Alexia S Peña

Aortic intima media thickness is an early marker of atherosclerosis in children with type 1 diabetes mellitus.

OBJECTIVE To compare aortic intima media thickness (aIMT) to carotid intima media thickness (cIMT) as a marker of early atherosclerosis in children with type 1 diabetes mellitus and to examine the associations of aIMT to known cardiovascular risk factors. STUDY DESIGN 66 children with type 1 diabetes mellitus (age, 14.1 +/- 2.5 years; 37 male) and 32 healthy control subjects (age, 14.2 +/- 3 years; 15 male) underwent assessment of vascular structure (cIMT and aIMT) and vascular function (flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]). Fasting blood tests were taken to measure levels of hemoglobin A1c, high sensitive C reactive protein, total homocyst(e)ine, serum folate, red cell folate, and lipids. RESULTS aIMT, but not cIMT, was significantly greater in the children with type 1 diabetes mellitus than in control subjects (P < .001). In children with type 1 diabetes mellitus, aIMT correlated with glycosylated hemoglobin (r = 0.31, P = .01) and was independently associated with age (beta = 0.38, P = .001) and low-density lipoprotein cholesterol level (beta = 0.38, P = .001). Vascular function (GTN) was worse in children with type 1 diabetes mellitus who had an aIMT >95th percentile, as defined with the control subjects. CONCLUSIONS aIMT is an earlier marker than cIMT of preclinical atherosclerosis in children with type 1 diabetes mellitus and relates to known cardiovascular risk factors and metabolic control.

The Diagnosis of Polycystic Ovary Syndrome during Adolescence

Background/Aims: The diagnostic criteria for polycystic ovary syndrome (PCOS) in adolescence are controversial, primarily because the diagnostic pathological features used in adult women may be normal pubertal physiological events. Hence, international pediatric and adolescent specialty societies have defined criteria that have sufficient evidence to be used for the diagnosis of PCOS in adolescents. Methods: The literature has been reviewed and evidence graded to address a series of questions regarding the diagnosis of PCOS during adolescence including the following: clinical and biochemical evidence of hyperandrogenism, criteria for oligo-anovulation and polycystic ovary morphology, diagnostic criteria to exclude other causes of hyperandrogenism and amenorrhea, role of insulin resistance, and intervention. Results and Conclusion: Features of PCOS overlap normal pubertal development. Hence, caution should be taken before diagnosing PCOS without longitudinal evaluation. However, treatment may be indicated even in the absence of a definitive diagnosis. While obesity, insulin resistance, and hyperinsulinemia are common findings in adolescents with hyperandrogenism, these features should not be used to diagnose PCOS among adolescent girls.

Early Atherosclerosis Relates to Urinary Albumin Excretion and Cardiovascular Risk Factors in Adolescents With Type 1 Diabetes: Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT)

OBJECTIVE The origins of cardiovascular and renal disease in type 1 diabetes begin during childhood. We aimed to evaluate carotid (cIMT) and aortic intima-media thickness (aIMT) and their relationship with cardiovascular risk factors and urinary albumin excretion in adolescents with type 1 diabetes in the Adolescent Type 1 Diabetes cardio-renal Intervention Trial (AdDIT). RESEARCH DESIGN AND METHODS A total of 406 adolescents with type 1 diabetes, who were 14.1 ± 1.9 years old with type 1 diabetes duration of 6.7 ± 3.7 years, and 57 age-matched control subjects provided clinical and biochemical data and ultrasound measurements of vascular structure (cIMT and aIMT). Vascular endothelial and smooth muscle function was also measured in 123 of 406 with type 1 diabetes and all control subjects. RESULTS In type 1 diabetic subjects, mean/maximal aIMT (P < 0.006; <0.008), but not mean/maximal cIMT, was greater than in control subjects. Mean/maximal aIMT related to urinary albumin-to-creatinine ratio (multiple regression coefficient [SE], 0.013 [0.006], P = 0.03; 0.023 [0.007], P = 0.002), LDL cholesterol (0.019 [0.008], P = 0.02; 0.025 [0.011], P = 0.02), and age (0.010 [0.004], P = 0.004; 0.012 [0.005], P = 0.01), independent of other variables. Mean/maximal cIMT was greater in males (0.023 [0.006], P = 0.02; 0.029 [0.007], P < 0.0001), and mean cIMT related independently to systolic blood pressure (0.001 [0.001], P = 0.04). Vascular smooth muscle function related to aIMT and cIMT but not to urinary albumin excretion. CONCLUSIONS aIMT may be a more sensitive marker of atherosclerosis than cIMT in type 1 diabetes during mid-adolescence. Higher urinary albumin excretion, even within the normal range, is associated with early atherosclerosis and should direct clinical attention to modifiable cardiovascular risk factors.

Hypoglycemia, but not glucose variability, relates to vascular function in children with type 1 diabetes.

