A prospective guide for clinical implementation of selected OGTT- derived surrogate indices for the evaluation of ß- cell function and insulin sensitivity in patients with transfusion-dependent ß- thalassaemia.

The gold standard for the measurement of insulin secretion is the hyperglycemic clamp and for insulin sensitivity the hyperinsulinemic euglycemic clamp, respectively. A number of surrogate indices, derived from plasma glucose and insulin levels at a fasting state or after oral glucose load, have been proposed to estimate ß-cell response, and the ability of ß-cells to compensate for changes of insulin sensitivity by modulating insulin secretion (disposition index). Starting from the current recommendations for the annual screening of glucose dysregulation in patients with transfusion dependent ß-thalassemia (ß-TDT), this article summarizes the most frequently used indirect indices of insulin secretion and resistance derived from the oral glucose tolerance test (OGTT) and discusses the strengths and weaknesses of selected indices and the basic concepts underlying each method for the appropriate evaluation of glucose regulation. Basal indices for ß-cell function and insulin sensitivity, albeit simple and cheap, have limited usefulness due to a high coefficient variation and the lack of data about response to glucose load. Therefore, measurement of indices during an OGTT, despite being costly and time-consuming, is suggested since it can detect, even subtle, dynamic changes in insulin secretion and glucose handling. In patients with ß-TDT, the indices derived from OGTT may offer an additional factor to evaluate the efficiency of iron chelation therapy and detect patients who may need intensification of iron chelation therapy and/or pharmacological intervention.

A Multicenter ICET-A Study on Age at Menarche and Menstrual Cycles in Patients with Transfusion-Dependent Thalassemia (TDT) who Started Early Chelation Therapy with Different Chelating Agents.

Introduction: To evaluate the effect of early chelation therapy (≤ 3 years) with a variety of chelating agents on age at menarche and menstrual characteristics in patients with transfusion-dependent thalassemia (TDT). Design: A retrospective multicenter study promoted by the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A). Setting: Eight of 13 International Thalassemia Centers (61.5%) in the ICET-A Network participated. Patients: Fifty-seven female TDT patients, aged 11 to 26 years, and with early iron chelation therapy, were eligible for the present study. They were enrolled from one center from Iran (33 patients), 3 centers from Bulgaria (9), 1 from Greece (8), one from Oman (4), 1 from Cyprus (2), and 1 from Italy (1). Seven patients were excluded, four still prepubertal (age 12-14 years) and 3 with primary amenorrhea. Therefore 50 patients were finally enrolled. Results: All fifty TDT patients developed spontaneous menarche at a mean age of 14.2 ± 2.24 years (range 9 - 20). A significant positive correlation was observed between age at menarche and serum ferritin levels (r: 0. 41, p=0.005). Regular menstrual cycles were reported from 32 (64%) patients, of whom 28 (83.3%) get menarche at age ≤ 14 years. Complications were more frequent in patients older than 14 years at menarche and in those with secondary amenorrhea. Conclusions: Age at menarche greater than 14 years was a forerunner of menstrual irregularities and associated complications in 36% of patients despite precocious chelation therapy. The poor adherence to treatment, to be demonstrated in future studies, could explain the finding.

Retrospective study on long-term effects of hormone replacement therapy (HRT) and iron chelation therapy on glucose homeostasis and insulin secretion in female ß- thalassemia major (ß-TM) patients with acquired hypogonadotropic- hypogonadism (AHH).

