Abstract: I. Introduction II. The Regulation of Thyroid Function in Normal Pregnancy A. The thyroid hormone transport proteins B. The thyroid hormones 1. Total thyroid hormones 2. Free thyroid hormones 3. Peripheral metabolism of thyroid hormones C. The serum levels of thyroglobulin (TG) D. The metabolism of iodine E. The hypothalamic-pituitary control of thyroid function and the role of hCG 1. Hypothalamic-pituitary-thyroid axis (HPTA) 2. Regulation of serum TSH 3. Thyrotropic action of hCG F. A global view of thyroidal economy in pregnancy III. Pathological Alterations of Thyroidal Regulation Associated with Pregnancy A. IDD 1. Consequences of iodine deficiency during pregnancy 2. Assessment of increased thyroidal stimulation 3. Gestational goitrogenesis and its prevention by iodine supplementation 4. Consequences of iodine deficiency for the offspring B. Hypothyroidism and pregnancy 1. Fertility and pregnancy outcome in hypothyroid women 2. Thyroid hormone replacement in the hypothyroid pregnant woman 3. Subclin...

Abstract: Oestrogen is considered to be the 'female' hormone, whereas testosterone is considered the 'male' hormone. However, both hormones are present in both sexes. Thus sexual distinctions are not qualitative differences, but rather result from quantitative divergence in hormone concentrations and differential expressions of steroid hormone receptors. In males, oestrogen is present in low concentrations in blood, but can be extraordinarily high in semen, and as high as 250 pg ml(-1) in rete testis fluids, which is higher than serum oestradiol in the female. It is well known that male reproductive tissues express oestrogen receptors, but the role of oestrogen in male reproduction has remained unclear. Here we provide evidence of a physiological role for oestrogen in male reproductive organs. We show that oestrogen regulates the reabsorption of luminal fluid in the head of the epididymis. Disruption of this essential function causes sperm to enter the epididymis diluted, rather than concentrated, resulting in infertility. This finding raises further concern over the potential direct effects of environmental oestrogens on male reproduction and reported declines in human sperm counts.

Abstract: The mammalian pancreas contains two distinct cell populations: endocrine cells which secrete hormones into the bloodstream, and exocrine cells, which secrete enzymes into the digestive tract. The four endocrine cell types found in the adult pancreas-(alpha, beta, delta and PP-synthesize glucagon, insulin, somatostatin and pancreatic polypeptide, respectively. All of these endocrine cells arise from common multipotent precursors, which coexpress several hormones when they start to differentiate. Expression of some homeobox genes in the early developing pancreas has been reported. The Pax4 gene is expressed in the early pancreas, but is later restricted to beta cells. Inactivation of Pax4 by homologous recombination results in the absence of mature insulin- and somatostatin-producing cells (beta and delta, respectively) in the pancreas of Pax4 homozygous mutant mice, but glucagon-producing alpha cells are present in considerably higher numbers. We propose that the early expression of Pax4 in a subset of endocrine progenitors is essential for the differentiation of the beta and delta cell lineages. A default pathway would explain the elevated number of alpha cells in the absence of Pax4.

Abstract: Traditionally, steroid hormone action has been described as the modulation of nuclear transcription, thus triggering genomic events that are responsible for physiological effects. Despite early observations of rapid steroid effects that were incompatible with this theory, nongenomic steroid action has been widely recognized only recently. Evidence for these rapid effects is available for steroids of all clones and for a multitude of species and tissues. Examples of nongenomic steroid action include rapid aldosterone effects in lymphocytes and vascular smooth muscle cells, vitamin D3 effects in epithelial cells, progesterone action in human sperm, neurosteroid effects on neuronal function, and vascular effects of estrogens. Mechanisms of action are being studied with regard to signal perception and transduction, and researchers have developed a patchy sketch of a membrane receptor-second messenger cascade similar to those involved in catecholamine and peptide hormone action. Many of these effects appear to involve phospholipase C, phosphoinositide turnover, intracellular pH and calcium, protein kinase C, and tyrosine kinases. The physiological and pathophysiological relevance of these effects is unclear, but rapid steroid effects on cardiovascular, central nervous, and reproductive functions may occur in vivo. The cloning of the cDNA for the first membrane receptor for steroids should be achieved in the near future, and the physiological and clinical relevance of these rapid steroid effects can then be established.

