Showing papers in "Endocrine Reviews in 1981"

Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications.

Abstract: THYROXINE (T4), measured as protein-bound iodine, was the first hormone to be quantitated in human serum. As a consequence, it was possible to demonstrate clear relationships between circulating T4 concentrations and many of the physiological manifestations of thyroid hormone excess or deficiency. In 1952, 3,5,3′-triiodothyronine (T3) was identified in human plasma and metabolic studies in man soon led to the realization that this hormone was 3–4 times as potent metabolically as T4 (1–4). At that time, the question was first raised as to whether T4 or T3 was the “active” thyroid hormone (3). This question became even more pertinent when it was suggested first in 1955 (5) and shown conclusively in 1970 that T4 could be converted to T3 by peripheral human tissues (6, 7). These studies were made possible by the development of methods for quantitating T3 in human serum, initially by competitive protein binding techniques, followed soon thereafter by specific and sensitive RIAs.

Gonadotropin-Releasing Hormone Receptors: Characterization, Physiological Regulation, and Relationship to Reproductive Function

Abstract: THE TONIC and cyclic secretion of gonadotropins is mediated by the hypothalamic production of gonadotropin releasing hormone (GnRH). The direct assessment of hypothalamic function has been hampered by the absence of reliable methods for the measurement of GnRH production and secretion. Endogenous hypothalamic GnRH probably never reaches the general circulation in sufficiently high concentration to be measured by RIA (1–5), since the pituitary gland has the capacity to metabolize the majority of the peptide secreted into the hypothalamo-hypophyseal portal circulation (6–10). Attempts to determine the rate and amplitude of GnRH secretion have shown that GnRH concentrations in hypophyseal stalk plasma fluctuate between 20 and 800 pM (11–14). Such studies have revealed that GnRH is released in a pulsatile fashion, although rapid changes in secretion rate cannot be detected during the long period required for sample collection. In addition to modulating the concentration of GnRH in hypophyseal portal plasma (1...

Transport of protein-bound hormones into tissues in vivo.

Abstract: THE STEROID and thyroid hormones circulate in the plasma tightly bound by albumin and by specific plasma globulins (1, 2). Consequently, hormones exist in two states at equilibrium in vitro, i.e. free (dialyzable) and protein-bound. A widely held hypothesis in endocrinology is that the fraction of hormone that is free in vitro is equivalent to the fraction of hormone that is free and available for transport into tissues in vivo. Therefore, in vitro measurements of free hormones may be commonly used as reliable indices of the free hormone in vivo for a variety of clinical states. The purpose of this review is to advance the concept that the large protein-bound moiety of plasma hormone is available for transport into tissues. Consequently, the fraction of plasma hormone that is available for transport in vivo may deviate greatly from the free fraction in vitro. Under some conditions, changes in the free hormone fraction in vitro and in the fraction of plasma hormone that is available for transport in vivo w...

Extrapituitary Actions of Gonadotropin-Releasing Hormone

Abstract: Harris (1) first proposed that the anterior pituitary gland is controlled by hypothalamic releasing factors. After the subsequent purification and sequencing of gonadotropin-releasing hormone (GnRH) (2, 3) and the synthesis of potent GnRH agonists and antagonists (4, 5), many laboratories have investigated the effects of these peptides on various reproductive functions. In both males and females, administration of GnRH or its potent agonists results in sustained increases in serum gonadotropins. In women, administration of GnRH causes preovulatory-like surges of gonadotropins (6, 7). In several animal species, a single injection of GnRH induces preovulatory- like surges of LH that trigger ovulation (8–11). Since pituitary gonadotropins are essential for normal gonadal functions and hypothalamic GnRH was believed to act solely on the pituitary gland, treatment with high doses of GnRH and its agonists had been predicted to be a potential means for enhancing fertility. Paradoxically, long term administration...

Neuroendocrine control of thyrotropin secretion.

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

Pancreatic Neuroendocrinology: Peripheral Neural Mechanisms in the Regulation of the Islets of Langerhans*

Abstract: The islets of Langerhans are richly vascularized and both the islet cells and blood vessels are intimately associated with a variety of autonomic nerves. Direct electrical stimulation of the nerves in vivo or pharmacological stimulation of the islets with neurotransmitters in vitro results in changes in the rate of release of islet hormones. The purpose of this paper is to describe the anatomy of the islet in relation to its vascular supply and both motor and sensory autonomic nerves, which may play a role in altering the secretion rate of islet hormones. Evidence for catecholaminergic, cholinergic, and peptidergic nerves as well as possible peptide neurotransmitters in the pancreas is examined. Secondly, physiological and pharmacological studies are reviewed that reveal how efferent autonomic neural activity leads to altered islet secretion rates. Third, because the complex structure of the islet is supplied with a variety of autonomic nerves, the evidence for excitation of these nerves via reflex activa...

