Showing papers in "Endocrine Reviews in 1992"

Molecular and Biological Properties of the Vascular Endothelial Growth Factor Family of Proteins

Abstract: I. Introduction THE establishment of a vascular supply is a critical requirement for cellular inflow of nutrients, outflow of waste products, and gas exchange in most tissues and organs (1). In endocrine glands, the vascularization not only serves such needs but also provides a pathway for the specific secretory products (2, 3). Furthermore, in the anterior pituitary (4–6) and in the adrenal medulla (7, 8), an unusual angioarchitecture, where a portal capillary plexus delivers venous blood originating from an adjacent gland, is intimately involved in the control of the secretory activity. In the adrenal medulla, this vascular design may even determine the ultimate secretory product (8). Not surprisingly, the cardiovascular system is the first organ system to develop and reach a functional state in an embryo (9–12). In the human, primitive blood vessels appear as early as day 15, and a circulation with a beating heart is already established by the end of the third week.

Modulation of Osteoclast Differentiation

Abstract: I. Introduction BONE is a complex tissue in which resorption and formation continue throughout life. This process is called bone remodeling. Osteotropic hormones such as 1α,25-dihydroxyvitamin D3 [1α,25(OH)2D3], PTH, and calcitonin preferentially modulate the process of bone resorption to maintain bone remodeling. The bone tissue contains various types of cells, of which the bone-forming osteoblasts and bone-resorbing osteoclasts are mainly responsible for bone remodeling. Osteoblasts are believed to be derived from undifferentiated mesenchymal cells, which further differentiate into osteocytes and are embedded in calcified tissues. Osteoclasts are multinucleated cells present only in bone. It is believed that osteoclast progenitors are of hemopoietic origin, and they are recruited from hemopoietic tissues such as bone marrow and circulating blood to bone. Osteoclast progenitors then proliferate and differentiate into mononuclear preosteoclasts and fuse with each other to form multinucleated osteoclasts. ...

Insulin in the brain: a hormonal regulator of energy balance.

Abstract: I. Introduction EARLY studies of brain glucose metabolism established the axiom that insulin is not required for utilization of glucose by the central nervous system (CNS) (1). A corollary to this concept was the belief that circulating insulin is incapable of crossing the bloodbrain barrier (BBB) and is therefore without effects in the brain. While the first of these tenets remains unchallenged, the second has been subjected to detailed scrutiny for over a decade, following the identification of both insulin (2) and its receptor (3) in the adult mammalian brain. Early reports of relatively high concentrations of insulin in brain extracts raised the possibility that insulin is synthesized and released locally in the CNS, as had been established for several other peptide hormones (2). Recent investigations, however, indicate that “brain insulin” is derived largely from the circulation (4), and a growing body of evidence suggests that its delivery into the neuropil may be facilitated by a specialized BBB tr...

The Clinical Significance of Epidermal Growth Factor Receptor (EGF-R) in Human Breast Cancer: A Review on 5232 Patients

Abstract: EGF-R positivity was shown to be present in 2500 (48%) of 5232 breast tumors in 40 different series of patients. The mean of the percentages of EGF-R positivity in the individual series reported by these 40 different groups of investigators is 45% (range 14-91%). Overall there are generally no clear differences between results obtained by radioligand binding assays, immunological methods, autoradiography, and measurement of EGF-R transcripts although the mean percentage of EGF-R-positive tumors determined by immunological methods tends to be somewhat lower. Nearly all studies indicate a negative relationship between EGF-R and steroid receptor status (28 of 31 studies for ER, 12/19 for PR) showing that EGF-R positivity is twice as high in ER or PR- negative tumors compared to ER or PR- positive tumors (approximately 50-60% vs. 30%). With regard to other prognostic factors the majority of investigators (10/18) also reported a significant (positive) correlation with tumor grade, but only a minority found a significant relationship between EGF-R status and patient age (2/9), menopausal status (1/7), histological type (3/7), tumor size (2/17), nodal status (5-9/20), ploidy (1/7), or proliferation indices (3/9). No relationship was observed with tumor insulin-like growth factor I receptor, PRL receptor (PRL-R), and LHRH receptor (LHRH-R) status, but an inverse relationship between EGF-R and somatostatin receptor may be present. However, it has to be stressed that the series in which the relationship between EGF-R status and other prognostic factors were investigated, contained relatively few patients (mostly less than 100). Therefore, when larger groups of patients are investigated, more significant relationships may be observed, especially with respect to nodal status, tumor ploidy, and proliferation indices. In fact, we calculated the presence of EGF-R positivity overall in 35% of 253 aneuploid tumors vs. in only 15% of 114 diploid tumors (P less than 0.0001). In addition most studies observed a trend, if no significant correlation, between higher EGF-R levels in tumors with the highest percentages of S-phase or Ki-67 expression. With regard to relapse-free and overall survival, five of nine different groups of investigators showed significant prognostic value of EGF-R after short-term (1- to 4-yr) follow-up, indicating that patients with EGF-R-positive tumors have a poor prognosis. However, three of five groups with a maximal follow-up of at least 6 yr found only a tendency for any relationship between EGF-R status and long-term outcome.