Abstract: There are two main classes of hormones in insects: 1) the true hormones produced by epithelial glands and belonging to the ecdysteroids or juvenile hormones and 2) the neuropeptide hormones produced by neurosecretory cells. Members of these classes regulate physiological, developmental, and behavioral events in insects. Detailed accounts are given on isolation, identification, structure-activity relationships, mode of action, biological function, biosynthesis, inactivation, metabolism, and feedback for hormones involved in 1) metabolic regulation such as the adipokinetic/hypertrehalosemic peptides and the diuretic and antidiuretic peptides; 2) stimulation or inhibition of muscle activity such as the myotropic peptides; 3) control of reproduction, growth, and development such as allatotropins, allatostatins, juvenile hormones, ecdysteroids, folliculostimulins and folliculostatins, ecdysis-triggering and eclosion hormones, pheromone biosynthesis activating neuropeptides, and diapause hormones; and 4) regulation of tanning and of color change. Because of the improvements in techniques for isolation and structure elucidation, there has been rapid progress in our knowledge of the chemistry of certain neuropeptide families. With the employment of molecular biological techniques, the genes of some neuropeptides have been successfully characterized. There are, however, areas that are still quite underdeveloped. These are, for example, 1) receptor studies, which are still in their infancy; 2) the hormonal status of certain sequenced peptides is not clarified; and 3) functional studies are lacking even for established hormones. The authors plead for a concerted effort to continue research in this field, which will also advance our knowledge into the use of insect hormones as safer and species-specific molecules for insect pest management.

Abstract: Obese subjects with excess intra-abdominal fat deposition suffer greater adverse metabolic consequences than do similarly overweight subjects with a predominantly subcutaneous distribution of adiposity. Little is known about the factors regulating the regional distribution of body fat. Leptin is a recently characterized protein secreted by adipocytes that appears to provide a long-term hormonal feedback signal regulating fat mass. No systematic evaluation of site-related differences in human adipocyte leptin expression has been reported to date. Levels of leptin mRNA were examined by quantitative reverse transcription-polymerase chain reaction in adipocytes isolated from omental and subcutaneous adipose depots of nonobese and mildly obese individuals undergoing elective surgery. In all individuals studied (n = 24), leptin mRNA levels were higher in subcutaneous than in omental adipocytes (P < 0.0001). In contrast, there were no consistent site-specific differences in the expression of glycerol-3-phosphate dehydrogenase mRNA. The subcutaneous-to-omental ratio of leptin mRNA expression was markedly higher in women (5.5 +/- 1.1-fold) than in men (1.9 +/- 0.2-fold) (P < 0.02). A significant relationship between BMI and leptin mRNA expression was demonstrable in the subcutaneous adipocytes of women (P < 0.006). Thus, leptin mRNA appears to be expressed predominantly by subcutaneous adipocytes, particularly in women. These findings suggest a possible role for leptin in the control of adipose tissue distribution and mass.

Abstract: I. Introduction II. Developmental Schedules A. Species specificity B. Developmental studies in the rat III. Thyroid Hormone Action A. Sources of T4 and T3 B. The role of maternal thyroid hormone in fetal brain development: direct or indirect? C. Intracerebral transport IV. Molecular Actions of Thyroid Hormone in the Developing Brain A. Nuclear receptors for thyroid hormone in brain B. Thyroid hormone receptor isoforms and their tissue distribution C. Interactions of ligand, receptor, and DNA D. Ontogeny of thyroid hormone receptor isoforms in brain E. Search for T3-responsive genes in the neonatal rat brain F. Regulation of gene expression by T3 through indirect molecular pathways? G. Extranuclear actions of T4? V. Theories and Speculations VI. Conclusions

