Progress in pediatric obesity: new and advanced therapies.

PURPOSE OF REVIEW: In this review, we discuss new medical and surgical options for the treatment of children and adolescents with obesity. We review the impact of COVID-19 on this vulnerable population. We also discuss the recent availability of screening tests for rare genetic causes of obesity. RECENT FINDINGS: COVID-19 increased the prevalence of obesity among children and adolescents. This population is at increased risk for severe disease. The field of pediatric obesity has benefited from the approval of two new antiobesity medications: liraglutide and setmelanotide. We discuss indications for their use. New guidelines for surgical options for the treatment of children and adolescents with obesity are reviewed. These options are increasingly used as part of the comprehensive care for these children. SUMMARY: The epidemic of childhood obesity continues. COVID-19 and the associated isolation contributed to the problem. However, promising new medical and surgical therapies and screening tests for rare genetic causes of obesity are available. These new diagnostic and therapeutic options bring renewed enthusiasm to the treatment of children and adolescents with obesity and increased recognition that obesity is a chronic disease starting in childhood deserving intervention to prevent consequences.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity.

BACKGROUND: Adolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT). METHODS: Retrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017. RESULTS: In 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]). CONCLUSIONS: In a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Diet and Physical Activity by Prediabetes Status Among U.S. Adolescents: National Health and Nutrition Examination Survey, 2007-2018.

Background: Prediabetes among adolescents is on the rise, yet it is unclear if modifiable risk factors vary by prediabetes status. Methods: This study examined associations between diet (primary objective) and physical activity (secondary objective) by prediabetes status among U.S. adolescents (12-19 years) who participated in the National Health and Nutrition Examination Survey from 2007-2018. Differences in Healthy Eating Index (HEI)-2015-2020 scores (total and 13 component scores), nutrients of public health concern, and physical activity were examined by prediabetes status (no prediabetes vs. prediabetes). Results: Adolescents (n = 2,487) with prediabetes had significantly lower whole grains component scores and intakes of vitamin D, phosphorus, and potassium (all p < .05), than adolescents without prediabetes. Physical activity levels were not optimal for either group, there were no differences by prediabetes status (n = 2,188). Conclusion: Diabetes prevention interventions for adolescents are needed and should promote a healthy diet target and encourage physical activity.

Special considerations for the adolescent with obesity: An obesity medicine association (OMA) clinical practice statement (CPS) 2024.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details special considerations for the management of the adolescent with obesity. The information in this CPS is based on scientific evidence, supported by medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS are based on scientific evidence, supported by the medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement addresses special considerations in the management and treatment of adolescents with overweight and obesity. Conclusions: This OMA Clinical Practice Statement on the adolescent with obesity is an overview of current recommendations. These recommendations provide a roadmap to the improvement of the health of adolescents with obesity, especially those with metabolic, physiological, and psychological complications. This CPS also addresses treatment recommendations and is designed to help the provider with clinical decision making.

Special considerations for the child with obesity: An Obesity Medicine Association (OMA) clinical practice statement (CPS) 2024.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details assessment and management of the child with overweight or obesity. The term "child" is defined as the child between 2 and 12 years of age. Because children are in a continual state of development during this age range, we will specify when our discussion applies to subsets within this age range. For the purposes of this CPS, we will use the following definitions: overweight in the child is a body mass index (BMI) ≥ 85th and <95th percentile, obesity in the child is a BMI ≥95th percentile, and severe obesity is a BMI ≥120% of the 95th percentile. Methods: The information and clinical guidance in this OMA Clinical Practice Statement are based on scientific evidence, supported by medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement provides an overview of prevalence of disease in this population, reviews precocious puberty in the child with obesity, discusses the current and evolving landscape of the use of anti-obesity medications in children in this age range, discusses the child with obesity and special health care needs, and reviews hypothalamic obesity in the child. Conclusions: This OMA Clinical Practice Statement on the child with obesity is an evidence based review of the literature and an overview of current recommendations. This CPS is intended to provide a roadmap to the improvement of the health of children with obesity, especially those with metabolic, physiological, psychological complications and/or special healthcare needs. This CPS addresses treatment recommendations and is designed to help the clinician with clinical decision making.

Setmelanotide: a promising advancement for pediatric patients with rare forms of genetic obesity.

