it is also found in smaller amounts in several other tissues, including brain3–7 The area of brain with the highest D-CaBP concentration is the cerebellum, where the protein is found only in the Purkinje cells7,8 We have now mapped D-CaBP immuno-histochemically throughout the brain of chicks and rats and present here a list of all positive nuclei Because certain of these neurones also contain 1,25-(OH)2D3 (ref 9), we suggest that they are target cells for this hormone, thus broadening the functional significance of vitamin D to include the brain and implicating vitamin D in a more widespread action than simply a role in the calcium translocation mechanism of epithelial cells

Abstract: THE GLYCOPROTEIN hormone TSH is the major regulator of the secretion of thyroid hormones (T4 and T3) from the thyroid gland. As the regulator of thyroid hormone release it plays an important, albeit indirect, role in the control of a variety of metabolic processes including protein synthesis, carbohydrate metabolism, thermogenesis, and cell growth. Historically, the concept of pituitary control of the thyroid gland stretches back to the observations of Niepce (1) in 1851 that cretins had markedly enlarged pituitary glands and of Rogowitsch (2) in 1889, who observed hypertrophy of the anterior pituitary after thyroidectomy in the rabbit. This concept was firmly established by the studies of Smith (3, 4) between 1916 and 1922, when he showed that ablation of the tadpole adenohypophysis resulted in thyroid attrition and prevented metamorphosis and that the atrophied thyroid gland could be made to hypertrophy by injections of beef anterior pituitary extracts.

Abstract: We infused epinephrine, glucagon, and cortisol in combination into health y overnight-fasted subjects in doses designed to simulate changes in severe stress. Whenall three hormones were infused simultaneously, glucose levels rose above 200 mg/dl in spite of a 100–200% increase in plasma insulin. In contrast, infusion of each hormone individually produced eithera mild (<120 mg/dl) or a transient elevation in the plasma glucoseconcentration. With the combined hormone infusion,the increment in plasmaglucose was 3-fold greater than the sum of the responses to the individual hormones (< 0.001). The marked hyperglycemia in this setting is a resultof ongoing glucose overproduction which is stimulated by epinephrine and glucagon and sustained by cortisol. Furthermore, epinephrine(and possibly cortisol) inhibited glucose disposal despite concomitant hyperinsulinemia. In contrast to their effects on glucoseregulation, the simultaneous infusion of epinephrine, glucagon, and cortisol failed to cause hyperketonemia. W...

Abstract: Recent studies have provided major new insights into the syndromes ofinappropriate secretion of thyroid-stimulating hormone(TSH), a heterogeneous group of disorders in which patients show

Abstract: Juvenile hormone (JH) is produced by the corpora allata (CA) of insects. It regulates development and reproduction and also plays a crucial role in polymorphism. These functions have been amply reviewed (13, 21, 23, 29, 30, 112, 141). However, little information is available on the mechanisms of these effects, mainly because of the difficulty in interpreting the results of in vivo experiments. For example, the experimental insect is often treated with JH or a JH analogue, but the exogenously supplied JH may interact with other insect hormones such as ecdysone and neurosecretory hormones (68), may be metabolized rapidly, and may interfere with endocrine feed­ back loops. An unequivocal explanation of the role of JH in insect development and reproduction will be obtained only with an approach in vitro, in which these disadvantages play no role. As suitable organ and tissue culture systems for insects have become available during the last few years, the mechanism of JH action may soon be resolved. The effect of any hormone is actually determined by three factors (29): (a) The concentration of the circulating hormone, i.e. the hormone titer, (b) The interaction between hormone and cellular receptors, and (c) Regu­ lation by the hormone or hormone-receptor complex of transcriptional,

Abstract: In rats subjected to thyroidectomy there was a two- to fourfold increase in cerebral cortex iodothyronine 5'-deiodinase activity within 24 hours. This increase was prevented by thyroxine replacement. The increased cortical 5'-deiodinase in chronically hypothyroid rats was normalized within 4 hours by a single intravenous injection of triiodothyronine. These results indicate that the adult central nervous system can give a very rapid biochemical response to thyroid hormone.

Abstract: Continuous cell lines have been established from a variety of biopsy and postmortem species of tumor from patients with small-cell carcinoma of the lung (SCCL) and have been maintained over several years. The medium from the cultures has been assayed for peptide, glycoprotein, and steroid hormones. Significant amounts of 14 hormones including calcitonin, adrenocorticotropin (ACTH), parathormone, luteinizing hormone, chorionic gonadotropin, glucagon, growth hormone, somatostatin, prolactin, beta-endorpin, lipotropin, oxytocin-neurophysin, vasopressin-neurophysin, and estradiol have been demonstrated. Up to ten different hormones have been produced by a single cell line. Most produce ACTH and all evaluated so far produce estradiol. These studies indicate that cells from SCCL have a potential for producing a wide variety of hormones and that this characteristic can be maintained for prolonged periods of culture in vitro.

