Expanding the phenotype of biallelic RNPC3 variants associated with growth hormone deficiency.

Pathogenic variants in components of the minor spliceosome have been associated with several human diseases. Recently, it was reported that biallelic RNPC3 variants lead to severe isolated growth hormone deficiency and pituitary hypoplasia. The RNPC3 gene codes for the U11/U12-65K protein, a component of the minor spliceosome. The minor spliceosome plays a role in the splicing of minor (U12-type) introns, which are present in ~700-800 genes in humans and represent about 0.35% of all introns. Here, we report a second family with biallelic RNPC3 variants in three siblings with a growth hormone deficiency, central congenital hypothyroidism, congenital cataract, developmental delay/intellectual deficiency and delayed puberty. These cases further confirm the association between biallelic RNPC3 variants and severe postnatal growth retardation due to growth hormone deficiency. Furthermore, these cases show that the phenotype of this minor spliceosome-related disease might be broader than previously described.

Blue Rubber Bleb Nevus Syndrome: A Possible Cause for Growth Retardation and Pubertal Delay.

OBJECTIVE: The aim of this paper was to describe a rare case of blue rubber bleb nevus (BRBNS) with growth retardation and pubertal delay. CLINICAL PRESENTATION AND INTERVENTION: A 16-year-old boy with severe iron deficiency anemia was diagnosed with BRBNS, showing growth retardation and pubertal delay simultaneously. The patient was treated conservatively with intravenous iron therapy, and his puberty advanced gradually. CONCLUSION: Given that growth retardation and pubertal delay are rare in BRBNS patients, this case reminds us to include BRBNS in the differential diagnosis of growth retardation.

Pathological fractures in paediatric patients with inflammatory bowel disease.

UNLABELLED: Paediatric inflammatory bowel disease (IBD), especially Crohn's disease (CD), is commonly associated with poor skeletal health, related to the direct effects of chronic inflammation, prolonged use of glucocorticoid (GC), poor nutrition, delayed puberty and low muscle mass. Low bone mineral density is commonly reported, although the prevalence of long bone fractures may not be increased in these patients. Emerging evidence however suggests that there may be an increased risk of vertebral fractures (VFs) in this group. VFs presenting at diagnosis of paediatric CD, prior to any GC exposure, have been reported, highlighting the deleterious effect of inflammation on skeletal health. This paper reviews the published literature on pathophysiology of skeletal morbidity and fractures in paediatric IBD, illustrated with a new case report of multiple VFs in a prepubertal girl with CD, soon after diagnosis, who received minimal amounts of oral GC. Optimising control of disease, addressing vitamin D deficiency, encouraging physical activity and ensuring normal growth and pubertal progression are paramount to management of bone health in these patients. Despite the lack of evidence, there may be a place for bisphosphonate treatment, especially in the presence of symptomatic pathological fractures, but this requires close monitoring by clinicians with expertise in paediatric bone health. CONCLUSION: Chronic inflammation mediated by pro-inflammatory cytokines may have adverse effects on skeletal health in paediatric patients with IBD. The risk of vertebral fractures may be increased, even without exposure to glucocorticoid. Clinical monitoring of these patients requires careful attention to the various factors that impact on bone health.

Menarcheal age of type 1 diabetic Bengali Indian females.

BACKGROUND: It has been observed that menstrual characteristics are generally influenced by lifestyle, socio-cultural and biological factors. AIM: The present study examines: (a) variation in menstrual characteristics between Type1 Diabetic females of rural and urban adolescents, i.e. the resident status; and (b) whether these characteristics can be predicted from various socio-economic, stress variables related to place of residence. SUBJECTS AND METHODS: The sample of the present study constituted 103T1DM females from West Bengal, a State of India. These girls belong to a Bengali-speaking ethnic group. Data on socio-economic variables and menstrual characteristics were collected using pretested questionnaires. RESULTS: Menstrual irregularity was common in our study participants, with age of menarche, but was not associated with current BMI, physical activity or insulin dose. CONCLUSIONS: Our study displays that age at menarche is delayed in young women with T1DM compared to the concurrent overall mean age at menarche in the West Bengal population.

