Study Background

Our current understanding of the early post-menarchal period in contemporary adolescent girls rests entirely on a 2008 observational study of 8 girls who provided daily urine samples for measurement of LH, FSH, estrone, and pregnanediol glucuronide for 3-22 months (median 10.5 months) 29. This study was limited by small sample size and utilized an ovulation detection algorithm developed for adult women without validating it in the adolescent subjects (such as by sonographic evidence of a corpus luteum). Thus, there have been no well-powered studies to investigate how ethnic background or recent secular changes in body weight and pubertal timing may affect the time to achieve regular ovulatory cycles.

Puberty has been identified as a critical “window of susceptibility” to breast cancer. This is because the exponential proliferation of mammary epithelial cells during puberty makes these cells uniquely sensitive to environmental carcinogens during this developmental stage. Recent secular changes in the timing and tempo of puberty in girls, including earlier thelarche and a longer time between thelarche and menarche, are also believed to increase future risk of breast cancer in part due to a prolonged period of unopposed estrogen action (i.e., high levels of estrogen without an accompanying increase in progesterone) on the breast. A delay in the development of ovulatory cycles, which are by definition associated with increased progesterone exposure, would be predicted to further exacerbate this risk by delaying breast maturation. There have been no studies thus far, however, to investigate the relationship between progesterone exposure and breast architecture on MRI. We are also interested in investigating how body weight, insulin sensitivity, inflammatory markers, and other reproductive hormones (androgens, estrogens) influence the maturation of the breast in the early post-menarchal period. In our Bodyweight and Puberty Study (BWPS), we found that overweight/obesity was associated with relatively delayed breast maturation, as determined with breast ultrasound (unpublished data).

This study will help us gain a better understanding of how reproductive hormones and the ovaries change during the transition from menarche (a girl’s first period) to the establishment of mature, regular cycles in healthy girls. This information will one day permit physicians to differentiate girls with irregular cycles who will go on to establish regular cycles from those who may be at high-risk for long term cycle irregularity and infertility. We are also interested in how reproductive hormones may affect breast development, the microbiome, and sleep schedules.

We therefore propose the following objectives: To determine the effects of internal factors and environmental factors (e.g., insulin resistance, body composition, microbiome, sleep schedules, physical activity levels, genetics) on the time needed to achieve regular ovulatory cycles. Also, to determine the effect of reproductive and metabolic hormones on breast architecture via serial MRI.