Mechanisms and pathogenesis of thyroid cancer in animals and man

The transformation of the normal fully differentiated thyroid follicular cell to the rapidly growing undifferentiated anaplastic thyroid carcinoma cell involves a number of stages which have been defined morphologically and are now being related to various growth pathways and to molecular biological defects. The two main factors involved in this transformation are growth stimulation and mutagenesis. Growth stimulation alone, through elevated TSH, can lead to the development of thyroid tumours, usually benign, and retaining TSH dependency in some cases. Mutagens alone, if growth is suppressed, do not produce tumours, the combination of mutagens and increased growth is a potent carcinogenic regime. Non-genotoxic carcinogenesis in the thyroid involves growth, without mutagenesis the agent often causes this through affecting one component of thyroid hormone synthesis or metabolism, leading to a fall in thyroid hormone levels and a rise in TSH. Growth stimulation increases the rate of cell division, and therefore increases the chance of a mutation. Continued growth increases the change of subsequent events, in particular loss of heterozygosity in a tumour suppressor gene. The main oncogenes involved in human thyroid carcinogens are ras in the follicular tumour pathway, and ret in the papillary carcinoma pathway. p53 is involved in the progression of either papillary or follicular adenoma to an undifferentiated carcinoma. In experimental thyroid carcinogenesis, ras is again involved, with a link between the mutagenic agent used and the type of ras gene showing mutation. Analysis of the involvement of different growth factors and oncogenes in thyroid carcinogenesis suggests that genes related to the two receptors concerned with normal TSH stimulated growth, TSH receptor and the IGF1 recpptor may be involved in the progression of thyroid tumours of follicular pathology. Several tyrosine kinase receptors with unknown ligands or of uncertain physiological function are linked to papillary carcinoma. The recent large increase in papillary carcinoma of the thyroid in children exposed to fallout from the Chernobyl nuclear accident underlines the importance of understanding the pathobiology of thyroid neoplasia.     

Mechanistic considerations for the relevance of animal data on thyroid neoplasia to human risk assessment

There are two basic mechanisms whereby chemicals produce thyroid gland neoplasia in rodents. The first involves chemicals that exert a direct carcinogenic effect in the thyroid gland and the other involves chemicals which, through a variety of mechanisms, disrupt thyroid function and produce thyroid gland neoplasia secondary to hormone imbalance. These secondary mechanisms predominantly involve effects on thyroid hormone synthesis or peripheral hormone disposition. There are important species differences in thyroid gland physiology between rodents and humans that may account for a marked species difference in the inherent susceptibility for neoplasia to hormone imbalance. Thyroid gland neoplasia, secondary to chemically induced hormone imbalance, is mediated by thyroid-stimulating hormone (TSH) in response to altered thyroid gland function. The effect of TSH on cell proliferation and other aspects of thyroid gland function is a receptor mediated process and the plasma membrane surface of the follicular cell has receptors for TSH and other growth factors. Small organic molecules are not known to be direct TSH receptor agonists or antagonists; however, various antibodies found in autoimmune disease such as Graves' disease can directly stimulate or inhibit the TSH receptor. Certain chemicals can modulate the TSH response for autoregulation of follicular cell function and thereby increase or decrease the response of the follicular cell to TSH. It is thus important to consider mechanisms for the evaluation of potential cancer risks. There would be little if any risk for non-genotoxic chemicals that act secondary to hormone imbalance at exposure levels that do not disrupt thyroid function. Furthermore, the degree of thyroid dysfunction produced by a chemical would present a significant toxicological problem before such exposure would increase the risk for neoplasia in humans.     

