Pituitary Hormone Production Research Articles

Curcumin (Diferuloylmethane) Inhibits Cell Proliferation, Induces Apoptosis, and Decreases Hormone Levels and Secretion in Pituitary Tumor Cells

Prolactinomas are the most prevalent functional pituitary adenomas. Dopamine D2 receptor (D2R) agonists, such as bromocriptine are the first line of therapy; however, drug intolerance/resistance to D2R agonists exists. Apart from D2R agonists, there is no established medical therapy for prolactinomas; therefore, identifying novel therapeutics is warranted. Curcumin, a commonly used food additive in South Asian cooking, inhibits proliferation of several tumor cell lines; however, its effect on pituitary tumor cell proliferation has not been determined. Our objectives were to: 1) determine whether curcumin inhibits proliferation of pituitary tumor cell lines; 2) identify the signaling intermediaries that mediate the effect of curcumin; 3) examine whether curcumin inhibited pituitary hormone production and release; and 4) examine whether curcumin could enhance the growth-inhibitory effect of bromocriptine. Using rat lactotroph cell lines, GH3 and MMQ cells, we report that curcumin had a robust dose and time-dependent inhibitory effect on GH3 and MMQ cell proliferation. Inhibitory effects of curcumin persisted, even on removal of curcumin, and curcumin also blocked colony formation ability of pituitary tumor cells. The growth-inhibitory effect of curcumin was accompanied by decreased expression of cyclin D3 and ser 780 phosphorylation of retinoblastoma protein. In addition, curcumin also induced apoptosis in both GH3 and MMQ cells. Furthermore, curcumin suppresses intracellular levels and release of both prolactin and GH. Finally, we show that low concentrations of curcumin enhanced the growth-inhibitory effect of bromocriptine on MMQ cell proliferation. Taken together we demonstrate that curcumin inhibits pituitary tumor cell proliferation, induces apoptosis, and decreases hormone production and release, and thus, we propose developing curcumin as a novel therapeutic tool in the management of prolactinomas.

Rational Design of Competitive Prolactin/Growth Hormone Receptor Antagonists

There is increasing evidence that prolactin (PRL) and growth hormone (GH) act as growth-promoters of breast tumors. Recent arguments have accumulated to suggest that when they are locally-produced within the mammary tissue, these hormones, acting by an autocrine-paracrine mechanism may have enhanced, or even specific functions compared to endocrine PRL and GH. Classical drugs blocking pituitary hormone production (dopamine and somatostatin analogs) are ineffective on extrapituitary expression of PRL/GH genes, therefore the undesirable effects of these locally-produced hormones remain a target of interest for alternative strategies. This has encouraged the development of competitive PRL and/or GH receptor antagonists, which involve engineered variants of natural receptor ligands (PRL or GH) aimed at blocking receptor activation rather than hormone production in peripheral tissues. This article overviews the rational design of this new class of molecules, their specific molecular features (receptor specificity, biological properties, etc.) and whenever available, the data that have been obtained in cell or animal models of breast cancer.

Androgens modulate testicular androgen production in African catfish ( Clarias gariepinus) depending on the stage of maturity and type of androgen

Previous work showed that androgen treatment suppressed testicular steroidogenesis in juvenile African catfish Clarias gariepinus. Similar to other vertebrates, however, circulating androgen levels increase during puberty in catfish. We therefore studied if androgen-induced inhibition of androgen production decreases during sexual maturation. As in other vertebrates, testosterone (T) is found in the circulation in fish but typically, 11-ketotestosterone (11-KT) is the quantitatively dominating androgen. In previous studies with juvenile catfish, these two androgens showed different biological activities as regards spermatogenesis or pituitary hormone production, but were equally effective in suppressing testicular steroidogenesis. Hence, the second question we studied was if the two types of androgens show distinct effects on the steroidogenic system in pubertal or adult males. The inhibitory effect of 11-KT on the testicular steroidogenic capacity waned with progressing sexual maturation, while T-mediated inhibition remained strong until adulthood reducing the in vitro steroid production 4- to 10-fold. However, the gonadotropin responsiveness of testicular tissue was not compromised and expression of testicular gonadotropin receptors did not respond differently to the two androgens. We conclude that the selective disappearance of the inhibitory effect of 11-KT contributes to allowing the pubertal increase of the plasma level of this androgen.