BACKGROUND Chronic sustained hyperglycemia unequivocally predicts vascular disease in diabetes. However, the vascular risk of glucose variability, including hypoglycemia, is uncertain. Vascular dysfunction is present in children with type 1 diabetes and is a critical precursor of atherosclerosis. We aimed to evaluate the relationship between glucose variability and vascular function in children with type 1 diabetes. SUBJECTS AND METHODS Fifty-two type 1 diabetes subjects (14 [SD 2.7] years old, 25 males) had continuous glucose monitoring that included 48 h of data used to evaluate glucose variability (mean amplitude of glycemic excursions [MAGE] and other measurements) and hypoglycemia indices (glycemic risk assessment diabetes equation [GRADE] hypoglycemia, Low Blood Glucose Index [LBGI], and observed duration of hypoglycemia). Children with type 1 diabetes and 50 age- and gender-matched controls had assessments of vascular function (flow-mediated dilatation [FMD] and glyceryl trinitrate-mediated dilatation [GTN]). RESULTS Children with type 1 diabetes had lower FMD and GTN than controls (P=0.02 and P<0.001, respectively). GRADE hypoglycemia and LBGI were inversely related to FMD (r=-0.36, P=0.009 and r=-0.302, P=0.03, respectively) but did not relate to GTN. GRADE hypoglycemia was independently related to FMD (regression coefficient=-0.25±0.09, P=0.006). MAGE and other measurements of glucose variability measurements did not relate to FMD or GTN. CONCLUSIONS Hypoglycemia, but not glucose variability, during continuous glucose monitoring relates to impaired vascular endothelial function in children with type 1 diabetes. Hypoglycemia may be an additional risk factor for early cardiovascular disease, but the effect of glucose variability, independent of glycosylated hemoglobin, on vascular function remains uncertain.

Adolescents with congenital adrenal hyperplasia because of 21-hydroxylase deficiency have vascular dysfunction

Context  Patients with congenital adrenal hyperplasia (CAH) because of 21‐hydroxylase deficiency have multiple vascular risk factors. Young adults with CAH have increased intima media thickness, but there have been no studies of vascular function and structure in children with CAH.

Hs-CRP is associated with weight, BMI, and female sex but not with endothelial function in children with type 1 diabetes.

Background:  Atherosclerosis is an inflammatory process, and high‐sensitivity C‐reactive protein (Hs‐CRP), a marker of inflammation, predicts cardiovascular events in adults. Vascular endothelial and smooth muscle dysfunction, measurable precursors of atherosclerosis, begin in childhood. Therefore, we sought to determine if Hs‐CRP is associated with vascular endothelial and smooth muscle dysfunction in children with type 1 diabetes mellitus (T1DM) and healthy control subjects.

Adiponectin relates to smooth muscle function and folate in obese children.

OBJECTIVE Adiponectin, an adipocyte-specific protein, stimulates nitric oxide production and may mediate associations between visceral obesity and vascular dysfunction. Adiponectin is lower in obese children but its relationship with vascular function has not been clarified in childhood. We aimed to evaluate the association between adiponectin and vascular function in obese and healthy children. METHODS Forty-nine obese and thirty-three non-obese children (aged 13.4+/-2.8 years, 37 males) participated in a cross-sectional study. We measured adiponectin, vascular endothelial and smooth muscle function (Flow mediated dilatation [FMD] and glyceryl trinitrate induced dilatation [GTN]), serum folate, red cell folate (RCF), homocysteine, lipids, glucose and insulin. Because adiponectin related to RCF we examined the effect of folate supplementation on adiponectin levels in obese children in a previously conducted randomized folate intervention trial. This included two assessments prior to intervention and two post intervention. RESULTS Adiponectin, FMD and GTN were lower in obese compared with non-obese children (p = 0.002, p = 0.03 and p < 0.001, respectively). In obesity, adiponectin related to GTN (beta = 0.46, p < 0.001), RCF (beta = 0.4, p = 0.001) and LDL cholesterol (beta = 0.33, p = 0.004). Adiponectin associations were affected by gender and adiponectin related to female gender (B = 0.22, p = 0.03). During the intervention trial, folic acid did not improve adiponectin levels (p = 0.8) in spite of increasing serum folate and RCF (p < 0.001, p < 0.001, respectively) and decreasing homocysteine levels (p = 0.008). CONCLUSIONS Obese children have lower adiponectin, which relates to decreased smooth muscle function and lower folate status. Despite adiponectin relating to folate status, folic acid supplementation does not improve adiponectin in obese children.

Vascular function and glucose variability improve transiently following initiation of continuous subcutaneous insulin infusion in children with type 1 diabetes

The effect of continuous subcutaneous insulin infusion (CSII) and glucose variability on vascular health in type 1 diabetes (T1D) is not known. We aimed to determine whether initiation of CSII improves vascular function and reduces glucose variability, independent of changes in HbA1c.

An International Consortium Update: Pathophysiology, Diagnosis, and Treatment of Polycystic Ovarian Syndrome in Adolescence.