Prevalence and Factors Associated With Delayed Puberty Among Adolescents on Boosted Protease Inhibitor-based Second-line Antiretroviral Therapy: A Cross-sectional Study at a Pediatric Infectious Diseases Clinic in Uganda.

BACKGROUND: Delayed puberty is a recognized phenomenon among children living with HIV type 1 infection but has not been widely reported among adolescents on second-line or newer treatments in high burden settings. The study aimed to determine the prevalence of, and factors associated with delayed puberty among adolescents on boosted protease inhibitor-based second-line antiretroviral therapy (ART) in Uganda. METHODS: Between December 2017 and May 2018, we conducted a cross-sectional study among adolescents living with HIV (ALWHIV) 10-19 years of age on atazanavir- and lopinavir-based regimens at the Paediatric Infectious Diseases Clinic, Kampala. Participants were on ART for at least 3 months and had a recent viral load. Sociodemographics, clinical measurements: body mass index for age Z score, height for age Z score, Tanner staging were collected. ART history was extracted from medical records. The outcome was delayed puberty defined as absence of signs of breast development in a girl 13 years of age or a testicular volume of less than 4 mL in a boy 14 years of age by Tanner staging, or an age for Tanner staging which was at least 2 standard deviations above the expected mean. RESULTS: Among 230 perinatally infected ALWHIV participants, 14.7 ± 3.1 years of age were included, 54.9% were female, 5.2% were wasted and the median duration on ART was 9.5 years (interquartile range 7.3-11.7). The prevalence of delayed puberty was 8.7% (10.4% females, 6.7% males). Overall mean age estimates at different Tanner stages by sex were significantly higher than reference populations. Age at ART initiation (adjusted odds ratio 1.37, 95% confidence interval: 1.06-1.77) and body mass index for age Z score (adjusted odds ratio: 7.63, 95% confidence interval: 1.80-32.38) were associated with delayed puberty. CONCLUSIONS: Timely initiation of ART and nutritional monitoring could optimize body weight and consequently, normal puberty for ALWHIV. Longitudinal studies could establish biological diagnoses and guide treatment of delayed puberty in this population.

A single-centre study on predictors and determinants of pubertal delay and growth impairment in Epidermolysis Bullosa.

BACKGROUND: Delayed puberty is a possible complication of Epidermolysis Bullosa (EB), though the actual incidence is still unknown. In chronic illnesses delayed puberty should be correctly managed since, if untreated, can have detrimental effects on adult height attainment, peak bone mass achievement and psychological health. AIMS AND METHODS: This is a single-centre study on pubertal development, growth and bone status in EB. Auxological, densitometric (areal Bone Mineral Density-aBMD Z-score, Bone Mineral Apparent Density-BMAD Z-score, Trabecular Bone Score-TBS and Bone Strain Index-BSI at Lumbar spine) and body composition data (Total Body DXA scans) were collected. Disease severity was defined according to Birmingham Epidermolysis Bullosa Severity (BEBS) score. RESULTS: Twenty-one patients (12 Recessive Dystrophic EB-RDEB, 3 Dominant Dystrophic EB, 3 Junctional EB-JEB, 2 EB Simplex and one Kindler EB) aged 13 years (females) or 14 years (males) and above were enrolled (age 16.2±2.5 years, M/F 11/10). Short stature was highly prevalent (57%, mean height -2.12±2.05 SDS) with 55% patients with height <-2SD their mid-parental height. 7/21 patients (33%, 6 RDEB and 1 JEB) had delayed puberty with a median BEBS of 50 (range 29 to 63), a height SDS of -2.59 SDS (range -5.95 to -2.22) and a median lumbar BMAD Z-score of -4.0 SDS (range -5.42 to -0.63 SDS). Pubertal status was negatively associated with BEBS, skin involvement, inflammatory state and positively with height SDS and BMI SDS. CONCLUSIONS: Pubertal delay is highly prevalent in EB, especially in patients with RDEB and JEB, high severity score and inflammatory state. Moreover, pubertal delay worsens growth impairment and bone health. A study on pubertal induction is ongoing to enlighten possible beneficial effects on adult height attainment and peak bone mass accrual.