Melatonin. A Mammalian Pineal Hormone

Abstract: PROBABLY no other organ in the body has suffered so long from a lack of its true functional recognition as the pineal gland. For more than two centuries the pineal was thought to be the seat of the soul or a vestigial remnant of the parietal eye. However, pineal research over the last 20 years has contributed significantly to unraveling the functional significance of this enigmatic endocrine gland. In this respect the isolation and characterization of melatonin by Lerner et al. (1) in 1958 constituted a landmark inasmuch as it was the first substance to be characterized in the pineal gland that reproduced many of the effects of pineal extracts or reversed the endocrine sequelae of pinealectomy. Today the pineal gland is recognized as an active functioning neuroendocrine organ that responds primarily to photic stimuli (and secondarily to hormonal signals originating in target tissues), exhibits circadian rhythms, and influences the metabolic activity of a host of endocrine glands.

The Neuroendocrine Regulation and Function of Growth Hormone and Prolactin in the Mammalian Fetus

Abstract: The neural control of fetal pituitary hormone secretion and the conceptualization of the integration of neural, neurotransmitter, neuromodulatory, and humoral signals in the fetus is an emerging field of interest. At an early stage in the construct of the neurosecretory neuron, Berta and Ernst Scharrer (1, 1a) proposed that neurosecretion is a phylogenetically “old and fundamental attribute of neural elements.” Not only is neurosecretion a primitive regulatory system but an increasing body of evidence suggests that neuroendocrine mechanisms differentiate and function from early in fetal life in many mammals, whereas in others with slower neural development this maturation occurs in the perinatal period. Among the earliest studies are those of Jost (2), who observed that decapitation of the male rabbit fetus impaired fetal testicular function. Neurohormones are present in the fetal hypothalamus at the time of its initial differentiation from the primitive forebrain, and it is likely that even before full m...

Folliculogenesis in the Primate Ovarian Cycle

Abstract: MUCH MORE is known about ovarian function in small mammals, especially laboratory rodents, than about the factors regulating cyclic ovarian function in primates. However, recent results, including our own, have enhanced the understanding of ovarian function in primates, bringing new and significant findings that now justify an assembly of knowledge on the regulation of the primate ovarian cycle. In this review, the major consideration is given to aspects of folliculogenesis in primate species. Where important similarities or differences in fundamental issues have been described in other mammals, limited discussion has been given to comparative aspects of follicular maturation. Consequently, we encourage readers of this subject to rely upon several scholarly reviews (1–7) that have recently developed comparative topics more fully than is either appropriate or intended here. Accordingly, we have restricted our attention to the dynamics of follicle growth during the primate ovarian cycle to focus on recent f...

Insulin Metabolism and Degradation

Abstract: INSULIN degradation is a complex and incompletely, understood process at present. In terms of overall clearance and metabolism, the liver is responsible for more than half of the total insulin degradation, with kidney responsible for most of the rest. The peripheral tissues, fat and muscle, probably degrade the remainder of the insulin in the body, but the absolute contribution of these tissues to insulin turnover is uncertain. It now appears that peripheral tissues can serve as a reservoir for insulin, presumably by the hormone binding reversibly to membrane receptors. The function of this remains to be established. At a cellular level in most tissues, insulin degradation is initiated by the hormone binding to specific receptors. The hormone-receptor complex is processed, including internalization and degradation of at least some of the hormone-receptor complexes. The enzyme or enzymes involved in the degradative process have not been established, but three systems have been implicated: insulin protease,...

Insulin receptor: structure and function.

Abstract: INSULIN receptor has been purified by affinity chromatography and studied by affinity labeling techniques. It is composed of two types of subunits, α (molecular weight ∼135,000) and β (molecular weight α90,000), which form a disulfide-linked heterotetramer (αβ)2. Both α- and β-subunits are glycoproteins. Both are exposed on the outer surface of the membrane, a is the subunit that is predominantly affinity labeled by insulin and is probably the insulin-binding subunit; however, β may also comprise a portion of the insulin-binding site. Receptors for insulin-like growth factors have also been affinity labeled. A photoaffinity labeling derivative of basic somatomedin affinity labels a protein with a subunit structure very similar to the insulin receptor. In contrast, multiplication-stimulating activity is affinity cross-linked to a protein with an entirely different subunit structure. After binding to cell surface receptors, insulin, along with its receptor, is internalized by an endocytic process, which in ...

