Ovarian reserve and fertility parameters in post-pubertal females with congenital adrenal hyperplasia: a case-control study.

OBJECTIVES: Congenital adrenal hyperplasia (CAH) is an autosomal recessive disorder characterized by impaired activity of the enzyme required for cortisol and aldosterone production, resulting in increased adrenal androgen synthesis. Factors affecting fertility in CAH patients include ambiguous genitalia and their complications, excessive androgen secretion, adrenal progesterone hypersecretion, and various psychosocial factors. Serum anti-Müllerian hormone (AMH) level is used to assess ovarian reserve in women. A few data on serum AMH levels in CAH patients are available in the literature. The aim of the study was to evaluate ovarian reserve in a group of post-menarche females diagnosed with CAH by measuring serum AMH level and assessing the number of antral follicles sonographically. METHODS: A case-control study was conducted on 17 post-pubertal CAH females and 17 age-matched healthy female controls; the mean age of the patient group was 15.09 ± 3.55 years ranging from 11 to 24 years, while the mean age of the control group was 16.04 ± 3.72 years ranging from 12 to 25 years, the mean post-menarchal age of the patients group was 3.29 ± 1.37 years ranging from 1 to 6 years while the mean post-menarchal age of the control group was 4.13 ± 1.62 years ranging from 1 to 9 years. The degree of hirsutism was compared between the two groups according to the modified Ferriman-Gallwey score, clitoral length was assessed using a digital caliber. Serum levels of adrenal androgens in addition to basal levels of serum follicle-stimulating hormone (FSH), luteinizing hormone (LH), estradiol, progesterone, and serum AMH were measured in both groups. RESULTS: Patients had smaller uterine volumes, and smaller ovarian volumes but a comparable number of antral follicles and comparable serum AMH levels relative to controls. CONCLUSIONS: Good compliance with treatment in patients with CAH results in good hormonal control, low risk of PCOS, good fertility parameters, and a good ovarian reserve.

Serum 25-hydroxyvitamin D threshold and risk of rickets in young children: a systematic review and individual participant data meta-analysis to inform the development of dietary requirements for vitamin D.

PURPOSE: The objective of this systematic review was to determine a minimum serum 25-hydroxyvitamin D (25OHD) threshold based on the risk of having rickets in young children. This work was commissioned by the WHO and FAO within the framework of the update of the vitamin D requirements for children 0-3 years old. METHODS: A systematic search of Embase was conducted to identify studies involving children below  4 years of age with serum 25OHD levels and radiologically confirmed rickets, without any restriction related to the geographical location or language. Study-level and individual participant data (IPD)-level random effects multi-level meta-analyses were conducted. The odds, sensitivity and specificity for rickets at different serum 25OHD thresholds were calculated for all children as well as for children with adequate calcium intakes only. RESULTS: A total of 120 studies with 5412 participants were included. At the study-level, children with rickets had a mean serum 25OHD of 23 nmol/L (95% CI 19-27). At the IPD level, children with rickets had a median and mean serum 25OHD of 23 and 29 nmol/L, respectively. More than half (55%) of the children with rickets had serum 25OHD below 25 nmol/L, 62% below 30 nmol/L, and 79% below 40 nmol/L. Analysis of odds, sensitivities and specificities for nutritional rickets at different serum 25OHD thresholds suggested a minimal risk threshold of around 28 nmol/L for children with adequate calcium intakes and 40 nmol/L for children with low calcium intakes. CONCLUSION: This systematic review and IPD meta-analysis suggests that from a public health perspective and to inform the development of dietary requirements for vitamin D, a minimum serum 25OHD threshold of around 28 nmol/L and above would represent a low risk of nutritional rickets for the majority of children with an adequate calcium intake.

Hormonal control during infancy and testicular adrenal rest tumor development in males with congenital adrenal hyperplasia: a retrospective multicenter cohort study.

IMPORTANCE: Testicular adrenal rest tumors (TARTs), often found in male patients with congenital adrenal hyperplasia (CAH), are benign lesions causing testicular damage and infertility. We hypothesize that chronically elevated adrenocorticotropic hormone exposure during early life may promote TART development. OBJECTIVE: This study aimed to examine the association between commencing adequate glucocorticoid treatment early after birth and TART development. DESIGN AND PARTICIPANTS: This retrospective multicenter (n = 22) open cohort study collected longitudinal clinical and biochemical data of the first 4 years of life using the I-CAH registry and included 188 male patients (median age 13 years; interquartile range: 10-17) with 21-hydroxylase deficiency (n = 181) or 11-hydroxylase deficiency (n = 7). All patients underwent at least 1 testicular ultrasound. RESULTS: TART was detected in 72 (38%) of the patients. Prevalence varied between centers. When adjusted for CAH phenotype, a delayed CAH diagnosis of >1 year, compared with a diagnosis within 1 month of life, was associated with a 2.6 times higher risk of TART diagnosis. TART onset was not predicted by biochemical disease control or bone age advancement in the first 4 years of life, but increased height standard deviation scores at the end of the 4-year study period were associated with a 27% higher risk of TART diagnosis. CONCLUSIONS AND RELEVANCE: A delayed CAH diagnosis of >1 year vs CAH diagnosis within 1 month after birth was associated with a higher risk of TART development, which may be attributed to poor disease control in early life.

