Showing papers in "Endocrine Reviews in 1993"
TL;DR: This review first briefly covers some historical perspective on the discovery of apoptotic cell death, the characteristic morphology that accompanies this process, and the numerous cell types and mediators with which programmed cell death is associated.
Abstract: I. Introduction DEATH, along with growth and differentiation, is a critical part of the life cycle of a cell. Homeostatic control of cell number is thought to be the result of the dynamic balance between cell proliferation and cell death. It is only in the past few years, however, that attention has been focused on the physiological occurrence of cell death and its role in homeostasis. Researchers have become increasingly more aware during this time that this type of “natural” death, which is now called apoptosis or programmed cell death, is a widespread phenomenon that plays a crucial role in a myriad of physiological and pathological processes. This review first briefly covers some historical perspective on the discovery of apoptotic cell death, the characteristic morphology that accompanies this process, and the numerous cell types and mediators with which programmed cell death is associated. The bulk of the review discusses our current understanding of the biochemical and molecular mechanisms by which...
1,060 citations
TL;DR: The specificity of thenuclear T3 receptors for thyroid hormone analogs closely parallels the biological potency of the compounds, and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T3 in most cases.
Abstract: I. Introduction THE biological importance of the thyroid gland has been recognized for centuries (1). The realization in the late 19th century that cretinism and myxedema result from loss of thyroid function led to the discovery of T4 (2) and T3 (3) as the predominant and most potent thyroid hormones, respectively. During the ensuing decades the plasma membrane (4), synapse (5), endoplasmic reticulum (6), and mitochondria (7) have all been considered as potential cellular sites of action of the thyroid hormones. In the 1960s, however, it was noted that many of the physiological actions of T3 were preceded by nuclear RNA transcription (8, 9), and high-affinity nuclear receptors for T3 were discovered soon thereafter (10,11). The specificity of the nuclear T3 receptors (TRs) for thyroid hormone analogs closely parallels the biological potency of the compounds (12, 13), and the levels of the nuclear TRs correlate well with the developmental and tissue-specific effects of T3 in most cases (14, 15). Thus, alth...
1,051 citations
TL;DR: The relationship between cell growth and the initiation and progression of events associated with differentiation has been a fundamental question challenging developmental biologists for more than a century as mentioned in this paper, and the relationship of growth and differentiation must be maintained and stringently regulated, both during development and throughout the life of the organism, to support tissue remodeling.
Abstract: I. Introduction A FUNCTIONAL relationship between cell growth and the initiation and progression of events associated with differentiation has been a fundamental question challenging developmental biologists for more than a century. In the case of bone, as observed with other cells and tissue, the relationship of growth and differentiation must be maintained and stringently regulated, both during development and throughout the life of the organism, to support tissue remodeling. For many years, bone was defined anatomically and examined largely in a descriptive manner by ultrastructural analysis and by biochemical and histochemical methods. These studies provided the basis for our understanding of bone tissue organization and orchestration of the progressive recruitment, proliferation, and differentiation of the various cellular components of bone tissue. Now, complemented by an increased knowledge of molecular mechanisms that are associated with and regulate expression of genes encoding phenotypic compone...
973 citations
TL;DR: It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc, but a great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.
Abstract: In humans, both aging and GH deficiency are associated with reduced protein synthesis, decreased lean body and bone mass, and increased percent body fat. In healthy individuals, spontaneous and stimulated GH secretion, as well as circulating IGF-I and IGFBP-3 levels, are significantly decreased with advancing age. The extent to which these age-related changes in GH and IGF-I contribute to alterations in body composition and function remains to be elucidated. GH treatment of GH-deficient adults or old men with reduced IGF-I levels with exogenous GH increases plasma IGF-I, nitrogen retention, and lean body mass, decreases percent body fat, and exerts little effect on bone mineral density. Short-term adverse effects of GH therapy have been minimized by using low-dose regimens, but it is still uncertain whether long-term GH supplementation in adult life increases the risk of metabolic abnormalities or malignancy. Administration of GHRH, which has been shown to maintain the pattern of pulsatile GH secretion in old men, may represent another possible physiological approach to therapy. It may be justifiable initially to limit use of GH to certain elderly patients such as those suffering from catabolic illnesses, malnourishment, burns, cachexia, etc. A great deal more research will be necessary to determine whether normalization of GH and IGF-I levels in healthy older persons will lead to improvements in their physical and psychological functional capacity and quality of life.