Gonadotropin-Releasing Hormone Action in the Pituitary: A Three Step Mechanism*

Abstract: CALCIUM fulfills the requirements of an intracellular mediator for gonadotropin-releasing hormone (GnRH; pyro-Glu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-GIU-NH2)-stimulated gonadotropin release from the pituitary (1). Evidence from our laboratory and others now suggests that GnRH action may be divided into three sequential steps: 1) interaction of GnRH with a specific plasma membrane receptor; 2) mobilization of ionic calcium (Ca2+); and 3) expulsion of the contents of the gonadotropin secretory granule to the extracellular space. At present, considerable work remains to be done regarding the mechanism of Ca2+ mobilization in response to GnRH and its precise locus of action. This review describes experiments that led to the development of this model and summarizes recent progress. A. Introduction Early studies with hemipituitaries and pituitary slices (2) suggested that the ionic makeup of the incubation medium, especially with regard to Ca2+, influenced the release of pituitary hormones. These studies relied up...

The glucagonoma syndrome: clinical features, diagnosis, and treatment.

Abstract: Islet cell tumors of the pancreas have been described for over 50 yr. Although carcinoma arising from islet tissue had been noted since the turn of the century (1), not until 1927 was the first case of a hormonally active pancreatic neoplasm, an insulinoma, recorded (2). For many years thereafter, pancreatic endocrine tumors were characterized as either insulin-producing or “nonfunctional,” the latter being derived from cells apparently devoid of clinically significant hormonal activity. With time, however, other islet cell secretory products were discovered and their tumors identified with various clinical syndromes. Whereas the hypoglycemia of insulinomas and hyperacidity of gastrinomas figured prominently in the initial recognition of these neoplasms, the clinical signs of glucagon-producing tumors were less readily apparent and not as easily attributable to specific hormone excess. Becker and co-workers (3) are credited with the first description of a glucagonoma. Their case, reported in 1947 but diag...

Lipoprotein utilization and cholesterol synthesis by the human fetal adrenal gland.

Abstract: A model proposed for regulation of steroidogenesis, lipoprotein utilization and cholesterol metabolism in HFA tissue is presented in Fig 17. We envision that the role of ACTH and cAMP in steroidogenesis and cholesterol metabolism is as follows. ACTH binds to specific receptors on the surface of the cells of the HFA gland and as a consequence, adenylate cyclase is activated, leading to increased formation of cAMP. cAMP causes activation of protein kinase that leads, presumably, to phosphorylation of specific proteins. This leads to the initiation of reactions that give rise to increased activity of key enzymes and levels of proteins involved in adrenal cholesterol metabolism. Presumably, the action of ACTH causes an increase in the activity of cholesterol side chain cleavage, the rate-limiting step in the conversion of cholesterol to steroid hormones. We suggest that once the mitochondrial cholesterol side-chain cleavage system is fully activated by ACTH, the supply of cholesterol to the mitochondria becomes rate-limiting for steroidogenesis. To meet this demand for cholesterol, a further action of ACTH results in an increase in the number of LDL receptors. LDL binds to specific receptors on the cell surface that are localized in coated pits. LDL is internalized by a process of adsorptive endocytosis and the internalized vesicles fuse with lysosomes and the protein component of LDL is hydrolyzed by lysosomal proteolytic enzymes to amino acids. The cholesteryl esters of LDL also are hydrolyzed to give rise to fatty acids and cholesterol. The liberated cholesterol is available for utilization in the biosynthesis of steroid hormones and other cellular processes. In addition, ACTH stimulates the activity of HMG CoA reductase and, thus, the rate of de novo cholesterol biosynthesis. In this way sufficient cholesterol is obtained to provide for precursor cholesterol to maintain the high rate of steroid synthesis by the HFA. HDL is not utilized as a source of cholesterol by the HFA. Because of the rapid rate of utilization of LDL by the HFA, fetal plasma levels of LDL are low and the activity of the HFA is a primary determinant of these levels. Thus, in the case of anencephaly, in which the activity of the adrenal is very low, plasma levels of LDL are 2--3 times higher than in normal fetuses, whereas plasma HDL levels are similar. In addition, in the normal neonate plasma LDL levels rise rapidly after birth, and this event is coincident with the involution of the fetal zone of the adrenal. The fetal liver is likely to be the major source ultimately of the LDL-cholesterol utilized by the HFA. Consequently, factors that regulate cholesterol and lipoprotein synthesis in the fetal liver may, in turn, affect the steroidogenic activity of the HFA through regulation of the supply of cholesterol precursor. Thus, if trophic factors for the HFA other than ACTH exist, an important site of their action might be the fetal liver, rather than a direct action to influence the rate of synthesis of steroids by the fetal adrenal.

