Thyroid pathology and female fertility: Myth or reality?

The relationship between thyroid state and female fertility is an area of particular interest for both clinicians and researchers worldwide. This is partially due to the increasing prevalence of infertility and to the understanding of its complex and multifactorial aetiology. Studies conducted in variable forms of female infertility (e.g., recurrent miscarriages or polycystic ovarian syndrome) together with the worldwide rising use of assisted reproduction technologies (ART) contributed the uncovering of the potential role of thyroid conditions in relation to ovarian function and fertility. However, as the title of this short review suggests, several aspects are yet to be elucidated and several questions are still awaiting an answer. This short review is mainly focusing on the distinct roles of thyroid dysfunction and thyroid autoimmunity in infertile women undergoing ART procedures.

The thyroid risk score (TRS) for nodules with indeterminate cytology.

Cytology is the gold standard method for the differential diagnosis of thyroid nodules, though 25-30% of them are classified as indeterminate. We aimed to set up a 'thyroid risk score' (TRS) to increase the diagnostic accuracy in these cases. We prospectively tested 135 indeterminate thyroid nodules. The pre-surgical TRS derived from the sum of the scores assigned at cytology, EU-TIRADS classification, nodule measurement, and molecular characterization, which was done by our PTC-MA assay, a customized array able to cost-effectively evaluate 24 different genetic alterations including point mutations and gene fusions. The risk of malignancy (ROM) increased paralleling the score: in the category >4 and ≤ 6 (low suspicion), >6 ≤ 8 (intermediate suspicion), and >8 (high suspicion); ROM was 10, 47 and 100%, respectively. ROC curves selected the score >6.5 as the best threshold to differentiate between malignant and benign nodules (P < 0.001). The TRS > 6.5 had a better performance than the single parameters evaluated separately, with an accuracy of 77 and 82% upon inclusion of noninvasive follicular thyroid neoplasm with papillary-like nuclear features among malignant or benign cases, respectively. In conclusion, for the first time, we generated a score combining a cost-effective molecular assay with already validated tools, harboring different specificities and sensitivities, for the differential diagnosis of indeterminate nodules. The combination of different parameters reduced the number of false negatives inherent to each classification system. The TRS > 6.5 was highly suggestive for malignancy and retained a high accuracy in the identification of patients to be submitted to surgery.

Efficacy Profile and Safety of Very Low-Dose Rituximab in Patients with Graves' Orbitopathy.

Background: Rituximab (RTX), a chimeric human-murine anti-CD20 monoclonal antibody, has been used for treatment of active moderate-severe Graves' orbitopathy (GO) since 2004 as second-line therapy in patients unresponsive to intravenous steroids. We conducted an open-label prospective study (EUDRACT 2012-001980-53) in which patients were treated with a single infusion of only 100 mg RTX to analyze the efficacy and safety of this low dose. Methods: Seventeen patients, of whom nine had disease that was unresponsive to intravenous methylprednisolone and eight with newly diagnosed GO, were enrolled. Disease activity was assessed with the clinical activity score (CAS) and severity with a composite ophthalmic score. Long-term surgical treatment and quality of life were also assessed, as well as treatment-related adverse events. Results: Mean baseline CAS was 4.56 ± 0.96 and decreased to 1.25 ± 1.14 at 24 weeks (p = 0.001). Disease inactivation occurred within 24 weeks in >90% of patients and was unrelated to disease duration. Severity improved in about 60% of patients, with no relapses. All patients showed peripheral depletion of CD20+ and CD19+ cells at the end of RTX infusion (60 minutes). Two patients required surgical orbital decompression because of optic neuropathy (ON). Among adverse events observed, there was one patient who developed a cytokine release syndrome. Conclusions: A dose of 100 mg RTX is effective in patients with active moderate-severe GO. Low doses are better tolerated, expose patients to immune suppression for a shorter period of time, and are extremely cost effective, compared with higher doses. This dose, consistently with all other immunosuppressants, does not prevent the progression of GO to dysthyroid ON.

Quantification of Global Ocular Motility Impairment in Graves' Orbitopathy by Measuring Eye Muscle Ductions.