BACKGROUND AND AIM: Hypogonadism and abnormalities of glucose homeostasis, resulting from iron-induced pituitary and pancreatic ß-cell dysfunction respectively, are the most frequently reported endocrine abnormalities in patients with ß-thalassemia major (ß-TM), also identified as transfusion-dependent thalassemia (TDT). STUDY DESIGN AND PATIENTS: The aim of the present retrospective study was to evaluate the long-term effects of hormone replacement therapy (HRT) on glucose metabolism and insulin secretion/sensitivity during 3-h oral glucose tolerance test (OGTT) in adolescent and young ß-TM women with acquired hypogonadototropic -hypogonadism (AHH).Twelve hypogonadal ß-TM females with AHH on HRT were followed for 8.26 ± 1.49 years. RESULTS: At baseline, 10 patients (83.3%) had normal OGTT, 1 patient presented with impaired glucose tolerance (IGT) and 1 patient had an isolated PG level of 165 mg/dL at 1-h during OGTT (H-NGT). At last evaluation, 7 patients (58.4 %) had normal OGTT, while 5 patients (41.6%) had abnormal OGTT. Reduced insulin sensitivity and impaired first-phase insulin secretion were also documented. Three of 4 ß-TM patients on treatment with estradiol hemihydrate MX 50 patches plus oral medroxyprogesterone acetate (MPA), associated with a very effective iron chelation therapy, maintained normal glucose tolerance from baseline to last evaluation. Significant adverse events due to HRT or additional endocrine complications were not documented in any cases during the follow-up. CONCLUSION: Deterioration of glycemia (dysglycemia) occurred in 45.4% (5/11) of thalassemic females on long-term HRT. Additional studies are needed to elucidate the validity of our preliminary observations.

Longitudinal study of ICET-A on glucose tolerance, insulin sensitivity and ß-cell secretion in eleven ß-thalassemia major patients with mild iron overload.

BACKGROUND: Iron chelation therapy (ICT) is the gold standard for treating patients with iron overload, though its long-term effects are still under evaluation. According to current recommendations regarding  transfusion-dependent  (TD)  ß-thalassemia major (ß-TM) patients, their serum ferritin (SF) levels should be maintained below 1,000 ng/mL and ICT should be discontinued when the levels are <500 ng/mL in two successive tests. Alternatively, the dose of chelator could be considerably reduced to maintain a balance between iron input and output of  frequent transfusions. STUDY DESIGN: Due to the paucity of information on long-term effects of ICT  in ß-TM with low SF levels on glucose homeostasis, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) promoted a retrospective and an ongoing prospective observational study with the primary aim to address the long-term effects of ICT on glucose tolerance and metabolism (ß-cell function and peripheral insulin sensitivity) in adult ß-TM patients with persistent SF level below 800 ng/mL. PATIENTS AND METHODS: 11 ß-TM patients (mean age: 35.5 ± 5.5 years; SF range: 345-777 ng/mL) with normal glucose tolerance test (OGTT) or abnormal glucose tolerance (AGT) for a median of 5.3(1.1-8.3) years. RESULTS: Abnormal glucose tolerance (AGT) was observed in 7 patients (63.6%) at first observation and ) persisted in 6 patients (54.5%) at last observation. None of them developed diabetes mellitus. AGT was reversed in two patients. One patient with NGT developed early glucose intolerance (1-h PG ≥155 and 2-h PG <140 mg/dL). Three out of  5 patients with isolated impaired glucose tolerance presented a variation of  ATG. Stabilization of low indices for ß-cell function and insulin sensitivity/resistance was observed. One patient developed hypogonadotrophic hypogonadism. Three out of 6 patients with SF below 500 ng/dL had hypercalciuria. CONCLUSION: Despite low SF level, the burden of endocrine complications remains a challenge in ß-TM patients. The ability to keep iron at near "normal" level with acceptable risks of toxicity remains to be established.

Glucose Homeostasis and Assessment of ß-Cell Function by 3-hour Oral Glucose Tolerance (OGTT) in Patients with ß-Thalassemia Major with Serum Ferritin below 1,000 ng/dL: Results from a Single ICET-A Centre.

