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The regulation of the female reproductive system is one of the most relevant actions of thyroid hormones. Adequate thyroid hormones production is essential for normal menstrual function and fertility as well as for the successful maintenance of pregnancy. The relationship between reproductive failure and thyroid disorders is particularly relevant and attracts attention worldwide. Thyroid autoimmunity (TAI), defined by the presence of circulating antithyroid antibodies targeting thyroid peroxidase (TPOAb) and thyroglobulin (TgAb), is prevalent among women of reproductive age and is the most frequent cause of thyroid dysfunction. Several studies addressed the association between TAI, thyroid function, and fertility as well as pregnancy outcome after spontaneous or assisted conception. Infertility, miscarriages, and fetal-maternal complications are described in overt autoimmune hypothyroidism. More debatable is the role of mild thyroid dysfunction, mainly subclinical hypothyroidism (SCH), and TAI in the absence of thyroid dysfunction in infertility and reproductive outcome. Assisted reproductive technology (ART) has become an integral element of care for infertility. Women with TAI undergoing ART are of particular interest since they carry a higher risk of developing hypothyroidism after the ovarian stimulation but whether TAI, in absence of thyroid dysfunction, adversely affects ART outcome is still controversial. Likewise, the role of levothyroxine (LT4) in improving fertility and the success of ART in euthyroid women with TAI is unclear. This review discusses the role of TAI, in the absence of thyroid dysfunction, in infertility and in ART outcome.

In previous studies we have demonstrated that the expression of the Major Histocompatibility Complex (MHC) class I gene in thyrocytes is controlled by several hormones, growth factors, and drugs. These substances mainly act on two regions of the MHC class I promoter a “tissue-specific” region (−800 to −676 bp) and a “hormone/cytokines-sensitive” region (−500 to −68 bp). In a previous study, we have shown that the role of the “tissue-specific” region in the MHC class I gene expression is dominant compared to that of the “hormone/cytokines-sensitive” region. In the present report we further investigate the dominant role of the “tissue-specific” region evaluating the effect of thyroid stimulating hormone (TSH), methimazole (MMI), phenylmethimazole (C10), glucose and thymosin-α1. By performing experiments of electrophoretic mobility shift assays (EMSAs) we show that TSH, MMI and C10, which inhibit MHC class I expression, act on the “tissue-specific” region increasing the formation of a silencer complex. Glucose and thymosin-α1, which stimulate MHC class I expression, act decreasing the formation of this complex. We further show that the silencer complex is formed by two distinct members of the transcription factors families activator protein-1 (AP-1) and nuclear factor-kB (NF-kB), c-jun and p65, respectively. These observations are important in order to understand the regulation of MHC class I gene expression in thyroid cells and its involvement in the development of thyroid autoimmunity.

Anti TSH receptor antibodies (TSHrAb) are a family of antibodies with different activity, some of them stimulating thyroid function (TSAb), others with blocking properties (TBAb), it is a common finding that antibodies with different function might coexist in the same patient and can modulate the function of the thyroid. However, most of the labs routinely detect all antibodies binding to the TSH receptor (TRAb, i.e. TSH-receptor antibodies detected by binding assay without definition of functional property). Classical use of TSHr-Ab assay is in Graves’ disease where they are tested for diagnostic and prognostic issues; however, they can be used in specific settings of chronic autoimmune thyroiditis (CAT) as well. Aim of the present paper is to highlight these conditions where detection of TSHr-Ab can be of clinical relevance. Prevalence of TSHrAb is different in in the 2 main form of CAT, i.e. classical Hashimoto’s thyroiditis and in atrophic thyroiditis, where TBAb play a major role. Simultaneous presence of both TSAb and TBAb in the serum of the same patient might have clinical implication and cause the shift from hyperthyroidism to hypothyroidism and vice versa. Evaluation of TRAb is recommended in case of patients with Thyroid Associated Orbitopathy not associated with hyperthyroidism. At present, however, the most relevant recommendation for the use of TRAb assay is in patients with CAT secondary to a known agent; in particular, after treatment with alemtuzumab for multiple sclerosis. In conclusion, the routine use of anti-TSH receptor antibodies (either TRAb or TSAb/TBAb) assay cannot be suggested at the present for diagnosis/follow up of patients affected by CAT; there are, however, several conditions where their detection can be clinically relevant.