921 citations
TL;DR: This review of syndromes of resistance to thyroid hormone summarizes all cases known to us, presents their common features as well as unusual manifestations, and presents the expected metabolic responses in the peripheral tissues.
Abstract: I. Introduction THE syndromes of resistance to thyroid hormone are characterized by reduced clinical and biochemical manifestations of thyroid hormone action relative to the circulating hormone levels. In practice, most patients are identified by the persistent elevation of serum levels of T4 and T3 with “inappropriately” nonsuppressed TSH, in the absence of intercurrent acute illness, drugs, or alterations of thyroid hormone binding to serum proteins. More importantly, administration of supraphysiological doses of thyroid hormone fail to produce the expected suppressive effect on the secretion of pituitary TSH and/or to induce the expected metabolic responses in the peripheral tissues. Since the publication of the index cases in 1967 (1), 347 subjects have been reported who exhibit the characteristics of the syndrome (Refs. 1–129 and our personal communications and observations). In this review, we summarize all cases known to us, present their common features as well as unusual manifestations, and attem...
813 citations
TL;DR: The tentative conclusion is drawn that the specificity of the hormonal response in different cells results from a combination of developmental restrictions both in the accessibility of genomic sequence and in the repertoire of regulatory proteins present in each particular cell.
Abstract: GENE regulation by steroid hormones is mediated by binding of the hormone ligand to the corresponding receptor that triggers a complex set of interactions of the hormone receptors with each other, with DNA in chromatin, and with a variety of other proteins. In this review we attempt to summarize what is known about these interactions using as the main example the regulation of mouse mammary tumor virus transcription by glucocorticoids and progestins. We describe in some detail the interaction of monomers and homodimers of the steroid receptors with their recognition sequences, and the molecular mechanism used to discriminate between the responsive elements for glucocorticoids/progestins and estrogens. We then review the interactions between homologous and heterologous hormone receptors on complex hormone regulatory regions, before devoting some attention to the synergistic and inhibitory interactions of hormone receptors with other transcription factors. Finally we briefly summarize some of the possible m...
761 citations
TL;DR: The potential for an agent that can increase bone mass and hence reverse the skeletal defect in patients with osteoporosis is great, particularly if in doing so it also repairs microarchitectural damage.
Abstract: I. Introduction PHYSICIANS have traditionally considered PTH to be an agent that is catabolic to the skeleton. However, as early as 60 yr ago, Albright and his colleagues (1) and later Selye (2) noted that the peptide extract could also be anabolic to the skeleton, producing increases in bone tissue in animals. The potential for an agent that can increase bone mass and hence reverse the skeletal defect in patients with osteoporosis is great, particularly if in doing so it also repairs microarchitectural damage. The agents currently available in the United States for treatment of osteoporosis, estrogens and salmon calcitonin, primarily stabilize bone mass and prevent further loss of bone, although a transient small increment in mass is often reported, particularly in patients with elevated levels of bone remodeling. This increase is not a true anabolic effect but is related to the temporal effects on turnover in which resorption declines initially followed by a reduction in formation that may take several ...
727 citations
TL;DR: It now appears that fetal thyroid hormones play an essential role in fetal brain development, and as some placental transport of thyroid hormones has been shown to occur, it is possible that maternal thyroid hormones might influence Fetal brain development.
Abstract: I. Introduction FOR YEARS thyroid hormones have been known to be important for normal neonatal brain development, and numerous reviews have covered this topic in depth. It now also appears that fetal thyroid hormones play an essential role in fetal brain development. In addition, as some placental transport of thyroid hormones has been shown to occur, it is possible that maternal thyroid hormones might influence fetal brain development. II. The Value of the Use of Animal Models in the Comprehension of the Role of Thyroid Hormones in Neurological Development Animal models have been used to study the influence of thyroid hormones on neurological] evelopment. Rats and mice have been the primary animals studied; however, a significant amount of data have come from studies on sheep and nonhuman primates. While the merit of application of animal data to human problems is frequently questioned, valuable information can be obtained when the animal data are properly interpreted. Furthermore, most of the informatio...