The human major histocompatibility complex and endocrine disease.

Abstract: ARELATIONSHIP is found between loci in the major histocompatibility complex (MHC) and susceptibility to several endocrine disorders. For the more common endocrine diseases the relationship is evidenced in statistical associations of disease with specific alleles, for which several explanations are possible. The most likely is that these associations indicate the influence of immune response genes in linkage disequilibrium with the marker allele, but this is by no means proven. A pervasive association is noted of the DR3 allele of the histocompatibility (HLA)-DR system with autoimmune endocrine disease; this may be by way of immunological facilitation rather than disease-specific predisposition. A more specific association between DR4 and insulindependent diabetes mellitus (IDDM) is seen, suggesting the existence of a diabetogenic gene in or near the MHC. Likewise, the association of DR5 with goitrous (and DR3 with atrophic) thyroiditis suggests a possible link to the mechanism of goiter formation. These a...

Guanine nucleotides: Key regulators of hormone receptor-adenylate cyclase interaction

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

Virilizing Adrenal Adenoma with Studies on the Steroid Content of the Adrenal Venous Effluent and a Review of the Literature

Abstract: THIS IS a report of a new instance of a patient with a virilizing adrenal adenoma in whom the steroid content of both adrenal venous effluents was assayed. In addition the study delineates the clinical and biochemical findings in the reported instances of virilizing adenoma including the available data on the steroid content of adrenal venous effluent. Pure virilizing adrenal adenoma in the adult female is a rare disorder. We have been able to collect only 34 such instances in the literature, including 3 of our own (1–30) (Table 1). For purposes of comparison, the details of the clinical features and biochemical values obtained in 18 reported children with virilizing adrenal adenoma (12, 31–45) (Table 2) are also presented, as well as some data on the adrenal venous effluent on all 8 adult female patients with pure virilizing adrenocortical carcinoma documented in the literature (9, 12, 46–49) (Table 3).

The Metabolism and Mechanism of Action of Aldosterone

Abstract: ALTHOUGH the clinical importance of the adrenal cortex in the regulation of electrolyte balance had long been realized (1), it was not until the early 1950s that the major regulatory steroid, aldosterone, was isolated and identified by Simpson et al. (2). Simpson and Tait used a sensitive mineralocorticoid bioassay based on changes of urinary 24Na/42K ratios in adrenalectomized rats to help isolate aldosterone (3). Aldosterone is still the most potent mineralocorticoid known: 30–50 times more potent than deoxycorticosterone and at least a thousand times more active than the glucocorticoids, cortisol and corticosterone. Aldosterone's greater potency is balanced by a reduced secretory rate compared with most other adrenal steroids (4, 5). Its synthesis, exclusively by the zona glomerulosa of the adrenal cortex, is responsive to dietary sodium and potassium manipulations and more acutely to ACTH, plasma potassium concentrations, and the renin-angiotensin system (5, 6). Many of the initial investigations were...

The biosynthesis, intracellular processing, and secretion of parathormone.

Abstract: EVOLUTIONARY pressures have brought into being a remarkable homeostatic mechanism in higher animals for the control of ionized calcium in the extracellular fluid. This system uses parathormone (PTH), the subject of this review, and two other hormones, calcitonin (1) and active metabolites of vitamin D3 (2–4), which in concert act on bone, kidney, and intestine to maintain the concentration of ionized serum calcium at its physiological set point, about 1.3 mM. This represents about one half of the total (ionized and bound) calcium in serum (5, 6). The parathyroid gland is the principal agent in this system since it responds to the moment to moment fluctuations of calcium in the extracellular fluids. When the concentration of ionized calcium in the blood perfusing the parathyroid drops below its set point, the gland immediately releases more PTH to the circulation (7). The hormone acts directly on osteoclasts to enhance resorption of bone and to bring the calcium and phosphate of the bone mineral into the c...