Disorders of Puberty in Girls.

Puberty is the process through which reproductive competence is achieved and comprises gonadarche and adrenarche. Breast development is the initial physical finding of pubertal onset in girls and typically occurs between 8 and 13 years. Menarche normally occurs 2 to 3 years after the onset of breast development. Pubertal onset is controlled by the gonadotropin-releasing hormone pulse generator in the hypothalamus; however, environmental factors such as alterations in energy balance and exposure to endocrine-disrupting chemicals can alter the timing of pubertal onset. Improvement in nutritional and socioeconomic conditions over the past two centuries has been associated with a secular trend in earlier pubertal onset. Precocious puberty is defined as onset of breast development prior to 8 years and can be central or peripheral. Delayed puberty can be hypogonadotropic or hypergonadotropic and is defined as lack of breast development by 13 years or lack of menarche by 16 years. Both precocious and delayed puberty may have negative effects on self-esteem, potentially leading to psychosocial stress. Patients who present with pubertal differences require a comprehensive assessment to determine the underlying etiology and to devise an effective treatment plan.

Increased androgen-related comorbidity in adolescents and adults born with hypospadias: A population-based study.

BACKGROUND: Hypospadias is a common congenital malformation often related to the effect of androgens in utero. While hypogonadism is associated with many potential health risks including metabolic and cardiovascular disease, the risk of clinical hypogonadism and comorbidities in men with hypospadias later in life has not been studied. OBJECTIVES: Investigate the risk of hypogonadism and somatic comorbidities in adolescents and men born with hypospadias. MATERIALS AND METHODS: We conducted a population-based cohort study using Swedish registers. Associations between hypospadias and hypogonadism, delayed puberty, metabolic, and cardiovascular disease respectively were estimated using Cox proportional hazards regression. Body measurements from military conscription were analysed in a subpopulation as indicators of growth and cardiometabolic risk. We used sibling comparison analyses to control for familial confounding. RESULTS: Using register data, a total of 2,165,255 men including 9,714 men born with hypospadias were followed from the age of 10 to a maximum of 60 years. We found an association between hypospadias and hypogonadism (Hazard ratio (HR) 3.27, 95% confidence interval (CI) 2.33-4.59) which was more pronounced in proximal hypospadias. Men with hypospadias had shorter average height than their brothers and the general population. We further found an increased risk of delayed puberty (HR 1.49, 95% CI 1.08-2.07), diabetes mellitus type 2 (HR 1.57, 95% CI 1.18-2.09) and cardiovascular disease (HR 1.47, 95% CI 1.27-1.71). DISCUSSION: We found an increased risk of hypogonadism, metabolic and cardiovascular disease in men born with hypospadias, increasing with severity of phenotype, as well as impacted growth. These results indicate discruptions in androgen function past childhood, although some of the associations may be due to other underlying aetiologies. CONCLUSION: Hypospadias is associated with an increased risk of androgen-related comorbidity in adolescence and adulthood. We suggest that this can be considered clinically, while further research is needed, especially in older populations.

Long-Term Outcomes of Paediatric-Onset Craniopharyngioma: A Retrospective Analysis from a Tertiary Care Centre in North India.