719 citations
TL;DR: In the 20 years since it was established that impairment of dihydrotestosterone formation is the cause of a rare form of human intersex, a wealth of information has accumulated about the genetics, endocrinology, and variable phenotypic manifestations, culminating in the cloning of cDNAs encoding two 5 alpha-reductase genes.
Abstract: In the 20 yr since it was established that impairment of dihydrotestosterone formation is the cause of a rare form of human intersex, a wealth of information has accumulated about the genetics, endocrinology, and variable phenotypic manifestations, culminating in the cloning of cDNAs encoding two 5 alpha-reductase genes and documentation that mutations in the steroid 5 alpha-reductase 2 gene are the cause of 5 alpha-reductase deficiency. Perplexing and difficult problems remain unresolved, e.g. whether the variability in manifestations is due to variable expressions of steroid 5 alpha-reductase 1 or to effects of testosterone itself. It is also imperative to establish whether defects in steroid 5 alpha-reductase 2, perhaps in the heterozygous state, are responsible for a portion of cases of sporadic hypospadias, to determine whether 5 alpha-reductase plays a role in progesterone action in women, and to elucidate the relation between androgen action and gender role behavior.
594 citations
TL;DR: The transition from palliative to curative measures in Graves' ophthalmopathy will require further advances in the understanding of the putative shared thyroid-eye antigens, demonstration that these antigen are etiologically important and concomitant advances in antigen-specific immune therapy.
Abstract: I. Introduction RECENT progress in the study of Graves' ophthalmopathy has been anything but stagnant. The past 20 yr have witnessed a rapid expansion in the collective understanding of basic pathophysiology, interdependence with thyroid pathology, and the effects of ocular or thyroidspecific therapy on disease course that threatens to erode the enigmatic nature of Graves' ophthalmopathy. In the past 5 yr alone, the central autoimmune target responsible for the hyperthyroidism of Graves' disease, the TSH receptor, has been cloned and sequenced (1,2), and an elucidation of exact antigenic epitopes using various techniques has begun (3–6). The availability of highly sensitive TSH assays has vastly simplified the diagnosis of subclinical hyperthyroidism (7), and improvements in TSH receptor autoantibody assays (8) have enhanced the ability of the clinician to identify subtle presentations of autoimmune thyroid disease. Exciting new work has suggested a primary pathogenetic role for the retroorbital fibroblas...
545 citations
TL;DR: The explosion of interest and research in this area in the last decade has demonstrated that the inositol phosphate-calcium signaling system plays a critical role in the mechanisms by which hormones regulate diverse processes such as muscle contraction, cell secretion, metabolism, and cell growth and differentiation.
Abstract: I. Introduction IN 1983, Michael Berridge proposed (1), and subsequently with collaborators demonstrated (2), that d-myo-inositol 1,4,5-trisphosphate [(1,4,5)IP3], generated in the course of receptor-activated inositol lipid turnover, was a second messenger signaling the release of stored calcium from intracellular sites to the cytoplasm of activated cells. The significance of this discovery was enormous. The explosion of interest and research in this area in the last decade has demonstrated that the inositol phosphate-calcium signaling system plays a critical role in the mechanisms by which hormones regulate diverse processes such as muscle contraction, cell secretion, metabolism, and cell growth and differentiation. Despite the consensus regarding the central role of (1,4,5)IP3 in intracellular Ca2+ mobilization, the extremely complex nature of Ca2+ signaling and inositol phosphate metabolism has spawned controversies. What is the meaning of the enigmatically complex pathways of inositol phosphate metab...
TL;DR: A better understanding of variation in fat topography and of the role played by adipose tissue in the regulation of whole body carbohydrate and lipid metabolism will likely require extensive in situ and in vivo investigations.
