Prolactin induces tuberoinfundibular dopaminergic neurone differentiation in Snell dwarf mice if administered beginning at 3 days of age.

The hypothalamic tuberoinfundibular dopaminergic (TIDA) neurones secrete dopamine, which inhibits prolactin secretion. TIDA neurone numbers are deficient in Ames (df/df) and Snell (dw/dw) dwarf mice, which lack prolactin, growth hormone and thyroid-stimulating hormone. Prolactin therapy initiated before 21 days maintains normal-sized TIDA neurone numbers in df/df mice and, when initiated as early as 7 days, maintains the maximum TIDA neurone numbers observed in dw/dw development, which are decreased compared to those in normal mice. The present study investigated the effect of prolactin dose and species on TIDA neurone development. Snell dwarf and normal mice were treated with saline, 5 microg of ovine prolactin (oPRL), 50 microg of oPRL, or 50 microg of recombinant mouse prolactin (rmPRL) beginning at 3 days of age. Brains were analysed at 45 days using catecholamine histofluorescence, and immunohistochemistry for tyrosine hydroxylase or bromodeoxyuridine. Normal mice had greater (P

Growth hormone-releasing hormone-producing and dopaminergic neurones in the mouse arcuate nucleus are independently regulated populations.

Differentiation of hypophysiotropic neurones that regulate the secretion of growth hormone (GH) and prolactin is influenced by GH and prolactin. Genetic GH and prolactin deficiency in mutant rodent models such as the Ames dwarf (df/df) mouse results in an increase in the number of GH-stimulatory GH-releasing hormone (GHRH) neurones and a reduction of prolactin-inhibitory tuberoinfundibular dopaminergic (TIDA) neurones in the arcuate nucleus during postnatal development. The present study tested the hypothesis that these concomitant changes in numbers of tyrosine hydroxylase (TH)- and GHRH-immunoreactive neurones in df/df hypothalamus might represent a neuronal population of fixed number that undergoes a partial change in phenotype during postnatal development. To evaluate this possibility, the postnatal reduction of the df/df TIDA population was prevented by administering prolactin neonatally to preserve TH phenotype; dwarf and normal sibling mice were treated with daily injections of ovine prolactin or vehicle starting at postnatal day 12 and continuing for 30 days. Following this treatment, numbers of arcuate neurones containing GHRH or TH, or both, were quantified using immunocytochemistry. It was hypothesized that prolactin preservation of TH-immunoreactive cell number would be accompanied by either a decrease in the GHRH-producing population or an increase in numbers of cells producing both TH and GHRH. In prolactin-treated normal (DF/df) mice, numbers of arcuate TH-immunoreactive neurones were similar to those in vehicle-treated normals. Numbers of TH-positive neurones in prolactin-treated dwarfs were higher than in vehicle-treated dwarfs, and did not differ from numbers in DF/df. Numbers of GHRH-immunoreactive cells in vehicle-treated df/df were higher than in vehicle-treated DF/df, and were not different in prolactin-treated groups of either dwarf or normal mice. Neurones containing both TH and GHRH constituted 15% of the TH population, and 76% of the GHRH population, in control normal mice; in control dwarfs, double-labelled cells were 9.3% of TH and 9.9% of GHRH. Numbers of cells immunoreactive for both TH and GHRH were not affected by prolactin treatment in either mouse type. These results demonstrate that the increase in number of GHRH-expressing neurones in the df/df arcuate nucleus does not occur at the expense of the TH phenotype, and that this increase is not influenced by prolactin feedback. Although coexpression of TH and GHRH in a subpopulation indicates that TIDA and GHRH populations are not exclusive, they appear to be influenced independently by prolactin and GH signals during development.

IGF-I causes an ultrasensitive reduction in GH mRNA levels via an extracellular mechanism involving IGF binding proteins.

