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Objective: To study the endocrine pancreas' function in transfusion-dependent β-thalassemia (β-TDT) patients with a normal glucose tolerance test (NGT) and hypoinsulinemia. In addition, the prospective long-term follow-up using an annual oral glucose tolerance test (OGTT) to detect any abnormality of glucose metabolism. Patients and methods: Seven β-TDT patients (mean age 22.4 ± 4.2 years) with NGT and inadequate insulin response (hypoinsulinemia) to OGTT were referred for a second opinion to an Italian Centre. Results: The first-phase insulin response (FPIR), expressed as the sum of 1 and 3 minutes insulin, to intravenous glucose tolerance test (IVGTT), was between the 1st and 3rd percentile in two patients and between the 3rd and 10th percentile in five. The results were not associated with β-cell autoimmunity. After 43 ± 26 months (range 11 - 80 months) of follow-up, two patients developed impaired glucose tolerance (IGT), three both IGT and impaired fasting glucose (IFG) and two overt diabetes mellitus (DM). Interestingly, the patients who developed DM had, at baseline, the lowest value of the insulinogenic index (IGI: 0.08 and 0.25), defined as the ratio of the increment of plasma insulin to plasma glucose during the first 30 minutes after OGTT. Moreover, a significant correlation was found between the IGI at baseline and at follow-up in the patients who developed IGT with or without IFG (R= 0.927; P: 0.023). A significant reduction of Matsuda insulin sensitivity index (ISIM) and Insulin Secretion-Sensitivity Index-2 (ISSI-2) was documented in the study cohort at the diagnosis of IFG, IGT, and DM. There was a significant inverse correlation between ISSI-2 and area under the curve plasma glucose (AUC-PG). Conclusions: These data demonstrated, for the first time, progressive deterioration in glucose homeostasis in β-TDT subjects with NGT and hypoinsulinemia and that the ISSI-2 index may be a valuable parameter to identify patients at high risk for developing glucose dysregulation. © 2021 Universita Cattolica del Sacro Cuore. All rights reserved.

Background: Data on the prevalence and type of endocrine disorders in β-thalassemia intermedia (β-TI) patients are scarce. This multicenter study was designed to determine the prevalence of endocrine complications and the associated risk factors in a large group of β-TI patients. Methods: In this cross-sectional multicenter study, 726 β-TI patients, aged 2.5–80 years, registered at 12 thalassemic centers, from nine countries, were enrolled during 2017. In a subgroup of 522 patients (mean age 30.8 ± 12.1; range: 2.5–80 years) from Qatar, Iran, Oman, Cyprus, and Jordan detailed data were available. Results: Overall, the most prevalent complications were osteopenia/osteoporosis (22.3%), hypogonadism (10.1%), and primary hypothyroidism (5.3%). In the subgroup multivariate analysis, older age was a risk factor for osteoporosis (Odds ratio: 7.870, 95% CI: 4.729–13.099, P < 0.001), hypogonadism (Odds ratio: 6.310, 95% CI: 2.944–13.521, P < 0.001), and non-insulin-dependent diabetes mellitus (NIDDM; Odds ratio: 17.67, 95% CI: 2.217–140.968, P = 0.007). Splenectomy was a risk factor for osteoporosis (Odds ratio: 1.736, 95% CI: 1.012–2.977, P = 0.045). Hydroxyurea was identified as a “protective factor” for NIDDM (Odds ratio: 0.259, 95% CI: 0.074–0.902, P = 0.034). Conclusions: To the best of our knowledge, this is the largest cohort of β-TI patients with endocrine disorders evaluated in extremely heterogenic thalassemic populations for age, clinical, hematological, and molecular composition. The study demonstrates that endocrine complications are less common in patients with β-TI compared with β-TM patients. However, regular monitoring with timely diagnosis and proper management is crucial to prevent endocrine complications in β-TI patients. © 2019, Springer Science+Business Media, LLC, part of Springer Nature.

At present, assessment of haemoglobin A1c (HbA1c) is widely used for the diagnosis and monitoring of treatment in diabetes mellitus (DM). However, the HbA1c level is affected by many factors such as those influencing the lifespan of red blood cells and the structure, function and amount of normal HbA. Therefore, the clinical significance of HbA1c assessment in thalassemia patients needs careful consideration, especially in transfusion dependent thalassemia patients (TDT) in whom circulating Hb is that of blood donors. Preliminary reports have documented that HbA1c estimation in efficiently transfused patients seems valuable in diagnosis and monitoring of treatment in DM and other glucose disturbances in TDT patients. Herein, a short review of HbA1c measurement in anemias, blood transfusions and hemoglobinopathies, and the debate of the credibility of Hb A1c assessment in TDT patients is reported. Copyright© of YS Medical Media ltd.