The thyrotropin receptor and the regulation of thyrocyte function and growth.

Abstract: I. Introduction IN classical physiology, the main regulation of the thyroid gland involves a positive control by pituitary TSH. The pituitary thyrotrophs that synthesize and secrete TSH are submitted to tonic stimulation by the hypothalamic TRH and to negative feedback by T3, which is generated in these cells from plasma T4 (1, 2). The predominant role of TSH in thyroid regulation is exemplified by physiological experiments and pathological situations. Hypophysectomy, or treatment with thyroid hormones that reduces plasma TSH levels without interfering with other pituitary functions, almost abolishes thyroid function and greatly reduces the weight and cell mass of the gland. Conversely, chronic inhibition of the synthesis of thyroid hormones, and thus of their secretion, which greatly enhances TSH plasma levels, enhances thyroid growth and iodine metabolism upstream from the inhibited step. In pathology, hyperthyrotropinemia caused by pituitary adenomas induces hyperthyroidism and goiter. Hypopituitarism ...

Newly identified actions of the vitamin D endocrine system.

Abstract: Introduction VITAMIN D is a seco-steroid in which the B-ring of the cyclopentanoperhydrophenanthrene structure is cleaved. The vitamin is either obtained from the diet or is synthesized in the skin from 7-dehydrocholesterol (Fig. 1) and is itself biologically inert (for reviews see Refs. 1–8). Vitamin D and its metabolites circulate in the blood primarily bound to and in equilibrium association with the vitamin D-binding globulin [DBP]. In the liver, the enzyme 25-hydroxylase converts the vitamin to the inactive hormonal precursor 25-hydroxyvitamin D [25(OH)D]. Subsequently, the renal lα-hydroxylase enzyme converts 25(OH)D to the biologically active form 1,25-dihydroxyvitamin D [1,25(OH)2D]. Both hydroxylase enzymes are cytochrome P450-containing enzymes. la-Hydroxylase activity is tightly controlled by a number of ionic and endocrine factors including stimulation by PTH and reduced plasma Ca2+ or inhibition by 1,25(OH)2D in a classic negative feedback loop. Although not illustrated in Fig. 1, under condi...

Insulin-like growth factors and ovarian follicular development.

Abstract: Introduction INSULIN-like growth factor-I (IGF-I) and its structural homologue, IGF-II, are low molecular weight peptides that promote cellular mitosis and differentiation in a variety of systems and are believed to play a role in cyclic ovarian follicular development. In 1978, IGF-I and IGF-II were purified and sequenced by Rinderkneckt and Humbel (1, 2), and since that time there has been an exponential accumulation of information regarding these peptides, as well as their receptors, and their binding proteins (IGFBPs), constituents of the “IGF autocrine/paracrine system.” These constituents have been examined in various tissues in vivo under a variety of physiological conditions and in vitro in numerous cell and tissue culture systems in several species (for review see Refs. 3–9). A decade ago, research on the IGFs focused on skeletal growth in childhood, a subspecialty of pediatric endocrinology. In the intervening years, the arena of research inquiry extended to other disciplines, including nephrolog...