IGF-I-dependent decreases in endogenous GH mRNA expression were studied in individual rat MtT/S somatotroph cells using in situ hybridization. It was first shown that increasing IGF-I concentrations (0-90 nM) decreased GH mRNA levels in a ultrasensitive manner when averaged over the entire population, such that the decrease occurred over a narrow range of IGF-I concentration with an EC50 of 7.1 nM. The degree of ultrasensitivity of the population average was expressed by calculating the Hill coefficient (nA), which had a value of -2.0. GH mRNA levels in individual dispersed cells from these cultures were then measured. These results were first summed for all cells to show that the average response of the population remained ultrasensitive (nA = -2.6, EC50 = 8.1 nM). Then, parameters for individual cells of the population were calculated using mathematical modeling of the distribution of individual cell GH mRNA levels after treatment with 0-90 nM IGF-I. Solution of the data from the individual cells yielded a Hill coefficient (nI = -0.65) and a heterogeneity coefficient (mI = -1.2) indicative of individual cell responsiveness to IGF-I that was not ultrasensitive and very heterogeneous. These results suggested that ultrasensitivity in the population may likely be caused by an extracellular mechanism regulating IGF-I concentrations, such as IGF binding proteins. Increasing concentrations of long (Arg)3IGF-1, an analog that binds the IGF type-1 receptor but not IGF binding proteins, showed a linear inhibition of GH mRNA levels. Treatment with IGF binding protein ligand inhibitor, an IGF-I analog that binds to IGF binding proteins but not the IGF type-1 receptor, decreased GH mRNA levels in the absence of exogenous IGF-I. Thus, IGF binding proteins provide the extracellular sequestration of IGF-I necessary for the precise and ultrasensitive regulation of GH mRNA levels in the entire cell population, although expression within individual cells is regulated in a graded fashion.

GH mRNA levels are elevated by forskolin but not GH releasing hormone in GHRH receptor-expressing MtT/S somatotroph cell line.

The MtT/S somatotroph cell line should be a growth hormone-releasing hormone (GHRH)-responsive model system for the study of physiological control of growth hormone (GH) transcription because GH secretion from these cells is stimulated by GHRH. To examine the GH transcriptional activity of these cells, endogenous GH mRNA levels were measured using a ribonuclease protection assay following treatment under a variety of hormonal conditions. While omission of serum led to reduction of GH mRNA to 22% of control levels by 2 days and to 8% by 5 days (P<0.05 for both), GH mRNA levels were maintained at control values in serum-free medium containing 5 nM dexamethasone and 30 pM triiodothyronine (TDM). However, the addition of 10 nM GHRH under any treatment condition did not significantly alter GH mRNA levels. Characterization of the MtT/S cells showed that GHRH-receptor (GHRH-R) mRNA was detectable by reverse transcription-polymerase chain reaction (RT-PCR) amplification. Measurement of extracellular cAMP showed that the MtT/S cells have basal levels of > or =20 nmol/10(6) cells per h in both serum-containing and serum-free media, and that GHRH had no effect on cAMP levels, suggesting constitutive activation. To rule out the possibility of autocrine stimulation by GHRH produced endogenously, GHRH mRNA was not detectable in MtT/S cells using RT-PCR amplification. The stimulatory G-protein alpha subunit, mutations of which are known to activate adenylate cyclase constitutively in acromegaly, was sequenced but found not to differ from normal pituitary in the regions most commonly mutated. Finally, treatment with 10 microM forskolin, to directly activate adenylate cyclase, increased GH mRNA to 140% of controls in TDM, and to 163% in serum-free medium after 2 days, and to 166% in TDM-treated cells and 174% in serum-free culture after 5 days (all P<0.05). Taken together, these data indicate that although MtT/S cells express the GHRH-R, GHRH cannot stimulate adenylate cyclase to increase GH transcription due to constitutive elevation of cAMP levels, by a means that may be similar to that in cases of acromegaly not caused by oncogenic gsp mutations.

Insulin-like growth factor-1 causes a switch-like reduction of endogenous growth hormone mRNA in rat MtT/S somatotroph cells.

