Effects of Glucagon-like Peptide-1 (GLP-1) Agonist in Neuro-reproductive Function in Obese Adolescent Females With Polycystic Ovary Syndrome (PCOS)

The prevalence of childhood obesity in the United States has more than tripled in the past four decades affecting one in every five adolescent girls and is disproportionally higher among racial and/or ethnic minorities. Normal puberty onset and progression is dependent on normal hypothalamic-pituitary-gonadal (HPG) axis which is affected by whole body metabolism. Gonadotropin-releasing hormone (GnRH) and gonadotropins, LH and FSH, are released in a pulsatile manner for appropriate sex steroids production and gonadal function. Proper pulsatility in the GnRH system is disrupted by a significant change in energy balance such as in obesity. Polycystic Ovary Syndrome (PCOS) is the most common neuroendocrine dysfunction in women of reproductive age.

Glucagon-like peptide-1 (GL-1), a peptide hormone secreted by the intestinal enteroendocrine L-cells following glucose and fat intake, stimulates insulin release by the pancreas in response to glucose, decreases gastric emptying and inhibits glucagon secretion. GLP-1 receptors are present in the hypothalamic nuclei and pituitary gland; and it is thought that GLP-1 may directly stimulate GnRH secretion and partially regulate reproduction. In animal studies, GLP-1 was found to stimulate GnRH secretion, to regulate kisspeptin (Kiss-1) mRNA and GnRH mRAN expression. GLP-1 receptor agonists are established diabetes drugs that are also promising anti-obesity drugs and are FDA-approved to treat adults and adolescents with obesity. Although the impact of GLP-1 receptor agonists in reproductive health has been investigated in preclinical trials, and in men with obesity and functional hypogonadism, no studies to date have investigated the impact of GLP-1 receptor agonists in female neuroendocrine function, particularly in youth.

The goal of this proposal is to gather critical preliminary data to investigate, in a group of obese adolescent females with oligomenorrhea due to PCOS, the impact of GLP-1 agonist administration in addition to lifestyle modifications on -

Aim 1. neuroendocrine rhythms - LH frequency and amplitude (principal); Aim 2. body composition; Aim 3. carbohydrate metabolism and insulin sensitivity. The investigators hypothesize that 16 weeks intervention with a GLP-1 agonist will result in improvement of gonadotropin release patterns.

To accomplish these aims, the investigators will recruit a cohort of up to 20 adolescents ages 12-18 years, at least 2 years post-menarche, with obesity (BMI-for-age equal to or more than the 95th percentile), with PCOS, by NIH criteria: oligomenorrhea and hyperandrogenism (testosterone level or free androgen index > refence range for tanner stage.), without carbohydrate intolerance and in otherwise good health. Research volunteers will be advised on lifestyle modifications of diet and exercise as per routine, and a GLP-1 agonist will be started according to the product's label as per FDA guidelines in children with obesity. Medication will be titrated to maximal therapeutic dose, as per routine clinical practice, and continued for a total of 16 weeks.

Principal Study Outcomes

• Reproductive measures will include change in: LH pulse frequency and amplitude, average levels of LH and FSH, and estradiol, total testosterone
• Body composition will be measured by dual x-ray absorptiometry (DXA) scan
• Carbohydrate metabolism and insulin sensitivity will be measured by HOMA-IR (using fasting insulin and glucose levels).

Inclusion criteria

• Diagnosed with PCOS, by NIH criteria: oligomenorrhea (menstrual cycles <21 or >35 days) and hyperandrogenism (testosterone level or free androgen index (FAI) > refence range for tanner stage) and in good overall health
• Obesity (equal to or more than the 95th percentile)
• Females ages 12 to 18 years, at least 2 years post-menarche
• Participants has persistent symptoms of PCOS and obesity despite lifestyle modifications for at least 4 months.

Exclusion criteria

• Has abnormal thyroid function tests at Screening.
• Has suspected or known Diabetes mellitus, impaired fasting glucose, or elevated hemoglobin A1c.
• Has non-classic congenital adrenal hyperplasia.
• Has hyperprolactinemia.
• Has a known history or family history of medullary thyroid carcinoma or MEN2 and history of pancreatitis
• Participants receiving prior treatment with metformin, GLP-1 agonists, oral contraception pills, progesterone, or other insulin sensitizers for at least 6 weeks prior to Screening.
• Is currently pregnant or has been pregnant.