Background: The overall changes of ocular motility in Graves' orbitopathy (GO) are not easily quantifiable with the methods currently available, especially in clinical studies. The aim of the present study was to calculate parameters that quantify the changes of ocular motility in GO in relation to the Gorman score for diplopia. Methods: We studied 100 GO patients (Group 1) and 100 controls (Group 2). We also included 30 patients treated with intravenous methylprednisolone (iv-MP), assessed at baseline and after 12 and 24 weeks (Group 3), and 66 patients submitted to squint surgery, assessed at baseline and after 12 weeks (Group 4). Ocular ductions were measured in four gaze directions by a perimeter arc and were used to calculate a total motility score (TMS) as the sum of ductions in each direction; a biocular TMS (b-TMS) as the sum of the TMS of two eyes; and an asymmetry ratio (AR) as the sum of the differences of the corresponding ductions between the two fellow eyes divided by the mean difference found in controls. Quality of life was accessed by a specific questionnaire (Graves' orbitopathy quality of life [GO-QoL] questionnaire). Results: TMS and b-TMS were lower, while AR was higher, in Group 1 compared with controls (p < 0.001). In Group 1, TMS and b-TMS were inversely correlated with the Gorman score (p < 0.001) and AR was higher in patients with constant diplopia compared with the others (p < 0.001). In Group 3, TMS and b-TMS increased after treatment in responders to iv-MP (p < 0.001). In Group 4, TMS and b-TMS improved in all patients after surgery (p < 0.01), while AR and GO-QoL score improved only in those without residual constant diplopia (p < 0.001). Conclusion: We describe a quantitative method to assess eye motility dysfunction in any stage of GO to be used as an outcome measure in clinical studies.

Therapy With Different Dose Regimens of Rituximab in Patients With Active Moderate-To-Severe Graves' Orbitopathy.

Background: Immunosuppressive therapy of Graves' orbitopathy (GO) is indicated during the active phase of disease. Intravenous steroids (IVGC) are effective in about 70% of patients, although unresponsiveness or relapse are observed. In previous studies, rituximab (RTX) has been shown to be effective in inactivating moderate-to-severe GO when used early in the disease, but its optimal dosage has never been studied in randomized clinical trials. Aim of this study was to compare the efficacy and safety of different doses of RTX, based on a post-hoc analysis of two open label studies and one prospective trial randomized to IVGC. Methods: of 40 patients (35 women, 5 men), with active moderate-to-severe GO treated with RTX, 14 received a single dose of 100 mg (Group 1), 15 a single dose of 500 mg (Group 2) and 11 two 1000 mg doses, administered one week apart (Group 3). Thyroid function, TSH-receptor antibodies (TRAb) and peripheral CD19+ cells were measured. Primary endpoint was disease inactivation, measured as a decrease of the Clinical Activity Score (CAS) of at least two points. Secondary endpoints were improvement of proptosis, diplopia, quality of life and safety. Results: Baseline CAS decreased significantly in all groups (P<0.0001), independently of GO duration or whether patients had newly occurring or relapsing GO after IVGC. Proptosis did not significantly change. There was an inverse correlation between the Gorman score for diplopia and RTX dose (P<0.01). The appearance score of the GO-QoL improved in Group 1 (P=0.015), and the visual function score, in Group 2 (P=0.04). A reduction of serum TRAb was observed in Group 1 (P=0.002) and Group 2 (P<0.0002), but not in Group 3. CD19+ cell decreased in all groups (P<0.01), independently of the dose. Conclusions: We studied the optimal dosage of RTX in the treatment of active moderate-to-severe GO. In this analysis, we considered the efficacy of RTX in inactivating GO, in changing its natural course, its effect on disease severity and on the patients' quality of life. Based on our clinical findings, and balancing the cost of therapy, a single 500 mg dose regimen is suggested in the majority of patients.

Prevention of Orbitopathy by Oral or Intravenous Steroid Prophylaxis in Short Duration Graves' Disease Patients Undergoing Radioiodine Ablation: A Prospective Randomized Control Trial Study.

