At the time of puberty, the hypothalamic gonadotropin-releasing hormone (GnRH) pulse generator reawakens, stimulating pituitary secretion of luteinizing hormone (LH) and follicle stimulating hormone (FSH) and consequent gonadal sex steroid secretion. While it is known that the GnRH pulse generator is initially reactivated only during sleep, there has been no investigation into the underlying physiology linking the sleep and reproductive systems during puberty. My preliminary studies demonstrated an association between LH pulse initiation and deep or slow-wave sleep (SWS) in pubertal children, suggesting that a critical amount of uninterrupted sleep may be important for normal pubertal maturation. Sleep architecture changes dramatically during adolescence. There is a >65% decline in delta power (a marker of SWS) that first occurs at age 11-12 years which is also the age of normal pubertal onset in boys and girls. While it has been hypothesized that sex steroids may play a role in shaping sleep architecture, the observational design of previous studies has precluded separation of the effects of pubertal maturation from age per se on sleep structure. Given the increasing trend of earlier sexual development in children, it is important to gain a deeper understanding of the complex interaction between sex steroids and the brain during adolescence and the potential consequences of early sex steroid exposure. This proposal will examine the critical and reciprocal interactions between sleep and the reproductive system during puberty.
In Specific Aim 1, I will use a SWS disruption protocol to determine whether pulsatile secretion of LH during puberty is specifically dependent on SWS.
In Specific Aim 2, I will study children with central precocious puberty before and after treatment with a GnRH analogue to investigate the effects of sex steroids on sleep architecture, independent of chronologic age. My research career development plan involves close mentoring by an experienced team of interdisciplinary clinical investigators with expertise in reproductive endocrinology, sleep medicine, and integrative physiology. I will gain formal training in sleep medicine through participation in coursework, weekly conferences, and national meetings, and will gain hands-on experience by shadowing my mentors and collaborators in sleep clinic polysomnographic reading sessions. I will continue to participate in didactic conferences in the Reproductive Endocrine Unit and at Children's Hospital Boston to expand my knowledge of endocrinology and relevant research tools. Frequent meetings with a core team of my mentors and collaborators, including Drs. Hall, Malhotra, and Butler, will help me to integrate my knowledge in sleep and reproductive endocrinology. Under a K23, I will gain the additional training in clinical research and sleep medicine that I need to attain my ultimate career goal of becoming an independent clinical investigator at an academic medical center bridging the fields of sleep medicine and pediatric reproductive endocrinology.

Public Health Relevance

The candidate for this Career Development Award is a pediatric endocrinologist studying 1) the effects of sleep disruption on reproductive hormone secretion during puberty and 2) the potential role of reproductive hormones in the changes in sleep structure that are seen across adolescence. This research will investigate whether sleep disruption, which is common in adolescence, interferes with hormone secretion and normal pubertal maturation.

National Institute of Health (NIH)
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Mentored Patient-Oriented Research Career Development Award (K23)
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Pediatrics Subcommittee (CHHD)
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Winer, Karen
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Massachusetts General Hospital
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Shaw, Natalie D; Brand, Harrison; Kupchinsky, Zachary A et al. (2017) SMCHD1 mutations associated with a rare muscular dystrophy can also cause isolated arhinia and Bosma arhinia microphthalmia syndrome. Nat Genet 49:238-248
McHill, Andrew W; Klerman, Elizabeth B; Slater, Bridgette et al. (2017) The Relationship Between Estrogen and the Decline in Delta Power During Adolescence. Sleep 40:
Shaw, Natalie D; McHill, Andrew W; Schiavon, Michele et al. (2016) Effect of Slow Wave Sleep Disruption on Metabolic Parameters in Adolescents. Sleep 39:1591-9
Shaw, N D; Butler, J P; Nemati, S et al. (2015) Accumulated deep sleep is a powerful predictor of LH pulse onset in pubertal children. J Clin Endocrinol Metab 100:1062-70
Shaw, N D; Srouji, S S; Welt, C K et al. (2015) Compensatory Increase in Ovarian Aromatase in Older Regularly Cycling Women. J Clin Endocrinol Metab 100:3539-47
Shaw, N D; Srouji, S S; Welt, C K et al. (2014) Evidence that increased ovarian aromatase activity and expression account for higher estradiol levels in African American compared with Caucasian women. J Clin Endocrinol Metab 99:1384-92
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Shaw, Natalie D; Goodwin, James L; Silva, Graciela E et al. (2013) Obstructive sleep apnea (OSA) in preadolescent girls is associated with delayed breast development compared to girls without OSA. J Clin Sleep Med 9:813-8
Costa-Barbosa, Flavia Amanda; Balasubramanian, Ravikumar; Keefe, Kimberly W et al. (2013) Prioritizing genetic testing in patients with Kallmann syndrome using clinical phenotypes. J Clin Endocrinol Metab 98:E943-53
Shaw, N D; Butler, J P; McKinney, S M et al. (2012) Insights into puberty: the relationship between sleep stages and pulsatile LH secretion. J Clin Endocrinol Metab 97:E2055-62