Dual functions of the steroid hormone receptor coactivator 3 in modulating resistance to thyroid hormone

Mutations of the thyroid hormone receptor beta (TRbeta) gene cause resistance to thyroid hormone (RTH). RTH is characterized by increased serum thyroid hormone associated with nonsuppressible thyroid-stimulating hormone (TSH) and impaired growth. It is unclear how the actions of TRbeta mutants are modulated in vivo to affect the manifestation of RTH. Using a mouse model of RTH that harbors a knockin mutation of the TRbeta gene (TRbetaPV mouse), we investigated the effect of the steroid hormone receptor coactivator 3 (SRC-3) on RTH. In TRbetaPV mice deficient in SRC-3, dysfunction of the pituitary-thyroid axis and hypercholesterolemia was lessened, but growth impairment of RTH was worsened. The lessened dysfunction of the pituitary-thyroid axis was attributed to a significant decrease in growth of the thyroid and pituitary. Serum insulin-like growth factor 1 (IGF-1) was further reduced in TRbetaPV mice deficient in SRC-3. This effect led to reduced signaling of the IGF-1/phosphatidylinositol 3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR) pathway that is known to mediate cell growth and proliferation. Thus, SRC-3 modulates RTH by at least two mechanisms, one via its role as a receptor coregulator and the other via its growth regulatory role through the IGF-1/PI3K/AKT/mTOR signaling.     

Arsenic Inhibits DNA Mismatch Repair by Promoting EGFR Expression and PCNA Phosphorylation

Both genotoxic and non-genotoxic chemicals can act as carcinogens. However, while genotoxic compounds lead directly to mutations that promote unregulated cell growth, the mechanism by which non-genotoxic carcinogens lead to cellular transformation is poorly understood. Using a model non-genotoxic carcinogen, arsenic, we show here that exposure to arsenic inhibits mismatch repair (MMR) in human cells, possibly through its ability to stimulate epidermal growth factor receptor (EGFR)-dependent tyrosine phosphorylation of proliferating cellular nuclear antigen (PCNA). HeLa cells exposed to exogenous arsenic demonstrate a dose- and time-dependent increase in the levels of EGFR and tyrosine 211-phosphorylated PCNA. Cell extracts derived from arsenic-treated HeLa cells are defective in MMR, and unphosphorylated recombinant PCNA restores normal MMR activity to these extracts. These results suggest a model in which arsenic induces expression of EGFR, which in turn phosphorylates PCNA, and phosphorylated PCNA then inhibits MMR, leading to increased susceptibility to carcinogenesis. This study suggests a putative novel mechanism of action for arsenic and other non-genotoxic carcinogens.     

The Effect and Potential Mechanism Analysis of Growth Hormone–Secreting Pituitary Adenomas on Thyroid Function

ObjectiveCurrent studies on the effect of high growth hormone (GH)/insulin-like growth factor (IGF)-1 on thyroid function are inconsistent. The aim was to explore the effect and potential mechanism of high GH/IGF-1 on thyroid function by analyzing the changes of thyroid function in patients with growth hormone–secreting pituitary adenoma (GHPA).MethodsThis was a retrospective cross-sectional study. Demographic and clinical data of 351 patients with GHPA who were first admitted to Beijing Tiantan Hospital, Capital Medical University, from 2015 to 2022 were collected to analyze the relationship between high GH/IGF-1 levels and thyroid function.ResultsGH was negatively correlated with total thyroxine (TT4), free thyroxine (FT4), and thyroid-stimulating hormone (TSH). IGF-1 was positively correlated with total triiodothyronine (TT3), free triiodothyronine (FT3), and FT4 and negatively correlated with TSH. Insulin-like growth factor–binding protein (IGFBP)-3 was positively correlated with TT3, FT3, and FT3:FT4 ratio. The FT3, TT3, TSH, and FT3:FT4 ratio of patients with GHPA and diabetes mellitus (DM) were significantly lower than those with GHPA but without DM. With the increase of tumor volume, thyroid function gradually decreased. GH and IGF-1 were correlated negatively with age in patients with GHPA.ConclusionThe study emphasized the complex interaction between the GH and the thyroid axes in patients with GHPA and highlighted the potential effect of glycemic status and tumor volume on thyroid function.     