Background: Radioiodine (RAI) is a known risk factor for activation or de novo occurrence of Graves' orbitopathy (GO). Several studies demonstrated that GO can be prevented by glucocorticoids (GCs) in patients with pre-existing GO. We have previously shown that Graves' disease duration (GDd) <5 years is a risk factor for RAI-induced GO. We studied the effect of prophylaxis with either oral GCs (OGCs) or intravenous GCs (IVGCs) on GO activation in patients with GDd. Methods: In total, 99 hyperthyroid patients without GO or with pre-existing inactive GO with GDd <5 years were randomized to receive IVGCs (N = 49) or OGCs (N = 50) before RAI; 22 patients with GDd >5 did not receive steroids and were studied as controls. All patients underwent ophthalmological assessment before and 45, 90, 180 days and for a 5-year follow-up after RAI. Serum thyrotropin (TSH) receptor antibodies (TRAbs), thyroid hormones, and thyroid volume (TV) were also measured in response to RAI therapy and steroid prophylaxis. Results: No patient on prophylaxis developed GO after RAI. One woman of the control group, without steroid prophylaxis, and who had a marked elevation of her TSH, showed transient reactivation of GO, which spontaneously improved after restoring euthyroidism. On follow-up at 12 and 20 months after RAI, two patients developed overt optic neuropathy. A smaller TV was associated with a higher prevalence of RAI-induced hypothyroidism. Serum TRAbs increased significantly after RAI (p < 0.0001) but less in patients receiving steroids than in those without prophylaxis at 45 days (p < 0.01). Conclusions: The risk of RAI-induced GO can be prevented in all patients with GDd <5 years by steroids. Such treatment may not be necessary in patients with GDd >5 years. The blunting of TRAb elevation after RAI may be related to the prophylactic effect of steroids.

Cholesterol Serum Levels and Use of Statins in Graves' Orbitopathy: A New Starting Point for the Therapy.

Graves' Orbitopathy (GO) is the most frequent extrathyroidal manifestation of Graves' disease (GD). Its ultimate cause remains unclear, but it is commonly considered an autoimmune disorder due to self recognition of autoantigens constitutively expressed by orbital fibroblasts (OFs), and thyroid epithelial cells. High dose intravenous glucocorticoids (ivGC) are the most commonly used treatment for moderately severe and active GO. However, based on the complex pathogenesis of GO, a number of factors may have a protective and maybe a therapeutic role. The use of other medications improving the effect of GC may increase the overall effectiveness of the therapy and reduce GC doses, thereby limiting side effects. Recently, a possible protective role of 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, the so-called statins, and perhaps of lowering cholesterol levels, has been proposed. Thus, statins have been reported to be associated with a reduced frequency of GO in GD patients and in recent cross-sectional and retrospective studies a significant correlation was found between the occurrence of GO and both total and LDL-cholesterol in patients with a GD of relatively recent onset, suggesting a role of cholesterol in the development of GO. Moreover, a correlation was found between the GO clinical activity score and total as well as LDL-cholesterol in untreated GO patients, depending on GO duration, indicating a role of cholesterol on GO activity. Therefore, statin treatment may be beneficial for GO. Here we review this subject, which offers new therapeutic perspectives for patients with GO.

Primary Adrenal Insufficiency During Lenvatinib or Vandetanib and Improvement of Fatigue After Cortisone Acetate Therapy.

Context: Two tyrosine kinase inhibitors (TKIs), lenvatinib and vandetanib, are often used to treat advanced radioiodine-refractory differentiated thyroid cancer (RAI-R DTC) and medullary thyroid cancer (MTC), respectively. Fatigue is a common adverse event during treatment with these and other TKIs and a common cause of drug discontinuation or dosage reduction. Cases Description: We evaluated the basal and stimulated adrenal function in 12 patients with advanced RAI-R DTC and MTC treated with lenvatinib or vandetanib, respectively. Ten patients complaining of fatigue showed a progressive ACTH increase with normal cortisol levels. Moreover, six of 10 patients had a blunted cortisol response after ACTH stimulation, thus confirming the diagnosis of primary adrenal insufficiency (PAI). The causal relationship between TKIs and PAI onset was also demonstrated by the repeated testing of adrenal function before and during treatment. Patients with PAI received cortisone acetate replacement therapy, with a substantial and prompt improvement in the degree of fatigue, as assessed by the Common Terminology Criteria for Adverse Events version 4.03, thus supporting the major impact of impaired adrenal function in the genesis of this adverse event. Conclusions: We show that the occurrence of PAI may be a common cause of fatigue during lenvatinib and vandetanib treatment, and we therefore recommend testing adrenal function for a prompt start of replacement therapy to avoid treatment discontinuation, dosage reduction, and potentially severe PAI complications.