Abstract: The role of inherited and nongenetic factors in individual differences observed in the level of sc fat on the trunk and abdominal areas and in the abdominal visceral deposit is reviewed. First, the metabolic and clinical implications of variation in body fat topography are summarized. Second, the results of genetic epidemiology studies on the heritability and other evidence for a role of the genotype in the amount of truncal-abdominal sc fat and abdominal visceral fat are reviewed. Third, the impact of total body fat, age, and gender on regional fat distribution is highlighted. Fourth, adipose tissue lipoprotein lipase activity is considered as a determinant of fat topography, with a discussion of site and gender differences, the effects of steroid hormones, and evidence from genetic epidemiology. Fifth, the contribution of adipose tissue lipolysis is reviewed with an emphasis on the various regulatory factors of the lipolytic pathways including catecholamines, insulin, adenosine, steroids, and other modulators. The role of lipolytic characteristics on fat topography is further assessed by considering changes with age, differences between men and women, effects of excess body fat, and data from heritability studies. Although the study of regional variation of in vitro adipose tissue metabolism has provided valuable information, a better understanding of variation in fat topography and of the role played by adipose tissue in the regulation of whole body carbohydrate and lipid metabolism will likely require extensive in situ and in vivo investigations. Sixth, as enlargement of a specific fat deposit is associated with increases in fat cell size and number, these topics are considered with an emphasis on the role of adipose cell differentiation. Seventh, the importance of blood levels of sex steroids and glucocorticoids for regional fat distribution is discussed. Then, a unifying hypothesis, defined as the hypothalamic arousal and neuroendocrine dysregulation model, is briefly described. Finally, the issue of whether body fat distribution can be altered by caloric restriction or regular exercise is addressed.
TL;DR: All receptors contain a highly conserved cysteine-rich region, the DNA- binding domain (DBD) that forms two “zinc-finger” structures that allow protein-DNA as well as proteinprotein interaction (4).
Abstract: I. Introduction NUCLEAR receptors mediate the signals of a broad variety of fat-soluble hormones, including the steroid and vitamin D3 hormones, thyroid hormones, and vitamin A-derived hormones and analogs (retinoids). The receptors represent one of the largest transcription factor families known (reviewed in Refs. 1–3). Only some of the members are ligand-binding receptors, while others are “orphan receptors” for which specific ligands have not yet been identified and may not exist. These proteins may therefore function as constitutive or negative transcription factors, or coregulators of ligand-binding receptors. The receptors regulate gene transcription by interacting with specific DNA sequences (called response elements) that are usually located in the promoter regions of the responsive genes. All receptors contain a highly conserved cysteine-rich region, the DNA- binding domain (DBD) that forms two “zinc-finger” structures that allow protein-DNA as well as proteinprotein interaction (4). A second but...
TL;DR: It is imperative to establish whether defects in steroid 5 alpha-reductase 2, perhaps in the heterozygous state, are responsible for a portion of cases of sporadic hypospadias, to determine whether 5alpha- reductase plays a role in progesterone action in women, and to elucidate the relation between androgen action and gender role behavior.
Abstract: I. Introduction BETWEEN 1968 and 1973 a large body of evidence accumulated in our laboratory and by others demonstrated that the conversion of testosterone to dihydrotestosterone plays a crucial role in androgen action, including virilization of the external genitalia in male embryos (reviewed in Ref. 1). We had postulated that mutations that impair dihydrotestosterone formation might be the cause of some cases of human male pseudohermaphroditism (2), and a candidate disorder for 5α-reductase deficiency was the rare autosomal recessive disorder termed pseudovaginal perineoscrotal hypospadias (3–7). In 1974 two siblings with pseudovaginal perineoscrotal hypospadias were ascertained in Dallas, and as the result of endocrine, phenotypic, and enzymatic studies it was established that these sisters did have a defect in 5 α-reductase activity (8). At the same time an extensive family from the Dominican Republic was described in whom male pseudohermaphroditism was also due to impairment of the conversion of test...
TL;DR: The receptor serves as the communicative link between the outside and inside of the cell and has the important function of activating signal transduction pathways by way of coupling to GTP-binding proteins (G proteins) or to autophosphorylate itself.
Abstract: I. Introduction THE COMPLEX metabolic activities of cells respond to environmental cues by sensing transmitter substances known as ligands or hormones. The mechanisms of such sensing involves the activation of signaling pathways resulting in changes in gene expression and cellular metabolism (1, 2). Small hydrophobic molecules such as steroid and thyroid hormones and retinoids readily traverse the plasma membrane of the cell and bind to and activate their cognate cytoplasmic or nuclear receptors (reviewed in Refs. 3–7). More complex ligands, however, such as peptide hormones, are unable to enter the cell directly and instead recognize and bind to receptors located on the surface of the cell. Thereby the receptor serves as the communicative link between the outside and inside of the cell. In addition to binding its specific ligand the receptor has the important function of activating signal transduction pathways by way of coupling to GTP-binding proteins (G proteins) (8, 9) or to autophosphorylate itself i...