Abstract: Prolonged fasting is associated with a number of changes in the thyroid axis manifested by low serum T3 and T4 levels and, paradoxically, low or normal TSH. This response is, at least partly, caused by suppression of proTRH gene expression in neurons of the hypothalamic paraventricular nucleus (PVN) and reduced hypothalamic TRH release. Because the fall in thyroid hormone levels can be blunted in mice by the systemic administration of leptin, we raised the possibility that leptin may have an important role in the neuroendocrine regulation of the thyroid axis, through effects on hypophysiotropic neurons producing proTRH. Adult male, Sprague-Dawley rats were either fed normally, fasted for 3 days, or fasted and administered leptin at a dose of 0.5 microg/gm BW i.p. every 6 h. Fasted animals showed significant reduction in plasma total and free T4 and T3 levels compared with controls, that were restored toward normal by the administration of leptin. Percent free T4, but not percent free T3, increased during fasting, further suggesting a reduction in plasma transthyretin levels that did not return to fed levels after leptin administration. By semiquantitative analysis of in situ hybridization autoradiograms, proTRH messenger RNA in medial parvocellular PVN neurons was markedly suppressed in the fasting animals but was restored to normal by leptin administration [fed vs. fast vs. fast/leptin (density units x 10(8)): 8.5 +/- 0.4, 3.2 +/- 0.2, 8.1 +/- 0.8]. In contrast, proTRH messenger RNA in adjacent neurons in the lateral hypothalamus that do not have a hypophysiotropic function remained unchanged by any of the experimental manipulations. These findings indicate that leptin has a selective, central action to modulate the hypothalamic-pituitary-thyroid axis by regulating proTRH gene expression in the PVN but does not have peripheral effects on thyroid-binding proteins. We propose that the fall in circulating leptin levels during fasting resets the set point for feedback inhibition by thyroid hormones on the biosynthesis of hypophysiotropic proTRH, thereby allowing adaptation to starvation.

Abstract: Background To detect recurrent disease in patients who have had differentiated thyroid cancer, periodic withdrawal of thyroid hormone therapy may be required to raise serum thyrotropin concentrations to stimulate thyroid tissue so that radioiodine (iodine-131) scanning can be performed. However, withdrawal of thyroid hormone therapy causes hypothyroidism. Administration of recombinant human thyrotropin stimulates thyroid tissue without requiring the discontinuation of thyroid hormone therapy. Methods One hundred twenty-seven patients with thyroid cancer underwent whole-body radioiodine scanning by two techniques: first after receiving two doses of thyrotropin while thyroid hormone therapy was continued, and second after the withdrawal of thyroid hormone therapy. The scans were evaluated by reviewers unaware of the conditions of scanning. The serum thyroglobulin concentrations and the prevalence of symptoms of hypothyroidism and mood disorders were also determined. Results Sixty-two of the 127 patients had...

Abstract: Although estrogen replacement therapy is associated with reduced risk of coronary heart disease and reduced extent of coronary artery atherosclerosis, the effects of combined (estrogen plus progestin) hormone-replacement therapy are uncertain. Some observational data indicate that users of combined hormone replacement consisting of continuously administered oral conjugated equine estrogens (CEE) and oral sequentially administered (7 to 14 days per month) medroxyprogesterone acetate (MPA) experience a reduction in risk similar to that of users of CEE alone. However, the effects of combined, continuously administered CEE plus MPA (a prescribing pattern that has gained favor) on the risk of coronary heart disease or atherosclerosis are not known. We studied the effects of CEE (monkey equivalent of 0.625 mg/d) and MPA (monkey equivalent of 2.5 mg/d), administered separately or in combination, on the extent of coronary artery atherosclerosis (average plaque size) in surgically postmenopausal cynomolgus monkeys fed atherogenic diets and treated with these hormones for 30 months. Treatment with CEE alone resulted in atherosclerosis extent that was reduced 72% relative to untreated (estrogen-deficient) controls (P < .004). Atherosclerosis extent in animals treated with CEE plus MPA or MPA alone did not differ from that of untreated controls. Although treatment had marked effects on plasma lipoprotein patterns, statistical adjustment for variation in plasma lipoproteins did not alter the between-group relationships in atherosclerotic plaque size, suggesting that these factors do not explain substantially the atheroprotective effect of estrogen or the MPA-associated antagonism. Although the mechanism(s) remains unclear, we conclude that oral CEE inhibits the initiation and progression of coronary artery atherosclerosis and that continuously administered oral MPA antagonizes this atheroprotective effect.