Analysis of therapy monitoring in the International Congenital Adrenal Hyperplasia Registry.

OBJECTIVE: Congenital adrenal hyperplasia (CAH) requires exogenous steroid replacement. Treatment is commonly monitored by measuring 17-OH progesterone (17OHP) and androstenedione (D4). DESIGN: Retrospective cohort study using real-world data to evaluate 17OHP and D4 in relation to hydrocortisone (HC) dose in CAH patients treated in 14 countries. PATIENTS: Pseudonymized data from children with 21-hydroxylase deficiency (21OHD) recorded in the International CAH Registry. MEASUREMENTS: Assessments between January 2000 and October 2020 in patients prescribed HC were reviewed to summarise biomarkers 17OHP and D4 and HC dose. Longitudinal assessment of measures was carried out using linear mixed-effects models (LMEM). RESULTS: Cohort of 345 patients, 52.2% female, median age 4.3 years (interquartile range: 3.1-9.2) were taking a median 11.3 mg/m2 /day (8.6-14.4) of HC. Median 17OHP was 35.7 nmol/l (3.0-104.0). Median D4 under 12 years was 0 nmol/L (0-2.0) and above 12 years was 10.5 nmol/L (3.9-21.0). There were significant differences in biomarker values between centres (p < 0.05). Correlation between D4 and 17OHP was good in multiple regression with age (p < 0.001, R2 = 0.29). In longitudinal assessment, 17OHP levels did not change with age, whereas D4 levels increased with age (p < 0.001, R2 = 0.08). Neither biomarker varied directly with dose or weight (p > 0.05). Multivariate LMEM showed HC dose decreasing by 1.0 mg/m2 /day for every 1 point increase in weight standard deviation score. DISCUSSION: Registry data show large variability in 17OHP and D4 between centres. 17OHP correlates with D4 well when accounting for age. Prescribed HC dose per body surface area decreased with weight gain.

Ambulatory Duchenne muscular dystrophy children: cross-sectional correlation between function, quantitative muscle ultrasound and MRI.

Duchenne muscular dystrophy (DMD) is a progressive genetic muscle disease. Quantitative muscle ultrasound (US), muscle MRI, and functional tools are important to delineate characteristics of muscle involvement. We aimed to establish correlations between clinical/functional and above-named imaging tools respecting their diagnostic and prognostic role in DMD children. A cross-sectional retrospective study of 27 steroid-naive, ambulant male children/adolescents with genetically-confirmed DMD (mean age, 8.8 ± 3.3 years). Functional performance was assessed using motor function measure (MFM) which assess standing/transfer (D1), proximal (D2) and distal (D3) motor function, and six-minute walk test (6MWT). Imaging evaluation included quantitative muscle MRI which measured muscle fat content in a specific location of right rectus femoris by mDixon sequence. Quantitative muscle US measured right rectus femoris muscle brightness in standardized US image as an indicator of muscle fat content. We found a highly significant positive correlation between the mean MFM total score and 6MWT (R = 0.537, p = 0.007), and a highly significant negative correlation between fat content by muscle US and MFM total score (R = -0.603, p = 0.006) and its D1 subscore (R =-0.712, p = 0.001), and a significant negative correlation between fat content by US and 6MWT (R = -0.529, p = 0.02), and a significant positive correlation between muscle fat content by mDixon MRI and patient's age (R = 0.617, p = 0.01). Quantitative muscle US correlates significantly with clinical/functional assessment tools as MFM and 6MWT, and augments their role in disease-tracking of DMD. Quantitative muscle US has the potential to act as a substitute to functional assessment tools.

Treatment of congenital adrenal hyperplasia in children aged 0-3 years: a retrospective multicenter analysis of salt supplementation, glucocorticoid and mineralocorticoid medication, growth and blood pressure.