Background: Neonatal thyrotropin (TSH) on dried blood spot (DBS), the most common screening strategy for primary congenital hypothyroidism (CH), is influenced by numerous factors that may hinder a true CH diagnosis. A second test can thus be performed to clarify the initial findings, although its application varies among screening programs.Objectives: The aim of this study was to evaluate the effect of maternal and neonatal factors on neonatal TSH levels and offer practical screening recommendations.Methods: We retrospectively analyzed screening data of 62,132 neonates born in Abruzzo, an Italian region considered mildly iodine deficient, between 2011 and 2016. We then performed a multiple linear regression to model the relationship between TSH (the dependent variable) and 13 independent variables extracted from blood collection cards.Results: Most neonates (53,551 of 62,132, 86%) had normal TSH and no clinical indications for a second screening. A minority (1,423, 2.3%) had elevated TSH in the initial DBS, which was confirmed in 97 cases (7%) on a second screen. The remaining neonates (6,594, 10.6%) had a normal initial TSH but underwent a second test in accordance with screening protocols, and were found to have delayed TSH elevation in 23 cases (0.4%). Those 120 newborns (97 + 23), considered highly suspicious for primary CH, were referred to a pediatrician for confirmatory testing and excluded from subsequent analysis of factors influencing TSH levels. Sex (β regression coefficient, β = 1.11 female to male, 95% CI 1.09, 1.12) and age at collection (β = 0.78 day 5 to days 2–3, 95% CI 0.74, 0.83) affected neonatal TSH, suggesting the utility of specific nomograms. In addition, prematurity (β = 0.85 term to preterm, 95% CI 0.80, 0.91), dopamine use (β = 0.71, 95% CI 0.62, 0.81), and birth weight (β = 1.40 normal vs. very low, 95% CI 1.05, 1.89) strongly influenced neonatal TSH.Conclusions: Neonatal TSH is influenced by several factors supporting the delineation of local sex- and age-adjusted TSH cutoffs, and the universal adoption of a second TSH test in neonates at risk of missed primary CH diagnosis.

Cinacalcet, a calcimimetic drug, is considered a safe and valid option for the treatment of hypercalcemia in patients with primary hyperparathyroidism who are unable to undergo parathyroidectomy. Hypocalcemia and gastrointestinal adverse reactions are the main side effects reported in patients treated with cinacalcet. We present here the case of an 80-years-old patient with primary hyperparathyroidism treated with cinacalcet for 17 months who developed a severe and symptomatic episode of hypocalcemia requiring hospitalization 1 month after reaching a daily dose of 180 mg. Follow-up laboratory and imaging exams showed remission of primary hyperparathyroidism and disappearance of the parathyroid adenoma, suggesting a possible association between cinacalcet therapy and parathyroid infarction resulting in normalization of the elevated serum parathyroid hormone levels and severe hypocalcemia. No known cases of iatrogenic parathyroid apoplexy have thus far been described. We report here the first case of parathyroid apoplexy associated with the administration of cinacalcet in a patient with primary hyperparathyroidism. Parathyroid apoplexy features heterogeneous clinical manifestations ranging from relatively asymptomatic to potentially life-threatening cases. The occurrence of this complication should be carefully considered in patients with primary hyperparathyroidism in therapy with cinacalcet.

Nuclear factor-kappa B (NF-κB) is a ubiquitous transcription factor that is involved in inflammatory and immune responses, as well as in regulation of expression of many other genes related to cell survival, proliferation, and differentiation. In mammals, NF-κB comprises five subunits that can bind to promoter regions of target genes as homodimers or heterodimers. The most common dimer is the p50/p65 heterodimer. The several combinations of dimers that can be formed contribute to the heterogeneous regulation of NF-κB target genes, and this heterogeneity is further increased by interactions of the NF-κB dimers with other transcription factors, such as steroid hormone receptors, activator protein-1 (AP-1), and cAMP response element binding protein (CREB). In the thyroid, several studies have demonstrated the involvement of NF-κB in thyroid autoimmunity, thyroid cancer, and thyroid-specific gene regulation. The role of NF-κB in thyroid autoimmunity was hypothesized more than 20 years ago, after the finding that the binding of distinct NF-κB heterodimers to the major histocompatibility complex class I gene is hormonally regulated. Further studies have shown increased activity of NF-κB in thyroid autoimmune diseases and in thyroid orbitopathy. Increased activity of NF-κB has also been observed in thyroid cancer, where it correlates with a more aggressive pattern. Of particular interest, mutation of some oncogenes or tumor suppressor genes involved in thyroid carcinogenesis results in constitutive activation of the NF-κB pathway. More recently, it has been shown that NF-κB also has a role in thyroid physiology, as it is fundamental for the expression of the main thyroid-specific genes, such as sodium iodide symporter, thyroid peroxidase, thyroglobulin, Pax8, and TTF-1 (NKX2-1).