Involvement of the calcium-binding protein secretagogin in pituitary adenoma hormone production

Calcium is a potent intracellular signal transducer whose fluctuations control numerous cellular processes among them hormone production. Secretagogin (SCGN) is an intracytoplasmatic protein belonging to the EF-hand calcium binding protein superfamily, which was initially isolated from a human pancreatic cDNA library and was shown to be involved in the regulation of insulin synthesis and secretion. Since SCGN was also detected in neuroendocrine cells in the anterior pituitary, we have studied the expression of SCGN both in normal and tumoral pituitary and have started to elucidate its role in pituitary cells. Our preliminary results obtained by Real time PCR analysis showed the expression of SCGN in a group of 4 normal human anterior pituitary glands and in 26 different pituitary adenomas. In the tumours, SCGN mRNA was downregulated in 2/4 somatotrophinomas, 6/7 nonfunctioning pituitary adenomas, 4/6 prolactinomas, 3/6 corticotrophinomas and 2/2 thyrotrophinomas when compared to the expression in normal pituitary tissue. The co-transfection of a rat SCGN expression plasmid with prolactin-luc reporter plasmid, GH-luc plasmid and POMC-luc reporter plasmid, respectively in mammosomatotroph GH3 cells and in corticotroph AtT-20 cells, showed that SCGN overexpression was able to induce a 46% increase in the activity of the prolactin gene promoter and a 60% increase in the activity of the GH gene promoter, while in AtT-20 cells the activity of POMC gene promoter showed an increase of 66%. The analysis of the different promoter elements showed an activation of CRE element in GH3 cells after SCGN plasmid co-transfection and an increase in cAMP production. In AtT-20 cells SCGN plasmid co-transfection was able to induce an increase in the activities of AP-1, Nbr-E and NurrRE elements, which was also accompanied by an increase in cAMP production. These preliminary findings suggest the involvement of SCGN in controlling the synthesis of pituitary hormones, therefore constituting a potential target for inhibiting the hormone production.

Cutis Laxa Associated with Central Hypothyroidism owing to Isolated Thyrotropin Deficiency in a Newborn

Cutis laxa is an uncommon entity characterized by laxity of the skin, which hangs in loose folds, producing an appearance of premature aging. It can be subdivided into congenital and acquired forms. Genetic forms of cutis laxa include at least three forms of recessive disease, an X-linked form also termed occipital horn syndrome and an autosomal dominant form. Isolated pituitary hormone deficiency can be induced by many causes including mechanical destruction of the hypothalamo-pituitary axis, neoplasm, inflammation, and injury and genetic defects of pituitary hormone production and secretion. Isolated-thyrotropin deficiency has been considered to be a rare disease. We report a newborn with autosomal recessive form of congenital cutis laxa, who had congenital hypothyroidism owing to isolated thyrotropin deficiency. To the best of our knowledge, this is the first instance of this association to be reported in the literature.

Immunohistochemical changes in production of pituitary hormones during artificial maturation of female Japanese eel Anguilla japonica

Specific antibodies against follicle-stimulating hormone β subunit (FSHs), prolactin (PRL), and somatolactin (SL) of the Japanese eel Anguilla japonica were produced. These antibodies, as well as antibodies against luteinizing hormone β subunit (LHs) and growth hormone (GH) produced previously, were used to examine changes in the production of pituitary hormones in female eels during maturation induced by salmon pituitary homogenate (SPH) injection. Immunohistochemical observations showed a decrease in FSH production after SPH injection, suggesting that SPH inhibits FSH production. In contrast, LH production increased markedly with maturation. The number of GH producing cells decreased gradually during maturation, possibly because of inhibition by exogenous GH present in the SPH and/or endogenous insulin-like growth factor-I produced by the stimulation of salmon GH. Although changes in the number of PRL producing cells with maturation were not evident, the number of SL producing cells showed a peak at the late vitellogenic stages, and thereafter decreased to the migratory nucleus stage. These results suggest that GH and SL are involved in sexual maturation in SPH injected eels, as in other fishes.