Objectives: International guidelines recommend additional salt supplementation during infancy in classic congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency. The influence of corticoid medication and growth has not been assessed. Aim: To investigate the current use of salt supplementation, fludrocortisone (FC) and hydrocortisone (HC) dosage as well as weight, height, BMI and blood pressure (BP) in CAH children aged 0-3 years. Methods: Retrospective multicentre analysis using data from the I-CAH registry. Salt-treated (ST) and non-salt-treated (NST) children were compared regarding FC and HC dosage, weight, height and BP at 0, 3, 6, 9, 12, 18, 24, 30, and 36 months. Results: We analysed 2483 visits of 331 patients born after year 2000 in 13 countries (male, n = 145) with 203 ST patients (61%). NST children had significantly higher FC dosages at 1.5-4.5 months and higher HC dosages until 1.5 months of age. No differences in weight, length and BP between subgroups were observed. Children of the whole cohort showed increased BMI-SDS during the study period and about half of the reported BP readings were >P95. Conclusion: In children treated with additional salt supplementation, FC and HC dosages are lower during the first months of life but without differences in weight, length and BP until 3 years of age compared to NST children. All children showed an increase in BMI-SDS and a high rate of BP readings >P95 until 3 years, indicating the start of weight gain and negative effects on blood pressure already in very early life.

Hypogonadism in the Prader-Willi syndrome from birth to adulthood: a 28-year experience in a single centre.

BACKGROUND: Hypogonadism is a key feature of Prader-Willi syndrome (PWS) but clear strategies for hormone replacement are lacking. OBJECTIVE: To evaluate gonadal status and outcome in patients attending a Scottish PWS clinic from 1991-2019. METHODS: In 93 (35F:56M) patients, median follow-up 11.2 years, gonadal and pubertal status were assessed clinically. Pelvic ultrasound findings and basal/stimulated gonadotrophins were compared with age-matched controls. RESULTS: Females: Of 22 patients aged >11, 9 had reached B4-5, while 5 were still at B2-3, and 6 remained prepubertal. Eight patients experienced menarche aged 9.8-21.4 years, none with a normal cycle. Uterine length and ovarian volumes were normal but uterine configuration remained immature, with low follicular counts. Gonadotrophins were unremarkable, serum estradiol 129 (70 - 520) pmol/L. Only 5 patients received oestrogen replacement. Males: Fifty-four (96%) patients were cryptorchid (9 unilateral). Weekly hCG injections resulted in unilateral/bilateral descent in 2/1 of 25 patients. Of 37 boys aged >11, 14 (9 with failed/untreated bilateral cryptorchidism) failed to progress beyond G1, 15 arrested at G2-3 (testes 3-10 ml), and 8 reached G4-5. Gonadotrophins were unremarkable except in boys at G2-5 in whom FSH was elevated: 12.3/27.3 vs 3.25/6.26 U/L in controls (p<0.001). In males aged >13, testosterone was 3.1 (0.5-8.4) nmol/L. Androgen therapy, given from 13.5-29.2 years, was stopped in 4/24 patients owing to behavioural problems. CONCLUSION: Despite invariable hypogonadism, few females and only half the males with PWS in this study received hormone replacement. Double-blind placebo-controlled crossover trials of sex steroids are required to address unproven behavioural concerns.

International practice of corticosteroid replacement therapy in congenital adrenal hyperplasia: data from the I-CAH registry.

OBJECTIVE: Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH. DESIGN: This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry. METHODS: Data were collected from 461 patients aged 0-18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits. RESULTS: The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0-14.5) mg/m2/day at age 1-8 years and the highest dose of 14.0 (11.6-17.4) mg/m2/day at age 12-18 years. Glucocorticoid doses decreased after 2010 in patients 0-8 years (P < 0.001) and remained unchanged in patients aged 8-18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement. CONCLUSIONS: Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Real-World Estimates of Adrenal Insufficiency-Related Adverse Events in Children With Congenital Adrenal Hyperplasia.