Background: Craniopharyngiomas are associated with long-term morbidity in the form of hormone deficiencies, visual deficits, and hypothalamic obesity. Objective: To study the long-term outcomes, including cure rates, endocrine dysfunction, visual dysfunction, hypothalamic obesity, and mortality in pediatric-onset craniopharyngiomas. Methods: A retrospective data analysis of pediatric (onset <18 years) craniopharyngioma diagnosed between 2003 and 2018. Data were collected from electronic hospital records, case files, and direct patient interviews. Results: The mean age at presentation was 10.4 ± 4.5 years (n = 62). The median duration of symptoms at diagnosis was 6 months (3-13 months). At presentation, central diabetes insipidus was present in four (6.5%), central hypothyroidism in 27 (43.5%), secondary adrenal insufficiency in 20 (32%) and delayed puberty in 15 (24%) patients. Hypothalamus was involved in 59/60 patients (98%). At last visit, 22.6% were obese in comparison to 4.6% at presentation, and anterior pituitary deficiency was present in 90% of the patients. Sixty-one percent patients (n = 62) had delayed puberty and 67% (n = 53) had short-stature. Out of 35 short children, nine (14%) children who received growth hormone had significant increase in height SD score (-3.8 (1.4) at start vs. -2.9 (1.2) at last follow-up; P = 0.008). Tumor progression was significantly less in the group that received RT compared to those who did not (8% vs. 39%; P = 0.002). Conclusion: Childhood-onset craniopharyngioma results in significant morbidity. The prevalence of pituitary hormones deficiency, visual deficits, and obesity are high at long-term follow-up. Incomplete tumor removal is also frequent. Thus, long-term monitoring is necessary for the timely management of the morbidities associated with craniopharyngioma.

Endocrinal Complications in Children and Adolescents with Thalassemia Major in Central India: An Observational Study.

OBJECTIVE: To determine the prevalence of short stature, delayed puberty, hypothyroidism, and diabetes mellitus in multiply transfused patients of beta thalassemia major and their correlation with serum ferritin. METHODS: A descriptive observational study was conducted in a tertiary care center in Indore, Madhya Pradesh from 2014 to 2016. All children with thalassemia major of the age group 8 to 18 y attending outpatient department or admitted in ward were included in the study. Detailed clinical history, demographic data, compliance to transfusion and chelation therapy, and growth parameters were recorded. Blood samples to look for endocrinopathies and serum ferritin were assessed. Tanner staging was done to assess for delayed puberty. RESULTS: Mean age of study participants (n = 50) was 15.98 ± 3.4 y. Short stature (n = 44; 88%), delayed puberty (n = 33; 71.7%), hypothyroidism (n = 6; 16%), and diabetes mellitus (n = 5; 10%) were the endocrinal abnormalities found. Mean serum ferritin level was 3122 ± 2117 ng/mL. Serum ferritin had significant positive correlation with serum TSH (thyroid stimulating hormone), fasting blood sugars, postprandial blood sugar, and delayed puberty. CONCLUSION: Evaluation of endocrinopatines must be carried out in thalassemia major patients regularly by pediatricians to detect and treat endocrinal complications. Importance of chelation therapy must be emphasized frequently to parents and patients.

Menarche delay and menstrual irregularities persist in adolescents with type 1 diabetes.

BACKGROUND: Menarche delay has been reported in adolescent females with type 1 diabetes (T1DM), perhaps due to poor glycemic control. We sought to compare age at menarche between adolescent females with T1DM and national data, and to identify factors associated with delayed menarche and menstrual irregularity in T1DM. METHODS: This was a cross-sectional study and females ages 12- 24 years (n = 228) with at least one menstrual period were recruited during their outpatient diabetes clinic appointment. The National Health and Nutrition Examination Survey (NHANES) 2001-2006 data (n = 3690) for females 12-24 years were used as a control group. RESULTS: Age at menarche was later in adolescent females with T1DM diagnosed prior to menarche (12.81 +/- 0.09 years) (mean+/- SE) (n = 185) than for adolescent females diagnosed after menarche (12.17 0.19 years, p = 0.0015) (n = 43). Average age of menarche in NHANES was 12.27 +/- 0.038 years, which was significantly earlier than adolescent females with T1DM prior to menarche (p < 0.0001) and similar to adolescent females diagnosed after menarche (p = 0.77). Older age at menarche was negatively correlated with BMI z-score (r = -0.23 p = 0.0029) but not hemoglobin A1c (A1c) at menarche (r = 0.01, p = 0.91). Among 181 adolescent females who were at least 2 years post menarche, 63 (35%) reported usually or always irregular cycles. CONCLUSION: Adolescent females with T1DM had a later onset of menarche than both adolescent females who developed T1DM after menarche and NHANES data. Menarche age was negatively associated with BMI z-score, but not A1c. Despite improved treatment in recent decades, menarche delay and high prevalence of menstrual irregularity is still observed among adolescent females with T1DM.