The natural history of the R120C PROP1 mutation reveals a wide phenotypic variability in two untreated adult brothers with combined pituitary hormone deficiency

Combined pituitary hormone deficiency (CPHD) corresponds to impaired production of growth hormone (GH) and other anterior pituitary hormones. The genetic form of CPHD may result from mutations in pituitary transcription factor genes, and PROP1 is the most commonly mutated gene in these cases. Patients with PROP1 mutations may have variable CPHD phenotypes but, because they are usually treated in childhood, the wide phenotypic variability caused by these mutations may not be thoroughly appreciated. Clinical follow-up and molecular analysis of PROP1 in two adult brothers with CPHD, born from consanguineous parents, and not treated until late adulthood. The homozygous R120C mutation was identified in the brothers. Their clinical follow-up showed a wide phenotypic variability: hypogonadism was severe and prevented pubertal development in both, but their final heights were remarkably different, pointing to different degrees in severity of GH/TSH deficiencies; cortisol deficiency developed late in both, but at least 10 yr apart. The lack of treatment in childhood and adolescence allowed the appreciation of the entire natural history of the CPHD caused by the R120C mutation, and it revealed a remarkable phenotypic variability even in siblings with a very similar genetic background.

High prevalence of PROP1 gene mutations in hungarian patients with childhood-onset combined anterior pituitary hormone deficiency

Combined pituitary hormone deficiency is characterized by the impaired production of pituitary hormones, commonly including growth hormone. The pathomechanism of the childhood-onset form of this disorder may involve germline mutations of genes encoding pituitary transcription factors, of which PROP1 gene mutations have been studied most extensively. However, controversy exists about the significance of PROP1 gene mutations, as both low and high frequencies have been reported in these patients. Because the different results may be related to differences in patient populations and/or the variability of clinical phenotypes, we performed the present study to examine the prevalence and spectrum of PROP1 gene mutations in 35 patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone deficiency. Genetic testing indicated the presence of disease-causing mutations in exons 2 and 3 of the PROP1 gene in 15 patients (43% of all patients; homozygous mutations in 10 patients and compound heterozygous mutations in 5 patients). Comparison of clinical data of patients with and without PROP1 gene mutations failed to show significant differences, except an earlier growth retardation detected in patients with PROP1 gene mutations. In one patient with PROP1 gene mutation, radiologic imaging showed an enlargement of the anterior lobe of the pituitary, whereas the other patients had hypoplastic or normal pituitary gland. All patients with PROP1 gene mutations had normal posterior pituitary lobe by radiologic imaging. These results indicate that using our inclusion criteria for genetic testing, PROP1 gene mutations can be detected in a high proportion of Hungarian patients with non-acquired childhood-onset growth hormone deficiency combined with at least one other anterior pituitary hormone defect.

Regulation of Pituitary Cell Function by Adiponectin

Adiponectin is a member of the family of adipose tissue-related hormones known as adipokines, which exerts antidiabetic, antiatherogenic, antiinflammatory, and antiangiogenic properties. Adiponectin actions are primarily mediated through binding to two receptors expressed in several tissues, AdipoR1 and AdipoR2. Likewise, adiponectin expression has been detected in adipocytes as well as in a variety of extra-adipose tissues, including the chicken pituitary. Interestingly, adiponectin secretion and adiponectin receptor expression in adipocytes have been shown to be regulated by pituitary hormones. These observations led us to investigate whether adiponectin, like the adipokine leptin, regulates pituitary hormone production. Specifically, we focused our analysis on somatotrophs and gonadotrophs because of the relationship between the control of energy metabolism, growth and reproduction. To this end, the effects of adiponectin on both GH and LH secretion as well as its interaction with major stimulatory regulators of somatotrophs (ghrelin and GHRH) and gonadotrophs (GnRH) and with their corresponding receptors (GHS-R, GHRH-R, and GnRH-R), were evaluated in rat pituitary cell cultures. Results show that adiponectin inhibits GH and LH release as well as both ghrelin-induced GH release and GnRH-stimulated LH secretion in short-term (4 h) treated cell cultures, wherein the adipokine also increases GHRH-R and GHS-R mRNA content while decreasing that of GnRH-R. Additionally, we demonstrate that the pituitary expresses both adiponectin and adiponectin receptors under the regulation of the adipokine. In sum, our data indicate that adiponectin, either locally produced or from other sources, may play a neuroendocrine role in the control of both somatotrophs and gonadotrophs.