The tissue-specific pathways regulating cell proliferation are inherited independently in somatic hybrid between thyroid and liver cells

Thyroid stimulating hormone (TSH) and insulin-like growth factors type 1 (IGF-I) regulate the proliferation and differentiation of cultured thyroid cells but not of cultured liver cells. We have examined the influence of TSH and IGF-I on the metabolic functions and proliferation of somatic hybrids obtained by fusing rat thyroid cells (FRTL5) with rat liver cells (BRL). While IGF-I is able to stimulate the proliferation of the hybrid cells (TxL) TSH fails to induce their growth. However, the hybrid TxL cells have surface TSH receptors with normal ligand characteristics. The addition of TSH to TxL cells led to typical enhancement of cAMP production and depolymerization of actin filaments. Yet, TSH failed to stimulate iodine uptake in the hybrid cells. Interestingly, iodine inhibited TxL proliferation induced by IGF- I but not by serum. It is concluded that the hybrid TxL cells inherited from the parental thyroid cells several important differentiated traits including mitogenic pathways induced and used by IGF-I, functional TSH receptors, and sensitivity to the inhibitory action of iodine.     

On the role of the peroxisome in cell differentiation and carcinogenesis

This article reviews the currently available data on the role of peroxisomal function in relation to the processes of cell differentiation and carcinogenesis. In regard to tumourigenesis, both genotoxic and non-genotoxic processes have been considered, and the peroxisomal relationships with these phenomena and with differentiation are described at the level of organelle characteristics, enzyme contents, and the involvement of retinoids, steroid hormones, oxygen free radicals, growth factors, apoptosis, omega-3 polyunsaturated fatty acids and the cellular signalling networks. Overall these data serve to illustrate the unique and distinctive role of the peroxisome in differentiation and carcinogenesis, and point to the advantages of considering the peroxisomal involvement in the holistic context of the differentiation dedifferentiation continuum rather than the narrower focus of non-genotoxic carcinogenesis. The review also outlines the potential for medical benefit arising from a fuller understanding of these peroxisomal affiliations.     

Thyroid-stimulating hormone stimulates increases in inositol phosphates as well as cyclic AMP in the FRTL-5 rat thyroid cell line.

Studies were conducted to determine whether thyroid-stimulating hormone (TSH; thyrotropin), a hormone known to increase cytosol concentrations of cyclic AMP, also stimulates the formation of inositol phosphates in thyroid cells. TSH and noradrenaline both stimulated [3H]inositol phosphate formation in a concentration-dependent manner in the rat thyroid cell line, FRTL-5 cells, which had been prelabelled with [3H]inositol. The threshold concentration of TSH required to stimulate inositol phosphate formation was more than 20 munits/ml, which is approx. 10(3)-fold greater than that required for cyclic AMP accumulation and growth in these cells. We also demonstrate that membranes prepared from FRTL-5 cells possess a guanine nucleotide-activatable polyphosphoinositide phosphodiesterase, which suggests that activation of inositide metabolism in these cells may be coupled to receptors by the G-protein, Gp. Our findings suggest that two second-messenger systems exist to mediate the action of TSH in the thyroid.     

Changes in thyroid function caused by continuous treatment with thiouracil in rats

Serum concentration evolution of thyroxine and triiodothyronine, and thyrotropin (TSH), have been studied in rats while they were given 6-propylthiouracil (PTU) as antithyroid drug, and during the recovery period after suppression of treatment. In the same way thyroid hypertrophy and plasmatic levels of thyrotropin were correlated. Animals received orally a daily dose of 1 mg/100 g body weight during thirty-five days and had a two week recovery period. Thyroid hormone concentrations in plasma were determined by immunoenzymatic assay ELISA with peroxidase as labelled enzyme. From the results obtained, it can be stated that chronic administration of PTU implies a continuous decrease in thyroid hormone concentrations in plasma, reaching nearly zero values, while after treatment, levels recover their normal values in a week's time. A parallelism exists between thyroid hypertrophy and pituitary TSH hypersecretion, due to a decrease in thyroid hormone levels.     