Aims: The primary aim of this study was to evaluate retrospectively the glucose homeostasis and surrogate indices of insulin sensitivity and resistance, during a 3-hour oral glucose tolerance test (OGTT), in ß-thalassemia major patients (ß-TM) with serum ferritin (SF) below 1,000 ng/mL. Patients and methods: The retrospective cohort study evaluated the medical records of 24 ß-TM patients from 2010 to 2022. At the year of study the mean age of patients was 31.0 ± 4.1 (20-37.11) years; 13 (54.1%) were females. The most commonly used iron chelator was deferoxamine (DFO: 75%), followed by deferiprone (DFP:12.5%) and deferasirox (DFX: 12.5%). Insulin sensitivity and resistance indices were derived from OGTT. A liver iron concentration (LIC) < 3 mg/g d.w. and a global heart T2* value > 20 ms were considered as conservative cut-off values for insignificant iron overload (IOL). Results: The mean SF levels in the whole study cohort population at the age of evaluation was 549.6 ± 232.3 ng/mL. Based on the SF levels, two groups were identified: Group A (N = 14) < 500 ng/mL and Group B (N=10) 500-1,000 ng/mL. Normal glucose tolerance (NGT) during OGTT was observed in 4 patients of Group A (28.5 %) and in 5 patients of Group B (50%) (P: 0.29). The remaining 15/24 patients (62.5%) had glucose dysregulation (GD). The mean age at starting iron chelation therapy (ICT) and the mean SF peak in Group A versus Group B were significantly higher in group A. The GD was associated with significantly attenuated IGI (first phase of insulin response) and impaired oral disposition index (oDI). Hypogonadotropic hypogonadism (HH) was the most common associated endocrine complication in both groups of patients. Conclusions: This study showed that efficient iron chelation monotherapy in patients with ß-TM and SF < 1,000 ng/ml did not entirely prevent glucose metabolism disorders, abnormalities of insulin secretion and sensitivity, and development of acquired hypogonadism.

Screening for glucose dysregulation in ß-thalassemia major (ß-TM): An update of current evidences and personal experience.

Glucose dysregulation (GD) in patients with ß-thalassemia major (ß-TM) usually develops gradually. Prediabetes consists of two abnormalities, impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), the latter detected by a standardized oral glucose tolerance test (OGTT). Diagnosis of prediabetes is essential for an early identification of high-risk individuals who will benefit from intensive iron chelation therapy and lifestyle modification. Therefore, patients with ß-TM should undergo annual screening for glucose abnormalities, according to international recommendations, starting from the age of 10 years. OGTT remains the preferred screening method as it is more sensitive for GD than fasting plasma glucose (FPG), although it is poorly reproducible. The use of HbA1c measurement has limited use as it is generally considered unreliable in patients with thalassemia. Continuous glucose monitoring system (CGMS) is an accurate method to detect the variability of glucose fluctuations and offers the opportunity for better assessment of glucose homeostasis in a selected group of ß-TM patients. Pancreatic Magnetic Resonance Imaging (MRI) associated with insulin secretion-sensitivity index-2 (ISSI-2) could be a complementary test, minimizing the necessity for OGTT and identifying high-risk patients before irreversible pancreatic damage occurs. The aims of this short report are to give practical guidance for an early identification of GD in ß-TM patients, to summarise our experience, and to offer an impetus for further research in the field.

A Retrospective Long-Term Study on Age at Menarche and Menstrual Characteristics in 85 Young Women with Transfusion-Dependent ß-Thalassemia (TDT).