TL;DR: Because of their abundance in peripheral tissues and in order to distinguish them from the GABAA or central benzodiazepine receptors, this class of benzodi...
Abstract: I. Introduction BENZODIAZEPINES, a class of drugs that includes compounds such as diazepam (Valium), are frequently prescribed because of their anxiolytic, anticonvulsant, musclerelaxant, and hypnotic properties. It has been shown that the pharmacological effects of benzodiazepines are mediated via a specific receptor complex located in the central nervous system (CNS); benzodiazepines bind to a domain that allosterically regulates chloride channel gating by γ-aminobutyric acid (GABA), on GABAA receptors (1–3). In 1977, while searching for specific benzodiazepine receptors, Braestrup and Squires (4) observed the presence of high density radiolabeled diazepam binding sites in the kidney. Since then, numerous papers have reported that this class of benzodiazepine binding sites is present apparently in all tissues examined including the CNS (Section III). Because of their abundance in peripheral tissues and in order to distinguish them from the GABAA or central benzodiazepine receptors, this class of benzodi...
TL;DR: This review concludes that the knowledge and experimental tools generated during the last 4 yr have given us new ammunition to address such important issues as the elucidation of the structural determinants of the LH/CG receptor that are involved in the different functions of this receptor.
Abstract: I. Introduction IN 1989 we published a review in this journal in which we summarized, criticized, and attempted to reconcile the conflicting data that existed on the structure of the mammalian LH/CG receptor (1). Based on our analysis of the existing data we concluded that the LH/CG receptor was composed of a single polypeptide chain. Since that review was published, complementary DNAs (cDNAs) for the LH/CG receptor from several species have been cloned, sequenced, and expressed, conclusively establishing that this receptor is indeed a single polypeptide chain (2–5). The cloning of the cDNAs for the LH/CG receptor has also generated new knowledge and experimental tools that are rapidly being used to probe novel aspects of the functions and regulation of this important receptor. Since the studies leading to the cloning of the first cDNA for the LH/CG receptor have been recently summarized (6), this review will only briefly touch on this aspect and focus mainly on what has been learned since the initial clo...
TL;DR: Examination of various aspects of the complex spatio-temporal patterning of peptidergic signaling that lead to synchronized development of neural events for the preovulatory LHRH discharge on proestrus finds the nature of neurochemical signaling between the two sites remains to be deciphered.
Abstract: I Introduction PITUITARY hormones are secreted in the form of episodic bursts At least two modalities of these periodic hormonal events have been identified in the rat Generally, low amplitude episodes occurring at more or less constant frequency dominate the pituitary secretory pattern On occasion, however, these ultradian intermittent secretory bursts are interrupted by high amplitude surges of hormone secretion lasting for a considerable length of time (1, 2) Well characterized examples of these latter events are the preovulatory gonadotropin (3, 4) and PRL (4, 5) surges in the female rat, the daily burst of ACTH secretion (6), and the periodic high mass and longer duration episodes of GH and PRL in both female and male rats (7, 8) The importance of these pituitary hormone surges in sustaining the internal milieu and the perceived corollary that subtle and progressive derangements in the periodicity and amplitude of these secretory events impel premature aging of reproductive processes are well r
TL;DR: Recent research has indicated that many milk hormones/growth factors survive the environment of the gut of the Neonate, become absorbed into the neonatal circulation, and exert important functions in the neonate.
Abstract: I. Introduction MILK and colostrum contain a variety of proteins, peptides, and steroids that possess biological activity. In studies in which the concentration of hormone/growth factor has been measured in both colostrum and milk, the highest concentrations occur in colostrum (1). This review will discuss pituitary, hypothalamic, pancreatic, thyroid, parathyroid, adrenal, gonadal, and gut hormones as well as growth factors, prostaglandins, and neuropeptides found in milk (see Table 1). Other biologically important proteins and peptides in milk such as the immunoglobulins, allergins, opiates, enzymes, casomorphins, and cyclic nucleotides will not be addressed. The reader is referred to excellent recently published reviews regarding hormones and other bioactive substances present in milk (2–4). Of the hormones and growth factors present in milk many exist in concentrations that exceed those found in maternal plasma (see Table 2). Some are rapidly transported into milk from the maternal circulation unchange...