Evidence for and possible mechanisms of non-genotoxic carcinogenesis in mouse skin

Most chemicals that produce skin cancer are genotoxic by in vitro and in vivo short-term assays and produce a high incidence of skin cancer within a year if optimal doses are applied. If in long-term skin painting studies one or two tumours in 50 mice are observed there is a general consensus that no carcinogenic activity can be claimed and it has been suggested that if up to 10% tumours are induced by irritant substances this could be due to an enhancement of spontaneous tumour incidence. Observations of skin tumour incidences higher than 10% with non-genotoxic substances, usually after a long latent period, is considered to represent evidence for a non-genotoxic mechanism. Examples of such substances include croton oil, 12-O-tetradecanoyl-phorbol-13-acetate (TPA), sodium hydroxide, potassium hydroxide, phenol, dodecylbenzene and petroleum-derived middle distillates. Two distinct mechanisms appear to be involved in the production of tumours by a non-genotoxic substance. The first of these is that seen with the strong promoting agents. These, by binding to and activating protein kinase C, appear to directly stimulate sustained epidermal hyperplasia without severe skin damage. The other appears to involve substances producing severe skin damage either by a direct caustic effect or by cumulative irritancy. These changes give rise to marked epidermal hyperplasia with repeated episodes of regeneration and damage. The tumour induction by both mechanisms probably results from oncogene activation and it is possible that oxidative enzymes from inflammatory cells may be involved in the activation process. Various reasons are given why non-genotoxic carcinogenesis in the skin is considered not to be relevant to man and ways of recognising and avoiding its occurrence in animals studies are recommended.     

Relationship among thyrotropin (TSH), thyroid stimulating immunoglobulins, and results of triiodothyronine (T3) suppression test in patients with Graves' disease

To investigate the relationship between TSH and abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease in whom normal thyroid hormone levels in the serum were maintained by antithyroid drug therapy and in patients with euthyroid Graves' disease, determinations were made of the TSH concentration, action of thyroid stimulating immunoglobulins (TSAb and TBII), and T3 suppression. Out of thirty-three patients with hyperthyroid Graves' disease, twelve patients with subnormal TSH levels were all non-suppressible according to the T3 suppression test results and the detectability of TSAb and/or TBII was as high as 75%. In three out of five patients with euthyroid Graves' disease, the serum TSH level was subnormal. All three showed non-suppressibility in the T3 suppression test and positive action of either TSAb or TBII. One of them became clinically thyrotoxic when the TSAb activity was further increased and TBII became positive, and was therefore diagnosed as having hyperthyroid Graves' disease. The present findings suggest that there are still abnormal thyroid stimulator(s) in patients with hyperthyroid Graves' disease who have low TSH, even if their thyroid hormone concentrations remain normal. Moreover, it is likely that some of the patients with euthyroid Graves' disease are actually in a state of subclinical hyperthyroidism because of the presence of abnormal thyroid stimulator(s).     

Growth factor receptors gene expression and Akt phosphorylation in benign human thyroid nodules are unaffected by chronic thyrotropin suppression

Levothyroxine (L-T4)-based suppression of thyrotropin (TSH) secretion is widely used to prevent the growth of benign thyroid nodules, although the effectiveness of this approach has been demonstrated only in a subset of patients. In this study, we analyzed the in vivo effects of L-T4-mediated TSH suppression on elements of insulin/IGF-1-dependent growth-regulating pathways in tissues from patients with benign thyroid nodules. Nodular and non-nodular tissue specimens were collected from 63 patients undergoing thyroidectomy. 32 had received preoperative TSH suppressive therapy with TSH levels consistently below 0.5 mU/l (L-T4 group). TSH suppression had not been used in the other 31, and their TSH levels were normal (0.8-4 mU/l (control group). Quantitative RT-PCR was used to measure mRNA levels for TSH receptor, IGF1, IGF-1 receptor, insulin receptor, insulin receptor substrate 1 in nodular and non-nodular tissues from the 2 groups. Akt and phosphorylated Akt protein levels were detected by Western blot. Mean levels of mRNA for all genes tested were similar in the 2 groups, in both nodular and non-nodular tissues. The 2 groups were also similar in terms of phosphorylated Akt protein levels (measured by densitometric scan in 10 randomly selected nodules from each group). This is the first demonstration based on the study of human thyroid tissues that TSH suppression does not affect the expression of components of the insulin/IGF-1-dependent signaling pathways regulating thyrocyte growth. This may explain the lack of effectiveness of TSH-suppressive therapy in a substantial percentage of benign thyroid nodules.     