Secretoneurin stimulates goldfish pituitary luteinizing hormone production

Secretoneurin (SN), a 33-34 amino acid neuropeptide is derived from endoproteolysis of secretogranin II (SgII), a member protein of the chromogranin family. SN is widely distributed in various tissues of vertebrates especially in pituitary and hypothalamus, and is a potential new hormone. In vivo, i.p. injection of SN increased luteinizing hormone (LH) release in goldfish pretreated with the dopamine antagonist domperidone. In 6-h static incubation of goldfish pituitary fragments, 10 and 100 nM but not 1 nM concentrations of goldfish SN had a direct stimulatory effect to increase LH release by 2.3- and 1.5-fold (p<0.05), respectively. In addition, 500 nM SN induced a 2.6-fold increase in LHbeta subunit messenger RNA (mRNA) levels in pituitary fragments, regardless of whether LHbeta mRNA levels were expressed relative to 18S ribosomal RNA or beta-actin mRNA. We suggest that the stimulatory actions of SN on LH release may be a part of a paracrine or autocrine feedback loop in the pituitary.

Enhanced prolactin levels in opium smokers

In Iran, opium is smoked for pleasure or as a medication by some people. It is a complex mixture of 40 different alkaloids, including morphine and codeine along with many impurities. Although it is well established that opioids or tobacco affect many physiological functions in humans, to our knowledge there has been no specific study looking at these effects in opium smokers. To assess that, we investigated the circulating levels of prolactin, TSH, LH, FSH and testosterone in male opium smokers who also smoke cigarettes (n=23, aged 28.4+/- 4.1 years), and comparing this with the corresponding values for nicotine abusers (n=12, 15-25 cigarettes/day) or a healthy control group (n=20) of the same age. Our results showed that 86.96% of the opium-dependent and 41.67 % of the nicotine-dependent group displayed high prolactin values (p<0.002). In addition, there was a positive correlation between the dose of opium and the plasma prolactin level of opium dependents (p=0.748, p<0.001). Low FSH was detected in 43.48% of the opium smokers and 50% of the cigarette smokers (p<0.001) with normal LH and testosterone levels. TSH of the opium smokers was also lower than that of the other two groups (p<0.002). In conclusion, the present data indicate that chronic opium and cigarette smoking may synergistically influence pituitary hormone production through the effects on neuropeptides produced either locally or systemic.

Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix

The extracellular matrix is a three-dimensional network of proteins, glycosaminoglycans and other macromolecules. It has a structural support function as well as a role in cell adhesion, migration, proliferation, differentiation, and survival. The extracellular matrix conveys signals through membrane receptors called integrins and plays an important role in pituitary physiology and tumorigenesis. There is a differential expression of extracellular matrix components and integrins during the pituitary development in the embryo and during tumorigenesis in the adult. Different extracellular matrix components regulate adrenocorticotropin at the level of the proopiomelanocortin gene transcription. The extracellular matrix also controls the proliferation of adrenocorticotropin-secreting tumor cells. On the other hand, laminin regulates the production of prolactin. Laminin has a dynamic pattern of expression during prolactinoma development with lower levels in the early pituitary hyperplasia and a strong reduction in fully grown prolactinomas. Therefore, the expression of extracellular matrix components plays a role in pituitary tumorigenesis. On the other hand, the remodeling of the extracellular matrix affects pituitary cell proliferation. Matrix metalloproteinase activity is very high in all types of human pituitary adenomas. Matrix metalloproteinase secreted by pituitary cells can release growth factors from the extracellular matrix that, in turn, control pituitary cell proliferation and hormone secretion. In summary, the differential expression of extracellular matrix components, integrins and matrix metalloproteinase contributes to the control of pituitary hormone production and cell proliferation during tumorigenesis.

Role of PKC in the regulation of gonadotropin subunit mRNA levels: interaction with two native forms of gonadotropin-releasing hormone