BACKGROUND: Menarche is an important milestone in a feminine reproductive life, and regular menstrual cycles reflect normal functioning of the hypothalamic-pituitary-ovarian axis, a vital sign of women's general health. AIM OF THE STUDY: We explored the age at menarche and the following menstrual cycles characteristics among 85 unmarried Transfusion-Dependent ß-Thalassemia (TDT) women, born between 1965 and 1995, concerning iron chelation therapy (ICT) with desferrioxamine (DFO) and nutritional status, assessed by body mass index (BMI). RESULTS: 53 adolescents who had begun ICT before the age of 10 years experienced menarche at 13,7 ± 1,6 years (mean ± DS), whereas 32 who began treatment after ten years experienced menarche significantly later (15.5 ± 1.9 yrs; p: 0.001). At the age of menarche: BMI-Z score (n= 67, -0,09 ±1) was inversely correlated with both age at starting ICT (r = -0,39; p = 0001) and age at menarche (-0,45, p = 0,0001). Serum ferritin levels (SF) were significantly correlated with the age at starting chelation therapy (n = 79; r = 0,34; p = 0,022). In 56 TDT adolescents who developed secondary amenorrhea (SA), the SF levels were significantly higher (4,098 ± 1,907 ng/mL) compared to 23 TDT adolescents with regular menstrual cycles (2,913±782 ng/mL; p = 0,005). Nutritional status of "thinness" at menarche was associated with a lower prevalence of subsequent regular menstrual cycles and a higher prevalence of early SA. CONCLUSION: An early ICT in TDT patients was associated with a normal "tempo" of pubertal onset and a higher frequency of subsequent regular menstrual cycles. In TDT patients, who developed SA, a diagnosis of acquired central hypogonadism was made, mainly due to the chronic exposure to iron overload, however other potential causes linked to nutritional status, deficient levels of circulating nutrients, and the chronic disease itself cannot be fully excluded.

Prevalence, attitude and practice of self-medication among adolescents and the paradigm of dysmenorrhea self-care management in different countries.

Self-medication (SM) is an important worldwide public health issue affecting children and adolescents. The pattern of SM varies in different communities, affected by factors such as age, sex, income, expense, self-care orientation, educational level and medical knowledge. It is a fairly common practice: for minor health problems, it often provides cheap, rapid, and convenient solutions, outside of the health care system of many countries. Painkillers, antipyretics, cough medicines, cold preparations, dermatological products, nutritional supplements and antibiotics are the drugs most frequently used. Potential risks include incorrect self-diagnosis, improper dosage, inappropriate choice of therapy, masking of severe disease and drug interactions. Lack of awareness of warnings and precautions, storage conditions, the recommended shelf-life and adverse reactions increase the risk of side effects. Little is known about the SM of dysmenorrhea by adolescent girls. Attitudes towards treatment are influenced by cultural, ethnic, and religious factors. Some girls discuss dysmenorrhea with family and friends, and the majority may not seek medical advice. As dysmenorrhea is a common problem for adolescents, it is essential that these girls be aware of the normal and abnormal symptoms of menstruation. In the light of these findings, the roles of family, school, health professionals and health authorities are of utmost importance for the implementation of measures to approach this health problem in a more efficient way.

Marital status and paternity in patients with Transfusion- Dependent Thalassemia (TDT) and Non Transfusion-Dependent Thalassemia (NTDT): an ICET - A survey in different countries.

BACKGROUND: More than five decades ago, thalassemia major (TDT) was fatal in the first decade of life. Survival and quality of life have improved progressively thanks to the implementation of a significant advance in diagnostic and therapeutic methods, consisting mainly of a frequent transfusion program combined with intensive chelation therapy. Improvement also includes imaging methods used to measure liver and cardiac iron overload. Improved survival has led to a growing number of adults requiring specialised care and counselling for specific life events, such as sexual maturity and acquisition of a family. AIMS OF THE STUDY: The main aim is to present the results of a survey on the marital and paternity status in a large population of adult males with TDT and NTDT living in countries with a high prevalence of thalassemia and a review of current literature using a systematic search for published studies. RESULTS: Ten out of 16 Thalassemia Centres (62.5%) of the ICET-A Network, treating a total of 966 male patients, aged above 18 years with ß- thalassemias (738 TDT and 228 NTDT), participated in the study. Of the 966 patients, 240 (24.8%) were married or lived with partners, and 726 (75.2%) unmarried. The mean age at marriage was 29.7 ± 0.3 years. Of 240 patients, 184 (76.6%) had children within the first two years of marriage (2.1 ± 0.1 years, median 2 years, range 1.8 - 2.3 years). The average number of children was 1.32 ± 0.06 (1.27 ± 0.07 in TDT patients and 1.47 ± 0.15 in NTDT patients; p: >0.05). Whatever the modality of conception, 184 patients (76.6%) had one or two children and 1 NTDT patient had 6 children. Nine (4.8%) births were twins. Of 184 patients, 150 (81.5%) had natural conception, 23 (12.5%) required induction of spermatogenesis with gonadotropins (hCG and hMG), 8 (4.3%) needed intracytoplasmic sperm injection (ICSI) and 3 adopted a child. 39 patients with TDT and NTDT asked for medical help as they were unable to father naturally: 7 TDT patients (17.9%) were azoospermic, 17 (37.7%) [13 with TDT and 4 with NTDT] had dysspermia and 15 (33.3%) [13 with TDT and 2 with NTDT] had other "general medical and non-medical conditions". CONCLUSIONS: Our study provides detailed information in a novel area where there are few contemporary data. Understanding the aspects of male reproductive health is important for physicians involved in the care of men with thalassemias to convey the message that prospects for fatherhood are potentially good due to progressive improvements in treatment regimens and supportive care.