Vitamin D and Pregnancy: The Maternal-Fetal Metabolism of Vitamin D

Abstract: A model of the maternal-fetal metabolism of vitamin D3 is depicted in Fig. 2. 25-OHD3 of maternal origin is metabolized by the maternal kidneys to the potent metabolite, 1,25-(OH)2D3, which acts on the maternal intestine, kidneys, and skeleton. The maternal kidneys and other organs can produce 24,25-(OH)2D3, although this pathway may be suppressed near the end of gestation. The placenta has selective permeability to the vitamin D3 metabolites, with 25-OHD3 crossing from the mother to the fetus more readily than the dihydroxylated metabolites. The onset of the placental synthesis of 1,25-(OH)2D3 during gestation is unknown. Likewise the regulation of the placental 25-OHD3-1 alpha-hydroxylase is unknown. 1,25-(OH)2D3 of placental origin may enter the maternal or the fetal circulation or act locally on the placenta by inducing the synthesis of proteins involved in the cellular transport of Ca. Perhaps one placenta cell type synthesizes 1,25-(OH)2D3 and another cell type possessing a cytoplasmic receptor for 1,25-(OH)2D3 responds to this metabolite. The function of the 24,25-(OH)2D3 produced by the placenta is unknown. The concentration of free 25-OHD3 and free 1,25-(OH)2D3 in the fetal circulation exceeds the maternal levels due to the differences in the DBP concentrations of the two bloodstreams. The 1,25-(OH)2D3 in the fetal bloodstream may originate from either the placenta or the fetal kidneys. The latter site may not be active in utero due to the hypercalcemia and hyperphosphatemia relative to the maternal levels of these ions. 1,25-(OH)2D3 in the fetal bloodstream acts on those fetal tissues containing cytoplasmic receptors for this metabolite. The intestinal mucosa apparently lacks these receptors until sometime during neonatal life. In contrast, fetal bone cells possess receptors for the 1,25-(OH)2D3. The 24,25-(OH)2D3 in the fetal bloodstream may also be involved in the growth and differentiation of the fetal skeleton. However, the precise role of both metabolites in the fetus remains conjectural.

The role of lysosomes and proteases in hormone secretion and degradation.

Abstract: In endocrine cells, complex relationships exist between the lysosome and hormone secretion. These relationships may have developed from a common evolutionary origin. As lysosomal and secretory systems evolved, diverse functional relationships developed between them. From a basic intracellular “digestive” role, lysosomes and their proteolytic enzymes developed new and varied origins and functions in hormone processing, release, and intraand extracellular degradation. 1.1 Proteolytic enzymes and hormone availability Hormone effects are a function of the availability of hormone at target receptors. Proteolytic enzymes can have an important role in regulating the availability of hormone by: 1) increasing the intracellular production of secreted forms from precursors, 2) facilitating release or exocytosis, 3) decreasing intracellular concentrations by degradation of excessive intracellular hormone, 4) inactivation or activation of hormone by proteolytic enzymes in serum, and 5) degradation of hormone in target...

Isolated Aldosterone Deficiency in Man: Acquired and Inborn Errors in the Biosynthesis or Action of Aldosterone*

Abstract: The combined efforts of clinical investigation and biochemical research have provided substantive insights into the homeostatic mechanisms that maintain concentrations of monovalent cations within a narrow physiological range in body fluids. For example, more precise knowledge of biochemical pathways subserving mineralocorticoid production in man has derived from recent detailed studies of certain “experiments in nature,” which comprise discrete inborn errors in aldosterone biosynthesis. Such conditions are biochemically and genetically distinct from congenital end-organ resistance to mineralocorticoid action (so-called pseudohypoaldosteronism). In addition, more comprehensive characterization has been attained of acquired, isolated defects in mineralocorticoid production in association with various clinical disorders. However, under any of these pathological conditions, defective hormonal regulation of sodium and potassium balance has created a spectrum of clinical disorders, ranging from life-threatenin...

Parathyroid Angiography: A Review of Current Knowledge and Guidelines for Clinical Application

Abstract: IN THE YEARS since the first localization (1) and visualization (2) of parathyroid lesions by arteriography, there has accumulated a large body of knowledge about the anatomical basis of parathyroid angiography, the proper and safe application of these techniques, and the subtilities of their interpretation. This information is now widely scattered in the radiographic, surgical, and internal medicine literature. This review is undertaken to provide the internist with a concise summary of this knowledge, in order to facilitate the optimum application of these techniques. We will review the pertinent facts about parathyroid embryology, vascular anatomy, and blood flow patterns. We will outline the goals, risks and interpretation of arteriography and venous sampling. Tentative guidelines are presented to aid in the selection of patients who are most likely to benefit from these techniques. Arterial Anatomy and Embryology Accurate performance and interpretation of parathyroid angiographic studies requires an ...