Abstract: Abnormalities contributing to the pathogenesis of non-insulin-dependent diabetes mellitus include impaired beta cell function, peripheral insulin resistance, and increased hepatic glucose production Glucocorticoids are diabetogenic hormones because they decrease glucose uptake and increase hepatic glucose production In addition, they may directly inhibit insulin release To evaluate that possible role of glucocorticoids in beta cell function independent of their other effects, transgenic mice with an increased glucocorticoid sensitivity restricted to their beta cells were generated by overexpressing the glucocorticoid receptor (GR) under the control of the insulin promoter Intravenous glucose tolerance tests showed that the GR transgenic mice had normal fasting and postabsorptive blood glucose levels but exhibited a reduced glucose tolerance compared with their control littermates Measurement of plasma insulin levels 5 min after intravenous glucose load demonstrated a dramatic decrease in acute insulin response in the GR transgenic mice These results show that glucocorticoids directly inhibit insulin release in vivo and identify the pancreatic beta cell as an important target for the diabetogenic action of glucocorticoids

Abstract: The diverse functions of thyroid hormones are thought to be mediated by two nuclear receptors, T3Rα1 and T3Rβ, encoded by the genes T3Rα and T3Rβ respectively. The T3Rα gene also produces a non‐ligand‐binding protein T3Rα2. The in vivo functions of these receptors are still unclear. We describe here the homozygous inactivation of the T3Rα gene which abrogates the production of both T3Rα1 and T3Rα2 isoforms and that leads to death in mice within 5 weeks after birth. After 2 weeks of life, the homozygous mice become progressively hypothyroidic and exhibit a growth arrest. Small intestine and bones showed a strongly delayed maturation. In contrast to the negative regulatory function of the T3Rβ gene on thyroid hormone production, our data show that the T3Rα gene products are involved in up‐regulation of thyroid hormone production at weaning time. Thus, thyroid hormone production might be balanced through a positive T3Rα and a negative T3Rβ pathway. The abnormal phenotypes observed on the homozygous mutant mice strongly suggest that the T3Rα gene is essential for the transformation of a mother‐dependent pup to an ‘adult’ mouse. These data define crucial in vivo functions for thyroid hormones through a T3Rα pathway during post‐natal development.

Abstract: The obese gene (ob) product, leptin, has recently been shown to be produced by adipocytes and to circulate in the plasma acting as a hormone to modulate appetite and metabolism. Intriguingly, the ob/o

Abstract: Dehydroepiandrosterone sulphate (DHEAS) and unconjugated dehydroepiandrosterone (DHEA) have been determined in the blood serum of normal subjects of both sexes from 1 month to 100 years of age. In total, 92 girls, 49 boys, 211 women and 110 men were investigated. The effects of age and sex on the levels of the hormones were measured. DHEAS levels declined rapidly during the first year of life and were maintained at a minimum level for 5 years. They increased significantly from 6 to 7 years of age and reached maximum levels in women at about 24 years and in men at about 30 years of age. They then declined rapidly in both sexes but the fall which occurred after 50 and 60 years of age respectively was only moderate. Age-related unconjugated DHEA levels were different. After the first month of life DHEA levels were relatively high and declined more slowly. The minimum level was observed in girls between 5 and 7 years and in boys between 5 and 9 years of age. A significant rise then began and levels reached a maximum in women as well as in men at about 20 years of age. In men levels then declined up to the age of 80. In women the DHEA levels declined during the next 15 years and from approximately 36 years of age they again rose significantly up to a second peak. A mild but significant decline then resumed. There was a difference in the levels of DHEA and DHEAS depending on sex. Unlike DHEAS, unconjugated DHEA was higher in women than in men. However, this difference was significant only in some age groups: during puberty (between 11 and 15 years of age), in the premenopausal period (between 36 and 45 years of age) and in the older group (after 60 years of age). Age- and sex-related dependencies were different between DHEAS and DHEA. They indicate the possible variable secretion and dynamics of their (inter)conversion. We have concluded that DHEA measurements cannot be a substitute for DHEAS and vice versa.