PURPOSE OF REVIEW: Examine Setmelanotide use in patients with rare genetic variants that disrupt the melanocortin pathway. RECENT FINDINGS: Between February 2017 and September 2018, 10 participants with pro-opiomelanocortin (POMC)/ proprotein convertase subtilisin/kexin type 1 (PCSK1) deficiency and 11 participants with leptin receptor (LEPR) deficiency were enrolled in open-label, phase 3 trials at 10 centers in the United States and internationally to assess the efficacy and safety of the melanocortin-4 receptor (MC4R) agonist Setmelanotide. 80% of POMC participants and 45% of LEPR participants achieved at least 10% weight loss at 1 year. Significant changes in hunger scores were seen for both cohorts as well. Setmelanotide was well tolerated with injection site reactions and hyperpigmentation being the most common adverse events reported. As a result, Setmelanotide was approved by the U.S. FDA in 2020 for chronic weight management in adult and pediatric patients ≥6 years of age with POMC, LEPR, or PCSK1 deficiency. In 2022, its approval was extended to include patients with Bardet-Biedel syndrome (BBS) after phase 3 trial data showed that, on average, Setmelanotide treatment resulted in a BMI loss of 7.9% for the 44 BBS participants. SUMMARY: Rare genetic variants such as POMC, LEPR, and PCSK1 deficiency disrupt MC4R pathway signaling, resulting in severe early-onset obesity, hyperphagia, and increased risk for metabolic co-morbidities. Patients with BBS also demonstrate severe early-onset obesity and hyperphagia, due in part to defective MC4R signaling. Setmelanotide has shown promising benefits in improving satiety scores and weight-related outcomes in patients with these early-life genetic obesity conditions, although longer-term studies are needed.

Clinical review: Guide to pharmacological management in pediatric obesity medicine.

Introduction: Newer pharmacotherapy agents (anti-obesity medication [AOM]) are revolutionizing the management of children and adolescents with obesity. Previously, treatment based on intensive behavioral therapy involved many patient and family contact hours and yielded improvements in obesity status of 1-3 percent of the 95th percentile of the body mass index (BMI). Newer AOMs are yielding more clinically significant improvement of 5-18 percent. This review provides guidance for practitioners in the care of children and adolescents with obesity who frequently have complex medical and behavioral health care needs. Specifically, we discuss the use of newer AOMs in these complex patients. Methods: This review details an approach to the care of the child and adolescent with obesity using AOMs. A shared decision-making process is presented in which the provider and the patient and family collaborate on care. Management of medical and behavioral components of the disease of obesity in the child are discussed. Results: Early aggressive treatment is recommended, starting with an assessment of associated medical and behavioral complications, weight promoting medications, use of AOMs and ongoing care. Intensive behavioral therapy is foundational to treatment, but not a specific treatment. Patients and families deserve education on expected outcomes with each therapeutic option. Conclusions: The use of new AOMs in children and adolescents has changed expected clinical outcomes in the field of pediatric obesity management. Clinically significant improvement in obesity status occurs when AOMs are used early and aggressively. Ongoing, chronic care is the model for optimizing outcomes using a shared decision-making between provider and patient/family. Depending on the experience and comfort level of the primary care practitioner, referral to an obesity medicine specialist may be appropriate, particularly when obesity related co-morbidities are present and pharmacotherapy and metabolic and bariatric surgery are considerations.

Artificial intelligence and obesity management: An Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) 2023.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) provides clinicians an overview of Artificial Intelligence, focused on the management of patients with obesity. Methods: The perspectives of the authors were augmented by scientific support from published citations and integrated with information derived from search engines (i.e., Chrome by Google, Inc) and chatbots (i.e., Chat Generative Pretrained Transformer or Chat GPT). Results: Artificial Intelligence (AI) is the technologic acquisition of knowledge and skill by a nonhuman device, that after being initially programmed, has varying degrees of operations autonomous from direct human control, and that performs adaptive output tasks based upon data input learnings. AI has applications regarding medical research, medical practice, and applications relevant to the management of patients with obesity. Chatbots may be useful to obesity medicine clinicians as a source of clinical/scientific information, helpful in writings and publications, as well as beneficial in drafting office or institutional Policies and Procedures and Standard Operating Procedures. AI may facilitate interactive programming related to analyses of body composition imaging, behavior coaching, personal nutritional intervention & physical activity recommendations, predictive modeling to identify patients at risk for obesity-related complications, and aid clinicians in precision medicine. AI can enhance educational programming, such as personalized learning, virtual reality, and intelligent tutoring systems. AI may help augment in-person office operations and telemedicine (e.g., scheduling and remote monitoring of patients). Finally, AI may help identify patterns in datasets related to a medical practice or institution that may be used to assess population health and value-based care delivery (i.e., analytics related to electronic health records). Conclusions: AI is contributing to both an evolution and revolution in medical care, including the management of patients with obesity. Challenges of Artificial Intelligence include ethical and legal concerns (e.g., privacy and security), accuracy and reliability, and the potential perpetuation of pervasive systemic biases.