BACKGROUND: Although congenital adrenal hyperplasia (CAH) is known to be associated with adrenal crises (AC), its association with patient- or clinician-reported sick day episodes (SDE) is less clear. METHODS: Data on children with classic 21-hydroxylase deficiency CAH from 34 centers in 18 countries, of which 7 were Low or Middle Income Countries (LMIC) and 11 were High Income (HIC), were collected from the International CAH Registry and analyzed to examine the clinical factors associated with SDE and AC. RESULTS: A total of 518 children-with a median of 11 children (range 1, 53) per center-had 5388 visits evaluated over a total of 2300 patient-years. The median number of AC and SDE per patient-year per center was 0 (0, 3) and 0.4 (0.0, 13.3), respectively. Of the 1544 SDE, an AC was reported in 62 (4%), with no fatalities. Infectious illness was the most frequent precipitating event, reported in 1105 (72%) and 29 (47%) of SDE and AC, respectively. On comparing cases from LMIC and HIC, the median SDE per patient-year was 0.75 (0, 13.3) vs 0.11 (0, 12.0) (P < 0.001), respectively, and the median AC per patient-year was 0 (0, 2.2) vs 0 (0, 3.0) (P = 0.43), respectively. CONCLUSIONS: The real-world data that are collected within the I-CAH Registry show wide variability in the reported occurrence of adrenal insufficiency-related adverse events. As these data become increasingly used as a clinical benchmark in CAH care, there is a need for further research to improve and standardize the definition of SDE.

Effect of long-term glucocorticoid therapy on cardiac functions in children with congenital adrenal hyperplasia.

BACKGROUND: Glucocorticoids play an important role in cardiac physiology. Chronic exposure and higher doses may cause adverse effects on the myocardium, especially in young patients receiving long-term therapy. OBJECTIVE: To assess cardiac function in children with congenital adrenal hyperplasia (CAH) and its relation to glucocorticoid dose and therapy duration. METHODS: Forty-seven patients with CAH due to 21-hydroxylase deficiency were compared to 47 controls. Patients were subdivided according to treatment duration (Group A: less than 6 years, Group B: more than 6 years). Mean daily glucocorticoid and cumulative glucocorticoid doses were calculated. Echocardiography was performed for patients and controls to evaluate cardiac functions, chamber dimensions and tissue Doppler valvular status. RESULTS: Compared to controls, patients had cardiac chamber hypertrophy reflected by higher M-mode dimensions. Patients had lower fractional shortening, defective ventricular relaxation, lower average mitral and tricuspid e´/a´ ratios (e´ early diastolic, a´ late diastolic) as well as s´ (systolic) velocities, higher average mitral E/e ratio and higher left ventricle TDI Tei index (P < .05). Group B had lower average mitral e´/a´ and tricuspid s´ velocities, and higher average mitral E/e ratio (P < .05). Cumulative glucocorticoid dose significantly correlated with different echocardiographic parameters. CONCLUSION: Long-term glucocorticoid therapy even within the recommended therapeutic range adversely affects cardiac functions in children with 21-hydroxylase deficiency.

For Debate: Assessment of HbA1c in Transfusion Dependent Thalassemia Patients.

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.

Striae distensae in adolescents: A mini review.

Striae distensae or stretch marks are mainly a cosmetic concern. They commonly occur in adolescence and in pregnant women. Although, generally more common in females; physiological striae atrophicae of adolescence are more common in males. The pathophysiology is multifactorial with mechanical stretching of the skin being the most important. Despite of an abundance of treatment modalities none is 100% effective.

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.

Long-term effects and significant Adverse Drug Reactions (ADRs) associated with the use of Gonadotropin-Releasing Hormone analogs (GnRHa) for central precocious puberty: a brief review of literature.

Central precocious puberty (CPP) is defined as an early pubertal development that occurs before the age of 9 years in boys and 8 years in girls. It results from premature activation of the hypothalamic-pituitary-gonadal axis. Gonadotropin-releasing hormone agonists (GnRHa) have been the gold standard therapy for CPP for more than 30 years. These compounds have a high affinity for the pituitary LHRH receptor and are resistant to enzymatic degradation. Through continuous stimulation, GnRHa inhibit the pulsatile secretion of gonadotropin, resulting in hormonal suppression, cessation of pubertal development, and normalization of growth and skeletal maturation rates. The goal of therapy is to halt pubertal progression and delay epiphyseal maturation that leads to improvement of final adult height. There are no widely accepted guidelines for how long to continue treatment with a GnRHa for CPP, and individual practice varies widely. Furthermore, conflicting results have been published on the long-term effects of GnRHa therapy in patients with CPP. Therefore, we reviewed the current literature focusing our attention on the long-term effects and the significant adverse drug reactions (ADRs) observed during treatment with GnRHa in patients with CPP. Our review may provide the necessary data to enable clinicians to administer GnRHa in the safest and most appropriate way. Further studies are necessary to identify the mechanisms of development of potential adverse drug reactions related to GnRHa therapy in CPP.

Thyroid Disorders in Homozygous ß-Thalassemia: Current Knowledge, Emerging Issues and Open Problems.