Abstract: Quality of life (QOL) is an important consideration as patients survive longer with cancer and is an area of increasing interest in patients with thyroid cancer who undergo long-term cancer surveillance. However, there are few disease-specific QOL tools available to evaluate QOL in patients with thyroid cancer. The purposes of this longitudinal, repeated-measures study were to: (1) test a new instrument, the QOL-Thyroid Scale, during thyroid hormone withdrawal; and (2) to evaluate the impact of thyroid hormone withdrawal on patients' perceived changes in quality of life. The sample included 34 subjects (mean age 40 years) undergoing thyroid hormone withdrawal in preparation for scanning procedures. Subjects completed three instruments (demographic data tool, the QOL-Thyroid, and the FACT-G) at four specific time points in relationship to scanning. The results demonstrated that the QOL-Thyroid tool is a reliable and valid measure of QOL. Cronbach's alpha coefficient of r = .78 between QOL-Thyroid and FACT-G indicated good concurrent validity. Second, the impact of thyroid hormone withdrawal on QOL showed significant changes in physical, psychological, and social well-being across the four testing points. The greatest changes occurred between peak hormone withdrawal and thyroxine (T4) therapy. While it is generally known that patients suffer troublesome physical symptoms relating to thyroid hormone withdrawal, the negative psychological, family, and work sequelae are less apparent. In conclusion, the QOL-Thyroid is a reliable and valid measure for use in evaluating patients undergoing scanning procedures and may be used to identify and target teaching and support for high-risk areas in patients lives that are negatively affected by hormone withdrawal.

Abstract: Abnormalities of thyroid hormone concentrations are seen commonly in a wide variety of nonthyroidal illnesses, resulting in low triiodothyronine, total thyroxine, and thyroid stimulating hormone co...

Abstract: Many goitrogenic xenobiotics that increase the incidence of thyroid tumors in rodents exert a direct effect on the thyroid gland to disrupt one of several possible steps in the biosynthesis, secretion, and metabolism of thyroid hormones. This includes (a) inhibition of the iodine trapping mechanism, (b) blockage of organic binding of iodine and coupling of iodothyronines to form thyroxine (T4) and triiodothyronine (T3), and (c) inhibition of thyroid hormone secretion by an effect on proteolysis of active hormone from the colloid. Another large group of goitrogenic chemicals disrupts thyroid hormone economy by increasing the peripheral metabolism of thyroid hormones through an induction of hepatic microsomal enzymes. This group includes central nervous system-acting drugs, calcium channel blockers, steroids, retinoids, chlorinated hydrocarbons, polyhalogenated biphenyls, and enzyme inducers. Thyroid hormone economy also can be disrupted by xenobiotics that inhibit the 5'-monodeiodinase that converts T4 in peripheral sites to biologically active T3. Inhibition of this enzyme by FD&C Red No. 3 lowers circulating T3 levels, which results in a compensatory increased secretion of thyroid-stimulating hormone (TSH), follicular cell hypertrophy and hyperplasia, and an increased incidence of follicular cell tumors in 2-yr or lifetime studies in rats. Physiologic perturbations alone, such as the feeding of an iodine-deficient diet, partial thyroidectomy, natural goitrogens in certain foods, and transplantation of TSH-secreting pituitary tumors in rodents also can disrupt thyroid hormone economy and, if sustained, increase the development of thyroid tumors in rats. A consistent finding with all of these goitrogens, be they either physiologic perturbations or xenobiotics, is the chronic hypersecretion of TSH, which places the rodent thyroid gland at greater risk to develop tumors through a secondary (indirect) mechanism of thyroid oncogenesis associated with hormonal imbalances.

Abstract: The pituitary gonadotropins luteinizing hormone and follicle-stimulating hormone (FSH) regulate the production of sex steroids necessary for pubertal development and fertility. Inherited genetic defects that cause hypogonadism have been identified at multiple levels of the hypothalamic–pituitary–gonadal axis.1 They include Kallmann's syndrome, which is caused by mutations in the KAL gene,2 and X-linked adrenal hypoplasia, which is caused by mutations in the DAX-1 gene.3 Both cause deficiency of hypothalamic gonadotropin-releasing hormone, and DAX-1 mutations also cause a defect in the production of gonadotropins by the pituitary.4 A homozygous mutation in the gene for the β-subunit of luteinizing hormone has been reported . . .