Reduction of mRNA expression from the endogenous GH gene by insulin-like growth factor 1 (IGF-1) in somatotroph-like rat MtT/S cells was measured. GH mRNA levels were reduced by 65 nM IGF-1 treatment in a time-dependent manner over 5 d of culture with a calculated GH mRNA half-life of 50 h, in line with previous values from primary cultures. Inhibition of inositol 3-phosphate kinase by wortmannin or LY-294,002 treatment was ineffective in blocking IGF-1 decreases in GH mRNA, as was inhibition of MAP kinase activity by PD 098059. The inhibition by IGF-1 also did not regulate Pit-1 (GHF-1) mRNA levels, which were constant during 65 nM IGF-1 treatment. MtT/S cells were shown to have both IGF-1 and insulin receptors as detected by Western blotting. There was also shown to be the suggestion of "hybrid" receptors containing different beta chains from each of these related heterotetrameric receptors. Analysis of the effects of IGF-1 and insulin on MtT/S cells showed that each reduced GH mRNA in a dose-dependent manner gave a calculated EC50 of 15.5 nM for IGF-1 and 0.6 nM for insulin, suggesting that the respective receptors for each hormone were activated. However, GH mRNA response to IGF-1 treatment was "ultrasensitive," exhibiting a switch-like effect; below 10 nM IGF-1, there was no decline in GH mRNA, but then maximal reduction occurred at IGF-1 concentrations above 20 nM. The degree of this ultrasensitive effect was calculated from the Hill equation for cooperativity, with a Hill coefficient of -4.1, greater than the classic cooperativity exhibited by hemoglobin binding to oxygen. The ultrasensitive response was specific for IGF-1, as insulin did not display this effect. These results suggest that the response evoked by the IGF-1 receptor could act as a binary molecular switch controlling GH mRNA expression in somatotrophs.

Mouse growth hormone transcription factor Zn-16: unique bipartite structure containing tandemly repeated zinc finger domains not reported in rat Zn-15.

Rat Zn-15 is a transcription factor activating GH gene expression by synergistic interactions with Pit-1, named for 15 DNA-binding zinc fingers, including fingers IX, X, and XI that are responsible for GH promoter binding. In this study, a mouse cDNA for Zn-15 was characterized. The predicted 2192-amino acid mouse protein is 89% identical to rat (r) Zn-15 overall, and is 97% similar in the C-terminal domain necessary for binding the GH promoter. However, the mouse cDNA encodes 16 zinc fingers, and sequences of rZn-15 pituitary cDNAs were the same as the mouse (m) Zn-16; the rat sequence in GenBank has a one nucleotide offset of a 17-bp segment in the finger V region. The mouse and corrected rat sequences contain four tandemly repeated fingers in the N-terminus, each separated by seven amino acids, typical of zinc finger proteins of the transcription factor IIIA-type. Analysis of mZn-16 expression by RT-PCR showed that the mRNA is, produced at similar levels in normal and GH-deficient Ames dwarf (Prop-1 ) mouse pituitaries at postnatal day 1. Mouse Zn-16 mRNA also was detected by ribonuclease protection assay in the pre-somatotrophic mouse cell line GHFT1-5. The Zn-16 protein is bipartite in that the N-terminal half displays tandem spacing typical of most zinc finger proteins, while the C-terminal portion contains long linkers between fingers that cooperatively bind to a DNA response element. Expression in early postnatal pituitary and in pre-somatotrophic cells suggests that Zn-16 could play a role in pituitary development prior to somatotroph differentiation.

Heritable disorders of pituitary development.

Basic and translational research achievements over the past 2 decades have disclosed the molecular mechanisms underlying several genetic forms of hypopituitarism. Disorders that are limited to the hypothalamic, pituitary, GH axis are caused by mutations in individual components of that axis. Disorders involving GH and one or more additional pituitary hormones are caused by mutations in the homeodomain transcription factors that direct embryological development of the anterior pituitary gland. Pit-1 has a POU-specific and a POU-homeo DNA-binding domain. The phenotype produced by mutations in the PIT1 gene involves deficiencies of GH, PRL, and TSH. Pituitary glands are either small or normally sized. The PROP1 gene encodes a transcription factor with a single paired-like DNA-binding domain. Persons with inactivating mutations in PROP1 have deficiencies of LH and FSH, as well as GH, PRL, and TSH. Their pituitary glands may be small, normally sized, or extremely large and show suprasellar extension. Pituitary degeneration may produce acquired deficiency of ACTH. Expression of the HESX1 gene precedes expression of PROP1 and PIT1, and it is much more widespread. The protein has a paired-like domain, and it competes with the product of PROP1 for DNA-binding. Homozygosity for inactivating mutations of HESX1 produces a complex phenotype that resembles septo-optic dysplasia. Much more needs to be learned about the role of HESX1 mutations in other forms of hypopituitarism.

