Human Endocrine Disease Research Articles

A resistance to thyroid hormone syndrome mutant operates through the target gene repertoire of the wild-type thyroid hormone receptor

Thyroid hormone receptors (TRs) play crucial roles in vertebrates. Wild-type (WT) TRs function primarily as hormone-regulated transcription factors. A human endocrine disease, Resistance to Thyroid Hormone (RTH)-Syndrome, is caused by inheritance of mutant TRs impaired in the proper regulation of target gene expression. To better understand the molecular basis of RTH we compared the target genes regulated by an RTH-TRβ1 mutant (R429Q) to those regulated by WT-TRβ1. With only a few potential exceptions, the vast majority of genes we were able to identify as regulated by the WT-TRβ1, positively or negatively, were also regulated by the RTH-TRβ1 mutant. We conclude that the actions of R429Q-TRβ1 in RTH-Syndrome most likely reflect the reduced hormone affinity observed for this mutant rather than an alteration in target gene repertoire. Our results highlight the importance of target gene specificity in defining the disease phenotype and improve our understanding of how clinical treatments impact RTH-Syndrome.

Pharmaceutical Analysis of Chemicals Related with Daily Life Products for Safe and Secure

An association between exposure to trace hazardous chemicals such as endocrine disrupting chemicals and an increased incidence of human endocrine disease might be continued to study. The accurate and sensitive analytical methods for determination of various chemicals in human biospecimen such as urine, blood and breast milk have been studied by techniques including chromatography. In order to obtain the safe and secure life, the pharmaceutical analytical approaches might be applicable with the hopes of realizing scientific risk assessment of the chemicals derived from daily life products as regulatory sciences.

Mitochondrial Dysfunction andβ-Cell Failure in Type 2 Diabetes Mellitus

Type 2 diabetes mellitus (T2DM) is the most common human endocrine disease and is characterized by peripheral insulin resistance and pancreatic islet β-cell failure. Accumulating evidence indicates that mitochondrial dysfunction is a central contributor to β-cell failure in the evolution of T2DM. As reviewed elsewhere, reactive oxygen species (ROS) produced by β-cell mitochondria as a result of metabolic stress activate several stress-response pathways. This paper focuses on mechanisms whereby ROS affect mitochondrial structure and function and lead to β-cell failure. ROS activate UCP2, which results in proton leak across the mitochondrial inner membrane, and this leads to reduced β-cell ATP synthesis and content, which is a critical parameter in regulating glucose-stimulated insulin secretion. In addition, ROS oxidize polyunsaturated fatty acids in mitochondrial cardiolipin and other phospholipids, and this impairs membrane integrity and leads to cytochrome c release into cytosol and apoptosis. Group VIA phospholipase A2 (iPLA2 β) appears to be a component of a mechanism for repairing mitochondrial phospholipids that contain oxidized fatty acid substituents, and genetic or acquired iPLA2 β-deficiency increases β-cell mitochondrial susceptibility to injury from ROS and predisposes to developing T2DM. Interventions that attenuate ROS effects on β-cell mitochondrial phospholipids might prevent or retard development of T2DM.

Signature of mitochondria of steroidal hormones-dependent normal and cancer cells: potential molecular targets for cancer therapy

The cross-talk between the cell nucleus and mitochondria appears to control hormone-induced signaling involved in the apoptosis, proliferation, and differentiation of both normal and malignant cells. Evaluation of the defects in genetics and physiology of human endocrine diseases, such as cancer, may manifest as a result of mitochondrial physiologic and metabolic compensation of genetic defects. Steroidal agents control biogenesis and maintenance of mitochondria through the crosstalk between nuclear and mitochondrial genomes. The regulation of mitochondrial transcription by steroidal hormones, presumably occurring through pathways similar to those that take place in the nucleus, opens a new way to better understand steroid hormone and vitamin action at the cellular level. In addition to the steroid hormone receptors, estrogen generated mitochondrial oxidants together with an estrogen-driven increase in epithelial cell proliferation have been shown to participate in the initiation and promotion of the neoplastic lesions in estrogen-sensitive tissues. Mitochondria generation of ROS appears to transduce signals to the nucleus for the activation of transcription factors involved in the cell cycle progression of estrogen-dependent cancer cells. Therefore, an in-depth analysis of such redox regulatory mechanisms is pertinent to the development of novel drugs and gene therapy strategies for the treatment of steroid hormone-dependent diseases related to mitochondrial disorders including cancer.