Abstract: Although the volume of the sexually dimorphic nucleus of the preoptic area (SDN-POA) of the adult rat has been shown to be modified by the hormone environment early in postnatal life, the present study was performed to clarify several fundamental questions related to this process. This study was designed to evaluate the ability of exogenous testosterone propionate (TP), or a gonadal graft, to influence SDN-POA volume in rats which were gonadectomized as neonates. Orchidectomy on day 1 resulted in an approximately 50% decrease in adult SDN-POA volume; however, the influence of the testes on their resulting SDN-POA volume was replaced affectively by the administration of 100 micrograms or 1 mg of TP on postnatal day 2 or by a testicular (but not ovarian) graft on the day of castration. In the female, ovariectomy on postnatal day 1 failed to alter SDN-POA volume relative to that of sham-operated females. Exogenous TP, but neither testicular nor ovarian grafts, resulted in a larger SDN-POA volume when observed in the adult female. Thus, the development of the SDN-POA of the neonatal male is significantly influenced by the hormonal activity of the testes at this time period. While the SDN-POA of the neonatal female is potentially responsive to androgen, the role played by the ovaries in the development of the SDN-POA remains unclear. In addition, the different response of the developing male and female SDN-POA to a testicular graft suggests that the hormonal sensitivity of this nucleus may differ in the two sexes.

Abstract: SYNOPSIS. In many species, social interactions rapidly modulate circulating hormone levels in the male. Sexual interaction or mere exposure to a conspecific female results in rapid, transient elevation of both plasma luteinizing hormone and testosterone concentrations in a variety of species. In contrast, aggressive interactions result in decreased plasma gonadotropin and testosterone levels and increased levels of adrenal corticoids. In general, these changes are more profound and of longer duration than those accompanying sexual interactions, particularly among subordinate males. These fluctuations in circulating hormone levels appear to be related to an individual's behavioral responsivity. For example, plasma concentrations of luteinizing hormone during a social encounter are positively correlated with the degree of sexual arousal shown by a male during the interaction. Similar correlations have been found between plasma androgen or corticoid levels and patterns of behavior shown by males during both sexual and aggressive interactions. The causal relationship between such rapid hormone fluctuations and behavior remains unclear. Are fluctuating hormone levels causing differences in behavior or aredifferent patterns of behavior causing differences in plasma hormone levels between males? Or is the correlation between these two variables caused by their relationship to another unidentified factor? There are some data favoring the first possibility. Increasing the magnitude of socially induced hormone fluctuations during an aggressive encounter or preventingsuch fluctuations entirely significantly alters an animal's behavior. These data suggest that the endocrine system may play a more important role in an individual's minute-to-minute response to critical social stimuli than was previously realized.

Abstract: The treatment of obesity by intestinal bypass provides a unique model for the investigation of gut hormone release from the functionally deranged bowel. We have examined the postprandial response of eight circulating gut or pancreatic peptide hormones in 16 preoperative obese patients, 20 patients with jejunoileal bypass, 38 patients with biliopancreatic bypass and 13 age and sex-matched controls. Basal and post-meal hormone concentrations were determined by specific radioimmunoassay methods. Reductions of the upper small intestinal hormones, motilin and gastric inhibitory polypeptide were found in both types of surgery. Conversely, the ileal hormones neurotensin and enteroglucagon were elevated following surgery. This pattern is consistent with the known distribution of these hormones. Variations of response due to surgical differences were noted for gastrin and the enteropancreatic axis, which was more markedly disturbed after biliopancreatic bypass. The alterations of hormone release closely reflect the anatomical changes induced by each particular surgical technique.

Abstract: We have attempted to ascertain the proportion of the rat hepatic genome that is under the selective influence of thyroid hormones and to describe the response patterns of individual mRNA sequences in the transition between hypothyroidism and euthyroidism and between euthyroidism and hyperthyroidism. Poly(A)+RNA was extracted from livers of thyroidectomized, intact, euthyroid rats and of thyroidectomized rats rendered euthyroid and hyperthyroid with daily doses of triiodothyronine. The extracted RNA was translated in a reticulocyte lysate system in the presence of [35S]methionine, and the products were analyzed by two-dimensional gel electrophoresis. Triiodothyronine attenuates as well as augments the expression of certain genes at a pretranslational level. This could represent either a direct or an indirect action of the hormone. Triiodothyronine influences approximately 8% of the 231 mRNA sequences visualized, stimulating activity in 11 and inhibiting activity in 7 sequences. Translational activity of at least one mRNA sequence decreased in both thyroidectomized and hyperthyroid animals, compared to euthyroid levels. The relationship of mRNA response to receptor occupancy varied with examples of linear and amplified responses and responses that were maximal at less than full nuclear occupancy.