Summary. The current outbreak of infections with SARS-CoV-2 is defined as Coronavirus Disease 2019 (COVID-19). The clinical symptoms of COVID-19 include fever, fatigue, cough, breathing difficulty that may lead to respiratory distress; a small population of patients may have diarrhea, nausea or vomiting. The highest infection rate occurs in adults; however, neonates, children, and adolescents can also be infected. As the outbreak continues to spread worldwide, attention has switched toward determinants of clinical manifestations and disease severity. The situation surrounding the outbreak is rapidly evolving and the information and recommendations are changing as new information becomes available. This paper summarises the current findings (April 3,2020) from a systematic literature review on the current knowledge of COVID-19 in adolescents (10-19 years according to the WHO definition) and reports the preliminary epidemiological data stated by the Italian National Institute of Health. (www.actabiomedica.it). © Mattioli 1885.

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. (www.actabiomedica.it). © Mattioli 1885.

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 β- 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. © 2019, Mattioli 1885. All rights reserved.

Background: Transfusion-dependent β-thalassemia (TDT) is associated with several complications necessitating a multidisciplinary approach for diagnosis, treatment and follow-up. Hypogonadism in female TDT patients is one of the most common endocrine complications, requiring hormone replacement therapy (HRT) throughout reproductive life. Little is known about the balance of benefits versus risks of treatment with sex steroids. Aim: The aim of this manuscript is to review the action and the associated adverse effects of HRT in hypogonadal TDT females. Design: Retrospective medical database records from a single centre, over a period of 38 years (January 1980 to June 2018), were reviewed. Study population: Forty-two cases of hypogonadism in TDT females followed in a pediatric and adolescent outpatient clinics, were in included in the study. Methods: Auxological, clinical, laboratory, hormonal and imaging investigations were reviewed, as well as all adverse events registered during HRT. Main results: In general, HRT was safe for most patients. There were few minor side effects and a couple of rare but serious adverse events. Conclusions: The study provides a representative clinical profile of long-term effects of HRT in hypogonadal adolescents and young adult TDT women. Our results highlight also the need for further research in other areas for which HRT may have a role. We hope this will contribute to a wider understanding, and potential improvement, of patient safety and quality of life. (www.actabiomedica.it). © Mattioli 1885.

In the last five decades an increasing number of studies and clinical reports demonstrated the importance of testicular volume assessment in pediatric and adolescent population. Reliable and accurate determination of testicular volume (TV) through infancy and adolescence is of great importance for assessing normal pubertal development to diagnose disturbances in development and to suspect certain genetic and endocrine diseases. Various approaches are available for the assessment of TV, including orchidometry, rulers, callipers, and ultrasonography (USG). Our report focuses on the importance of the evolution of TV from birth to adulthood and debates the main factors influencing the accuracy of different TV measurements. We endorse that any method for the evaluation of TV must satisfy certain criteria: a. be applicable to persons of all ages from pre-adolescence, through the pubertal spurt to full maturity, b. be simple to use, c. be free from observer error as possible, and d. have a high degree of correlation with other observable developmental characteristics. Copyright© of YS Medical Media ltd.

Summary. Juvenile fibromyalgia syndrome (JFMS) is a chronic condition characterized by symptoms of chronic diffuse musculoskeletal pain and multiple painful tender points on palpation. It is often accompanied by fatigue, disorders of sleep, chronic headaches, irritable bowel syndrome, and subjective soft tissue swelling. The complexity of the presenting clinical picture in JPFS has not been sufficiently defined in the literature. Similarities to adult fibromyalgia syndrome in JFMS are often difficult to compare, because many of the symptoms are “medically unexplained” and often overlap frequently with other medical conditions. However, a valid diagnosis of JFMS often decreases parents’ anxiety, reduces unnecessary further investigations, and provides a rational framework for a management plan. The diagnostic criteria proposed by Yunus and Masi in 1985 to define JFMS were never validated or critically analyzed. In most cases, the clinical diagnosis is based on the history, the physical examination that demonstrates general tenderness (muscle, joints, tendons), the absence of other pathological conditions that could explain pain and fatigue, and the normal basic laboratory tests. Research and clinical observations defined that JFMS may have a chronic course that impacts the functional status and the psychosocial development of children and adolescents. This paper briefly reviews the existing knowledge on JFMS focusing on the diagnosis, clinical and the epidemiological characteristics in children and adolescents for better understanding of this disorder. (www.actabiomedica.it). © Mattioli 1885.