Current treatment of hypoparathyroidism: Theory versus reality waiting guidelines for children and adolescents.

The diagnosis of hypoparathyroidism(HPT)is readily made in the presence of hypocalcemia with markedly reduced or absent parathormone (PTH) levels. Currently available treatments for HPT include high dose vitamin D (ergocalciferol, D2 and cholecalciferol, D3) or, the active metabolite dihydroxy vitamin D (calcitriol), in addition to calcium supplements.This regimen, if not well monitored, can lead to hypercalciuria, as PTH deficiency impairs renal calcium reabsorption. Thus the goal of treatment, is to maintain serum calcium at the low end of the normal range. Undertreatment can cause symptomatic hypocalcemia, while overtreatment hypercalciuria, which may lead to nephrolithiasis, nephrocalcinosis, and renal insufficiency. At present, there is no consensus on the management of HPT in children and adolescents and only few studies are available on the long term outcome of patients with recombinant HPT treatment. The purpose of this article is to review, in a comprehensive manner, the major aspects of HPT management in children and adolescents waiting for authoritative guidelines for the treatment of HPT in this group of patients. Further research, addressing specific questions for this population are urgently needed to improve long-term safety of patients. Educational interventions are also needed for professionals, parents and patients to enable them to improve knowledge, quality of life and effective management care at home.

Hypogonadism in male thalassemia major patients: pathophysiology, diagnosis and treatment.

Failure of pubertal growth, delay or absence of sexual development, infertility and sexual dysfunction due to hypogonadism and defective spermatogenesis are frequent and well recognized disturbances among male patients with transfusion dependent (TD) thalassaemia major (ß-thal). These problems are attributed mainly to the damage caused by chronic anaemia and the deposition of excess iron in the pituitary gland and testicles. This is a short review of male pubertal disorders in patients with ß-thal written by pediatric endocrinologists and haematologists with an interest and active involvement, in the diagnosis and management of these complications in this group of patients. A vigilant clinical evaluation of growth and puberty, as well as an appropriate hormonal evaluation in poly-transfused (TD ß-thal) patients is strongly recommended for early detection and treatment of endocrine dysfunction. Of crucial importance also, is the implementation of an efficient chelation regime from early life, to prevent severe iron load and permanent damage to the endocrine glands, particularly those responsible for gonadal function.

An ICET- A survey on Hypoparathyroidism in Patients with Thalassaemia Major and Intermedia: A preliminary report.