Assessment, differential diagnosis, and initial clinical evaluation of the pediatric patient with obesity: An Obesity Medical Association (OMA) Clinical Practice Statement 2022.

Background: The Obesity Medical Association (OMA) Clinical Practice Statement (CPS) on the assessment, differential diagnosis, and initial clinical evaluation of pediatric patients with obesity is intended to provide clinicians with an overview of clinical practices applicable to children and adolescents with body mass indexes greater than or equal to the 95th percentile for their ages, particularly those with adverse consequences resulting from increased body mass. The information in this CPS is based on scientific evidence, supported by the medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS is based upon referenced evidence and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement on assessment, differential diagnosis, and initial clinical evaluation of pediatric patients with obesity provides clinical information regarding classification of children and adolescents with overweight or obesity, differential diagnoses to consider, and a roadmap for the initial clinical evaluation. Conclusions: This OMA Clinical Practice Statement on assessment, differential diagnosis, and initial clinical evaluation of pediatric patients with obesity is an overview of current recommendations. Assessment of pediatric patients with obesity is the first step in determining treatments leading to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications.

Obesity pillars roundtable: Obesity and individuals from the Mediterranean region and Middle East.

Background: The rates of obesity in Mediterranean and Middle East regions are increasing. This may be related to worsening physical inactivity, and gravitation away from more healthful nutrition. Methods: This roundtable discussion includes 4 obesity specialists with experience in the clinical management of obesity. Included in this discussion are citations regarding obesity and populations from the Mediterranean and Middle East regions. Results: Among the most studied nutritional dietary pattern having evidence-based data supporting improved cardiometabolic health is the Mediterranean Diet. Prospective studies such as the PREvención con DIeta MEDiterránea (PREDIMED) study support the cardiometabolic benefits of dietary consumption of plant-based, higher fiber foods having a relatively high proportion of unsaturated fats. Cuisine from the Middle East has both similarities and some differences compared to the Mediterranean Diet. Interim analyses of the PREDIMED-Plus study suggest the Mediterranean Diet plus caloric restriction and physical activity intervention reduces body weight and improves cardiometabolic risk factors. As with any dietary intake, Mediterranean and Middle Eastern food choices and preparation affect their nutritional healthfulness. Conclusion: The panelists of this roundtable discussion describe their practical diagnostic processes and treatment plans for patients with obesity from the Mediterranean Region and Middle East.

Corrigendum to "Social consequences and genetics for the child with overweight and obesity: An obesity medicine association (OMA) clinical practice statement 2022" [Obes. Pillars 3 (2022) 100032].

[This corrects the article DOI: 10.1016/j.obpill.2022.100032.].

Metabolic, behavioral health, and disordered eating comorbidities associated with obesity in pediatric patients: An Obesity Medical Association (OMA) Clinical Practice Statement 2022.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children. This CPS will be followed by a companion CPS covering further comorbidities, including genetics and social consequences related to overweight and obesity. These CPSs are intended to provide clinicians with an overview of clinical practices applicable to children and adolescents with body mass indices greater than or equal to the 95th percentile for their ages, particularly those with adverse consequences resulting from increased body mass. The information in this CPS is based on scientific evidence, supported by the medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS is based upon referenced evidence and derived from the clinical perspectives of the authors. Results: This OMA statement details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children. It provides clinical information regarding identifying and treating metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children over the 95th percentile of weight/height for age. Conclusions: This OMA clinical practice statement details metabolic, behavioral health, and disordered eating comorbidities associated with obesity in children and provides an overview of current recommendations. These recommendations lay out a roadmap to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications.

Social consequences and genetics for the child with overweight and obesity: An obesity medicine association (OMA) clinical practice statement 2022.

Background: This Obesity Medicine Association (OMA) clinical practice statement (CPS) covers two topics: 1) genetics and 2) social consequences for the child with overweight and obesity. This CPS is intended to provide clinicians with an overview of clinical practices applicable to children and adolescents with body mass indices greater than or equal to the 85th percentile for their ages, particularly those with adverse consequences resulting from increased body mass. The information in this CPS is based on scientific evidence, supported by the medical literature, and derived from the clinical experiences of members of the OMA. Methods: The scientific information and clinical guidance in this CPS is based upon referenced evidence and derived from the clinical perspectives of the authors. Results: This OMA clinical practice statement details two topics: 1) genetics and 2) social consequences for the child with overweight and obesity. Conclusions: This OMA clinical practice statement on genetics and social consequences for the child with overweight and obesity is an overview of current literature. The literature provides a roadmap to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications.