THERAPY OF ENDOCRINE DISEASE: Endocrine dilemma: management of Graves' orbitopathy.

Management of Graves' orbitopathy (GO) must be based on the correct assessment of activity and severity of the disease. Activity is usually assessed with the Clinical Activity Score, whereas severity is classified according to a European Group On Graves' Orbitopathy (EUGOGO) consensus statement as mild, moderate-to-severe, and sight-threatening. Myopathic and chronic congestive forms are uncommon clinical presentations of GO. Restoration and maintenance of stable euthyroidism are recommended in the presence of GO.In moderate-to-severe disease, steroids have been widely employed and have shown to possess an anti-inflammatory activity, but about 20-30% of patients are not responsive and present recurrence. Some novel immunosuppressors have already been employed in clinical studies and have shown interesting results, although the lack of randomized and controlled trials suggests caution for their use in clinical practice. Potential targets for therapy in GO are the thyroid-stimulating hormone and the insulin-like growth factor 1 receptor on the fibroblasts, inflammatory cytokines, B and T cells, and the PIK3/mTORC1 signaling cascades for adipogenesis. A recent open study has shown that tocilizumab, an anti-sIL-6R antibody, inactivates GO. Consistent reports on the efficacy of rituximab have recently been challenged by randomized controlled trials.As the main goal of treatment is the well-being of the patient, the therapeutic strategy should be addressed to better suit the patient needs, more than improving one or more biological parameters. The increasing availability of new therapies will expand the therapeutic options for GO patients and allow the clinician to really personalize the treatment to better suit the patients' personal needs.

THE LONG-TERM IMPACT OF CONTROLLED OVARIAN HYPERSTIMULATION ON THYROID FUNCTION.

OBJECTIVE: Evidence on the long-term impact of controlled ovarian hyperstimulation (COH) on thyroid function is scarce. To investigate this, we report on serum thyroid-stimulating hormone (TSH) modifications in euthyroid and hypothyroid women during COH and 3 months after the end of the stimulation cycle. METHODS: Women who underwent in vitro fertilization (IVF) and who did not become pregnant were eligible. Cases were women with treated hypothyroidism and basal serum TSH <2.5 mIU/L. Controls were euthyroid women matched to cases by age and basal serum TSH. Women could be included if serum TSH was available at 4 time points: prior to initiating COH (time 1); at the time of human chorionic gonadotropin (hCG) administration (time 2); 16 days after hCG administration (time 3); and 3 months after the end of the IVF cycle (time 4). RESULTS: Thirty-seven case-control pairs were included. Serum TSH at times 1, 2, 3, and 4 was 1.7 ± 0.6, 3.1 ± 1.4, 3.1 ± 1.3, and 2.7 ± 1.7 mIU/L, and 1.7 ± 0.6, 2.9 ± 1.0, 2.7 ± 1.0, and 1.9 ± 0.7 mIU/L among cases and controls, respectively. A statistically significant difference emerged at time 4 (P<.001). In both groups, serum TSH was higher at time 4 compared to time 1. Serum TSH exceeded the recommended threshold of 2.5 mIU/L at time 4 in 51% of cases (95% confidence interval [CI], 35 to 68%) and in 16% of controls (95% CI, 4 to 28%) (P = .003). CONCLUSION: COH seems to have a long-term impact on TSH levels. The magnitude of this effect is particularly pronounced in hypothyroid women.

B Cell Activating Factor (BAFF) and BAFF Receptor Expression in Autoimmune and Nonautoimmune Thyroid Diseases.

