A Natural History of Genetic and Environmental Predictors of Pubertal Timing Among Youth With Obesity

Overview

Background: Obesity affects 1 in 5 children in the United States. Childhood obesity often persists into adolescence and adulthood. It can also raise the risk of sleep apnea, fatty liver disease, and fluid buildup in the brain and lead to early-onset puberty. This natural history study will explore how factors such as genes, hormones, diet, and chemical exposures affect puberty in children with obesity. Objective: To learn which factors predict the early start of puberty in children with obesity vs those of normal weight. Eligibility: Children aged 5 to 7 years with obesity or of normal weight. Design: Participants will have clinic visits every 6 months until they reach age 12. Each clinic visit will include these tests and procedures: A physical exam. Collection of blood, urine, and saliva samples. Some samples will be used for genetic tests. Questions about medical history and medications and supplements. A questionnaire about their physical activity over the previous week. A silicone wrist band. Participants will wear a soft wristband for a week prior to each visit. It will tell researchers what chemicals the children were exposed to during that time. Breast ultrasound, for girls. A gel will be applied, and a wand will be pressed against the skin. The wand uses sound waves to see the tissue inside the breast. DXA whole body scan. Once a year, participants will have a DXA (dual energy X-ray absorptiometry) scan. This scan measures the amount of bone, muscle, and fat in the body. Optional food diary. Parents may record everything the participant eats for two 24-hour periods ...

Detailed description

Study Description:

This is a longitudinal study to predict pubertal timing in 5-12-year-old girls and boys with obesity. We hypothesize that: 1) Children with obesity with exposure to estrogenic environmental compounds will demonstrate earlier puberty than those without such an exposure. 2) A polygenic risk score (PRS) of alleles that confer risk for voice break in boys will associate with age at Tanner II pubertal development in boys with obesity. 3) A polygenic risk score (PRS) of alleles that confer risk for menarche in girls will associate with age at stage II pubertal development in girls with obesity. 4) Children with obesity who demonstrate a decrease in BMI percentile of \> 5 percentage points will demonstrate later stage II pubertal development than children with no change or an increase in BMI percentile but will demonstrate earlier pubertal development than peers of normal weight.

Objectives:

* Primary Objective: To identify predictors of pubertal timing in 5-12-year old children with obesity. * Secondary Objectives: To determine the effect of obesity on reproductive hormones and adrenarche.

Endpoints:

* Primary Endpoint: pubertal markers by questionnaire, physical exam (testicular volume, breast development), and ultrasound (breast morphological stage). Pubertal development will be defined as breast morphological stage B and a testicular volume of 4 cc. * Secondary Endpoints: Tanner pubic hair staging, reproductive hormones (luteinizing hormone (LH), Follicle-stimulating hormone (FSH), estradiol, total testosterone, dehydroepiandrosterone sulfate (DHEAS), androstenedione)

Interventions

• Behavioral Weight loss intervention
  Pediatric Weight Management Clinic, which utilizes multiple, individualized strategies to effect weight loss (such as nutrition, behavioral therapy, exercise programs)
• Behavioral No Weight loss intervention
  No strategies for weight loss

Primary outcome measures

• To identify predictors of pubertal timing in 5-12-year-old children with obesity [Time frame: 1. Every 6 months2. Every 6 - 12 months, investigator discretion]

Secondary outcome measures (1)

• To determine the effect of obesity on reproductive hormones and adrenarche. [Time frame: Every 6 months]

Eligibility criteria

• INCLUSION CRITERIA:

To be eligible to participate in this study, an individual must meet all of the following criteria:

• Stated willingness to comply with all study procedures and availability for the duration of the study, including sharing medical records
• Male or female, aged 5 to 7 years at the screening visit
• Normal weight (defined as BMI > 5th percentile and <85th percentile for age and sex) or Obese weight (defined as BMI > 95th percentile for age and sex)
• Ability of parent or guardian to understand and willingness to sign a written informed consent document. And ability of the participant (child) to provide verbal assent and/or to sign a written assent document.

Exclusion criteria

An individual who meets any of the following criteria will be excluded from participation in this study:

• Known diagnosis of syndromic/genetic form of obesity
• Current use of medications or supplements that affect reproductive hormones (e.g., estrogen, progesterone, testosterone, puberty blockers, regular use of lavender oil or tea tree oil)
• Chronic medical conditions (e.g., type 1 or type 2 diabetes, cancer, renal failure, lupus, etc.), at the discretion of the Principal Investigator
• Clinically significant abnormal laboratory values, at the discretion of the Principal Investigator
• International adoptee (associated with earlier puberty)

Individuals who do not meet the criteria for participation in this study (screen failure) because of an acute, reversible or transient medical reason may be rescreened upon reversal, improvement or stabilization of their clinical status. Participants who develop an acute, reversible or transient medical condition during the study may return upon reversal, improvement or stabilization of their clinical status.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Observational model

Cohort

Study locations

United States · 1 center

• National Institute of Environmental Health Sciences Clinical Research Unit — Research Triangle Park

Publications

• Li W, Liu Q, Deng X, Chen Y, Liu S, Story M. Association between Obesity and Puberty Timing: A Systematic Review and Meta-Analysis. Int J Environ Res Public Health. 2017 Oct 24;14(10):1266. doi: 10.3390/ijerph14101266. PMID 29064384
• Ortega MT, McGrath JA, Carlson L, Flores Poccia V, Larson G, Douglas C, Sun BZ, Zhao S, Beery B, Vesper HW, Duke L, Botelho JC, Filie AC, Shaw ND. Longitudinal Investigation of Pubertal Milestones and Hormones as a Function of Body Fat in Girls. J Clin Endocrinol Metab. 2021 May 13;106(6):1668-1683. doi: 10.1210/clinem/dgab092. PMID 33630047
• Carlson L, Flores Poccia V, Sun BZ, Mosley B, Kirste I, Rice A, Sridhar R, Kangarloo T, Vesper HW, Duke L, Botelho JC, Filie AC, Adams JM, Shaw ND. Early breast development in overweight girls: does estrogen made by adipose tissue play a role? Int J Obes (Lond). 2019 Oct;43(10):1978-1987. doi: 10.1038/s41366-019-0446-5. Epub 2019 Aug 28. PMID 31462689

Identifiers

NCT: NCT07437976 · 10002237 · 002237-E

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