Association of Thyroid Function During Pregnancy With the Risk of Pre-eclampsia and Gestational Diabetes Mellitus

ObjectiveTo estimate the association of maternal thyroid dysfunction with the risk of gestational hypertension and diabetes. Whether the association was affected by gestational age at diagnosis and thyroid autoimmunity was further explored.MethodsA cohort study of 41 647 participants was conducted. Thyroid function (ie, thyroid-stimulating hormone [TSH] and free thyroxine [FT4]) was measured by electrochemiluminescence immunoassay. Thyroid antibody positivity (eg, thyroperoxidase, thyroglobulin, and TSH receptor antibody) was indicated if the values of these antibodies exceeded the upper targets of the reference range. The relationship between maternal thyroid dysfunction and the risk of pre-eclampsia (PE) and gestational diabetes mellitus (GDM) was assessed by multivariate logistic regression.ResultsIsolated hypothyroxinemia (defined as 5th ≤ TSH ≤ 95th percentile, FT4 < 5th percentile) was associated with the risk of PE (odds ratio [OR], 1.32; 95% CI, 1.10-1.58). Overt hypothyroidism (TSH > 95th percentile; FT4 < 5th percentile) was related to the risk of severe PE (OR, 2.59; 95% CI, 1.05-6.37). Being positive for TSH receptor antibody was associated with a decreased risk of GDM (OR, 0.49; 95% CI, 0.35-0.70). A marginally significant association between overt hypothyroidism detected at the first trimester and the risk of GDM was found (OR, 1.60; 95% CI, 1.00-2.83). The association of thyroid dysfunction with the risk of PE and GDM was stronger among pregnant women who were negative for autoantibodies.ConclusionSome types of thyroid dysfunction during pregnancy were associated with the risk of PE and GDM. The associations varied by gestational age at diagnosis and by thyroid autoantibody status.     

Targeting thyroid diseases with TSH receptor analogs

The thyroid-stimulating hormone (TSH) receptor (TSHR) is a major regulator of thyroid function and growth, and is the key antigen in several pathological conditions including hyperthyroidism, hypothyroidism, and thyroid tumors. Various effective treatment strategies are currently available for many of these clinical conditions such as antithyroid drugs or radioiodine therapy, but they are not devoid of side effects. In addition, treatment of complications of Graves’ disease such as Graves’ ophthalmopathy is often difficult and unsatisfactory using current methods. Recent advances in basic research on both in vitro and in vivo models have suggested that TSH analogs could be used for diagnosis and treatment of some of the thyroid diseases. The advent of high-throughput screening methods has resulted in a group of TSH analogs called small molecules, which have the potential to be developed as promising drugs. Small molecules are low molecular weight compounds with agonist, antagonist and, in some cases, inverse agonist activity on TSHR. This short review will focus on current advances in development of TSH analogs and their potential clinical applications. Rapid advances in this field may lead to the conduct of clinical trials of small molecules related to TSHR for the management of Graves’ disease, thyroid cancer, and thyroid-related osteoporosis in the coming years.     