Management of hypoparathyroidism (hypoPT), depends on the etiology and the severity of hypocalcemia. Treatment goals include control of hypocalcemic symptoms preserving serum calcium in the low-normal range and phosphate in the high normal range. While correction of serum calcium to low-normal range does not fully correct mineral and bone metabolism it may be associated with increased risk of complications such as nephrolithiasis, nephrocalcinosis and soft tissue calcifications. Therefore, it is imperative to find out ways to individualize treatment of patients with hypoPT to achieve the best prognosis while minimizing complications. Replacement therapy with recombinant human PTH (rhPTH) was recently tested for optimizing treatment of hypoPT in a small number of patients. For children and adolescents, further studies are needed to evaluate the long-term effects and safety of rhPTH. In this short review we summarize current knowledge on the management of hypoPT and debate our gaps on the long-term management of children and adolescents with hypoPT. Copyright© of YS Medical Media ltd.

In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it). © Mattioli 1885.

PubMedID: 30657116 In adult thalassemia major (TM) patients, a number of occult and emerging endocrine complications, such as: central hypothyroidism (CH), thyroid cancer, latent hypocortisolism, and growth hormone deficiency (GHD) have emerged and been reported. As the early detection of these complications is essential for appropriate treatment and follow-up, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) promoted a survey on these complications in adult TM patients, among physicians (pediatricians, hematologists and endocrinologists) caring for TM patients in different countries. The data reported by 15 countries are presented.The commonest endocrine complications registered in 3.114 TM adults are CH and GHD (4.6 % and 3.0 %, respectively), followed by latent hypocortisolism (1.2%). In 13 patients (0.41%) a cytological papillary or follicular thyroid carcinoma was diagnosed in 11 and 2 patients, respectively, and a lobectomy or thyroidectomy was carried out. Of 202 TM patients below the age of 18 years, the reported endocrine complications were: GHD in 4.5%, latent hypocortisolism in 4.4% and central hypothyrodisim in 0.5%. Transition phase was an area of interest for many clinicians, especially as patients with complex chronic health conditions are responding to new treatments extending their lifespan beyond imagination.. In conclusion, our survey provides a better understanding of physicians’ current clinical practices and beliefs in the detection, prevention and treatment of some endocrine complications prevailing in adult TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are recommended. (www.actabiomedica.it). © Mattioli 1885.

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. (www.actabiomedica.it). © Mattioli 1885.

Summary. Significant advances have been made over recent decades in the treatment of childhood malignancies. These advances had an incredible cost, as an increasing number of young survivors suffer subfertility or infertility, because of the high sensitivity of testicular cells, especially the rapidly dividing germ cells, to cyto-toxic drugs and irradiation. Therefore, the impact of treatment on future fertility is of significant concern, both to parents and patients. Assessment of fertility damage in childhood remains problematic. For post-pubertal males, semen analysis represents a good indicator of spermatogenesis and testicular function, and allows for sperm cryopreservation. The available method for prepubertal children is only gonadal tissue cryopreservation. This method is still experimental and raises ethical concerns. Ideally, a multidisciplinary team approach needs to be used in addressing the needs of fertility preservation for this population. Precise knowledge of these issues would help pediatric oncologists and endocrinologists to counsel their patients and inform them for factors and resources that may protect or preserve parenthood options in the future. (www.actabiomedica.it). © Mattioli 1885.

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. © 2017 Informa UK Limited, trading as Taylor & Francis Group.

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.