Food insecurity and age at menarche among adolescent girls in Jimma Zone Southwest Ethiopia: a longitudinal study.

BACKGROUND: Age at menarche is the reflection of cumulative pre-adolescent exposure of girls to either adverse environment such as food insecurity or affluent living conditions. Food insecurity could result in inadequate nutrient intake and stress, both of which are hypothesized to have opposing effects on the timing of menarche through divergent pathways. It is not known whether food insecure girls have delayed menarche or early menarche compared with their food secure peers. In this study we test the competing hypothesis of the relationship between food insecurity and age at menarche among adolescent girls in the Southwest Ethiopia. METHODS: We report on 900 girls who were investigated in the first two rounds of the five year longitudinal survey. The semi-parametric frailty model was fitted to determine the effect of adolescent food insecurity on time to menarche after adjusting for socio-demographic and economic variables. RESULTS: Food insecure girls have menarche one year later than their food secure peer (median age of 15 years vs 14 years). The hazard of menarche showed a significant decline (P = 0.019) as severity of food insecurity level increased, the hazard ratio (HR) for mild food insecurity and moderate/severe food insecurity were 0.936 and 0.496, respectively compared to food secure girls. Stunted girls had menarche nearly one year later than their non-stunted peers (HR = 0.551, P < 0.001). CONCLUSION: Food insecurity is associated with delay of age at menarche by one year among girls in the study area. Stunted girls had menarche one year later than their non-stunted peers. Age at menarche reflects the development of girls including the timing of sexual maturation, nutritional status and trajectory of growth during the pre-pubertal periods. The findings reflect the consequence of chronic food insecurity on the development and well-being of girls in the study area.

Circulating miR-30b levels increase during male puberty.

OBJECTIVE: The role of miRNA as endocrine regulators is emerging, and microRNA mir-30b has been reported to repress Mkrn3. However, the expression of miR-30b during male puberty has not been studied. DESIGN AND METHODS: Circulating relative miR-30b expression was assessed in sera of 26 boys with constitutional delay of growth and puberty (CDGP), treated with low-dose testosterone (T) (n =11) or aromatase inhibitor letrozole (Lz) (n =15) for 6 months and followed up to 12 months (NCT01797718). The associations between the relative expression of miR-30b and hormonal markers of puberty were evaluated. RESULTS: During the 12 months of the study, circulating miR-30b expression increased 2.4 ± 2.5 (s.d.) fold (P = 0.008) in all boys, but this change did not correlate with corresponding changes in LH, testosterone, inhibin B, FSH, or testicular volume (P = 0.25-0.96). Lz-induced activation of the hypothalamic-pituitary-gonadal (HPG) axis was associated with more variable miR-30b responses at 3 months (P < 0.05), whereas those treated with T exhibited significant changes in relative miR-30b levels in the course the study (P < 0.01-0.05). CONCLUSIONS: Circulating miR-30b expression in boys with CDGP increases in the course of puberty, and appears to be related to the activity of the HPG axis.

Gonadal dysfunction and pelvic sonographic findings in females with thalassaemia major.