Medication-induced weight gain and advanced therapies for the child with overweight and obesity: An Obesity Medicine Association (OMA) Clinical Practice Statement 2022.

Background: This Obesity Medicine Association (OMA) Clinical Practice Statement (CPS) details medication-induced weight gain and advanced therapies for the child with overweight or obesity. Methods: The scientific information and clinical guidance in this CPS are based on scientific evidence, supported by the medical literature, and derived from the clinical perspectives of the authors. Results: This OMA Clinical Practice Statement addresses medication-induced weight gain and advanced therapies for the child with overweight or obesity. Conclusions: This OMA Clinical Practice Statement on medication induced-weight gain and advanced therapies for the child with overweight or obesity is an overview of current recommendations. These recommendations provide a roadmap to the improvement of the health of children and adolescents with obesity, especially those with metabolic, physiological, and psychological complications. This CPS also addresses treatment recommendations. This section is designed to help the provider with clinical decision making.

13-Year-Old Boy Presenting with Bilateral Femur Fractures in the Setting of Severe Vitamin D Deficiency.

BACKGROUND: Femur fractures in adolescents are rare. Severe vitamin D deficiency has important implications for bone health. We describe the case of a 13-year-old boy with autism spectrum disorder (ASD) who presented with low-impact bilateral femur fractures in the setting of severe vitamin D deficiency. Case Presentation. A 13-year-old boy with ASD presented with bilateral leg pain after an unwitnessed fall. Laboratory investigations revealed severe hypocalcemia (S. calcium 4.9 mg/dL) and severe vitamin D deficiency (25(OH)D < 4 ng/mL). Lower extremity X-rays revealed bilateral distal femoral metaphyseal fractures. CONCLUSION: This is the youngest known case of bilateral femoral fractures in the setting of severe 25(OH)D deficiency. Children with ASD are especially at risk for 25(OH)D deficiency as many have inadequate nutritional intake. As such, primary care providers may provide a pivotal role in the routine laboratory screening of 25(OH)D in this population.

Changes in body mass index in children on gonadotropin-releasing hormone agonist therapy with precocious puberty, early puberty or short stature.

Background The use of gonadotropin-releasing hormone agonists (GnRHa) for pubertal suppression has been associated with increased body mass index (BMI) in female subjects with central precocious puberty (CPP), although results have been so far conflicting. This study examined the effects of GnRHa therapy in both genders and in subjects treated for CPP, early puberty or short stature. Methods This was a longitudinal retrospective study of subjects followed at outpatient pediatric endocrinology clinics of an academic medical center from 2005 to 2014 receiving GnRHa therapy. Results At 12 months, subjects on depot GnRHa had a statistically significant increase in BMI standard deviation score (SDS) from baseline (0.13 ± 0.35, p < 0.02). Subjects with short stature (0.17 ± 0.34, p < 0.02) but not early or precocious puberty, and subjects with normal baseline BMI (0.18 ± 0.38, p < 0.02) had significant increases in BMI SDS; no significance was noted at 24 months. Male subjects did not have a significant increase in BMI SDS, whereas female subjects did (0.11 ± 0.36, p < 0.01). Conclusions Subjects with short stature, normal BMI at baseline and female sex had significant increases in BMI SDS at 12 months. This is the first study to show an increase in BMI SDS in children treated with GnRHa for short stature, and is one of the few studies to assess BMI changes in males.

Growth Failure and Excessive Weight Gain in a 10 Year Old Male With Obesity: Approach to Diagnosis, Management, and Treatment of Acquired Hypothyroidism.

We report the case of a 10 year old male with severe obesity who presented with a 2 year history of significant growth failure and excessive weight gain that was subsequently diagnosed with serum negative Hashimoto's thyroiditis and acquired hypothyroidism. Initial investigations revealed a markedly elevated thyroid stimulating hormone (TSH) concentration >100 uIU/mL and an undetectable free thyroxine with total thyroxine 0.56 ug/dL. Thyroid antibodies were negative, however ultrasound findings were consistent with Hashimoto's thyroiditis. After treatment with levothyroxine supplementation, he had significant weight loss and marked improvement in his growth velocity. This case emphasizes the need to recognize excessive weight gain and growth failure as an initial presentation of Hashimoto's thyroiditis and highlights management and approach to treatment. Diagnosis and treatment is vital as prolonged undiagnosed hypothyroidism can result in incomplete catch up growth and compromised final adult height.