BACKGROUND: The B cell activating factor (BAFF) is a member of the tumor necrosis factor family, which controls the survival/proliferation of B cells and is involved in the pathogenesis of a number of autoimmune diseases. The objective of the present study was to investigate the expression of BAFF and BAFF receptor (BAFF-R) in the thyroid tissue of patients affected with autoimmune thyroid disorders (AITD) or multinodular goiter (MNG) compared with those with normal thyroids. METHODS: Immunohistochemistry was performed using a panel of antibodies against BAFF, BAFF-R, CD3, CD4, CD8, CD20, CD34, CD79a, CD1a, CD68, and CD163 on the thyroid sections of 27 patients affected with Graves' disease (GD), 23 with Hashimoto's thyroiditis (HT), 16 with nontoxic nodular goiter (NTG), and 15 with toxic nodular goiter (TG), submitted to total thyroidectomy between 2000 and 2011. RESULTS: The overall BAFF-R expression in thyrocytes was weak and not different in AITD and MNG. Conversely, a stronger BAFF expression was observed in MNG compared with AITD. BAFF and BAFF-R expression in the infiltrating lymphocytes was higher in AITD compared with MNG. Interestingly, in lymphocytes of follicular-like structures observed in HT, BAFF and BAFF-R were localized in the germinal center or in the mantle, respectively. CONCLUSIONS: This study shows that BAFF and BAFF-R are expressed in the thyrocytes derived from patients with either AITD or MNG, in addition to the expected expression of BAFF and its receptor in the infiltrating immune cells of GD and HT. These findings suggest a possible involvement of BAFF and its receptors in the pathophysiology of AITD.

Levothyroxine dose adjustment in hypothyroid women achieving pregnancy through IVF.

OBJECTIVE: About one out of two women with primary hypothyroidism has to increase the dosage of exogenous levothyroxine (L-T4) during pregnancy. Considering the detrimental impact of IVF on thyroid function, it has been claimed but not demonstrated that L-T4 dose adjustment may be more significant in hypothyroid women who become pregnant after IVF. DESIGN: Retrospective cohort study. METHODS: Hypothyroid-treated women who achieved a live birth through IVF were reviewed. Women could be included if thyroid function was well compensated with L-T4 before the IVF cycle (i.e., serum TSH <2.5  mIU/l and serum free T4 within the normal range). Serum TSH and dose adjustment were evaluated at five time points during pregnancy. The trimester ranges for serum TSH considered as reference to adjust L-T4 therapy were 0.1-2.5  mIU/l for the first trimester, 0.2-3.0  mIU/l for the second trimester, and 0.3-3.0  mIU/l for the third trimester. RESULTS: Thirty-eight women were selected. During the whole pregnancy 32 women (84%; 95% CI: 72-96%) required an increase in the dose of L-T4. In most cases (n=28), this occured within the first 5-7 weeks of gestation (74%, 95% CI: 58-85%). At 5-7 weeks of gestation, the median (interquartile range) increase of L-T4 dose for the whole cohort was 26% (0-50%). At 30-32 weeks, it was 33% (14-68%). In order to identify predictive factors of dose adjustment, we compared women who did (n=28) and did not (n=10) adjust L-T4 dosage at 5-7 weeks' gestation. Significant differences emerged for thyroid autoimmunity prevalence and for the distribution of hypothyroidism aetiology. CONCLUSIONS: The vast majority of hypothyroid-treated women who achieve pregnancy through IVF need an increase in the L-T4 dose during gestation. This requirement tends to occur very early during gestation.

Impact of estrogen and progesterone receptor expression on the clinical and molecular features of papillary thyroid cancer.