OBJECTIVE: To investigate pubertal and menstrual problems and evaluate pelvic sonographic findings in patients with beta-thalassaemia major. MATERIAL AND METHODS: Twenty-five female patients followed for thalassaemia major constituted the study population. Sexual maturation and hormonal status were assessed. Pubertal and menstrual problems were investigated. RESULTS: There was one patient with delayed puberty and five patients with arrested puberty. Mean ferritin level in this group of patients was slightly but not significantly higher than patients with normal pubertal maturation (2620 +/- 994 ng/ml vs. 2409 +/- 1348 ng/ml, p > 0.05). There were 10 patients with primary amenorrhoea, three with secondary amenorrhoea, five with oligomenorrhoea and irregular menstruation and one with regular menstruation. Compared to menstruating patients, the mean uterine size was smaller (4.1 +/- 3.5 cm(3) vs. 52.8 +/- 14.5 cm(3)) in all patients with delayed and arrested puberty (p < 0.05). Ten patients were taking hormone replacement therapy (HRT). The mean uterine size in these patients was larger than that in patients with amenorrhoea who were not taking HRT, but smaller than that in menstruating patients (9.1 +/- 15.9 cm(3), 2.7 +/- 1.3 cm(3) and 52.8 +/- 14.5 cm(3), respectively) (p < 0.05). CONCLUSION: Thalassaemia major has important side effects on the hypothaloma-pituitary-gonadal axis resulting in pubertal and menstrual abnormalities. HRT should be given to provide normal sexual maturation in these patients.

Long-Term Follow-Up and Treatment of a Female With Complete Estrogen Insensitivity.

CONTEXT: We previously reported the first female with a causative ESR1 gene variant, who exhibited absent puberty and high estrogens. At age 15 years, she presented with lower abdominal pain, absent breast development, primary amenorrhea, and multicystic ovaries. The natural history of complete estrogen insensitivity (CEI) in women is unknown. OBJECTIVE: The purpose of this report is to present the neuroendocrine phenotype of CEI, identify potential ligands, and determine the effect of targeted treatment. DESIGN: We have characterized gonadotropin pulsatility and followed this patient's endocrine profile and bone density over 8 years. Seventy-five different compounds were tested for transactivation of the variant receptor. A personalized medicine approach was tailored to our patient. SETTING: Academic medical center. PATIENT OR OTHER PARTICIPANTS: A 24-year-old adopted white female with CEI. INTERVENTION(S): The patient was treated with diethylstilbestrol (DES) for approximately 2.5 years. MAIN OUTCOME MEASURE(S): Induction of secondary sexual characteristics. RESULTS: Luteinizing hormone (LH) pulse studies demonstrated normal pulsatile LH secretion, elevated mean LH, and mildly elevated mean follicle-stimulating hormone (FSH) in the presence of markedly increased estrogens. DES transactivated the variant ESR1 in vitro. However, DES treatment did not induce secondary sexual characteristics in our patient. CONCLUSIONS: Treatment with DES was not successful in our patient. She remains hypoestrogenic despite the presence of ovarian cysts with a hypoestrogenic vaginal smear, absent breast development, and low bone mineral mass. Findings suggest additional receptor mechanistic actions are required to elicit clinical hormone responses.

Beneficial effects of propylthiouracil plus L-thyroxine treatment in a patient with a mutation in MCT8.

CONTEXT: Mutations of the monocarboxylate transporter 8 (MCT8) gene determine a distinct X-linked phenotype of severe psychomotor retardation and consistently elevated T(3) levels. Lack of MCT8 transport of T(3) in neurons could explain the neurological phenotype. OBJECTIVE: Our objective was to determine whether the high T(3) levels could also contribute to some critical features observed in these patients. RESULTS: A 16-yr-old boy with severe psychomotor retardation and hypotonia was hospitalized for malnutrition (body weight = 25 kg) and delayed puberty. He had tachycardia (104 beats/min), high SHBG level (261 nmol/liter), and elevated serum free T(3) (FT(3)) level (11.3 pmol/liter), without FT(4) and TSH abnormalities. A missense mutation of the MCT8 gene was present. Oral overfeeding was unsuccessful. The therapeutic effect of propylthiouracil (PTU) and then PTU plus levothyroxine (LT(4)) was tested. After PTU (200 mg/d), serum FT(4) was undetectable, FT(3) was reduced (3.1 pmol/liter) with high TSH levels (50.1 mU/liter). Serum SHBG levels were reduced (72 nmol/liter). While PTU prescription was continued, high LT(4) doses (100 microg/d) were needed to normalize serum TSH levels (3.18 mU/liter). At that time, serum FT(4) was normal (16.4 pmol/liter), and FT(3) was slightly high (6.6 pmol/liter). Tachycardia was abated (84 beats/min), weight gain was 3 kg in 1 yr, and SHBG was 102 nmol/liter. CONCLUSIONS: 1) When thyroid hormone production was reduced by PTU, high doses of LT(4) (3.7 microg/kg.d) were needed to normalize serum TSH, confirming that mutation of MCT8 is a cause of resistance to thyroid hormone. 2) High T(3) levels might exhibit some deleterious effects on adipose, hepatic, and cardiac levels. 3) PTU plus LT(4) could be an effective therapy to reduce general adverse features, unfortunately without benefit on the psychomotor retardation.