Abstract: The metabolism of 4-[4-14C]androstene-3,17- dione was studied in the microsomal fraction of rat livers after continuous administration of human GH (hGH) in Alzet osmotic minipumps under varying conditions. hGH caused a complete feminization of hepatic steroid metabolism (i.e. increased the 5α- reductase and decreased the 6β- and 16α-hydroxylase activities) in normal male rats when infused at a rate of 5 μg/h for 7 days. Hypophysectomy and castration or adrenalectomy and thyroidectomy of male rats did not reduce the feminizing capacity of hGH, indicating that the adrenals and the thyroid gland are not involved in the mediation of the feminizing effect of hGH. The same dose (5 μg/h for 7 days) of hGH was also able to refeminize the liver steroid metabolism in hypophysectomized-ovariectomized female rats. The effect of the homologous hormones, rat PRL and rat GH on hepatic steroid metabolism was also investigated. Either hormone was infused at a rate of 10 μg/h for 7 days, a dose which was sufficient to incr...

Abstract: Publisher Summary This chapter discusses the current status of the chemistry, biology, and clinical applications of the well-defined thymic hormones. The first biologically active polypeptide to be isolated from among the highly acidic components of bovine thymosin fraction 5 has been termed thymosin α1. This peptide is highly active in amplifying T-cell immunity and is active in modulating the expression of terminal deoxynucleotidyl transferase. The ultimate application of the thymosins and other thymic hormones and factors in cancer treatment should be in providing a means of safely augmenting specific T lymphocyte functions in patients with diminished thymic-dependent immunity. In anergic cancer patients, thymic hormones may be of importance as an adjunct to conventional treatments by increasing T-cell function in response not only to tumor cells but also to pathogens, thus reducing the high incidence of infection that often accompanies cancer treatment.

Abstract: A FALL in blood glucose to hypoglycemic levels usually triggers a prompt release of catecholamines, glucagon, growth hormone, and cortisol. These so-called counterregulatory hormones are believed t...

Abstract: We have investigated the effect of the D-Trp6 analogue of luteinizing hormone-releasing hormone (LH-RH), a superactive analogue of LH-RH, on the growth of two different models of prostate tumors in rats. Chronic administration of D-Trp6-LH-RH in a dose of 25 micrograms/day for 14-21 days significantly inhibited the growth of the chemically induced squamous cell carcinoma 11095 in Fisher 344 male rats. The weights of the ventral prostate and testes were also significantly reduced by treatment with this analogue. After 21 days of treatment, the animals no longer showed increases in serum luteinizing hormone and follicle-stimulating hormone levels in response to D-Trp6-LH-RH. Treatment of male Copenhagen F-1 rats bearing the Dunning 3327 prostate adenocarcinoma with 25 micrograms of D-Trp6-LH-RH per day for 42 days decreased the weights of both the ventral prostate and testes but had no effect on the weight of the anterior pituitary gland. The percentage increase in tumor volume was decreased to one-third and the actual tumor weight was decreased by 58% compared to untreated controls. The tumor doubling time was more than 4 times longer in rats receiving D-Trp6-LH-RH than in controls. Serum levels of luteinizing hormone and follicle-stimulating hormone were significantly decreased in rats receiving this analogue. In both Fisher 344 and Copenhagen F-1 rats, serum prolactin and testosterone levels were significantly decreased after treatment with D-Trp6-LH-RH, whereas progesterone levels were increased.

Abstract: It is apparent that pituitary gonadotropin release changes quantitatively during various endocrine states, such as those found during ovarian cyclicity, lactation, aging, and ovariectomy. In the present work, we have used a radioligand prepared from a nondegradable, superagonist of gonadotropin-releasing hormone (GnRH) to determine the number and binding affinity of GnRH receptors during these endocrine states. While receptor affinity was unaltered (range 1.6-2.7 x 1O10 M-1), marked differences were observed in the receptor number throughout the estrous cycle [maximal in late diestrus II and proestrus immediately preceding the luteinizing hormone (LH) spike]. Lactating animals and old animals also had diminished concentrations (number per milligram of protein) of GnRH receptors as compared with young precycling females. Ovariectomy increased the number of receptors, and injections of estradiol benzoate to ovariectomized animals reversed this increase within 3 hr. Throughout the study, elevated receptor numbers were generally associated with elevated LH levels, although this alone did not appear to be sufficient for increased LH secretion. The present results suggest that regulation of the GnRH receptor may be one mechanism through which gonadotrope sensitivity is regulated.