Pituitary hormones as neurotrophic signals: update on hypothalamic differentiation in genetic models of altered feedback.

Studies of mutant mice that are growth hormone (GH)- and prolactin (PRL)-deficient have provided evidence that these pituitary hormones have trophic, as well as dynamic, feedback effects on the hypothalamic neurons that regulate GH and PRL secretion (1). This review examines further evidence, from those animals and from recent transgenic models, for GH and PRL effects on neuronal differentiation. Characterization of the Ames dwarf (Prop-1) mutation and discovery of other genes important to pituitary differentiation reveal an expression sequence of transcription factors, Hesx1 (Rpx) to P-Lim to Prop-1 to Pit-1, that heralds influence on hypothalamic differentiation. Occasional expression of GH and PRL in the Ames dwarf pituitary may result from the "partial loss of function" nature of the Ames Prop-1 mutation. In transgenic mice with moderately or extremely elevated GH levels, neurons that regulate GH exhibit respective maximum and minimum expression and cell number in inhibitory somatostatin (SRIH) and in stimulatory GH-releasing hormone (GHRH). The phenomenon is inverted in GH-lacking dwarfs, and patterns of SRIH underexpression and GHRH overexpression are established early in postnatal development. The differentiation of PRL-inhibiting dopaminergic (DA) neurons is supported not only by PRL, but by human GH, which is lactogenic in rodents. Transgenic mice with peripherally expressed hGH have increased numbers of DA neurons, as opposed to the decreased DA population in PRL-deficient dwarf mice. Rats engineered to express hGH in GHRH neurons do not show this increase, whereas spontaneously GH-deficient dwarf rats show increased DA neuron number. These findings may be explained by feedback on neurons that co-express GHRH and DA. Current studies suggest that Snell (Pit-1) dwarf mice show a more severe and earlier DA neuron deficiency than Ames dwarfs, and that PRL feedback must occur prior to 20 days of postnatal age to maintain the DA neuronal phenotype. Insights into the mechanisms of GH and PRL effects on hypophysiotropic neurons include receptor localization on identified neuronal phenotypes, including intermediate neurons that mediate dynamic feedback, and elucidation of signal transduction pathways for GH and PRL in peripheral cell types. New transgenic models of altered GH, PRL, or receptor expression offer further study of neurotrophic effects.

Prolactinoma manifesting with symptomatic hydrocephalus.

Prolactinomas are the most common secretory adenomas of pituitary origin. They typically manifest with symptoms referable to their endocrinologic effects or, if of sufficient size, to visual changes due to compression of the optic chiasm. Pituitary adenomas manifesting with hydrocephalus are rare. To our knowledge, only three such cases have previously been reported. We describe an 81-year-old woman with a pituitary adenoma that manifested with hydrocephalus. In addition, we review the literature and discuss therapeutic options.

Indications, technique, and efficacy of alcohol injection of enlarged parathyroid glands in patients with primary hyperparathyroidism.