Brain and Pituitary Angiotensin

Abstract: I. Introduction Angiotensin(ANG II) was discovered about 50 yr ago (1, 2), and a complete peripheral system for the formation and metabolism of ANG II was soon characterized. It was named the renin-angiotensin system, based on the rate-limiting enzyme, renin, and the active principle, ANG II (3). In the classical peripheral RAS system, a precursor molecule, angiotensinogen (AOGEN), originates in the liver and is cleaved to the essentially inactive decapeptide angiotensin I (ANG I) by an aspartyl protease, renin, synthesized and released to the circulation mainly by the juxtaglomerular cells of the kidney. ANG I is converted to ANG II, the effector peptide of this system, by the angiotensin-converting enzyme (ACE) (4). Circulating ANG II acts on high affinity ANG II receptors located in the vascular smooth muscle, zona glomerulosa of the adrenal gland, and kidney to produce vasoconstriction, aldosterone release, and sodium retention, respectively. Thus, the peripheral RAS is a hormonal system with importan...

Dopamine agonists and pituitary tumor shrinkage

Abstract: The primary aim of this review has been to clarify the tumor shrinking effects of dopamine agonists on pituitary macroadenomas of different cell types. Shrinkage is most dramatic for macroprolactinomas and is due to cell size reduction. Seventy-nine percent of 271 definite macroprolactinomas were reduced in size by at least 25%, and 89% shrank to some degree. Most shrinkage occurs during the first 3 months of treatment, although in a minority shrinkage is delayed. Dopamine agonist resistance during long-term therapy is exceptional. Drug withdrawal nearly always leads to a return of hyperprolactinemia, even after several years treatment, although early tumor reexpansion is unusual. About 10% of true macroprolactinomas do not shrink with dopamine agonists; the molecular mechanisms of such resistance have yet to be determined. Alternative formulations of BC and new dopamine agonists (CV 205-502 and cabergoline) are useful for the minority of patients unable to tolerate oral BC, but do not seem to further improve overall shrinkage rates. The risks of pregnancy have probably been overstated, and BC is suitable primary treatment for women with prolactinomas of all sizes; the drug can be used safely during pregnancy in the event of clinically relevant tumor expansion. The interpretation of different degrees of hyperprolactinemia is discussed and management strategies suggested. Most patients with macroprolactinomas now avoid surgery, but drug-induced, time-dependent tumor fibrosis should be remembered if surgery is contemplated. Nonfunctioning pituitary tumors are mostly of gonadotroph cell origin and may be associated with significant disconnection hyperprolactinaemia. Seventy-six of 84 well-characterized tumors showed no tumor shrinkage during dopamine agonist therapy. Possible explanations include abnormalities of dopamine receptor number and function. Preliminary evidence suggests that dopamine agonists may restrain the growth of some functionless tumors; most of these tumors, however, can be satisfactorily debulked using transsphenoidal surgery. In contrast to macroprolactinomas, other functioning pituitary tumors (GH-, TSH-, and ACTH-secreting) rarely shrink during dopamine agonist therapy, although the number of tumors studied is small.

Interferons as hormones of pregnancy.

Abstract: I. Introduction ABOUT 5 yr ago it was discovered that a protein which was secreted in quantity by preimplantation sheep conceptuses and implicated in preventing luteolysis during the second and third weeks of pregnancy was, in fact, structurally related to type I interferons (IFN), proteins best known for their antiviral and immunomodulatory activities. This discovery attracted considerable attention because it revealed a new and completely unsuspected role for a cytokine as a reproductive hormone. Several reviews have been published on various aspects of this topic (1–10). In the more comprehensive updated article that follows, we describe how IFN came to be implicated as antiluteolytic agents in domestic ruminant species, the properties of these IFN, and some of the unusual features pertaining to their expression and transcriptional regulation. We address the questions as to whether these IFN have any unique biological and structural properties, as to how they evolved, and as to whether type I IFN in ge...

Receptor-effector coupling by G proteins: implications for normal and abnormal signal transduction.

