The Pathophysiology of Amenorrhea

The Pathophysiology of Amenorrhea in the Adolescent N EVILLE H. G OLDEN AND J ENNIFER L.
C ARLSON 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 23 years after menarche. Prolonged amenorrhea, however, is not normal and can be associated 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 better 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 3years after menarche. Prolonged amenorrhea, however, is not normal and can be associated with significant medical 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 amenorrhea in adolescents and to serve as an overview for the more detailed discussions of specific etiologic conditions 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: 650-6940660; 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 17years in the mid-1800s to approximately 12.5years in the mid1900s, presumably because of better nutrition and improved 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 welldeveloped countries. Using a national probability sample of 2,510 girls aged 8.0 to 20.0years, Chumlea et al. found that the median age of menarche in the United States is 12.43years and 80% of all girls begin to menstruate between 11.0 and 13.75years. Fewer than 10% are menstruating by age 11 and 90% are doing so by age of 13.75years. 1 By the age of 15years, 98% of all girls have reached menarche. 2 Both pubertal development and age at menarche vary by race, with black
girls entering puberty earlier than their white counterparts and reaching menarche before them. 3 In the United States, mean age of menarche is 12.06years in blacks, 12.25years of age in Mexican Americans, Ann. N.Y. Acad. Sci. 1135: 163178 (2008). C 2008 New York Academy of Sciences. doi: 10.1196/annals.1429.014 163 164 Annals of the New York Academy of Sciences FIGURE 1. Regulation of pulsatile GnRH secretion by leptin and neurotransmitters. and 12.55years of age in non-Hispanic whites. 1 There is a known relationship between age of menarche and BMI, with early menarche associated with higher BMI. 4 , 5 What is not known, however, is the direction of the associationwhether increased body fat leads to early menarche or whether early sexual maturation is the reason for an increase in the amount of body fat and a change in its distribution. Physiology of the Normal Menstrual Cycle
An understanding of the physiology of the normal menstrual cycle (see the chapter by Dr. Hillard in this volume) is essential in order to understand the variability of menstrual cycles that occurs during adolescence. Gonadotropin-releasing hormone (GnRH), a decapeptide produced by the neurosecretory neurons of the preoptic area of the hypothalamus, is released at the axon terminals of the neurosecretory cell at the median eminence of the hypothalamus. The hormone is secreted into the capillaries of the hypophysial portal system and is transported to the anterior pituitary, where it stimulates the synthesis and secretion of luteinizing hormone (LH) and follicle-stimulating hormone (FSH). The GnRH is released in pulses in response to serum levels of gonadal steroids. Secretion of GnRH is also regulated by a number of neurotransmitters, including dopamine, endogenous opioids, norepinephrine, gamma amino butyric acid (GABA),andcorticotropin-releasinghormone(CRH). Some of these neurotransmitters (e.g., dopamine) are released by the tuberoinfundibular neurons which abut the neurosecretory cells of the median eminence. 6 The modulation of GnRH release by the neurotransmitters is complex. with interactions between the different regulatory systems (F IG .1). For example, infusion of dopamine inhibits the LH pulsatile release induced by naloxone, an opioid receptor antagonist. 7
Other neurotransmitters (e.g., serotonin, neuropeptide Y, and neurotensin) may be involved in the regulation of GnRH secretion, but their exact role is not clear. The GnRH pulses increase in amplitude and frequency during puberty. Each GnRH pulse is followed

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The Pathophysiology of Amenorrhea in the Adolescent N EVILLE H. G OLDEN AND J ENNIFER L.

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