Delayed menarche in young German women with type 1 diabetes mellitus: recent results from the DPV diabetes documentation and quality management system.

BACKGROUND: Findings have been inconsistent regarding the effect of T1DM (type 1 diabetes) on age at menarche. OBJECTIVE: The purpose was to investigate in young German women with T1DM menarcheal age and factors potentially affecting menarche, including glycemic control, BMI (body mass index), relative T1DM duration (proportion of life with diabetes), insulin dose, and insulin therapy intensity. Initiated in 1990, the DPV program is an ongoing, prospective long-term longitudinal follow-up study to benchmark the quality of care provided to pediatric and, more recently, adult diabetes patients. Two hundered two German diabetes centers participated in nationwide data collection. Based on ethnicity and the availability of menarche and T1DM onset data as the main inclusion criteria, 643 young German women were selected from 11,629 female T1DM patients aged <20 years, recruited by referral, clinic or hospital ascertainment, or self report. Mean age at menarche (+/-SD) was 13.22 +/- 1.31 years, representing a delay of 0.52 years (p < 0.001) relative to the general population. Significant delay (p < 0.05) was also found for relative T1DM duration, BMI SD score, insulin dose, and HbA1c level, with a 1% increase in HbA1c resulting in a delay in menarche by 0.07 years. CONCLUSIONS: Age at menarche is delayed in type 1 diabetes mellitus. The delay increases with relative T1DM duration and poor quality of glycemic control.

Assessment of puberty in relation to L-carnitine and hormonal replacement therapy in beta-thalassemic patients.

OBJECTIVE: To investigate puberty in a group of thalassemic patients with delayed or arrested pubertal development and to compare the effects of hormonal and L-carnitine therapy on puberty in those patients. PATIENTS: Thirty-two -thalassemic patients with arrested or failure of puberty were enrolled for 1 year in this study. METHOD: Clinical pubertal assessment and laboratory investigations were done for all patients at the beginning, 6 months later clinical pubertal assessment was done. Patients were divided into two groups (16 each): first group received L-carnitine therapy, while the second group received hormonal therapy. Pubertal and laboratory assessment were done 6 months after hormonal and L-carnitine therapy. RESULTS: Failure of puberty was confirmed in 71.4% of boys and 33.3% of girls, while arrested puberty was observed in 28.6% of boys and 66.7% of girls. All girls had amenorrhea, primary amenorrhea in 88.9% and secondary amenorrhea in 11.1%. Menses occurred in 20% of female patients after L-carnitine therapy and in 37.5% of them after hormonal therapy. Improvement of pubertal staging was observed in 50% of males after L-carnitine therapy compared to 75% of them after hormonal therapy. While improvement of pubertal staging was seen in 90% of females after L-carnitine therapy compared to 100% of females after hormonal treatment. However, these results showed no significant difference between both groups. CONCLUSION: Delayed puberty in beta-thalassemia major is either due to failure of gonads or failure of the whole hypothalamic pituitary gonadal axis. L-carnitine as well as hormonal replacement therapy had a positive effect on puberty in the thalassemic patients. Further studies are needed to clarify the role of L-carnitine on puberty in these patients.