Gonadotropin-releasing hormone (GnRH) is an important regulator of reproduction in all vertebrates through its actions on the production and secretion of pituitary gonadotropin hormones (GtHs). Most vertebrate species express at least two GnRHs, including one form, designated chicken (c)GnRH-II or type II GnRH, which has been well conserved throughout evolution. The goldfish brain and pituitary contain salmon GnRH and cGnRH-II. In goldfish, GnRH-induced luteinizing hormone (LH) secretion involves PKC; however, whether PKC mediates GnRH stimulation of GtH subunit mRNA levels is unknown. In this study, we used inhibitors and activators of PKC to examine its possible involvement in GnRH-induced increases in GtH-alpha, follicle-stimulating hormone (FSH)-beta and LH-beta mRNA levels in primary cultures of dispersed goldfish pituitary cells. Treatment with PKC inhibitors calphostin C and GF109203X unmasked a basal repression of GtH subunit mRNA levels by PKC; both inhibitors increased GtH subunit mRNA levels in a dose-dependent manner. PKC activators, 12-O-tetradecanoylphorbol 13-acetate (TPA), and 1,2-dioctanoyl-sn-glycerol, stimulated GtH subunit mRNA levels, whereas an inactive phorbol ester (4-alpha-TPA) was without effect. Thus, a dual, inhibitory and stimulatory, influence for PKC in the regulation of GtH subunit mRNA levels is suggested. In contrast, PKC inhibitor- and activator-induced effects were, for the most part, additive to those of GnRH, suggesting that conventional and novel PKCs are unlikely to be involved in GnRH-stimulated increases in GtH subunit mRNA levels. Our data illustrate major differences in the signal transduction of GnRH effects on GtH secretion and gene expression in the goldfish pituitary.

Dietary Soybean Enhances Pit-1 Dependent Pituitary Hormone Production in Iodine Deficient Rats

Reports have shown that soybeans are goitrogenic. In the present study, we investigated the effects of a high soybean diet in rats that were fed normal or iodine-deficient chow on the regulation of anterior pituitary hormone production. Iodine deficiency alone resulted in thyroid hyperplasia, reduced serum thyroxine levels, and a tendency towards an increase in serum thyroid stimulating hormone (TSH). The combination of a high soybean and low iodine diet (ID + DS) acted synergistically to induce thyroid hypertrophy, reduce serum thyroxine and tri-iodothyronine, and markedly increase serum TSH. Immunohistochemical analysis revealed that rats fed the ID + DS diet exhibited a marked increase in their number of pituitary TSH, prolactin (PRL), and growth hormone (GH) producing cells. Pituitary transcription factor-1 (Pit-1) which is involved in the expression of the TSH, PRL, and GH genes was also increased in ID + DS fed rats. These results suggest that a diet high in soybean products modulates anterior pituitary hormone production by regulating Pit-1 induction, in iodine-deficient animals.

Ontogeny of pituitary thyrotrophs and regulation by endogenous thyroid hormone feedback in the chick embryo

Increased thyroid hormone production is essential for hatching of the chick and for the increased metabolism necessary for posthatch endothermic life. However, little is known about the ontogeny and distribution of pituitary thyrotrophs during this period or whether pituitary thyroid-stimulating hormone (TSH) production is regulated by endogenous thyroid hormones during chick embryonic development. This study assessed the abundance and location of pituitary thyrotrophs and the regulation of TSH(beta) peptide and mRNA levels by endogenous thyroid hormones prior to hatching. TSH(beta)-containing cells were first detected on embryonic day (e) 11, and the thyrotroph population increased to maximum levels on e17 and e19 and then decreased prior to hatching (d1). Thyrotroph distribution within the cephalic lobe of the anterior pituitary was determined on e19 by whole-mount immunocytochemistry for TSH(beta) peptide and by whole-mount in situ hybridization for TSH(beta) mRNA. Thyrotroph distribution within the cephalic lobe was heterogeneous among embryos, but most commonly extended from the ventral medial region to the dorsal lateral regions, along the boundary of the cephalic and caudal lobes. Inhibition of endogenous thyroid hormone production with methimazole (MMI) decreased plasma thyroxine (T4) levels and increased pituitary TSH(beta) mRNA levels on e19 and d1. However, control pituitaries contained significantly more TSH(beta) peptide than MMI-treated pituitaries on e17 and e19, suggesting higher TSH secretion into the blood in MMI-treated groups. We conclude that thyrotroph abundance and TSH production increase prior to hatching, that thyrotrophs are localized heterogeneously within the cephalic lobe of the anterior pituitary at that time, and that TSH gene expression and secretion are under negative feedback regulation from thyroid hormones during this critical period of development.