Context: Over the years lower TSH cutoffs have been adopted in some screening programs for congenital hypothyroidism (CH) worldwide. This has resulted in a progressive increase in detecting additional mild forms of the disease, essentially with normally located and shaped thyroid. However, the question of whether such additional mild CH cases can benefit from detection by newborn screening and early thyroid hormone treatment is still open. Objective: The aim of this study was to estimate the frequency of cases with mild increase of TSH at screening in the Italian population of babies with permanent CH and to characterize these babies in terms of diagnosis classification and neonatal features. Methods: Data recorded in the Italian National Registry of infants with CH were analyzed. Results: Between 2000 and 2006, 17 of the 25 Italian screening centers adopted a TSH cutoff at screening of < 15.0 mu U/mL. It was found that 21.6% of babies with permanent CH had TSH at screening of 15.0 mu U/mL or less, whereas this percentage was 54% in infants with transient hypothyroidism. Among the babies with permanent CH and mild increase of TSH at screening (

Background: In March 2015, the International Network of Clinicians for Endocrinopathies in Thalassemia and Adolescent Medicine (ICET-A) implemented a two-step survey on central adrenal insufficiency (CAI) assessment in TM patients and after analysis of the collected data, recommendations for the assessment of hypothalamic-pituitary- adrenal (HPA) axis in clinical practice were defined. Methods: To ascertain the current practice for assessment of CAI in thalassemia, the Coordinator of ICET-A sent two questionnaires by email: i) The first to evaluate the current interpretation of basal serum cortisol level (first step) and ii) The second to assess the current usage of ACTH test and the variability in practice" (second step). Based on the surveys the core ICET-A group prepared the recommendations for the assessment of suspected CAI in thalassemia (third step). Results: A total of 19 thalassemologists/endocrinologists have participated in the first survey and 35 specialists participated in the second step questionnaire. The study demonstrated a considerable variability in almost all aspects of relevant current criteria used for the diagnosis of CAI. An ROC analysis using peak value > 20 μg/dl (> 550 nmol/L), after ACTH stimulation test, was performed with the aim of identifying the optimal basal serum cortisol cut-off. The optimal threshold that maximizes sensitivity plus specificity for morning basal cortisol against peak post-ACTH value >20 μg/dl (>550 nmol/L) was 10 μg/dl (275 nmol/L). Furthermore, the values associated with the highest negative predictive value (NPV) and highest, positive predictive value (PPV) were 4.20 (115 nmol/L) and 18.45 μg/dl (510 nmol/L), respectively. Surprisingly, 20 specialists in thalassemia working in blood bank, thalassemia centres (day hospital), internal medicine, hematology and onco-hematology had poor knowledge and experience in testing for CAI and stopped filling the questionnaire after the second question. In contrast, 9 endocrinologists (8 pediatricians) and 6 hematologists working in collaboration with endocrinologists completed the questionnaire. Conclusions: While waiting for more extensive adequately powered and targeted studies, physicians should adopt an acceptable policy for accurate assessment of HPA in TM patients. Regular surveillance, early diagnosis, treatment and follow-up in a multi-disciplinary specialized setting are also recommended. The ICET-A recommendations are reported in order to facilitate for interested physicians the approach to a successful assessment of adrenal function in thalassemia. © 2016.

We report final height data of patients with Turner's syndrome collected by the Italian Study Group for Turner's Syndrome. One hundred and thirty-five patients reached their final height during GH therapy with different therapeutic regimens (dose and combination). They were divided into 3 groups: group A, 74 patients with high doses of GH (1 IU/kg/week) for at least 2 yr; group A1, GH alone and estrogen therapy added not before 14 yr of chronological age (47 patients, of whom 30 were treated for >4 yr and 10 for >6 yr); group A2, GH plus ethinyl estradiol (17 patients) or GH plus oxandrolone (10 patients); group B, 51 patients with low doses of GH (0.5 IU/kg-week) and high doses of GH for less than 2 yr; and group C, 10 patients with high doses of GH with spontaneous menarche. In contrast to the patients of groups B and C, the patients of group A showed a significantly higher final height (mean, 147.5+/-6.5 cm) than their projected height (mean, 142.9+/-6.4 cm). They showed also a significantly higher final height compared to the subjects of groups B (mean, 145.6+/-5.7 cm) and C (mean, 143.0+/-5.3). Among the patients of group A, the best results were obtained in the patients of group A1 treated with GH alone at high doses and for a longer period (4 yr, 149.3+/-6.4 cm; 6 yr, 153.8+/-4.0 cm). Karyotype, GH secretion, and birth weight did not influence the efficacy of GH therapy. A low target height and a high prevalence of a spontaneous ovarian activity or menarche may negatively influence the effect of GH therapy. Estrogens did not improve final height when added to GH therapy. The use of small doses of oxandrolone was not effective in our experience. GH therapy provides a satisfactory auxological result, especially with high doses of GH alone, given for a long period of time. Optimization of the treatment would seem to require the identification of the ideal age for starting therapy, and this is only possible with a specially designed multicenter study.