Graves’ disease is the most common cause of thyrotoxicosis in women of childbearing age. Approximately 1% of pregnant women been treated before, or are being treated during pregnancy for Graves’ hyperthyroidism. In pregnancy, as in not pregnant state, thyroid-stimulating hormone (TSH) receptor (TSHR) antibodies (TRAbs) are the pathogenetic hallmark of Graves’ disease. TRAbs are heterogeneous for molecular and functional properties and are subdivided into activating (TSAbs), blocking (TBAbs), or neutral (N-TRAbs) depending on their effect on TSHR. The typical clinical features of Graves’ disease (goiter, hyperthyroidism, ophthalmopathy, dermopathy) occur when TSAbs predominate. Graves’ disease shows some peculiarities in pregnancy. The TRAbs disturb the maternal as well as the fetal thyroid function given their ability to cross the placental barrier. The pregnancy-related immunosuppression reduces the levels of TRAbs in most cases although they persist in women with active disease as well as in women who received definitive therapy (radioiodine or surgery) before pregnancy. Changes of functional properties from stimulating to blocking the TSHR could occur during gestation. Drug therapy is the treatment of choice for hyperthyroidism during gestation. Antithyroid drugs also cross the placenta and therefore decrease both the maternal and the fetal thyroid hormone production. The management of Graves’ disease in pregnancy should be aimed at maintaining euthyroidism in the mother as well as in the fetus. Maternal and fetal thyroid dysfunction (hyperthyroidism as well as hypothyroidism) are in fact associated with several morbidities. Monitoring of the maternal thyroid function, TRAbs measurement, and fetal surveillance are the mainstay for the management of Graves’ disease in pregnancy. This review summarizes the biochemical, immunological, and therapeutic aspects of Graves’ disease in pregnancy focusing on the role of the TRAbs in maternal and fetal function.

Since the discovery 60 years ago of the long-acting thyroid stimulator by Adams and Purves, great progress has been made in the detection of thyroid-stimulating hormone (TSH) receptor autoantibodies (TRAbs) in Graves’ disease. Today, commercial assays are available that can detect TRAbs with high accuracy and provide diagnostic and prognostic evaluation of patients with Graves’ disease. The present review focuses on the development of TRAbs bioassays, and particularly on the role that Leonard D. Kohn had in this. Indeed, 30 years ago, the Kohn group developed a bioassay based on the use of FRTL-5 cells that was characterized by high reproducibility, feasibility, and diagnostic accuracy. Using this FRTL-5 bioassay, Kohn and his colleagues were the first to develop monoclonal antibodies against the TSH receptor. Furthermore, they demonstrated the multifaceted functional nature of TRAbs in patients with Graves’ disease, with the identification of stimulating and blocking TRAbs, and even antibodies that activated pathways other than cAMP. After the cloning of the TSH receptor, the Kohn laboratory constructed human TSH receptor–rat luteinizing hormone/ chorionic gonadotropin receptor chimeras. This paved the way to a new bioassay based on the use of nonthyroid cells transfected with the Mc4 chimera. The new Mc4 bioassay is characterized by high diagnostic and prognostic accuracy, greater than for other assays. The availability of a commercial kit based on the Mc4 chimera is spreading the use of this assay worldwide, indicating its benefits for these patients with Graves’ disease. This review also describes the main contributions made by others researchers in TSH receptor molecular biology and TRAbs assay, especially with the development of highly potent monoclonal antibodies. A comparison of the diagnostic accuracies of the main TRAbs assays, as both immunoassays and bioassays, is also provided.