Interaction involving the thymus and the hypothalamus-pituitary axis, immunomodulation by hormones

Perfectly projected and impeccably created, the endocrine system precisely regulates the most delicate immune processes. The immune and neuroendocrine systems are two essential physiological components of mammalian organisms important for protection from the infection and disease on one hand, and on the other, for regulation of metabolism and other physiological activities; namely, the evidence has been found indicating that there is active and dynamic collaboration of these systems in the execution of their designated functions. These interactions occur at many stages of embryonic and neonatal development, and they are a continual part of normal homeostatic balance necessary to preserve health. There is communication between neuroendocrine and immune system via cytokines, neurotransmitters and peptide hormones which act, in both systems,, through the same receptor molecules (Scheme 1). Many investigators have reported the increased thymic weight in experimental animals due to both castration and adrenalectomy. The discovery from 1898 revealing that thymus was enlarged in castrated rabbits has been considered the embryo of hybrid medical discipline, i.e. the immunoendocrinology. In the actual literature, at least in that available to us, it has not been noted that the appearance of the eunuchs, i.e. the castrates, stimulated the analytical approach to this phenomenon. Endocrine influences appear to be a part of bidirectional circuitry, namely, thymic hormones also regulate the release of hormones from the pituitary gland. Physiologically, thymus is under neuroendocrine control. It is apparent that the circulating levels of distinct peptide hormones are necessary to maintain a series of biological functions related both to microenvironmental and lymphoid cells of the organ. The neuroendocrine control of the thymus appears to be extremely complex, with apparent presence of complete Intrathymic biological circuitry involving the production of pituitary hormones, as well as the expression of their respective receptors by thymic cell. The influence of gonadectomy on the humoral immunity has been controversial. All investigations agree that women have higher titres of all classes of circulating antibodies than men. The application of estrogens stimulated the formation of antibodies in the circulation. Then, if there were no sex glands, the immune response of the individual would be enhanced. Both the cellular and the humoral immune response is more powerful in the adult normal women than in men of the same age. The immune response is different in different sexes meaning that there is a sexual dimorphism. This difference has not been noted before the puberty. It has been noticed that the substitution therapy has alleviated the late skin hypersensitivity. The estrogens have also curtailed the rejection time of the transplant and all reactions in which T-effector lymphocytes have been involved. NK-cells and T-lymphocytes activities have been decreased by the action of estrogens, as well as the release of thymus hormones. Cortical RE cells express a surface antigen, gp200-MR6, which plays a significant role in thymocyte differentiation. Irrespectively of which pathway may be triggered by neuroendocrine factors, the effects are pleiotropic and result in modulation of the expression of several genes in different cell types. Thymic neuroendocrine polypeptides are the source of self-antigens presented by MHC molecules enabling the differentiation of haematopoietic stem cells. Thymic nurse cells also produce thymosins beta 3 and beta 4 and display a neuroendocrine cell specific immunophenotype (IP): Thy-1+, A2B5+, TT+, TE4+, UJ13/A+, UJ127.11+, UJ167.11+, UJ181.4+ and presence of common leukocyte antigen (CLA+). GH enhances thymocyte release from TNCs, as well as the reconstitution of these lymphoepithelial complexes. Similarto its role as a regulator of bone metabolism through regulating osteoprotegerin (OPG) production, the estrogen is involved in the processes of thymocyte development although aromatase mRNA has not been detectable in the thymus. While the increase of TNC number during lactation may be linked to the process of reconstruction of the thymic lymphoid population, the increased activity of lymphoepithelial interactions on GD14 may be associated with thymic engagement in pregnancy-induced immune processes The major antigens in the experimental autoimmune hypophysitis in rats are growth hormone, thyrotropin, and luteinizing hormone. The intrathymic T-lymphocyte selection is a complex, multistep process, influenced by several functionally specialised RE cells and under immuno-neuroendocrine regulation control reflecting the dynamic changes of the mammalian organism. In HIV-1-infected adults treated with growth hormone, thymic mass and circulating naive CD4 T cells are increased. The treatment would be easier for the diseased, as well as to us, the physicians, if we were aware of two millennia old wisdom--that the disease is a visit of God.

Effects of housing on the thymic deficiency in dwarf mice and its reversal by growth hormone administration

Initial studies on T cell development in the Snell Dwarf ( dw/dw) strain of mice, which are deficient in the production of anterior pituitary hormones, have been interpreted to indicate a clear dependence of T cell development on endocrine system-derived factors. However, normal thymopoiesis in this strain has also been reported. The aim of the present study was to reconcile these contradictory data in order to define the role of anterior pituitary hormones in the thymus. The results indicated that if female dw/dw mice are housed together with their normal-sized littermates, thymic cellularity and the frequency of CD4 +CD8 + thymocytes are markedly reduced. However, administration of growth hormone could reverse these decreases seen in the double-positive T progenitor cells. Taken together, the data indicate that stress is the unifying parameter that can explain the disparate dw/dw mouse literature and suggest that endocrine effects on the T cell development can best be understood by interpreting the literature in this context.