Abstract: I. Introduction THE ROLE of heterotrimeric guanine nucleotide binding proteins (G proteins) in signal transduction was first covered in Endocrine Reviews in 1981, when three distinct G proteins involved in visual transduction and regulation of cAMP formation were recognized (1). This topic was updated in Endocrine Reviews in 1989 by which time the number of mammalian G proteins identified had doubled, and their roles in regulation of various phospholipases and ion channels had been recognized (2). Barely 3 years later, the number of distinct mammalian G proteins recognized has again doubled, multiple G proteins have been identified in invertebrates, plants, and single-celled eukaryotes, and the number of cellular functions shown to be regulated by G proteins has increased correspondingly. Numerous excellent reviews covering various aspects of this topic have recently appeared (3–9), but given the rapidity of progress in this field, an update in Endocrine Reviews appears timely. This review summarizes rece...

Anatomy of the steroid receptor zinc finger region

Abstract: I. Introduction LIKE many transcriptional regulatory proteins, nuclear hormone receptors are single polypeptides that are organized into relatively discrete functional domains (1). This common domain organization groups these receptors into a superfamily of functionally and most likely structurally related, hormonally regulable, transcription factors. The superfamily includes receptors for steroid hormones, such as glucocorticoids, progesterone, estrogen, aldosterone, and androgens, as well as hormonal forms of vitamins A and D, thyroid hormone, and peroxisomal activators (2–6). Several other receptorlike proteins whose ligands have yet to be identified have recently been isolated utilizing molecular cloning techniques. In the same way, several putative nuclear receptors from Drosophila that appear to act as regulators of early development (Refs. 7–10; reviewed in Ref. 11) have been identified, including a receptor for the insect steroid ecdysone (12). Upon association with a particular ligand, nuclear re...

Intracellular signaling in the gonads

Abstract: The regulation of steroidogenesis in both the ovary and testis involves a complex interaction of a diversity of hormones and intracellular signaling pathways. The recent cloning of LH and FSH receptors has paved the way for an increased understanding of the mechanisms of receptor conformation, ligand-receptor interaction, and facilitation of post-receptor activity. The dominant role played by LH in the regulation of steroid production appears to be mediated by more than one intracellular signaling pathway. In addition to the stimulation of the adenylate cyclase-cAMP pathway, also known to be stimulated by FSH, the actions of LH may be additionally mediated by other intracellular messengers, such as those derived from the PLC pathway. Steroidogenesis in the gonads appears to be modulated by a variety of factors in addition to the gonadotropins. In this review, those factors of intracellular signaling mechanisms of which we have some understanding have been discussed. These include GnRH, PGF2 alpha, Ang II, VIP, GHRH, TNF alpha, CRF, EGF, and TGF alpha. Many of these factors have been shown to be locally synthesized, and specific receptors have been identified in the gonads. Many gonadal factors have the capacity to exert effects on steroidogenesis independent of the gonadotropins. Alternately, they have been demonstrated to alter the gonadal response to the gonadotropins via autocrine, paracrine, and intracrine mechanisms. As yet, our understanding of the intracellular signaling mechanisms used by novel gonadal regulators is limited. The involvement of the PLC, PLA2, and PLD pathways in this regard has been reviewed. It is becoming apparent that multiple signaling pathways may be stimulated by a single hormone, as in the case of GnRH, PGF2 alpha, and LH. The complexity of intracellular signal transduction in the gonads is enhanced by the potential cross-talk at numerous steps in the signaling cascades.

Mutations in the insulin receptor gene.

Abstract: I. Introduction THE insulin receptor is a cell surface glycoprotein that mediates the action of insulin upon target cells. The receptor was originally identified by its ability to bind the hormone (1–3). Over the past two decades, considerable progress has been made in defining the structure of the receptor molecule (4–7) as well as the biochemical mechanism by which it mediates insulin action (8–10). In addition, the insulin receptor has been identified as a target for pathological processes in human disease. In this review, we describe mutations in the insulin receptor gene that have been identified in patients with genetic forms of insulin resistance (6). Identification of these mutations has elucidated the molecular mechanisms that cause disease in these patients. In addition, the mutations have provided significant insights into the structure and function of the insulin receptor. II. Expression of the Insulin Receptor Gene The human insulin receptor gene contains 22 exons, and occupies in excess of 1...