Abstract: The Bio Breeding/Worcester (BB/W) rat develops spontaneous insulin-dependent diabetes mellitus secondary to lymphocytic infiltration and destruction of the pancreatic beta-cells. This destructive process in the pancreas has been postulated to be based on a thymus-dependent cell-mediated autoimmune process. In view of the well recognized association in man of diabetes mellitus and another autoimmune endocrinopathy, chronic thyroiditis (Hashimoto's thyroiditis), the present studies were carried out to determine whether lymphocytic thyroiditis occurred with increased frequency in the diabetic, insulin-treated BB/W rat. The incidence of lymphocytic thyroiditis was strikingly increased in 8-10-mo-old diabetic rats (59%) as compared with their nondiabetic cohorts (11%) (P less than 0.001). Relative thyroid weight was significantly greater in diabetic as compared with nondiabetic rats (P less than 0.01) and in diabetic rats with thyroiditis than in diabetic rats without thyroiditis (P less than 0.025). Lymphocytic thyroiditis was not accompanied by any consistent changes in serum T4, T3, and TSH concentrations or in the serum TSH response to thyrotropin-releasing hormone (TRH) suggesting that the thyroiditis was not of sufficient severity or duration to induce primary thyroid gland failure. The BB/W rat represents the first animal model of multiple autoimmune endocrinopathies and provides a unique opportunity to study the pathogenesis of these disorders.

Abstract: MANY polypeptide hormones, prostaglandins, and catecholamines exert their physiological (and pathophysiological) effects by increasing intracellular cAMP concentration in their respective target cells. The first step in hormone action, binding to a specific plasma membrane receptor, leads to activation of the membranebound enzyme AC1 and formation of cAMP. Understanding how hormones activate AC, then, is central to understanding the mechanism of hormone action. Studies from numerous laboratories performed over the past decade have begun to clarify this problem. One of the major concepts to emerge from these studies is that guanine nucleotides (GN) play a critical role in mediating the effects of hormones on AC. This review will focus on the involvement of GN in regulation of hormone receptor-AC interaction. We will 1) detail the evidence that GN are required for hormonal stimulation of AC; 2) describe experiments showing that GN interact with a G unit2 and that the G unit is a discrete component of the AC...

Abstract: Epithelial cells isolated from rat intestine were analyzed for their responsiveness in vitro to parathyroid hormone (PTH) and to 1,25-dihydroxycholecalciferol [1,25-(OH)2D3]. Criteria included determination of whether the agonists promoted extracellular liberation of lysosomal enzyme activities above control values during incubation in Ringer's solution at 22 C. PTH-augmented release of the representative hydrolase activities, cathepsin B and acid phosphatase, to the particle-free supernatant fraction of the medium was evident within 5 min of hormone treatment and was sustained in statistically significant degree for at least 30 min to greater than 20% above control levels. Basal release rarely exceeded 15% of the total cellular content of these enzymic activities. Lactate and succinate dehydrogenase activities were undetectable in the particle-free supernatant fraction under conditions of maximal hormone effect, indicating integrity of the cells and selectivity of the organellar response. Treatment of corresponding cells with 1,25-(OH)2D3 resulted in similar time of onset, magnitude, and duration of response. The most sensitive indicator of limited lysosomal labilization by either hormone was beta-N-acetyl-D-glucosaminidase activity, which underwent accentuated extracellular liberation in the presence of as little as 10(-16) M PTH or 10(-11) M 1,25-(OH)2D3, the latter eliciting a response of greater than 40% above control levels. Parathyroidectomy diminished basal release of the hydrolase activities and sensitized the intestinal cells to the action of PTH vs. preparations from intact or sham-operated animals, as judged by excess liberation of the glycosidase. Nontarget lung cells failed to respond to supramaximal levels of either hormone by the criterion of reduced latency of lysosomal hydrolases. In additional acute experiments with intestinal cells, both PTH and 1,25-(OH)2D3 promoted enhanced 45Ca2+ accumulation above control values. Collectively, these data indicate that PTH is capable of provoking direct effects on intestinal cells, similar in onset and extent to those elicited by 1,25-(OH)2D3.