Abstract: Dehydroepiandrosterone (DHEA) and its sulfate, DHEA-S, are plentiful adrenal steroid hormones that decrease with aging and may have significant neuropsychiatric effects. In this study, six middle-aged and elderly patients with major depression and low basal plasma DHEA and/or DHEA-S levels were openly administered DHEA (30–90 mg/d × 4 weeks) in doses sufficient to achieve circulating plasma levels observed in younger healthy individuals. Depression ratings, as well as aspects of memory performance significantly improved. One treatment-resistant patient received extended treatment with DHEA for 6 months; her depression ratings improved 48–72% and her semantic memory performance improved 63%. These measures returned to baseline after treatment ended. In both studies, improvements in depression ratings and memory performance were directly related to increases in plasma levels of DHEA and DHEA-S and to increases in their ratios with plasma cortisol levels. These preliminary data suggest DHEA may have antidepressant and promemory effects and should encourage double-blind trials in depressed patients.

Abstract: Outcome was compared in 1004 patients with differentiated thyroid carcinoma (DTC) who underwent thyroid remnant ablation with 131I (n = 151) or were either treated with thyroid hormone alone (755) ...

Abstract: Background Exposure to estrogens reduces the risk for coronary artery disease and associated clinical events; however, the mechanisms responsible for these observations are not clear. Supraphysiological levels of estrogens act as antioxidants in vitro, limiting oxidation of low-density lipoprotein (LDL), an event implicated in atherogenesis. We investigated the conditions under which physiological concentrations of 17β-estradiol (E2) inhibit oxidative modification of LDL. Methods and Results Plasma incubated with E2 (0.1 to 100 nmol/L) for 4 hours yielded LDL that demonstrated a dose-related increase in resistance to oxidation by Cu2+ as measured by conjugated diene formation. This effect was dependent on plasma, because incubation of isolated LDL with E2 at these concentrations in buffered saline produced no effect on Cu2+-mediated oxidation. Incubation of plasma with E2 had no effect on LDL α-tocopherol content or cholesteryl ester hydroperoxide formation during the 4-hour incubation. Plasma incubation ...

Abstract: Functions of the terminal nerve (TN) are largely unknown. To examine whether gonadotropin-releasing hormone (GnRH)-immunoreactive TN cells (TN-GnRH cells) are involved in the control of reproductive b

Abstract: Iodine plays a central role in thyroid physiology, being both a major constituent of thyroid hormones (THS) and a regulator of thyroid gland function. This review concerns those aspects of thyroid physiology in which significant advances have been made in recent years. We have known for decades that the thyroid gland concentrates iodine (I-) against an electrochemical gradient by a carrier-mediated mechanism driven by ATP. A similar I- uptake mechanism is found in other organs, including salivary glands, stomach, choroid plexus, and mammary glands, but only in the thyroid does TSH regulate the process. This past year saw a major advance with the cloning of the thyroid I- transporter. This development opens the way to an elucidation of the regulation of I- transport in the normal gland and in thyroid neoplasms that lack this property ("cold" nodules). All of the subsequent steps in TH biosynthesis, from oxidation and organification of iodide to the secretion of T4 and T3 into the circulation, are stimulated by TSH and inhibited by excess iodine. Recently, some of the regulatory mechanisms have been clarified. The function of the major TH-binding proteins in plasma is to maintain an equilibrium between extracellular and cellular hormone pools. Transthyretin, the principal T4-binding protein in cerebrospinal fluid, may play a similar role in the central nervous system. Although it generally is agreed that cellular uptake of TH is a function of the unbound (free) form of the hormone, there is evidence that certain TH-binding plasma proteins (i.e., apolipoproteins) may serve specific transport functions. The intracellular concentration of T3, the active TH, is determined by the rates of cellular uptake of T4 and T3, the rates of metabolic transformation, including conversion of T4 to T3, and the rate of T3 efflux. The latter has been assumed to be a passive process. However, recent studies by our group in San Francisco have shown that T3 is transported out of cells by a specific, saturable, verapamil-inhibitable mechanism. This T3 efflux system is widespread among cells from many tissues, and, at least in liver, modulates intracellular and nuclear concentration of the hormone and thereby influences TH action.