Contemporary aspects of discrete peak-detection algorithms. II. The paradigm of the luteinizing hormone pulse signal in women

Abstract: I. Introduction ALONG-STANDING axiom in endocrine physiology is that normal reproductive function requires a highly coordinated interplay of events both within and among the components of the gonadal axis. Central to this axis are the gonadotropes, pituitary cells that synthesize and release the gonadotropins, LH and FSH. Of pivotal importance is the recognition that these trophic hormones, which are responsible for stimulating both the production of gonadal hormones and gametogenesis, are themselves secreted in a pulsatile fashion. Such pulsatile gonadotropin release reflects the integration of signals of both neural and gonadal origin that impinge upon the gonadotropes (Fig. 1). Indeed, the frequency with which the gonadotropins are released is believed in general to reflect the frequency with which quanta of GnRH are discharged by the hypothalamus, transported through the hypothalamic-hypophyseal portal circulation, and interact with appropriate receptors on responsive gonadotropes (1–6). The synthesis...

Corticotropin-releasing hormone in humans.

Abstract: I. A Brief History of Corticotropin-Releasing Hormone (CRH) and Vasopressin as Mediators of Pituitary-Adrenal Activation in Humans HARRIS' 1948 hypothesis (1) that anterior pituitary function is regulated by hypothalamic factors released into and carried by the hypothalamic-hypophysial portal blood to the adenohypophysis was not lost upon clinical investigators. Soon thereafter G. W. Liddle, for example, referred to this regulatory influence of the central nervous system as the “pituitary driving mechanism” (2), recognizing that such a mechanism was essential for explaining the diurnal rhythm in pituitary-adrenal axis function and its response to stress. According to this concept, the pituitary driving mechanism was the variable force against which cortisol exerted its negative feedback inhibitory action on ACTH secretion. Long before CRH [ovine CRH (oCRH) mol wt = 4671; human CRH (hCRH) mol wt = 4758] was isolated, characterized, and synthesized (3), vasopressin [either arginine vasopressin (AVP) or lysi...

Phosphorylation of Steroid Hormone Receptors

Abstract: Many observations with intact cells as well as cell-free systems suggest that receptors of the steroid hormone superfamily, along with other transcription factors, are regulated by phosphorylation. All receptors that have been analyzed carefully so far have turned out to be phosphoproteins. They are basally phosphorylated in the absence of ligand, and in many cases become hyperphosphorylated in the presence of hormone or other agonists, and sometimes of antagonists. Several studies indicate that hyperphosphorylation of receptors follows activation, and may require nuclear binding of the receptor. Serines are the predominant phosphorylated residues detected in receptors, with minor amounts of threonine. Tyrosine phosphorylation of the estrogen receptor is a subject of controversy. With various receptors, evidence has been found for phosphorylation in vivo of the N-terminal, hormone-binding, and DNA-binding domains, as well as of the hinge region. All but one of the phosphorylated sites identified in progesterone and glucocorticoid receptors by phosphopeptide mapping and sequencing are in the N-terminal domain; one is in the hinge region. Even after hormone treatment most of those sites are only partly phosphorylated, which means that several subpopulations of receptors, characterized by different states of phosphorylation and potentially different biological activities, must coexist. The majority of identified phosphorylated sites lie in consensus sequences for the PDPK. Many parallels can be discerned between phosphorylation of receptors and of other transcription factors. For example, several transcription factors become hyperphosphorylated on stimulation, and much indirect evidence points to regulation of both receptors and transcription factors by kinases and phosphatases, with cycling between different phosphorylated states. Functions of receptors that are regulated by phosphorylation are only beginning to be investigated. With transcription factors a substantial body of information is already available, and functions that appear to be thus regulated include dimerization, interactions with other proteins, binding to DNA, nuclear-cytoplasmic localization, and transcriptional activity. These and other functions may be found to be regulated by phosphorylation of receptors.