TL;DR: The current understanding of the biology and multiple functions of MIS including its activation, regulation, and mechanism of action are summarized and areas of interest in ongoing research are discussed.
Abstract: Mullerian inhibiting substance (MIS) is the gonadal hormone that causes regression of the Mullerian ducts, the anlagen of the female internal reproductive structures, during male embryogenesis. MIS is a member of the large transforming growth factor-beta (TGF beta) multigene family of glycoproteins that are involved in the regulation of growth and differentiation. The proteins in this gene family are all produced as dimeric precursors and undergo posttranslational processing for activation, requiring cleavage and dissociation to release bioactive C-terminal fragments. Similarly, the 140 kilodalton (kDa) disulfide-linked homodimer of MIS is proteolytically cleaved to generate its active C-terminal fragments. The sexually dimorphic expression of MIS in Sertoli cells of the testis and granulosa cells of the ovary is critical for normal differentiation of the internal reproductive tract structures. A number of extra-Mullerian functions such as control of germ cell maturation and gonadal morphogenesis, induction of the abdominal phase of testicular descent, suppression of lung maturation, and growth inhibition of transformed cells have also been proposed for this growth-inhibitory hormone and will be discussed. This article will summarize the current understanding of the biology and multiple functions of MIS including its activation, regulation, and mechanism of action and discuss areas of interest in ongoing research.
TL;DR: The etiology of the AITDs remains unclear but it is now generally believed that both genetic and environmental factors contribute to their development and some recent findings have begun to directly and indirectly implicate the possibility of infectious agents in the pathogenesis of AITD.
Abstract: The etiology of the AITDs remains unclear but it is now generally believed that both genetic and environmental factors contribute to their development Some recent findings have begun to directly and indirectly implicate the possibility of infectious agents in the pathogenesis of AITD, and these data serve as the basis for this review Classical AITD (ie Graves' disease and Hashimoto's thyroiditis) has been shown to be associated with a variety of infectious agents (eg Yersinia enterocolitica, retroviruses) while infections of the thyroid gland (eg subacute thyroiditis, congenital rubella) have been shown to be associated with thyroid autoimmune phenomena However, the causative role of infectious agents in AITD has not been definitively demonstrated in humans although AITD can be induced in experimental animals by certain viral infections Infectious agents may induce thyroid autoimmunity by a variety of diverse mechanisms, such as inducing modifications of self-antigens, mimicking self-molecules, inducing polyclonal T cell activation (for example by superantigens), altering the idiotypic network, forming immune complexes, and inducing expression of MHC molecules on thyroid epithelial cells While indirect data suggesting involvement of the infecting organisms in the pathogenesis of human AITD is abundant, only a limited number of studies have employed direct approaches Such a direct approach would involve isolation or molecular identification of the potentially infecting organisms from the thyroid gland and the subsequent induction of AITD in an experimental model
TL;DR: The skin is the sole source of cholecalciferol or vitamin D3 (D3), the precursor for a family of vitamin D metabolites whose best understood role is the regulation of bone mineral homeostasis.
Abstract: I. Introduction THE SKIN is the sole source of cholecalciferol or vitamin D3 (D3), the precursor for a family of vitamin D metabolites whose best understood role is the regulation of bone mineral homeostasis (see Fig. 1). In the skin D3 is produced by a two-step mechanism from 7-dehydrocholesterol (7-DHC) (1). The first step, the breaking of the B ring after UV irradiation, results in the formation of pre-D3; the second step, the thermal conversion of pre-D3 to D3, provides for a sustained release of D3 to the body where it undergoes subsequent metabolism first in the liver to 25-hydroxyvitamin D3 (25OHD3) and then in a variety of tissues to additional metabolites, the most potent of which is 1,25- dihydroxyvitamin D3 [1,25(OH)2D3]. The plant sterol ergosterol undergoes a similar photoactivation to ergocalciferol or vitamin D2 (D2). D2 differs from D3 in that it contains a double bond between C22–23 and a methyl group at C24 of the side chain. In humans the metabolism of D2 and the potency of its metaboli...