Resistance to thyroid hormone (RTH) syndrome reveals novel determinants regulating interaction of T3 receptor with corepressor

Thyroid hormone receptors (T3Rs) both repress and activate gene transcription by interacting with auxiliary factors denoted corepressors and coactivators. Resistance to thyroid hormone (RTH) syndrome in humans is manifested as a failure to respond properly to elevated circulating thyroid hormone. RTH syndrome has been mapped to T3Rβ mutations that alter the transcriptional properties of the receptor, resulting in a dominant negative phenotype. We report here a characterization of a series of RTH mutant T3Rs that exhibit unusual interactions with corepressor. Two mutations in receptor helix 11 (Δ430, Δ432) greatly enhance the ability of the mutant receptors to bind to corepressor. A distinct mutation, V264D, in an ‘omega loop’ region of the receptor, impairs corepressor release but does not fully eliminate the ability to recruit coactivator. These mutations reveal novel determinants that regulate the interaction of the T3R with important ancillary cofactors, and that are disrupted in a human endocrine disease.

Rodent Leydig Cell Tumorigenesis: A Review of the Physiology, Pathology, Mechanisms, and Relevance to Humans

Leydig cells (LCs) are the cells of the testis that have as their primary function the production of testosterone. LCs are a common target of compounds tested in rodent carcinogenicity bioassays. The number of reviews on Leydig cell tumors (LCTs) has increased in recent years because of its common occurrence in rodent bioassays and the importance in assessing the relevance of this tumor type to humans. To date, there have been no comprehensive reviews to identify all the compounds that have been shown to induce LCTs in rodents or has any review systematically evaluated the epidemiology data to determine whether humans were at increased risk for developing LCTs from exposure to these agents. This review attempts to fill these deficiences in the literature by comparing the cytology and ontogeny of the LC, as well as the endocrine and paracrine regulation of both normal and tumorigenic LCs. In addition, the pathology of LCTs in rodents and humans is compared, compounds that induce LC hyperplasia or tumors are enumerated, and the human relevance of chemical-induced LCTs is discussed. There are plausible mechanisms for the chemical induction of LCTs, as typified by agonists of estrogen, gonadotropin releasing hormone (GnRH), and dopamine receptors, androgen receptor antagonists, and inhibitors of 5a-reductase, testosterone biosynthesis, and aromatase. Most of these ultimately involve elevation in serum luteinizing hormone (LH) and/or LC responsiveness to LH as proximate mediators. It is expected that further work will uncover additional mechanisms by which LCTs may arise, especially the role of growth factors in modulating LC tumorigenesis. Regarding human relevance, the pathways for regulation of the hypothalamo-pituitary-testis (HPT) axis of rats and humans are similar, such that compounds that either decrease testosterone or estradiol levels or their recognition will increase LH levels. Hence, compounds that induce LCTs in rats by disruption of the HPT axis pose a risk to human health, except for possibly two classes of compounds (GnRH and dopamine agonists). Because GnRH and prolactin receptors are either not expressed or are expressed at very low levels in the testes in humans, the induction of LCTs in rats by GnRH and dopamine agonists would appear not to be relevant to humans; however, the potential relevance to humans of the remaining five pathways of LCT induction cannot be ruled out. Therefore, the central issue becomes what is the relative sensitivity between rat and human LCs in their response to increased LH levels; specifically, is the proliferative stimulus initiated by increased levels of LH attenuated, similar, or enhanced in human vs. rat LCs? There are several lines of evidence that suggest that human LCs are quantitatively less sensitive than rats in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. This evidence includes the following: (1) the human incidence of LCTs is much lower than in rodents even when corrected for detection bias; (2) several comparative differences exist between rat and human LCs that may contribute, at least in part, to the greater susceptibility of the rat to both spontaneous and xenobiotic-induced LCTs; (3) endocrine disease states in man (such as androgen-insensitivity syndrome and familial male precocious puberty) underscore the marked comparative differences that exist between rats and man in the responsiveness of their LC's to proliferative stimuli; and (4) several human epidemiology studies are available on a number of compounds that induce LCTs in rats (1,3-butadiene, cadmium, ethanol, lactose, lead, nicotine) that demonstrate no association between human exposure to these compounds and induction of LC hyperplasia or adenomas. After considering the human incidence of LCTs, the comparative differences between rats and humans, human endocrine disease states, and epidemiology, the weight of evidence suggests that human LCs are quantitatively less sensitive than rat LCs in their proliferative response to LH, and hence in their sensitivity to chemically induced LCTs. It can be concluded that no observable effect levels for the induction of LCTs in rodent bioassays provide an adequate margin of safety for protection of human health and that the data support a nonlinear mode of action (i.e., threshold response). In conclusion, the data suggest that nongeno toxic compounds that induce LCTs in rats most likely have low relevance to humans under most exposure conditions because humans are quantitatively less sensitive than rats. In a recent international multidisciplinary workshop on LC tumorigenesis, seven research needs were identified. In this review, we have begun to address two of these needs (comparative sensitivity differences and epidemiology), and as the other areas of research are further investigated, these data will help to critically test the conclusions in this review.