Hypoparathyroidism (HPT) is a rare disease with leading symptoms of hypocalcemia, associated with high serum phosphorus levels and absent or inappropriately low levels of parathyroid hormone (PTH). In patients with thalassemias it is mainly attributed to transfusional iron overload, and suboptimal iron chelation therapy. The main objectives of this survey were to provide data on the prevalence, demographic and clinical features of HPT in thalassemia major (TM) and intermedia (TI) patients living in different countries, and to assess its impact in clinical medical practice. A questionnaire was sent to all Thalassemia Centres participating to the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescence Medicine (ICET-A) Network.Seventeen centers, treating a total of 3023 TM and 739 TI patients, participated to the study. HPT was reported in 206 (6.8%) TM patients and 33 (4.4%) TI patients. In general, ages ranged from 10.5 to 57 years for the TM group and from 20 to 54 years for the TI group. Of the 206 TM patients and 33 TI patients with HPT, 117 (48.9%) had a serum ferritin level >2.500 ng/ml (54.3% TM and 15.1% TI patients) at the last observation. Hypocalcemia varied in its clinical presentation from an asymptomatic biochemical abnormality to a life-threatening condition, requiring hospitalization. Calcium and vitamin D metabolites are currently the cornerstone of therapy in HPT. In TM patients, HPT was preceded or followed by other endocrine and non-endocrine complications. Growth retardation and hypogonadism were the most common complications (53.3% and 67.4%, respectively). Although endocrine complications were more common in patients with TM, non-transfused or infrequently transfused patients with TI suffered a similar spectrum of complications but at a lower rate than their regularly transfused counterparts.In conclusion, although a large international registry would help to better define the prevalence, comorbidities and best treatment of HPT, through the result of this survey we hope to give a clearer understanding of the burden of this disease and its unmet needs. HPT requires lifelong therapy with vitamin D or metabolites and is often associated with complications and comorbidities.Therefore, it is important for endocrinologists and other physicians, who care for these patients, to be aware of recent advances of this disorder.

Gonadal dysfunction in adult male patients with thalassemia major: an update for clinicians caring for thalassemia.

INTRODUCTION: Hypogonadism is the most frequently reported endocrine complication, affecting 40%-80% of thalassemia major (TM) patients. The prevalence and severity of hypogonadism in TM varies among studies, depending on patients' age, genotype, transfusion frequency and starting age and efficiency of iron chelation. Areas covered: The diagnosis requires careful clinical assessment and appropriate laboratory testing. Its management is more complex compared to other 'classical' causes of hypogonadism because of multiple associated disorders (cardiac, hepatic and endocrine) and other contributing factors basically iron overload and iron toxicity. Expert commentary: Early recognition and treatment of hypogonadism in TM patients is most important to prevent late complications and to enhance the chances of parenthood. The goal of management is to restore deficient glandular function. If fertility is the issue and the testis is under-stimulated because of gonadotropin deficiency, it is possible to induce or restore spermatogenesis with exogenous gonadotropins in some patients. Assisted reproductive techniques may supplementary help to overcome previously untreatable causes of male infertility. These positive achievements should encourage health care providers to pay closer attention to the reproductive health of TM patients. This would involve the collaboration of clinicians caring for thalassemia with endocrinologists and specialists in assisted reproductive technologies.

Review and Recommendations on Management of Adult Female Thalassemia Patients with Hypogonadism based on Literature Review and Experience of ICET-A Network Specialists.