BACKGROUND: Thyroid cancer is highly prevalent in women during the fertile age, which suggests a possible impact of hormonal and reproductive factors. METHODS: We studied the expression of estrogen receptor α (ERα or ESR1) and progesterone receptor (PR or PGR) in 182 female and male patients with papillary thyroid cancer and correlated it to clinical and molecular features. RESULTS: ERα and PR expression was found in 66.5 and 75.8% of patients respectively and was significantly correlated with larger tumor size and with a non-incidental diagnosis. Moreover, a trend toward a higher prevalence of local metastases was observed in ER- and PR-expressing tumors, which possibly indicates a more aggressive behavior. Interestingly, the occurrence of the 'receptor conversion' phenomenon, which has already been reported to have a negative prognostic effect in breast cancer, was demonstrated for the first time in thyroid tumors. Indeed, almost all of the ERα-positive primary tumors analyzed had ERα-negative metastatic lymph nodes. At the genetic analyses, BRAF(V600E) mutation was detected in 23.2% of the tumors and had a higher prevalence in larger tumors and in those with a stronger ERα or PR staining. CONCLUSIONS: The whole of the findings reported in the present study argue for an association between ERα and PR sex hormone receptor expression and a more aggressive presentation. Although no impact on outcome was found, the evaluation of ERα and PR receptor expression could add insights into the biological behavior of tumors and could modify the follow-up, particularly in fertile women affected with persistent disease.

Fetal cell microchimerism: a protective role in autoimmune thyroid diseases.

OBJECTIVE: The physiological persistence of fetal cells in the circulation and tissue of a previously pregnant woman is called fetal cell microchimerism (FCM). It has been hypothesized to play a role in systemic autoimmune disease; however, only limited data are available regarding its role in autoimmune thyroid disease (AITD). DESIGN: Circulating FCM was analyzed in a large series of previously pregnant women with Graves' disease (GD), Hashimoto's thyroiditis (HT), or no disease (healthy controls (HCs)). To exclude the possible bias related to placental factors, the polymorphic pattern of human leukocyte antigen-G (HLA-G) gene, which is known to be involved in the tolerance of fetal cells by the maternal immune system, was investigated. METHODS: FCM was evaluated by PCR in the peripheral blood, and the Y chromosome was identified by fluorescence in situ hybridization in some GD tissues. HLA-G polymorphism typing was assessed by real-time PCR. RESULTS: FCM was significantly more frequent in HC (63.6%) than in GD (33.3%) or HT (27.8%) women (P=0.0004 and P=0.001 respectively). A quantitative analysis confirmed that circulating male DNA was more abundant in HC than it was in GD or HT. Microchimeric cells were documented in vessels and in thyroid follicles. In neither GD/HT patients nor HC women was the HLA-G typing different between FCM-positive and FCM-negative cases. CONCLUSION: The higher prevalence of FCM in HC as compared to GD and HT patients suggests that it plays a possible protective role in autoimmune thyroid disorders. Placental factors have been excluded as determinants of the differences found. The vascular and tissue localization of microchimeric cells further highlights the ability of those cells to migrate to damaged tissues.

Statins may increase the risk of liver dysfunction in patients treated with steroids for active graves' orbitopathy.

CONTEXT: Intravenous glucocorticoids (IVGC) administered at high doses for the treatment of active moderate-severe Graves' orbitopathy (GO) may induce liver toxicity. Cumulative doses should not exceed 8 g and strict monitoring of liver function is recommended to avoid potentially life-threatening side effects. The 3-hydroxy-3-methylglutaryl-coenzyme reductase inhibitors, also known as statins, are employed to prevent major cardiovascular events. Patients with active GO, requiring immunosuppression with IVGC, are often treated with statins also. OBJECTIVE: We studied a 64-year-old man and a 58-year-old woman who developed significant liver toxicity after moderate doses of IVGC (methylprednisolone 2.3 g and 5 g in patients 1 and 2, respectively) and concomitant administration of statins. DESIGN AND INTERVENTION: Liver function tests were monitored every two weeks. Hepatitis virus markers and serology for autoimmune hepatitis were negative. At the occurrence of liver dysfunction (5-fold increase of serum aspartate aminotransferase/alanine aminotransferase concentrations), in patient 1 we stopped simvastatin indefinitely and discontinued IVGC for 2 weeks, whereas in patient 2, ongoing treatment with rosuvastatin was discontinued 3 weeks after IVGC therapy. RESULTS: In patient 1, off simvastatin, liver function remained normal after resuming IVGC. In patient 2, a further increase of the aminotransferase values was observed 3 weeks after IVGC discontinuation, with a progressive normalization only after statin withdrawal. CONCLUSIONS: Our study shows that statins, when concomitantly employed with methylprednisolone, may be a cause of liver dysfunction during IVGC in active GO. An accurate pharmacological history of all patients who are candidates for IVGC treatment is suggested to identify subjects at risk for hepatotoxicity.