BACKGROUND: Percutaneous alcohol ablation of the parathyroid gland (PAAP) has been proposed as an alternative treatment for primary hyperparathyroidism in patients unsuitable for surgery. The current study aimed to determine the (1) selection criteria, (2) associated morbidity, and (3) efficacy of PAAP. METHODS: From 1987 to 1998, 36 patients with primary hyperparathyroidism (mean age 65 years) underwent PAAP. The indications for PAAP were (1) medical comorbidity, (2) technically unsafe reoperative surgery, (3) partial ablation of a single remaining gland, and (4) patient choice. RESULTS: There were no long-term complications. Two patients had temporary recurrent laryngeal nerve injury and 4 had temporary hypocalcemia. Over a median follow-up of 16 months, 12 (33%) of the patients remained eucalcemic. For analysis purposes patients were separated into 2 separate groups: 29 with attempted complete ablation and 7 with partial ablation of a single remaining gland only. Ten of the complete ablation group (34%) remained eucalcemic. In the partial ablation group only 2 remained eucalcemic, but all had adequately controlled serum calcium levels. CONCLUSION: PAAP should be considered for hyperparathyroid patients with excessive reoperative morbidity or prohibitive medical comorbidity or those in whom the intent is to partially ablate a single remaining enlarged gland. In these patients close follow-up of serum calcium is required, and repeat treatments may be necessary because recurrence of hypercalcemia is likely.

Clinical and molecular characterization of a Brazilian patient with Pit-1 deficiency.

We studied a 14 year-old girl with extreme short stature (-9.5 SDS), normal psychomotor development and signs of progressive hypothyroidism. Basal IGF-I and T4 were low. Serum GH was low after insulin-induced hypoglycemia and GH-releasing hormone administration. Both TSH and prolactin were low and did not rise after TRH administration. Gonadotropins were normal and cortisol levels were elevated. In contrast, DHEA-S levels were low and she did not develop pubic hair until 26 years of age, compatible with deficiency of a putative pituitary adrenal androgen stimulating hormone. Pituitary size was reduced on magnetic resonance imaging. Sequencing of the Pit-1 gene revealed a heterozygous C to T transition in codon 271 resulting in substitution of tryptophane for a highly conserved arginine. Her parents were homozygous normal for this locus indicating a de novo mutation with dominant expression. Genetic and phenotypic heterogeneity of patients with Pit-1 gene mutations, particularly the R271W mutation, may reveal further information about the nature of genetic silencing, imprinting, and epigenetic inheritance. The relationship of Pit-1 deficiency to abnormal adrenal secretion remains to be elucidated.

Growth hormone releasing hormone expression during postnatal development in growth hormone-deficient Ames dwarf mice: mRNA in situ hybridization.

Several genetic mutations in mice and rats that produce lifelong growth hormone (GH) deficiency result in overexpression of GH-releasing hormone (GHRH) mRNA in hypothalamic arcuate nucleus neurons. In order to examine the development of this condition, GHRH mRNA expression was quantified in Ames dwarf (df/df) and normal (DF/?) mice at 1 (day of birth), 3, 7, 14, 21 and 60 postnatal days (d) following in situ hybridization. Total mRNA was assessed using computer-assisted densitometry after X-ray film autoradiography, and mRNA expression per neuron was quantified by counts of grains per cell after emulsion autoradiography. Total GHRH mRNA was the same in dwarf and normal mice at 1, 3 and 7d. GHRH mRNA in dwarfs increased at 14d to 240% of that in DF/? (p < 0.005); the percentage overexpression in dwarf mice remained >/=200% through 60d, although total GHRH mRNA increased in both dwarfs and normals during this period. GHRH mRNA per neuron was the same in normal and dwarf mice at 1d, then increased in dwarfs to 190% of that in normals at 3d (p < 0.05), and rose to 300% of normal levels by 7d and beyond (p < 0. 005). There was no sexual dimorphism in expression by either measure in normal or dwarf mice. These results indicate that an increase in GHRH mRNA in Ames dwarf mice is first detectable at 3d, a period of approximately 7d after the failure to initiate GH production, which occurs normally at embryonic day 17.5. The onset of GHRH overexpression occurs earlier than the decline of either hypophysiotropic somatostatin or dopamine in Ames dwarf mice. This difference may be due to the stimulatory action of GHRH, as opposed to the inhibitory effects of factors examined previously.

Central hypothyroidism reveals compound heterozygous mutations in the Pit-1 gene.

