As many as 25% of adolescent and young adult endurance athletes develop amenorrhea, and factors that cause amenorrhea to occur in some, but not all, athletes have not been well characterized. Recent data indicate the critical importance of a negative energy balance state and leptin in regulating the hypothalamo- pituitary-gonadal (H-P-G) axis. However, these factors do not completely account for alterations in this axis, and other contributing factors are unclear. Our preliminary data indicate the importance of low fat mass and fat related hormones in mediating hypogonadism in young athletes. This study will confirm these data and determine whether low fat mass and altered levels of adipokines, such as leptin and adiponectin, and hormones regulated by fat mass, such as ghrelin and peptide YY (PYY), determine alterations in LH pulsatility. A very concerning impact of amenorrhea in athletes is low bone mineral density (BMD). Preliminary data indicate lower BMD in adolescent athletes with amenorrhea (AA) compared with eumenorrheic athletes (EA) and non-athletic controls. The high prevalence of AA in adolescents is particularly concerning, because this population is potentially at greater risk as it is actively accruing bone. Of importance, bone microarchitecture, a better predictor of bone strength than BMD, has not been studied in AA. Because pubertal increases in estrogen are integral to optimizing peak bone mass, and AA is characterized by hypoestrogenism, this randomized study of transdermal estrogen versus oral estrogen or no estrogen will also examine whether estrogen replacement increases BMD and improves bone microarchitecture in adolescent AA 14-21 years old. EA and sedentary controls will be followed without intervention for this period. Despite the prevalent practice of prescribing oral contraceptives in AA, there is a paucity of data regarding benefits of this intervention in teenagers. Because transdermal estrogen, unlike oral estrogen, does not suppress IGF-1, an important bone anabolic factor, we expect effects of transdermal estrogen to exceed those of oral estrogen or no therapy. In addition, preliminary data indicate that low fat mass and alterations in fat related hormones may contribute to decreased bone accrual rates in athletes, and will be confirmed in this study. To summarize, a better understanding of the pathophysiology of reproductive dysfunction is critical to develop therapeutic strategies that will normalize the reproductive axis and bone accrual, and these are the questions that this study aims to answer.

Public Health Relevance

Many high school and college athletes stop having their periods, and loss of periods has deleterious effects on bone health. Factors that lead to loss of periods are not completely understood. This research proposal will examine the impact of low fat mass and related hormones on absence of periods in these young women, and strategies to increase bone density at this critical time.

Agency
National Institute of Health (NIH)
Institute
Eunice Kennedy Shriver National Institute of Child Health & Human Development (NICHD)
Type
Research Project (R01)
Project #
5R01HD060827-05
Application #
8484855
Study Section
Integrative and Clinical Endocrinology and Reproduction Study Section (ICER)
Program Officer
Winer, Karen
Project Start
2009-09-10
Project End
2014-06-30
Budget Start
2013-07-01
Budget End
2014-06-30
Support Year
5
Fiscal Year
2013
Total Cost
$433,575
Indirect Cost
$176,964
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
Barron, Elizabeth; Cano Sokoloff, Natalia; Maffazioli, Giovana D N et al. (2016) Diets High in Fiber and Vegetable Protein Are Associated with Low Lumbar Bone Mineral Density in Young Athletes with Oligoamenorrhea. J Acad Nutr Diet 116:481-9
Misra, Madhusmita; Ackerman, Kathryn E; Bredella, Miriam A et al. (2016) Racial Differences in Bone Microarchitecture and Estimated Strength at the Distal Radius and Distal Tibia in Older Adolescent Girls: a Cross-Sectional Study. J Racial Ethn Health Disparities :
Misra, Madhusmita; Klibanski, Anne (2016) Anorexia Nervosa and Its Associated Endocrinopathy in Young People. Horm Res Paediatr 85:147-57
Misra, Madhusmita; Golden, Neville H; Katzman, Debra K (2016) State of the art systematic review of bone disease in anorexia nervosa. Int J Eat Disord 49:276-92
Mitchell, Deborah M; Tuck, Padrig; Ackerman, Kathryn E et al. (2015) Altered trabecular bone morphology in adolescent and young adult athletes with menstrual dysfunction. Bone 81:24-30
Ackerman, Kathryn E; Cano Sokoloff, Natalia; DE Nardo Maffazioli, Giovana et al. (2015) Fractures in Relation to Menstrual Status and Bone Parameters in Young Athletes. Med Sci Sports Exerc 47:1577-86
Cano Sokoloff, Natalia; Eguiguren, Maria L; Wargo, Katherine et al. (2015) Bone parameters in relation to attitudes and feelings associated with disordered eating in oligo-amenorrheic athletes, eumenorrheic athletes, and nonathletes. Int J Eat Disord 48:522-6
Singhal, Vibha; Maffazioli, Giovana D N; Cano Sokoloff, Natalia et al. (2015) Regional fat depots and their relationship to bone density and microarchitecture in young oligo-amenorrheic athletes. Bone 77:83-90
Singhal, Vibha; Lawson, Elizabeth A; Ackerman, Kathryn E et al. (2014) Irisin levels are lower in young amenorrheic athletes compared with eumenorrheic athletes and non-athletes and are associated with bone density and strength estimates. PLoS One 9:e100218
Misra, Madhusmita (2014) Neuroendocrine mechanisms in athletes. Handb Clin Neurol 124:373-86

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