BACKGROUND: Multi-transfused thalassemia major (TM) patients frequently develop severe endocrine complications, mainly due to iron overload, anemia, and chronic liver disease, which require prompt diagnosis, treatment and follow-up by specialists. The most common endocrine complication documented is hypogonadotropic hypogonadism which increases with age and associated comorbidities. It is thus important for physicians to have a clear understanding of the pathophysiology and management of this disorder. Also to be aware of the side effects, contraindications and monitoring of sex steroid therapy. In this paper, practical ICET-A recommendations for the management of hypogonadism in adult females with TM are addressed. METHODS: In March 2015, the Coordinator of the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) conducted a two-step survey to assess the attitudes and practices of doctors in the ICET-A network taking care of adult female TM patients with hypogonadism. They were clinically characterized by the absence of pubertal development or discontinuation or regression of the maturation of secondary sex characteristics, and biochemically by persistent low FSH, LH and estradiol levels. Recently a supplementary survey on adult female hypogonadism in TM was undertaken within the ICET-A network. RESULTS: The completed questionnaires were returned by 16 of 27 specialists (59.2%) following 590 female TM patients over the age of 18 years; 315 patients (53.3%) had hypogonadism, and only 245 (74.6%) were on hormone replacement therapy (HRT). Contraceptive oral pills (COC) were the first treatment choice in 11 centers (68.7%). A wide range of COCs was used with different progestin contents. In general, the patients' compliance to treatment was reported as good in 81.2 % of centers. The frequency of required tests for follow-up HRT, in addition to the regular check-up for thalassemia, was variable in the participating centers. CONCLUSIONS: Doctors taking care of TM patients should have sound knowledge of the pathophysiology of hypogonadism in adult females with TM. They should know the potential effects of HRT including advantages and disadvantages of estrogen and progestins. Moreover, they should keep in consideration the emotional needs of these patients dreaming of attaining a full pubertal development.

Effect of different starting doses of levothyroxine on growth and intellectual outcome at four years of age in congenital hypothyroidism.

To evaluate the effect of different initial levothyroxine (LT4) replacement doses on growth and intellectual outcome in patients with congenital hypothyroidism (CH) detected by neonatal screening program, the longitudinal growth and intelligence quotient (IQ) were assessed and compared at 4 years of age in 83 patients with CH. The patients were divided into three groups according to the initial LT4 dose used: (1) group 1 (n = 42) received the previously recommended dose of 6.0-8.0 microg/kg per day; (2) group 2 (n = 21) received a dose of 8.1-10.0 microg/kg per day; (3) Group 3 (n = 20) a dose of 10.1-15.0 microg/kg per day. The IQ, evaluated by the Wechsler Preschool and Primary Scale of Intelligence test at 4 years of age, was significantly higher in group 3 (IQ 98 +/- 9) compared to group 1 (IQ 88 +/- 13; p < 0.05) but not compared to group 2 (IQ 94 +/- 13). However, the IQs were below the normal range (< 85) in six patients from group 2 (28%), but in none of the patients from group 3 (p = 0.03). Patients from group 3, with severe CH at diagnosis, had an IQ (97 +/- 9) at 4 years of age, which was not different from that of patients from the same group with moderate CH at diagnosis (IQ 99 +/- 9). Similar results were also observed in patients from group 2 however, mean IQ scores in these patients (93 +/- 12) were several points lower than those observed in patients from group 3 (95 +/- 15). After the first month of treatment, optimal serum levels of thyroxine (T4) and free thyroxine (FT4) were achieved in all groups, however, only patients from group 3 were able to normalize thyrotropin (TSH) (group 1, 16.0 +/- 12.0; group 2, 9.2 +/- 10.0; and group 3, 2.4 +/- 3.3 mU/L; p < 0.0001). Twelve patients from group 2 treated with an initial LT4 dose above 9 microg/kg per day were able to normalize TSH levels within the first 3 months of life and this resulted in a better IQ (97 +/- 16) compared to the remaining patients from the same group (IQ 90 +/- 9). In the whole group of 83 patients the IQ at 4 years of age was positively correlated to both initial LT4 dosage (r = 0.27, p < 0.02) and FT4 concentrations after the first month of treatment (r = 0.29, p < 0.02), and negatively correlated to TSH concentrations after the first month of treatment (r = -0.27, p < 0.02). No significant differences were observed in height, weight, head circumference, and bone age maturation among the three groups of patients. No clinical signs or symptoms of overtreatment were observed during follow-up in patients receiving the higher LT4 dosage. Our results indicate that high LT4 starting doses rapidly normalize serum TSH concentrations resulting in an improvement of the IQ at 4 years of age, even in patients with severe CH at diagnosis. Growth and bone age maturation are not affected by such a high dose.