Modulation of diabetes with gonadotropin-releasing hormone antagonists in the nonobese mouse model of autoimmune diabetes.

The nonobese mouse model of autoimmune diabetes (NOD mouse) exhibits a strain-dependent preponderance of disease in females. Castration of male NOD mice leads to an increased incidence of diabetes, suggesting that testosterone directly modulates the expression of diabetes in the NOD mouse. However, castration also modulates hypothalamic and pituitary hormone production via removal of the negative feedback effects of testosterone. One hypothalamic hormone with immunomodulatory properties whose expression is increased by castration is GnRH. To test whether the increased incidence of diabetes in castrated male NOD mice is related to an increase in GnRH activity, we treated castrated male NOD mice with Antide, a GnRH receptor antagonist, to determine the effect on the incidence and timing of onset of diabetes. The prevalence of diabetes at 40 wk of age in male NOD mice was 50% in sham-operated mice, compared with an 83% prevalence in castrated males. Antide administration prevented the increased incidence of diabetes in the castrated male mice. Antide reduced total serum IgG levels, IL-6 cytokine expression in cultured splenocytes, and the lymphocytic infiltration of islets. GnRH administration exerted reciprocal effects, leading to earlier timing of onset of diabetes and increases in serum total IgG levels. We conclude that GnRH modulates the expression of diabetes in the NOD mouse independently of gonadal steroids.

Production of Pituitary Hormone by Human Pituitary Adenoma is under Autocrine and Paracrine Regulation of Hypothalamic Hormones Secreted from Adenoma Cells

Two hypotheses, the hypothalamic and pituitary hypotheses, have been suggested concerning the pathogenesis of pituitary adenoma. The recent demonstration of the monoclonality of most human pituitary adenomas has led to wider acceptance of the pituitary hypothesis, which suggests that pituitary adenoma results from monoclonal expansion of a single adenohypophyseal cell with subcellular abnormalities. Meanwhile, the role of hypothalamic hormones in the development of pituitary adenoma has recently attracted the attention of investigators. The present paper discusses the expression of growth hormone-releasing hormone (GHRH) in somatotroph adenoma, and corticotropin-releasing hormone (CRH) in corticotroph adenoma. Locally generated hypothalamic hormones and expression of associated receptors in human pituitary adenoma cells play significant roles in autocrine/paracrine regulation of pituitary hormone production.

Adiposity and diabetes.

At a symposium titled “Adipose Tissue as a Secretory Organ” at the American Diabetes Association (ADA), San Francisco, June 2002, Jeffrey Flier (Boston, MA) discussed the effects of visceral obesity. While reviewing the differing components of the metabolic syndrome, which to large extent are driven by insulin resistance, he asked, “Where does the insulin resistance come from?” The existence of a common underlying factor related to visceral obesity, which is more strongly associated with the syndrome than total obesity, might be important. A role for abnormal glucocorticoid metabolism in adipose tissue as the mechanism of the syndrome would explain many of its features. Glucocorticoids regulate adipose tissue function and distribution and in excess produce Cushing’s syndrome, which is characterized by visceral obesity, insulin resistance, and diabetes. The prevalent forms of obesity, however, are not associated with increased circulating glucocorticoid levels. Flier pointed out that the adipocyte is an active endocrine cell that produces hormones, in particular leptin, cytokines, complement factors, and important enzymes, such as angiotensinogen. Cortisol, produced in the adrenal gland, acts on cellular glucocorticoid receptors but importantly shows metabolism within cells, with 11-β-hydroxysteroid dehydrogenase (HSD)-2 degrading cortisol into the inactive cortisone, while HSD-1 is a reductase that produces cortisol from cortisone. The standard understanding of the hypothalamic pituitary adrenal axis is of negative feedback between cortisol and pituitary adrenocorticotropic hormone (ACTH) production, an incomplete model that does not take into account the pathways for activation and for inactivation of cortisol in a variety of cells. In the kidney, HSD-2 is critical to protect mineralocorticoid receptors from activation by circulating glucocorticoids, while HSD-1 in liver, adipose tissue, and brain leads to increased glucocorticoid action. HSD-1 is expressed to a greater extent in visceral adipose tissue, which also express greater levels of cortisol receptors. HSD-1 in adipose tissue may in …