This paper represents an international collaboration of paediatric endocrine and other societies (listed in the Appendix) under the International Consortium of Paediatric Endocrinology (ICPE) aiming to improve worldwide care of adolescent girls with polycystic ovary syndrome (PCOS)1. The manuscript examines pathophysiology and guidelines for the diagnosis and management of PCOS during adolescence. The complex pathophysiology of PCOS involves the interaction of genetic and epigenetic changes, primary ovarian abnormalities, neuroendocrine alterations, and endocrine and metabolic modifiers such as anti-Müllerian hormone, hyperinsulinemia, insulin resistance, adiposity, and adiponectin levels. Appropriate diagnosis of adolescent PCOS should include adequate and careful evaluation of symptoms, such as hirsutism, severe acne, and menstrual irregularities 2 years beyond menarche, and elevated androgen levels. Polycystic ovarian morphology on ultrasound without hyperandrogenism or menstrual irregularities should not be used to diagnose adolescent PCOS. Hyperinsulinemia, insulin resistance, and obesity may be present in adolescents with PCOS, but are not considered to be diagnostic criteria. Treatment of adolescent PCOS should include lifestyle intervention, local therapies, and medications. Insulin sensitizers like metformin and oral contraceptive pills provide short-term benefits on PCOS symptoms. There are limited data on anti-androgens and combined therapies showing additive/synergistic actions for adolescents. Reproductive aspects and transition should be taken into account when managing adolescents.

Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome

Study Question: What is the recommended assessment and management of women with polycystic ovary syndrome (PCOS), based on the best available evidence, clinical expertise, and consumer preference? Summary Answer: International evidence-based guidelines including 166 recommendations and practice points, addressed prioritized questions to promote consistent, evidence-based care and improve the experience and health outcomes of women with PCOS. What Is Known Already: Previous guidelines either lacked rigorous evidence-based processes, did not engage consumer and international multidisciplinary perspectives, or were outdated. Diagnosis of PCOS remains controversial and assessment and management are inconsistent. The needs of women with PCOS are not being adequately met and evidence practice gaps persist. Study Design, Size, Duration: International evidence-based guideline development engaged professional societies and consumer organizations with multidisciplinary experts and women with PCOS directly involved at all stages. Appraisal of Guidelines for Research and Evaluation (AGREE) II-compliant processes were followed, with extensive evidence synthesis. The Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) framework was applied across evidence quality, feasibility, acceptability, cost, implementation and ultimately recommendation strength. Participants/Materials, Setting, Methods: Governance included a six continent international advisory and a project board, five guideline development groups, and consumer and translation committees. Extensive health professional and consumer engagement informed guideline scope and priorities. Engaged international society-nominated panels included pediatrics, endocrinology, gynecology, primary care, reproductive endocrinology, obstetrics, psychiatry, psychology, dietetics, exercise physiology, public health and other experts, alongside consumers, project management, evidence synthesis, and translation experts. Thirty-seven societies and organizations covering 71 countries engaged in the process. Twenty face-to-face meetings over 15 months addressed 60 prioritized clinical questions involving 40 systematic and 20 narrative reviews. Evidence-based recommendations were developed and approved via consensus voting within the five guideline panels, modified based on international feedback and peer review, with final recommendations approved across all panels. Main Results and the Role of Chance: The evidence in the assessment and management of PCOS is generally of low to moderate quality. The guideline provides 31 evidence based recommendations, 59 clinical consensus recommendations and 76 clinical practice points all related to assessment and management of PCOS. Key changes in this guideline include: i) considerable refinement of individual diagnostic criteria with a focus on improving accuracy of diagnosis; ii) reducing unnecessary testing; iii) increasing focus on education, lifestyle modification, emotional wellbeing and quality of life; and iv) emphasizing evidence based medical therapy and cheaper and safer fertility management. Limitations, Reasons for Caution: Overall evidence is generally low to moderate quality, requiring significantly greater research in this neglected, yet common condition, especially around refining specific diagnostic features in PCOS. Regional health system variation is acknowledged and a process for guideline and translation resource adaptation is provided. Wider Implications of the Findings: The international guideline for the assessment and management of PCOS provides clinicians with clear advice on best practice based on the best available evidence, expert multidisciplinary input and consumer preferences. Research recommendations have been generated and a comprehensive multifaceted dissemination and translation program supports the guideline with an integrated evaluation program. Study Funding/Competing Interest(S): The guideline was primarily funded by the Australian National Health and Medical Research Council of Australia (NHMRC) supported by a partnership with ESHRE and the American Society for Reproductive Medicine. Guideline development group members did not receive payment. Travel expenses were covered by the sponsoring organizations. Disclosures of conflicts of interest were declared at the outset and updated throughout the guideline process, aligned with NHMRC guideline processes. Full details of conflicts declared across the guideline development groups are available at https://www.monash.edu/medicine/sphpm/mchri/pcos/guideline in the Register of disclosures of interest. Of named authors, Dr Costello has declared shares in Virtus Health and past sponsorship from Merck Serono for conference presentations. Prof. Laven declared grants from Ferring, Euroscreen and personal fees from Ferring, Euroscreen, Danone and Titus Healthcare. Prof. Norman has declared a minor shareholder interest in an IVF unit. The remaining authors have no conflicts of interest to declare. The guideline was peer reviewed by special interest groups across our partner and collaborating societies and consumer organizations, was independently assessed against AGREEII criteria and underwent methodological review. This guideline was approved by all members of the guideline development groups and was submitted for final approval by the NHMRC