Mutations in the gene encoding the Pit-1 transcriptional activator interfere with the embryologic determination and ultimate functions of anterior pituitary cells that produce growth hormone (GH), prolactin (Prl) and thyroid-stimulating hormone (TSH). Central hypothyroidism is often the presenting feature of combined pituitary hormone deficiency (CPHD), but it is not detected in screening programs that rely upon elevation of TSH. We report a child whose hypothyroidism was recognized clinically at age 6 weeks, and subsequently found to have GH and Prl as well as TSH deficiency. With thyroxine and GH replacement he has reached the 70th percentile for height and has normal intelligence. Molecular analysis of genomic DNA for Pit-1 revealed the presence of compound heterozygous recessive mutations: a nonsense mutation in codon 172 and a novel missense mutation substituting glycine for glutamate at codon 174. This case is the first demonstration of CPHD due to compound heterozygous Pit-1 point mutations, as most reported cases of the CPHD phenotype involve either the dominant negative R271W allele or homozygosity for recessive Pit-1 mutations. Therefore, in cases of CPHD, the possibilities of compound heterozygosity for two different Pit-1 mutations, or homozygosity for mutations in the epigenetic gene, Prop-1, should be considered.

Cloning and sequence determination of the chloroplast psbA gene in Magnolia pyramidata (Magnoliales; Magnoliaceae).

The full length gene encoding the D1 protein of photosynthesis (psbA) has been cloned and sequenced from Magnolia pyramidata (Magnoliaceae). Despite considerable investigation into psbA structure and function in many algal lineages and a few agricultural plants, there has been little effort invested toward characterizing a broader range of plant psbA genes. This is the first report of a psbA gene sequence from a primitive angiosperm. The DNA and deduced amino acid sequences maintain high overall conservation with other taxa, suggesting a role for psbA in broad based angiosperm phylogenetic reconstruction.

Update on primary osteoporosis.

Osteoporosis is the most common bone disorder encountered in clinical practice. It is also one of the most important diseases facing our aging population. In the United States alone, an estimated 1.5 million fractures that occur annually are attributed to osteoporosis, and they account for an estimated $13 billion annually. With the projected increase in life expectancy for the global population, osteoporosis and osteoporosis-related fractures have the potential to become an even larger health-care problem in the future. This article focuses on the evaluation and treatment of primary osteoporosis in women.

Hypophysiotropic somatostatin expression during postnatal development in growth hormone-deficient Ames dwarf mice: mRNA in situ hybridization.

Lifelong deficiency of growth hormone (GH) in spontaneous or transgenic dwarf mice has been shown to be accompanied by reduced hypophysiotropic somatostatin (somatotropin release-inhibiting hormone, SRIH) expression in hypothalamic anterior periventricular nucleus (PeN). However, the postnatal developmental pattern of SRIH expression in the absence of GH is unknown. Therefore, SRIH mRNA levels in GH-deficient Ames dwarf (df/df) mice and normal (DF/?) littermates were determined both in adults, to compare with other GH-deficient models, and at selected days of postnatal development, to determine the effects of GH deficiency on SRIH neuron development. DF/? and df/df mice of both sexes at postnatal ages 1, 3, 7, 14, 21 and 60 days (adult) were examined. In situ hybridization and image analysis were used to quantify the relative abundance of total SRIH mRNA in the PeN, and SRIH mRNA per cell was determined in PeN and medial basal hypothalamus (MBH). In adult df/df mice, total PeN SRIH mRNA was 45% (p < 0.05) of that in DF/? littermates, which is consistent with studies of other GH-deficient dwarf mice. In developing animals, SRIH expression in the PeN of DF/? mice began at 3 days of age and increased at subsequent ages to reach adult levels. In df/df mice, PeN SRIH mRNA levels at 60 days were significantly greater than at 1-21 days of age (p < 0.05). However, levels were not different over 1-21 days of age, and were consistently lower in df/df than DF/? mice. The difference in total PeN SRIH mRNA between df/df and DF/? mice was statistically significant at 7 days, and at each subsequent age. There were no differences between DF/? and df/df mice in the number of grains per cell in either PeN or MBH at any age. Thus, the reduced total hypophysiotropic SRIH mRNA in GH-deficient Ames dwarf mice appears developmentally shortly after initial detectability of SRIH in the PeN. Because SRIH mRNA per cell was the same for DF/? and df/df mice, the decreased total mRNA in dwarfs suggested reduced SRIH cell numbers in PeN, which was corroborated by immunocytochemical findings. The reduction of SRIH in df/df mice at 7 days of age suggests that GH production during embryonic or very early postnatal development is important to activation of PeN SRIH transcription.