Clinical counterpoint: vitamin D: new actions, new analogs, new therapeutic potential.

Abstract: Introduction AN EXCITING new era has developed in the vitamin D field with the discovery of new target tissues, mechanisms of action, and selective analogs. As a clinical counterpoint article, this review will emphasize the potential clinical applications of these new discoveries. Many of the applications to be discussed remain untested, whereas others remain in their infancy. A major reason for optimism in predicting an expanding list of therapeutic applications for the vitamin D metabolites and analogs stems from the development of analogs of calcitriol that differ in their biological effects. In particular, analogs are now available that appear to separate the effects of calcitriol on growth and differentiation from effects on intestinal calcium absorption or bone mobilization. This apparent selectivity may reflect altered pharmacokinetic properties or may involve mechanistic differences at the cellular level as well. Regardless, the development of these drugs is likely to lead to clinical applications...

The molecular biology of RU486. Is there a role for antiprogestins in the treatment of breast cancer

Abstract: I. Introduction ENDOCRINE therapy used either prophylactically or therapeutically for the treatment of locally advanced or metastatic breast cancers offers many advantages to patients whose tumors contain functional estrogen and progesterone receptors (ER and PR). The range of treatments defined as endocrine include surgical ablation of endocrine glands, administration of pharmacological doses of steroid hormones, chemical blockade of steroid hormone biosynthesis, and inhibition of endogenous steroid hormone action at the tumor with synthetic antagonists. The last of these approaches is the most widely used, making the antiestrogen tamoxifen the preferred first-line therapeutic agent for treatment of hormone-dependent metastatic breast cancer. The wide-spread use of tamoxifen reflects its efficacy and low toxicity, and the fact that it makes good physiological sense to block the local proliferative effects of estrogens directly at the breast. But are estrogens the only hormones with a proliferative impact...

The Impact of Gonadal Steroid Hormone Action on Growth Hormone Secretion During Childhood and Adolescence

Abstract: I. Introduction PHYSIOLOGIC regulation of GH secretion has been an active subject of investigation recently. In particular, the interaction with, and independent functions of, the sex steroid hormones and GH have been the subjects of a large number of studies, both in the basic sciences and in the clinical arena. Based on the results of multiple clinical studies, it has been observed that GH secretion is amplified in the presence of gonadal steroid hormones. During the course of male and female puberty, either normal, precocious, or pharmacologically induced, spontaneously circulating GH levels increase via an amplitude- modulated phenomenon. Using recently available mathematical modeling techniques, it has been possible to demonstrate that the mechanism of this increase is via sex steroid hormone-induced amplification of endogenous GH production rate, without demonstrable alterations of the frequency of secretory episodes or of hormone half-life. We intend to review what is understood about this relation...

Molecular Basis of the Specificity of Binding of Glycoprotein Hormones to Their Receptors

Abstract: Introduction THREE glycoprotein hormones are synthesized and secreted by the pituitary under hypothalamic control. Two of them are the gonadotropins, LH and FSH, and the third one is TSH. During gestation in primates and equidaes an additional gonadotropin, CG, is secreted by the placenta. Pituitary gonadotropins play pivotal roles in the control of reproductive function in both the female (1, 2) and the male (3) while the main role of TSH is in the control of thyroid gland activity (4). Although the human (h) and equine (e) CGs (the latter previously named PMSG) have been studied extensively, the full extent of their roles remains equivocal (5, 6). Glycoprotein hormones form a family of structurally related molecules that are among the most complex molecules possessing hormonal activities. Despite their extensive homologies, these hormones exhibit high specificities, indispensable for their respective and often coordinated physiological roles. The present review is an attempt to summarize and interpret t...

The molecular biology of thyroid peroxidase: cloning, expression and role as autoantigen in autoimmune thyroid disease.