Changes in thyroid function and thyroid function tests occur in patients with ß-thalassemia major (TM). The frequency of hypothyroidism in TM patients ranges from 4% to 29 % in different reports. The wide variation has been attributed to several factors such as patients' genotype, age, ethnic heterogeneity, treatment protocols of transfusions and chelation, and varying compliance to treatment. Hypothyroidism is the result of primary gland failure or insufficient thyroid gland stimulation by the hypothalamus or pituitary gland. The main laboratory parameters of thyroid function are the assessments of serum thyroid-stimulating hor-mone (TSH) and serum free thyroxine (FT4). It is of primary importance to interpret these measurements within the context of the laboratory-specific normative range for each test. An elevated serum TSH level with a standard range of serum FT4 level is consistent with subclinical hypothyroidism. A low serum FT4 level with a low, or inappropriately normal, serum TSH level is consistent with secondary hypothyroidism. Doctors caring for TM patients most commonly encounter subjects with subclinical primary hypothyroidism in the second decade of life. Several aspects remain to be elucidated as the frequency of thyroid cancer and the possible existence of a relationship between thyroid dysfunction, on one hand, cardiovascular diseases, components of metabolic syndrome (insulin resistance) and hypercoagulable state, on the other hand. Further studies are needed to explain these emerging issues. Following a brief description of thyroid hormone regulation, production and actions, this article is conceptually divided into two parts; the first reports the spectrum of thyroid disease occurring in patients with TM, and the second part focuses on the emerging issues and the open problems in TM patients with thyroid disorders.

Normal Growth despite Combined Pituitary Hormone Deficiency.

BACKGROUND: The paradox of normal growth despite a lack of growth hormone (GH) is an unexplained phenomenon described in some pathological (sellar, suprasellar, and hypothalamic disorders) and overgrowth syndromes. It has been suggested that the paradoxical growth is due to other GH variants, GH-like moieties, prolactin, insulin, insulin-like growth factors (IGFs), and unidentified serum factors or growth mechanisms. The objective of this study was to determine the mechanism underlying this normal growth without GH. CASE DESCRIPTION: We describe here growth, hormonal, and genetic analyses for an adolescent boy with panhypopituitarism who achieved an adult height above his genetic potential. RESULTS: Normal growth was observed despite low serum GH, IGF-I, IGF-II, IGF binding protein 3 (IGFBP-3) and acid labile subunit (ALS) concentrations, but the IGF-II/IGFBP-3 molar ratio was slightly high. Panhypopituitarism was associated with a heterozygous missense mutation of HESX1, with variable penetrance in heterozygous relatives. Exome analysis detected heterozygous missense mutations of various genes involved in intracellular signaling pathways. The growth-promoting activity of the patient's serum was unable to induce AKT phosphorylation in the MCF-7 cell line. CONCLUSION: The high IGF-II/IGFBP-3 molar ratio was not the cause of the sustained high growth velocity, due to the low affinity of IGF-II for IGF type 1 receptor. The key finding was the HESX1 mutation, as similar cases have been described before, suggesting a common mechanism for growth without GH. However, the variable penetrance of this variant in heterozygous relatives suggests that modifier genes or mechanisms involving combinations with mutations of other genes involved in intracellular signaling pathways might be responsible.

The experience of a tertiary unit on the clinical phenotype and management of hypogonadism in female adolescents and young adults with transfusion dependent thalassemia.

BACKGROUND: Transfusion-dependent ß-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.

An ICET-A survey on occult and emerging endocrine complications in patients with ß-thalassemia major: Conclusions and recommendations.

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.

A pilot study on sperm DNA damage in ß-thalassemia major: is there a role for antioxidants?

Excess iron deposition in patients with beta thalassemia major (BTM) causes excess free radical formation, damages the hypothalamic pituitary testicular axis and production of sperms with DNA defects. As antioxidants were reported to improve fertility in healthy males; their effectiveness to improve sperm DNA defects in adult males with BTM was studied. Twenty fully pubertal BTM patients were included consecutively, all had semen analysis; 10 were found to be azoospermic, so further analysis for sperms and DNA defects was conducted on the remaining 10 participants. Semen was analyzed for antioxidants in seminal plasma and sperms for defects including the DNA fragmentation index, sperm deformity index, teratozospermia index and acrosomal index. Participants were then given L-carnitine and N-acetylcysteine for 6 months. All semen parameters were reassessed after treatment. The sperm deformity index and teratozospermia index increased significantly after treatment from 1.90±0.33 to 2.46±0.61 and from 1.59±0.22 to 1.86±0.28 respectively. So, apparently antioxidants accentuated sperm deformities in men with BTM. Therefore, the results of this study are not in favour with the use of antioxidants in BTM patients for improving potential fertility. Larger studies, however, are needed to confirm these preliminary results.