Induced radioactivity of LDEF materials and structural components.

We present an overview of the Long Duration Exposure Facility (LDEF) induced activation measurements. The LDEF, which was gravity-gradient stabilized, was exposed to the low Earth orbit (LEO) radiation environment over a 5.8 year period. Retrieved activation samples and structural components from the spacecraft were analyzed with low and ultra-low background HPGe gamma spectrometry at several national facilities. This allowed a very sensitive measurement of long-lived radionuclides produced by proton- and neutron-induced reactions in the time-dependent, non-isotropic LEO environment. A summary of major findings from this study is given that consists of directionally dependent activation, depth profiles, thermal neutron activation, and surface beryllium-7 deposition from the upper atmosphere. We also describe a database of these measurements that has been prepared for use in testing radiation environmental models and spacecraft design.

Evaluation and management of multinodular goiter.

Nodular goiters are encountered commonly in clinical practice by primary care physicians, endocrinologists, surgeons, and otolaryngologists. Epidemiologic data suggest that in the United States, the incidence of such goiters is approximately 0.1% to 1.5% per year, translating into 250,000 new nodules annually. Nodular goiters are more common in women than in men, with advancing age, and after exposure to external irradiation. These goiters may be asymptomatic, with normal TSH levels (nontoxic), or may be associated with systemic thyrotoxic symptoms (toxic MNG or Plummer's disease). Diagnostic evaluation of patients with nodular goiters consists of clinical evaluation, biochemical testing, FNA, and imaging studies. The serum TSH level is a sensitive and reliable index of thyroid function. FNA results are pivotal to assess cancer risk in patient management for prominent palpable and suspicious nodules. Chest radiography, high-resolution ultrasonography, and computed tomography help to delineate the size and extent of a goiter in evaluating compression symptoms. Indications for treatment in patients with MNG include hyperthyroidism, local compression symptoms attributed to the goiter, cosmesis, and concern about malignancy based on FNA results. The use of levothyroxine suppression therapy to effectively decrease and control MNG size is controversial. Thyroid hormone should not be used, however, in patients with suppressed serum TSH levels, to avoid the development of toxic symptoms. Management of toxic MNG by surgery is well established. Radioiodine is also effective therapy for many of these patients. When treatment is necessary for nontoxic MNG, surgical excision is preferred. Our recommendations are as follows. For patients who have small, nontoxic multinodular goiters that are clinically asymptomatic, who are biochemically euthyroid according to serum TSH levels, and who have prominent palpable or suspicious nodules benign by FNA, yearly evaluation with serum TSH determinations and thyroid palpation is sufficient. Patients with modest but stable MNG size and normal serum TSH levels may also be managed by yearly clinical observation. In this second group, levothyroxine suppression therapy is often unsuccessful and has the potential for untoward effects from exogenous hyperthyroidism. For large nontoxic multinodular goiters with local compression symptoms, the preferred treatment is surgery. In patients with toxic MNG, treatment with either surgery or radioiodine is recommended, although patients with large goiters and large, autonomously functioning nodules become euthyroid more quickly following surgery.

Thyroid nodular disease: is it toxic or nontoxic, malignant or benign?

The thyroid gland is known to become more nodular with age. The clinical questions in a given patient are whether the nodule(s) is benign or malignant and euthyroid or toxic. Toxic multinodular goiter (MNG) is more common in the elderly than Graves' disease but is not associated with the classic eye or skin findings. Drug therapy is usually effective, but total thyroidectomy may be preferred. Nontoxic MNG is common among older women. Treatment remains controversial because of potential side effects of suppressive therapy. Although thyroid carcinoma is rare, most of the more aggressive tumors are seen after age 50. Fine-needle aspiration and cytologic examination are useful in separating benign from malignant tumors.