Abstract: I. Introduction THYROID peroxidase (TPO) is the primary enzyme involved in thyroid hormone synthesis, catalyzing iodide oxidation, iodination of tyrosine residues, and coupling of iodotyrosines to generate the iodothyronines T3 and T4 (1). It is a membrane-bound glycoprotein with a heme prosthetic group. In addition to the pivotal physiological role of TPO, there was strong immunological evidence, even before its molecular cloning, that this enzyme was the elusive “thyroid microsomal antigen” in autoimmune thyroid disease (discussed below). The molecular cloning of the complementary DNA for a protein provides powerful new opportunities for studying protein structure and function at an unprecedented level of detail. In t h e past decade, three of the four major thyroid-specific proteins have been cloned, namely thyroglobulin (TG) (2–4), TPO (see below), and the TSH receptor (5–8). Molecular cloning of the thyroid iodide transporter may occur soon (9). As might be expected, these advances have been followed...

Neurochemical Regulation of Oxytocin Secretion in Lactation

Abstract: I. Introduction: Physiological Patterns of Oxytocin Secretion THE nonapeptide oxytocin (OT) is an excellent example of a messenger molecule with diverse physiological actions as well as modes of delivery to its target cells (1, 2). After release from neurosecretory terminals in the neurohypophysis, OT exerts effects as a hormone carried by the systemic circulation to distant target organs, perhaps the most important of which are the mammary gland and uterus (1). In addition, OT may serve as a hypophyseotropic factor, released from nerve terminals in the median eminence into the pituitary portal vasculature, to affect anterior pituitary secretion (2–7), as a peptidergic neurotransmitter or neuromodulator acting within the central nervous system to influence a variety of neuroendocrine, behavioral, and autonomic functions (2, 8–13), and as a paracrine regulatory peptide in the ovary and testis (14–18). Although its most widely investigated physiological actions across all of these modalities are related to ...

Calcium oscillations in anterior pituitary cells.

Abstract: I Introduction OVER the last two decades it has become evident that intracellular Ca2+ signals are critically important for the control of cellular activities including excitability, exocytosis, and contraction, as well as cell growth, differentiation, and division Elevations of [Ca2+]i occur spontaneously or in response to agonist stimulation and are commonly expressed as prominent Ca2+ oscillations in single cell studies Such oscillations are dependent on the entry of Ca2+ and/or its release from intracellular stores In many cell types, both mechanisms are involved in the generation of Ca2+ oscillations The cellular pathways involved in the regulation of Ca2+ entry include VSCC, receptor- and second messenger-operated Ca2+ channels, and mechanically operated Ca2+ channels Ca2+ discharge from intracellular Ca2+ pools also occurs through calcium channels; one of these is the inositol 1,4,5-trisphosphate [Ins(1,4,5)P3]-sensitive- and another is the ryanodine-sensitive Ca2+ release channel (1) In pit

Basic counterpoint: mechanisms and pathways of gonadal steroid modulation of growth hormone secretion.

Abstract: In spite of the different patterns of GH secretion observed in male and female rats, it can be argued that there are limited differences between the mechanism of action of androgens and estrogens as reported in the literature. However, we feel that it is possible to organize the available data into a unique physiological model explaining the sex-based differences in GH secretion in the rat. Thus, it can be proposed that the greater spontaneous GH peaks observed in the male with respect to the female rat may be due to an androgen-mediated enhancement of both GHRH secretion at the hypothalamic level and GH secretion at the pituitary level. The lower GH troughs observed in the male as compared to the female rat may be due to increased interpeak somatostatin secretion induced by the androgens with respect to the estrogens. It is likely that these high GH peaks and low GH troughs establish a recycling mechanism through established feedback mechanisms. That is, the high GH peak, induced by GHRH, stimulates somatostatin secretion such that a very low GH trough follows. In turn, this low GH trough, in the high somatostatin environment, establishes the correct neuroendocrine milieu for the next high GH peak, and so on. Additional studies will help clarify this model and hopefully provide a better understanding of the mechanisms regulating the interaction between gonadal steroids and GH.