Evidence for an association between thyroid-stimulating hormone and insulin-like growth factor 1 receptors: a tale of two antigens implicated in Graves' disease

Thyroid-stimulating hormone receptor (TSHR) plays a central role in regulating thyroid function and is targeted by IgGs in Graves' disease (GD-IgG). Whether TSHR is involved in the pathogenesis of thyroid-associated ophthalmopathy (TAO), the orbital manifestation of GD, remains uncertain. TSHR signaling overlaps with that of insulin-like grow factor 1 receptor (IGF-1R). GD-IgG can activate fibroblasts derived from donors with GD to synthesize T cell chemoattractants and hyaluronan, actions mediated through IGF-1R. In this study, we compare levels of IGF-1R and TSHR on the surfaces of TAO and control orbital fibroblasts and thyrocytes and explore the physical and functional relationship between the two receptors. TSHR levels are 11-fold higher on thyrocytes than on TAO or control fibroblasts. In contrast, IGF-1R levels are 3-fold higher on TAO vs control fibroblasts. In pull-down studies using fibroblasts, thyrocytes, and thyroid tissue, Abs directed specifically against either IGF-1Rbeta or TSHR bring both proteins out of solution. Moreover, IGF-1Rbeta and TSHR colocalize to the perinuclear and cytoplasmic compartments in fibroblasts and thyrocytes by confocal microscopy. Examination of orbital tissue from patients with TAO reveals similar colocalization to cell membranes. Treatment of primary thyrocytes with recombinant human TSH results in rapid ERK phosphorylation which can be blocked by an IGF-1R-blocking mAb. Our findings suggest that IGF-1R might mediate some TSH-provoked signaling. Furthermore, they indicate that TSHR levels on orbital fibroblasts are considerably lower than those on thyrocytes and that this receptor associates with IGF-1R in situ and together may comprise a functional complex in thyroid and orbital tissue.     

Investigating the Different Mechanisms of Genotoxic and Non-Genotoxic Carcinogens by a Gene Set Analysis

Based on the process of carcinogenesis, carcinogens are classified as either genotoxic or non-genotoxic. In contrast to non-genotoxic carcinogens, many genotoxic carcinogens have been reported to cause tumor in carcinogenic bioassays in animals. Thus evaluating the genotoxicity potential of chemicals is important to discriminate genotoxic from non-genotoxic carcinogens for health care and pharmaceutical industry safety. Additionally, investigating the difference between the mechanisms of genotoxic and non-genotoxic carcinogens could provide the foundation for a mechanism-based classification for unknown compounds. In this study, we investigated the gene expression of HepG2 cells treated with genotoxic or non-genotoxic carcinogens and compared their mechanisms of action. To enhance our understanding of the differences in the mechanisms of genotoxic and non-genotoxic carcinogens, we implemented a gene set analysis using 12 compounds for the training set (12, 24, 48 h) and validated significant gene sets using 22 compounds for the test set (24, 48 h). For a direct biological translation, we conducted a gene set analysis using Globaltest and selected significant gene sets. To validate the results, training and test compounds were predicted by the significant gene sets using a prediction analysis for microarrays (PAM). Finally, we obtained 6 gene sets, including sets enriched for genes involved in the adherens junction, bladder cancer, p53 signaling pathway, pathways in cancer, peroxisome and RNA degradation. Among the 6 gene sets, the bladder cancer and p53 signaling pathway sets were significant at 12, 24 and 48 h. We also found that the DDB2, RRM2B and GADD45A, genes related to the repair and damage prevention of DNA, were consistently up-regulated for genotoxic carcinogens. Our results suggest that a gene set analysis could provide a robust tool in the investigation of the different mechanisms of genotoxic and non-genotoxic carcinogens and construct a more detailed understanding of the perturbation of significant pathways.     

Valoración de la función tiroidea durante la gestación: intervalos de referencia de tirotropina y tiroxina no unida a proteína durante el primer trimestre