Efficacy of B-cell targeted therapy with rituximab in patients with active moderate to severe Graves' orbitopathy: a randomized controlled study.

BACKGROUND: Preliminary studies have shown that rituximab (RTX) is effective in the treatment of active Graves' orbitopathy (GO). METHODS: We conducted a double-blind, randomized trial (European Clinical Trials Database [EudraCT] 2007-003910-33) to compare RTX with iv methylprednisolone (ivMP) in patients with active moderate to severe GO. Thirty-two patients were randomized to receive either ivMP (7.5 g) or RTX (2000 or 500 mg). The primary end point was the decrease of the clinical activity score of 2 points or to less than 3 at week 24. Changes of proptosis, lid fissure, diplopia and eye muscle motility, and quality of life score were secondary end points. The number of therapeutic responses, disease reactivation, and surgical procedures required during follow-up and the patients' quality of life were also assessed. RESULTS: The clinical activity score decreased with both treatments but more after RTX at 16, 20, and 24 weeks (P < .04, P < .02, P < .006, respectively), whether 1000 mg RTX twice or 500 mg RTX once was used (P = NS). At 24 weeks 100% of RTX patients improved compared with 69% after ivMP (P < .001). Disease reactivation was never observed in RTX patients but was observed in five after ivMP. Patients treated with RTX scored better motility at 52 weeks in both the right (P = .014) and the left eye (P = .026). Overall rehabilitative surgical procedures carried out during follow-up (at 76 wk) were 12 in 16 ivMP patients and 5 in 15 RTX patients (P = .049). CONCLUSIONS: The results of this trial confirm preliminary reports on a better therapeutic outcome of RTX in active moderate to severe GO, when compared with ivMP, even after a lower RTX dose. The better eye motility outcome, visual functioning of the quality of life assessment, and the reduced number of surgical procedures in patients after RTX seem to suggest a disease-modifying effect of the drug.

Feasibility study for the introduction of a new treatment method for benign thyroid nodules in a teaching and research hospital.

RATIONALE, AIMS AND OBJECTIVES: Numerous scientific publications have confirmed that percutaneous laser thermal ablation (LTA) represents a possible therapeutic option in selected patients with benign thyroid nodules. A study was carried out to evaluate the feasibility of adopting the LTA technique to treat benign thyroid nodules in a teaching and research hospital in northern Italy. METHODS: A cost analysis from a company's perspective determined the impact of adoption of the new technique on the overall Hospital budget, considering currently available equipment, infrastructure and personnel, equipment costs and treatment tariffs. RESULTS: The cost analysis shows that, strictly from an economic point of view, any provision of the LTA technique will result as a loss on the Hospital's balance sheet. However, it does not estimate the extent of the impact on the overall budget because it did not evaluate the savings that such a technique would make with respect to alternative therapeutic treatments. Therefore, the Hospital policy management decided to extend the current agreement with a private authorized health care structure that already carries out LTA. Also, although difficult to express in economic terms, this new technique would undoubtedly raise the profile and enhance the reputation of the Hospital. CONCLUSIONS: Using the new technique in these patients could cut costs for the entire regional health care system, widen the experience of the Hospital's endocrinology team and offer the potential for the procedure also to be provided by operators on a freelance basis within the Hospital.

Ultrasound-guided percutaneous ethanol injection in papillary thyroid cancer metastatic lymph-nodes.

UNLABELLED: Post-operative neck nodal metastases are detected in 9-20 % of papillary thyroid cancer (PTC). Ultrasound-guided ethanol injection (UPEI) has been used with promising results in the treatment of PTC patients with limited number of lymph-node metastases. CLINICAL CASE: We report the imaging and biochemical documentation of UPEI results in four metastatic neck lymph-nodes of papillary thyroid-cancer. A significant reduction both in the diameter of the lymph-nodes and in the serum thyroglobulin levels were observed in all cases and have been reported in a step-by-step sequence. CONCLUSION: the UPEI treatment is a simple and suitable tool for the treatment of PTC cervical lymph-node metastases.