The Role of Selenium in Thyroid Hormone Action

Abstract: I. Introduction RECENT progress in the field of thyroid hormone deiodination has led to a greater understanding, not only of this critical process, but also of mechanisms more basic to protein synthesis in general. The cloning of the type I deiodinase, demonstration that this enzyme is a selenoprotein, and subsequent identification of selenocysteine insertion sequences in the noncoding portion of the gene have provided considerable insight into the mechanism of incorporation of this unusual amino acid into proteins. The purpose of this review is to discuss some of these advances and their implications. We begin by providing a brief background of the deiodination process and the discovery of the enzymes involved, followed by a discussion of some of the extensive characterization studies that have been performed on these enzymes over the years. Comprehensive reviews of these earlier studies have been published previously (1, 2). We next describe the expression cloning of the type I deiodinase and its identi...

Intercellular Communication Within the Anterior Pituitary Influencing the Secretion of Hypophysial Hormones

Abstract: I. Introduction THE study of paracrine and autocrine interactions within the anterior pituitary—cell to cell interactions which influence the secretion of other hormones with extrapituitary physiological actions—has been the focus of expanding research efforts in the last 3–4 yr. It is undeniable that many earlier investigations have aimed to delineate paracrine interactions. In this regard the efforts of Carl Denef (1) and numerous investigators who have studied the pituitary angiotensin II system (see, for example, Ref. 2) cannot be overstated. Nevertheless, the numbers of studies and breadth of investigation have clearly increased recently. Indeed, the prompting of this review is due in no small measure to the simple observation of the increasing number of papers, relevant to paracrine interactions in the anterior pituitary, presented at the Annual Meeting of The Endocrine Society over the past 3 yr. Why has this occurred? One simple explanation is that the adaptation of novel methodology to the study ...

Biology of Normal Luteinizing Hormone-Releasing Hormone Neurons During and After Their Migration from Olfactory Placode

Abstract: I. Introduction SINCE the initial report that LHRH-expressing neurons migrate during development from their birth place on the medial side of the olfactory placode into the brain (1), two sorts of questions have received additional experimentation and discussion. First, what light does this unusual migration into the developing brain shed on the nature of LHRH-expressing cells, and what are the implications for their normal roles in the adult brain? Second, what would be the implications of migration disturbances for human reproductive physiology, including Kallmann's and other syndromes (see companion paper by Dr. Crowley)? Accordingly, the purposes of this review are to reexamine some of the evidence concerning normal controls over LHRH neurons in light of what these cells are supposed to do in the adult brain; to review the burgeoning evidence that they actually originate in the olfactory pit and migrate into the developing forebrain; and to introduce the subject of Kallmann's syndrome (see companion p...

Secretion of peptides and proteins lacking hydrophobic signal sequences: the role of adenosine triphosphate-driven membrane translocators.

Abstract: In this review, we will emphasize the role of ATP-dependent membrane transporters in protein export and intracellular protein trafficking in prokaryotic and eukaryotic cells. ATP-binding-cassette (ABC)-transport proteins, also termed "traffic ATPases," belong to a superfamily of ubiquitous ATP-driven membrane transporters that share extensive sequence similarity and highly conserved domain organization. They are implicated in a remarkable variety of transmembrane transport processes, including the transport of ions, heavy metals, sugars, anticancer drugs, amino acids, oligopeptides, and proteins. Bacterial ABC-proteins include the well-characterized periplasmic permeases involved in nutrient uptake, but also include protein secretion systems, such as the exporter for the Escherichia coli enterotoxin hemolysin A. Prominent eukaryotic members of this superfamily include the human P-glycoprotein (which is associated with the phenomenon of multiple drug resistance in tumor cells), the product of the cystic fibrosis gene (CFTR), the gene (pfmdr) implicated in chloroquine resistance of the malarial parasite, putative peptide transporters encoded at the locus for the class II major histocompatibility complex (MHC), and the yeast Ste6 transporter which mediates export of a peptide hormone that lacks a classical hydrophobic signal peptide. The well-established function of prokaryotic ABC-transporters in the secretion of proteins without typical signal sequences, and the example set by the Ste6 transporter, have led to the reasonable hypothesis that certain ABC-proteins in animal cells may be operating by a similar mechanism to mediate the export of a new class of secretory proteins, those lacking a classical hydrophobic signal peptide.