The Pathophysiology of Amenorrhea in the Adolescent NEVILLE H. GOLDEN AND JENNIFER L. CARLSON Division of Adolescent Medicine, Stanford University School of Medicine, Mountain View, California, USA Menstrual irregularity is a common occurrence during adolescence, especially within the first 2–3years after menarche. Prolonged amenorrhea, however, is not normal and can be associ- ated with significant medical morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. Estrogen-deficient amenorrhea is associated with reduced bone mineral density and increased fracture risk, while estrogen-replete amenorrhea can lead to dysfunctional uterine bleeding in the short term and predispose to endometrial carcinoma in the long term. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a bet- ter understanding of the normal menstrual cycle and its variability. Hypothalamic amenorrhea is the most prevalent cause of amenorrhea in the adolescent age group, followed by polycystic ovary syndrome. In anorexia nervosa, exercise-induced amenorrhea, and amenorrhea associated with chronic illness, an energy deficit results in suppression of hypothalamic secretion of GnRH, mediated in part by leptin. Administration of recombinant leptin to women with hypothalamic amenorrhea has been shown to restore LH pulsatility and ovulatory menstrual cycles. The use of recombinant leptin may improve our understanding of the pathophysiology of hypothalamic amenorrhea in adolescents and may also have therapeutic possibilities. Key words: amenorrhea; adolescents Menstrual irregularity is a common occurrence during adolescence,especially within the first 2 to 3 years af- ter menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medi- cal morbidity, which differs depending on whether the adolescent is estrogen-deficient or estrogen-replete. In both situations, appropriate intervention can reduce morbidity. Old paradigms of whom to evaluate for amenorrhea have been challenged by recent research that provides a better understanding of the normal menstrual cycle and its variability. The aim of this chapter is to review the pathophysiology of amenor- rhea in adolescents and to serve as an overview for the more detailed discussions of specific etiologic con- ditions in the chapters to follow. Priorities for future research will be proposed on the basis of review of the recent literature. Address for correspondence: Neville H. Golden, M.D., Chief, Division of Adolescent Medicine, Stanford University School of Medicine, 1174 Castro Street, Suite 250 A, Mountain View, CA 94040. Voice: 650-694- 0660; fax: 650-694-0664. ngolden@stanford.edu The Normal Menstrual Cycle Menarche In the United States and Europe, the median age of menarche declined from 16 to 17 years in the mid-1800s to approximately 12.5 years in the mid- 1900s, presumably because of better nutrition and im- proved socioeconomic living conditions. Over the past 30years, however, the median age of menarche in the United States has remained relatively stable. Age of menarche varies in different countries and tends to be higher in less-developed countries and lower in well- developed countries. Using a national probability sam- ple of 2,510 girls aged 8.0 to 20.0 years, Chumlea et al. found that the median age of menarche in the United States is 12.43 years and 80% of all girls begin to men- struate between 11.0 and 13.75 years. Fewer than 10% are menstruating by age 11 and 90% are doing so by age of 13.75 years. 1 By the age of 15 years, 98% of all girls have reached menarche. 2 Both pubertal develop- ment and age at menarche vary by race, with black girls entering puberty earlier than their white coun- terparts and reaching menarche before them. 3 In the United States, mean age of menarche is 12.06 years in blacks, 12.25 years of age in Mexican Americans, Ann. N.Y. Acad. Sci. 1135: 163–178 (2008). C  2008 New York Academy of Sciences. doi: 10.1196/annals.1429.014 163