Therapeutic outcomes of high-dose intravenous steroids in the treatment of dysthyroid optic neuropathy.

BACKGROUND: While pulsed intravenous methylprednisolone (iv-MP) has been shown to be effective and well tolerated in moderate to severe Graves' orbitopathy (GO), limited data are available on dysthyroid optic neuropathy (DON). The objective of this retrospective study was to investigate the efficacy of iv-MP in the treatment of DON and to seek parameters predictive of response. METHODS: Twenty-four DON patients (40 eyes) treated with iv-MP from 2007 to 2012 were included in the study. Concurrent neurological or ophthalmologic diseases or signs of corneal exposure were considered as exclusion criteria. Iv-MP was administered daily for three consecutive days and repeated the following week. At six months, eyes not requiring surgery to preserve visual function were considered as responsive to treatment. Visual acuity, color sensitivity, visual field, and optic discs were analyzed at two and four weeks, and at 3, 6, and 12 months after treatment. Activity of GO was graded using a clinical activity score (CAS). Visual and clinical characteristics of the eyes responsive to iv-MP were studied by comparison to those of nonresponsive eyes. RESULTS: At six months, 17 of 40 (42.5%) eyes had complete visual recovery and were spared from surgical decompression. At two weeks, visual acuity, color sensitivity, and visual field improved significantly in almost all eyes, but GO inactivated (CAS<4) only in the eyes that permanently responded to iv-MP (p<0.01). The CAS at two weeks was a good predictor of response (cutoff ≥4; 66.7% sensitivity, 76.9% specificity). Optic disc swelling at diagnosis was highly predictive for unresponsiveness to iv-MP (34% sensitivity, 100% specificity). At baseline, high CAS (cutoff >5; 40.2% sensitivity, 94.1% specificity) and severely altered visual field mean defect (cutoff ≤6.31 dB; 73.9% sensitivity, 58.8% specificity) were associated with unresponsiveness to steroids. No major side effects were observed. CONCLUSIONS: High-dose iv-MP was effective in permanently restoring visual function in about 40% of the eyes treated. When successful, it generally induced inactivation of the orbital disease within two weeks and normalization of visual function within one month. The presence of optic disc swelling at diagnosis and persistent active disease at two weeks were good predictors of unresponsiveness to steroids.

Incidence of elevation of serum thyroid-stimulating hormone during controlled ovarian hyperstimulation for in vitro fertilization.

OBJECTIVE: To evaluate the rate of euthyroid women encountering an elevation of serum TSH above the threshold of 2.5 mIU/L during controlled ovarian hyperstimulation (COH) for IVF. STUDY DESIGN: Six-month prospective cohort study on 175 consecutive euthyroid women undergoing their first IVF cycle. Serum TSH assessments were performed before COH, at the time of hCG administration and at +16 days after hCG administration. Women were eligible if serum TSH tested the month preceding the IVF cycle was 0.4-2.5 mIU/L. A history of thyroid disorders was an exclusion criterion. RESULTS: Serum concentrations of TSH at the three scheduled assessments were 1.5±0.5, 2.2±1.0 and 2.1±1.1 mIU/L, respectively. A statistically significant increase occurred between basal levels and levels at the time of hCG administration (p<0.001). Afterwards, levels remained stable (p=0.49). Serum TSH at the time of hCG administration exceeded the threshold of 2.5 mIU/L in 61 subjects, corresponding to 35% (95% CI: 28-42%). At +16 days after hCG administration, this event was observed in 47 subjects (27%, 95% CI: 21-34%). Baseline characteristics of women who did and did not exceed the threshold were similar apart from basal serum TSH, which was higher in the former group. The OR was 7.6 (95%CI: 2.9-20.2) per mIU/L (p<0.001). Cycle outcome and pregnancy rate were also similar. CONCLUSION: Serum TSH exceeds the threshold of 2.5 mIU/L during COH in one out of three women who are euthyroid prior to enter an IVF cycle. Further evidence is warranted to elucidate the clinical relevance of our findings.