Pediatric Obesity Algorithm: A Practical Approach to Obesity Diagnosis and Management.

Childhood obesity is a growing global health problem. Despite the highest rates of childhood obesity in the United States and other developed countries over the last 30 years, there is still no clear treatment strategy. Practitioners often do not know where to turn to find guidance on managing the nearly one third of their population who present for medical care either with obesity that coexists with other medical problems or because of obesity. The Pediatric Obesity Algorithm is an evidence based roadmap for the diagnosis and management of children with obesity. In this article, we summarize topics from the Pediatric Obesity Algorithm pertaining to pediatric obesity diagnosis, evaluation, and management including assessment, differential diagnosis, review of systems, diagnostic work up, physical exam, age specific management, comorbidities, use of medications and surgery, and medication associated weight gain. Identifying and treating children with obesity as early as possible is important, as is identifying comorbid conditions. Earlier and more comprehensive management through resources such as the Pediatric Obesity Algorithm serve to help guide health care practitioners with a practical and evidence based approach to the diagnosis and management of children with obesity, and provide families with the tools needed for a healthy future.

Vitamin D Deficiency Associated With Markers of Cardiovascular Disease in Children With Obesity.

Adult studies have reported associations of low 25-hydroxyvitamin D (25OHD) with dyslipidemia and cardiovascular disease; however, there are scarce pediatric data regarding relationships between vitamin D status and specific lipid markers affecting cardiovascular risk. In this cross-sectional study of children evaluated at university-based pediatric endocrinology clinics, 178 patients meeting criteria for overweight or obesity had 25OHD levels assessed over a 2-year period; 60 of 178 had non-HDL (high-density lipoprotein) cholesterol and fasting lipid parameters performed. Patients with 25OHD <20 ng/mL had significantly higher non-HDL cholesterol (134.76 ± 47.32 vs 108.85 ± 31.14, P < .03), triglyceride (TG)/HDL ratio (3.09 ± 2.26 vs 1.82 ± 1.18, P = .03), total cholesterol (TC)/HDL ratio (4.23 ± 1.23 vs 3.40 ± 1.05, P < .01), TC (184.15 ± 40.19 vs 158.89 ± 30.10, P < .01), and TG (134.76 ± 47.32 vs 78.93 ± 37.46, P < .03) compared with 25OHD ≥20 ng/mL. Vitamin D deficiency was significantly associated with increase in atherogenic lipids and markers of early cardiovascular disease. These findings suggest that vitamin D deficiency may have negative effects on lipid parameters with increase in cardiovascular risk.

Long-term follow-up of gonadal dysfunction in morbidly obese adolescent boys after bariatric surgery.

Background Elevated body mass index (BMI) is associated with hypogonadism in men but this is not well described in adolescents. The aim is to evaluate gonadal dysfunction and the effects of weight loss after gastric banding in obese adolescent boys. Methods Thirty-seven of 54 boys (age 16.2±1.2 years, mean BMI 48.2 kg/m2) enrolled at the Center for Adolescent Bariatric Surgery at Columbia University Medical Center had low total testosterone for Tanner 5 <350 ng/dL. Sixteen had long-term hormonal data for analysis at baseline (T0), 1 year (T1) and 2 years (T2) post-surgery. T-tests, chi-squared (χ2) tests, correlation and linear mixed models were performed. Results At T0, the hypogonadal group had higher systolic blood pressure (SBP) (75th vs. 57th percentile, p=0.02), fasting insulin (19 vs. 9 µIU/mL, p=0.0008) and homeostatic index of insulin resistance (HOMA-IR) (4.2 vs. 1.9, p=0.009) compared to control group. Total testosterone was negatively correlated with fasting insulin and HOMA-IR. In the long-term analysis, BMI, weight, waist circumference (WC), and % excess weight decreased at T1 and T2 compared to T0. Mean total testosterone at T0, T1 and T2 were 268, 304 and 368 ng/dL, respectively (p=0.07). There was a statistically significant negative correlation between BMI and testosterone after 2 years (r=-0.81, p=0.003). Conclusions Low testosterone levels but unaltered gonadotropins are common in this group and associated with insulin resistance. While a significant increase in testosterone was not found over time, the negative relationship between BMI and testosterone persisted, suggesting there may be an optimal threshold for testosterone production with respect to BMI. Long-term studies are needed.