TL;DR: The regulation of this series of events is of primary interest to the endocrinologis...
Abstract: I. Introduction IN ORDER to reproduce and multiply, every cell must execute an orderly series of events, generally called the cell cycle, at some time during its life span. The cell cycle was first thought to consist of mitosis and interphase as determined from morphological analysis. As new techniques were developed, a period of DNA synthesis, the S phase, was detected; this was temporally separated from the previous mitosis by a “gap,” the G1 phase, and from the subsequent mitosis by another “gap,” the G2 phase (Fig. 1). The G1 phase is the decision phase in which cells either commit to undergo another round of DNA synthesis and continue to cycle or to exit the cell cycle to enter a quiescent state frequently referred to as G0. Cells in the G0 phase either terminally differentiate or resume proliferation upon addition of an appropriate mitogen (Fig. 1). When DNA synthesis is completed, cells normally proceed to mitosis. The regulation of this series of events is of primary interest to the endocrinologis...
TL;DR: Studying of GnRH peptides and their genes have altered views on the origin, function, and regulation of this neuropeptide, and novel functions, in addition to the release of gonadotropins exist.
Abstract: I. Introduction GONADOTROPIN-releasing hormone (GnRH) plays a pivotal role in reproduction. The existence of this neuropeptide, also called LHRH, was predicted in the 1950s (1), but the structure of the 10 amino acid peptide for porcine and ovine brains was not reported until the 1970s (2, 3). In the 20 yr since then, only one form of GnRH has been identified in most placental mammals, and this is still considered to be the sole neuropeptide causing the release of LH and FSH. The structure and functions of the mammalian form of GnRH have been reviewed a number of times (4s–8). Meanwhile, both mammalian GnRH and related forms of GnRH are now known to be present in primitive placental mammals, nonplacental mammals, and other vertebrates. Novel functions, in addition to the release of gonadotropins, exist. Studies of GnRH peptides and their genes have altered our views on the origin, function, and regulation of this neuropeptide.
TL;DR: Evidence that this endogenous neuropeptide is important to limitation of fever and inflammation in mammals, including man, suggests that αMSH has retained a role as a modulator of host r...
Abstract: I. Introduction α-MELANOCYTE-stimulating hormone (αMSH), a basic tridecapeptide, is derived from the precursor molecule POMC(l). The amino acid sequence of αMSH is identical to the 1–13 (N-terminal) amino acid sequence of ACTH although αMSH has little direct influence on glucocorticoid release from the adrenal gland. αMSH is found mainly in the pituitary, but it also occurs in lower concentrations in the central nervous system (CNS), the skin, and other sites (1). This peptide was named for its effect on pigmentation in amphibian skin, although its distribution in tissues of higher organisms suggests that it is important to other functions. Phylogenetically, αMSH is an “ancient” molecule, little changed over the last few hundred million years, and there is remarkable conservation of its amino acid sequence across species. Evidence that this endogenous neuropeptide is important to limitation of fever and inflammation in mammals, including man, suggests that αMSH has retained a role as a modulator of host r...
TL;DR: The interrelationship between the neuroendocrine and the immune systems has long been a neglected subject of study, but the last decade has experienced an explosive growth of the number of papers dealing with physiological and pathological immunoendocrine interactions.
Abstract: I. Introduction THE interrelationship between the neuroendocrine and the immune systems has long been a neglected subject of study. In spite of the pioneering work of the group of Besedovsky and Sorkin (1), this area was apparently deemed too suspicious of polypragmatism for most neurologists, endocrinologists, and immunologists. Only after scientists from all of these fields decided to combine their expertise, immunoendocrinology became a discipline of its own, and the last decade has experienced an explosive growth of the number of papers dealing with physiological and pathological immunoendocrine interactions. Many excellent reviews on this topic have appeared (2–5). Several of these also appeared in Endocrine Reviews, specifically some classics on the subject of the physiological and pharmacological effects of glucocorticoid hormones (GC) in stress and aging (6, 7), and also on the immunoendocrine dialogue via the hypothalamo-pituitary-adrenal (HPA) axis (8). The potential modulatory role of this feed...
TL;DR: Although medical therapies for Cushing's syndrome have proliferated, no single agent has yet been identified as a potential therapeutic agent.
