Reproductive Axis Maturation in the Early Post-Menarchal Years

The broad goal of these studies is to determine the physiologic and pathophysiologic underpinnings of irregular menstrual cycles among adolescents in general and those with increased genetic risk for polycystic ovarian syndrome (PCOS) in the early postmenarchal

period. Irregular menstruation affects > 2.5 million reproductive-age women in the US each year1. Most adult women with oligomenorrhea of unknown etiology reporting symptoms dating back to early adolescence. Importantly, irregular menstrual cycles during the teenage years may be a harbinger of future health risks extending beyond the reproductive system; among the nearly 80,000 female participants the Nurses' Health Study II, those with irregular and long cycles during adolescence and adulthood had a greater risk of premature mortality, particularly related to cardiovascular disease. While a period of cycle irregularity is well-described in the first few years after menarche, a lack of understanding of the basic mechanisms of normal reproductive axis development in the post-menarchal female has hampered our ability to distinguish abnormal from normal developmental trajectories. Moreover, the commonly held belief that menstrual irregularity among teenage girls is normal has also delayed detection of pathology in reproductive development, precluding institution of early preventative strategies to curtail future reproductive morbidity.

• Part 1 - Pre-menarche monitoring ("holding pattern"):

Inclusion criteria

• Age 8-14.5 years old
• Healthy weight, defined as having a body weight >85% of expected (EBW) and a body mass index (BMI) <99th percentile
• Some breast development
• Pre-menarche

Exclusion criteria

• Taking or planning to take medications that affect reproductive hormones in the next 2 to 3 years (e.g. birth control pills, biotin supplements).
• Planning to move more than 60 miles from the CRU within the next 2 to 3 years
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• First-degree relative with polycystic ovarian syndrome, premature ovarian insufficiency, hypogonadotropic hypogonadism, or other pubertal development disorder
• Excessive exercise (defined as running >20 miles per week or its equivalent)
• Pregnancy

Part 2 - Post-menarche cycle tracking:

Inclusion criteria

• Age at menarche 10-14.5 years old
• Healthy weight, defined as having a body weight >85% of expected (EBW) and a body mass index (BMI) <99th percentile
• Approximately < 6 months post-menarchal (will typically have completed 4 or fewer menstrual cycles)
• Biochemical criteria: normal thyroid hormone, prolactin, and testosterone levels

Exclusion criteria

• Taking or planning to take medications that affect reproductive hormones in the next 2 to 3 years (e.g. birth control pills, biotin supplements).
• Planning to move more than 60 miles from the CRU within the next 2 to 3 years
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• First-degree relative with polycystic ovarian syndrome, premature ovarian insufficiency, hypogonadotropic hypogonadism, or other pubertal development disorder
• Excessive exercise (defined as running >20 miles per week or its equivalent)
• Anemia (defined as hemoglobin <12.0 g/dl)

--Participants with hemoglobin between 11.5 g/dl and 12.0 g/dl may still participate by providing dried blood spots, or no more than 18 ml of blood during any given interval.

• Pregnancy

Part 3 - Intensive monitoring of ovarian follicle growth

Inclusion criteria

• Age at menarche 10-14.5 years old
• Healthy weight, defined as having a body weight >85% of expected (EBW) and a body mass index (BMI) <99th percentile
• Within 1 year of menarche
• Biochemical criteria: normal thyroid hormone, prolactin, and testosterone levels

Exclusion criteria

• Taking or planning to take medications that affect reproductive hormones in the next 1-2 years (e.g. birth control pills, biotin supplements).
• Planning to move more than 60 miles from the CRU within the next year
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• First-degree relative with polycystic ovarian syndrome, premature ovarian insufficiency, hypogonadotropic hypogonadism, or other pubertal development disorder
• Excessive exercise (defined as running >20 miles per week or its equivalent)
• Anemia (defined as hemoglobin <12.0 g/dl)

--Participants with hemoglobin between 11.5 g/dl and 12.0 g/dl may still participate by providing dried blood spots, or no more than 18 ml of blood during any given interval.

• Pregnancy

Part 4 - Late Post-menarche cycle tracking:

Inclusion criteria

• Age 11-17.5 years old
• Approximately 2-5 years post-menarchal
• Biochemical criteria: normal thyroid hormone and prolactin

Exclusion criteria

• Taking or planning to take medications that affect reproductive hormones in the next 2 to 3 years (e.g. birth control pills, biotin supplements).
• Planning to move more than 60 miles from the CRU within the next 6 months
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• Anemia (defined as hemoglobin <12.0 g/dl)

--Participants with hemoglobin between 11.5 g/dl and 12.0 g/dl may still participate by providing dried blood spots, or no more than 18 ml of blood during any given interval.

• Pregnancy

Adolescent girls, at-risk daughters, or sisters of women with PCOS

The girls with mothers or sisters with PCOS group will complete the Screening Visit and Parts 1-3. The same inclusion and exclusion criteria apply for Parts 1, 2, and 3 as stated above except that these individuals must have a first-degree relative with PCOS and they can have high androgen levels, excess body hair, and severe acne at screening.

Women with known PCOS (activities for 8 weeks only)

Inclusion criteria

• Age >=18-34 years old
• PCOS diagnosis
• at least 3-years post-menarchal with irregular menstrual cycles
• Biochemical (blood) or clinical signs of high androgen levels

Exclusion criteria

• Cannot be taking any medications that affect reproductive or metabolic hormones (e.g. birth control pill, biotin supplements, spironolactone, metformin).
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• Pregnancy

Healthy control women (Activities x 2 menstrual cycles)

Inclusion criteria

• Age >=18-34 years old
• at least 3-years post-menarchal with regular menstrual cycles every 21-35 days

Exclusion criteria

• Cannot be taking any medications that affect reproductive or metabolic hormones (e.g. birth control pill, biotin supplements, spironolactone, metformin).
• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• PCOS diagnosis or first-degree relative with disorder
• Pregnancy

Mothers of pediatric participants (Activities for 8 weeks / 2 menstrual cycles)

Inclusion criteria

• Age >=18-65 years old
• Biological mother of A Girl's First Period participant

Exclusion criteria

• Chronic medical condition, including but not limited to diabetes mellitus, congenital adrenal hyperplasia, cystic fibrosis, sickle cell disease, inflammatory bowel disease, juvenile rheumatoid arthritis, and lupus.
• Pregnancy