Background and objectivesThe physiological changes that occur during pregnancy affect the physiology of the thyroid gland. Consequently, interpretation of thyroid function markers during pregnancy requires trimester-specific reference intervals. The aims of our study were to: 1) establish first-trimester reference intervals for biochemical markers of thyroid function [thyroid-stimulating hormone (TSH) and free thyroxine (T4)] and 2) to establish the prevalence of autoimmune thyroid disease in pregnant women resident in Cartagena (Murcia, Spain).Patients and methodA total of 441 women between weeks 11 and 13 of pregnancy were included in this study. A blood sample was extracted from all women to measure TSH, free T4 and antithyroid antibodies. Reference intervals for TSH and free T4 were determined in 400 pregnant women without autoimmune thyroid disease or known thyroid disease.ResultsAutoimmune thyroid disease was detected in 23 pregnant women (5.2%) who showed TSH levels higher than those in pregnant women without thyroid autoimmunity. First-trimester reference intervals were as follows: TSH: 0.130–3.710 mUI/L; free T4: 0.89–1.50 ng/dL. These reference intervals differed from the non-pregnant reference intervals used in our laboratory.ConclusionsThe reference intervals established are useful to evaluate thyroid function in women between 11 and 13 weeks of pregnancy. Interpretation of thyroid function requires intervals established in a reference population without autoimmune thyroid disease and with the methodology usually used to analyze these markers.     

Cell kinetics of a rat thyroid transplantable tumour

Changes in morphology and cell kinetics are described in a rat thyroid transplantable tumour (TTT) during the first few transplant generations. The growth of TTT in animals was possible only with an increased circulation level of the thyroid stimulating hormone (TSH). With serial transplantation subcutaneously in isologous animals, the morphology of TTT changed dramatically from that of a follicular tumour in the 3rd passage to become, by the 9th generation, a poorly differentiated tumour with a trabecular arrangement of cells. This change in tumour morphology was accompanied by an increase in the number of proliferating cells--mitotic index (MI), [3H]thymidine labelling index (LI), growth fraction (GF)--and cell loss factor (O) as well as a decrease in the cell cycle time (Tc) and potential population doubling time (TPD). TTT belongs to the class of tumours with a low proliferative activity and might be used in a variety of cell kinetic, radiobiological and chemotherapy studies.     

Decrease in Acromegaly-Associated Thyroid Enlargement after Normalization of IGF-1 Levels: A Prospective Observation and in Vitro Study

Objective: Goiter occurs at high frequency in acromegaly patients. Whether normalization of insulin-like growth factor 1 (IGF-1) levels could decrease goiter and thyroid volume remains unclear.Methods: Thyroid hormone levels and ultrasound measurements were assessed in 101 acromegaly patients, compared with 108 patients with nonfunctioning pituitary adenoma (NFPA) and 55 healthy controls. Thirty-four acromegaly patients underwent repeat evaluation 1 year post–transsphenoidal surgery. The effect of IGF-1 on thyroid cell proliferation, cell cycle, and apoptosis was evaluated in vitro.Results: Acromegaly patients showed larger thyroid volume than those with NFPAs (18.32 mL vs. 9.91 mL; P<.001) and healthy controls (18.32 mL vs. 9.63 mL; P<.001). Duration of acromegaly was shown to be independently associated with thyroid volume enlargement (B = 0.259; 95% confidence interval, 0.162 to 0.357) in multivariate analysis. At follow-up, the median thyroid volume decreased from 22.74 to 17.87 mL in the cured group (n = 20; P = .003), but the number of nodular goiters showed no significant change. Serum free thyroxine levels decreased from 13.76 to 10.08 pmol/L in the cured group (P = .006) but increased from 9.28 to 12.09 pmol/L in the active group (P = .013). Change in thyroid volume was significantly correlated with IGF-1 level (r = 0.37; P = .029). In vitro, IGF-1 time- and dose-dependently promoted proliferation and secretory function of thyroid cells by enhancing cell cycle shift from the G1/S to G2/M phase and suppressing apoptosis.Conclusion: Acromegaly-associated thyroid volume increase, but not nodular goiter, could be reversed in cured acromegaly. IGF-1 time- and dose-dependently promoted the proliferation and secretory function of thyroid cells.Abbreviations: CCK-8 = Cell Counting Kit-8; fT3 = free triiodothyronine; fT4 = free thyroxine; GH = growth hormone; IGF-1 = insulin-like growth factor 1; MRI = magnetic resonance imaging; NFPA = nonfunctioning pituitary adenoma; qRT-PCR = quantitative real-time–polymerase chain reaction; TSH = thyroid-stimulating hormone