Abstract: I. Introduction WITH the advent of synthetic glucocorticoids in the late 1940s, adrenalectomy ushered in the modern era of treatment for Cushing's syndrome. Nearly two decades later, the development of transsphenoidal microsurgical techniques allowed the treatment of Cushing's disease with preservation of anterior pituitary function. Medical treatment for hypercortisolism has also progressed during this time. In the 1950s and 1960s, steroidogenic blocking agents, metyrapone and aminoglutethimide, and the adrenolytic agent, mitotane, first achieved use, later to be joined by the imidazole derivative, ketoconazole. As understanding of ACTH neuroregulation advanced in subsequent decades, agents such as bromocriptine, cyproheptadine, and valproate achieved some clinical use. Most recently, a different class of agent, the steroid receptor antagonist RU-486, has been added to the list of potential therapeutic agents. Although medical therapies for Cushing's syndrome have proliferated, no single agent has yet ac...
TL;DR: Analysis of ET genes revealed the existence of three distinct ET genes that encode different mature ET sequences, designated endothelin-1 (ET-1), ET-2, and ET-3 (Fig. 1), which suggest its importance in blood pressure maintenance and generation of vasospasm.
Abstract: I. Introduction ENDOTHELIN (ET) is a potent vasoconstrictive peptide which was originally isolated from the conditioned medium of cultured endothelial cells (1). It comprises 21 aminoacid residues, including four cysteine residues that form two disulfide bonds (see Fig. 1). ET elicits a sustained pressor response when administrated intravenously, which suggests its importance in blood pressure maintenance and generation of vasospasm. Accordingly, many investigators have been interested in this peptide. Analysis of ET genes revealed the existence of three distinct ET genes that encode different mature ET sequences, designated endothelin-1 (ET-1), ET-2, and ET-3 (Fig. 1) (2). Two and six amino acid residues of ET-1 are replaced in ET-2 and ET-3, respectively. There are no species differences among isoforms of human, porcine, rat, bovine, or dog. Interestingly, the structure of snake venom sarafotoxins are very similar to those of ETs. In endothelial cells, ET-1 is predominant, but ET-2 and ET-3 are not dete...
TL;DR: The molecular mechanisms underlying regulatory genes controlling developmental pathways in organisms such as Drosophila and the nematode Caenorhabditis elegans are studied.
Abstract: I. Introduction CASCADES of interacting regulatory genes controlling developmental pathways have been defined in organisms such as Drosophila (1–9) and the nematode Caenorhabditis elegans (10–12). The developmental regulators include transcription factors, kinases, phosphatases, growth factors,receptors, and cell-adhesion molecules. In Drosophila, products of maternally expressed genes control expression of zygotic segmentation genes, the products of which regulate homeotic gene expression; regulation is also exerted between genes of the same class. As a result, the embryo is divided into a meshwork of metameric units, each expressing a unique combination of homeotic genes. These genes contain a conserved homeobox, encoding a 60-amino acid homeodomain which functions in DNA binding. By acting as transcription factors, the homeodomain proteins orchestrate activation of a unique combination of target genes which makes the cells enter a specific morphogenetic pathway. The molecular mechanisms underlying regu...
TL;DR: CG is a placental hormone that maintains the corpus luteum of pregnancy and is used to detect pregnancy at early stages and to monitor the progress of pregnancy during the first trimester.
Abstract: I. Introduction CHORIONIC gonadotropin (CG) is a placental hormone that maintains the corpus luteum of pregnancy. Because CG is expressed at high levels soon after fertilization and implantation, it is used to detect pregnancy at early stages and to monitor the progress of pregnancy during the first trimester (1). CG is also produced in trophoblastic disease and in a variety of different malignancies, and it is useful as a tumor marker in these conditions (2). The mechanisms that control CG production have been investigated extensively, and there are several recent comprehensive reviews (3, 4). CG is a heterodimer composed of α- and β-subunits (Fig. 1). The α-subunit is identical to that in other members of the glycoprotein hormone family (TSH, FSH, LH), whereas the β-subunits in each of the hormones are distinct and confer receptor and biological specificity (5). Little hormone is stored intracellularly and, for the most part, hormone secretion reflects de novo biosynthesis. Therefore, many recent studie...