Transgenic models of pituitary diseases.

Transgenic mice are valuable experimental models of human endocrine diseases. Targeted ablation of specific cell lineages or insertion of genes coding for releasing factors, hormones, growth factors, and oncogenes fused with appropriate promoters, or mutated genes, can induce several pituitary disorders. Various hyposecretory and hypersecretory states have been induced, some of them due to functioning pituitary adenomas. Adenohypophysial changes in such disorders have been thoroughly investigated in many of the transgenic lines. Functioning and silent pituitary adenomas resemble those seen in human patients, and are invaluable models of tumorigenesis. The available models have not been sufficiently exploited and new models are expected in the near future. In this review, the morphologic changes of the pituitary are described in transgenic mice and, when available, the ultrastructural alterations are included.

19-nor-10-azasteroids: a novel class of inhibitors for human steroid 5alpha-reductases 1 and 2.

Steroid 5alpha-reductase is a system of two isozymes (5alphaR-1 and 5alphaR-2) which catalyzes the NADPH-dependent reduction of testosterone to dihydrotestosterone in many androgen sensitive tissues and which is related to several human endocrine diseases such as benign prostatic hyperplasia (BPH), prostatic cancer, acne, alopecia, pattern baldness in men and hirsutism in women. The discovery of new potent and selective 5alphaR inhibitors is thus of great interest for pharmaceutical treatment of these diseases. The synthesis of a novel class of inhibitors for human 5alphaR-1 and 5alphaR-2, having the 19-nor-10-azasteroid skeleton, is described. The inhibitory potency of the 19-nor-10-azasteroids was determined in homogenates of human hypertrophic prostates toward 5alphaR-2 and in DU-145 human prostatic adenocarcinoma cells toward 5alphaR-1, in comparison with finasteride (IC50 = 3 nM for 5alphaR-2 and approximately 42 nM for 5alphaR-1), a drug which is currently used for BPH treatment. The inhibition potency was dependent on the type of substituent at position 17 and on the presence and position of the unsaturation in the A and C rings. delta9(11)-19-Nor-10-azaandrost-4-ene-3,17-dione (or 10-azaestra-4,9(11)-diene-3,17-dione) (4a) and 19-nor-10-azaandrost-4-ene-3,17-dione (5) were weak inhibitors of 5alphaR-2 (IC50 = 4.6 and 4.4 microM, respectively) but more potent inhibitors of 5alphaR-1 (IC50 = 263 and 299 nM, respectively), whereas 19-nor-10-aza-5alpha-androstane-3,17-dione (7) was inactive for both the isoenzymes. The best result was achieved with the 9:1 mixture of delta9(11)- and delta8(9)-17beta-(N-tert-butylcarbamoyl)-19-nor-10-aza-4- androsten-3-one (10a,b) which was a good inhibitor of 5alphaR-1 and 5alphaR-2 (IC50 = 127 and 122 nM, respectively), with a potency very close to that of finasteride. The results of ab initio calculations suggest that the inhibition potency of 19-nor-10-azasteroids could be directly related to the nucleophilicity of the carbonyl group in the 3-position.

LH-RH Stimulated LH Secretion in Human Endocrine Disease

The application of LH-RH provides means to describe the functional state of the hypothalamo-pituitary-gonadal axis and has helped to understand the regulation of gonadotropin secretion both under normal and pathological circumstances. At present, diagnostic LH-RH application appears to be most useful in patients with delayed puberty, where a biphasic response during an infusion of LH-RH excludes hypogonadotropic hypogonadism at an early clinical stage. An enhanced LH-RH induced response following exogenous intermittent LH-RH administration identifies the subgroup of hypogonadotropic patients who are suitable for subsequent LH-RH substitution therapy. In addition, subtle derangements of gonadotropin secretion have been described in a score of clinical conditions including the endocrine disorders discussed in this review. However, interesting as these observations may be theoretically, their practical value is often limited since a multitude of interfering factors, both exogenous and endogenous, results in a great variability in the obtained results, thus limiting the diagnostic value of the test in a specific patient. As of recently the clinical use of LH-RH includes its therapeutic application to replace low endogenous levels of LH-RH, whereas long-acting analogues of the natural decapeptide are employed to suppress gonadotropin secretion in an increasing field of endocrine disorders.