The Menstrual Cycle in Adolescents: A vital sign of bone health
In Contemporary OB/GYN: Translating Science into Sound Clinical Practice, March 2010, Volume 55, Number 3
By Lawrence M. Nelson, MD
Menstrual regularity in adolescent girls provides valuable clues about current and future bone integrity. This article explains the importance of using this often-overlooked health factor to help your patients achieve and maintain optimum lifelong skeletal health.
Menstruation is a Jekyll-and-Hyde phenomenon, depending on cultural context.1 As Hamlet says: "There is nothing either good or bad, but thinking makes it so." Many anthropologic accounts stress the importance of menarche as a sign of a girl's transition into womanhood, physical maturity, and fertility, and something to be celebrated. Some American Indian cultures mark the first menses with an elaborate celebration, such as the Apache Sunrise Dance. Such rituals are a positive and enabling social force. For these American Indian tribes, the first menstrual cycle places the girl in an empowered state in which she can influence the well-being of others.2 In some cultures, however, including in the United States, menstruation is viewed as a nuisance and a source of physical and psychological problems. Research suggests that girls in the United States are not knowledgeable about menstruation and that their expectations regarding it are negatively biased.3
Transition into womanhood is accompanied by remarkable skeletal growth. The teen years are a critical time for building bone; peak volumetric bone mineral density and bone size are almost fully attained during late adolescence.4 It has been said that osteoporosis is a pediatric disease with geriatric consequences.5 Bone density can be compared to a bank account: We need to take care of it when we are young so it is there to take care of us in our old age.
Bone health presents an opportunity to say something positive about menstruation and give the menstrual cycle due respect. In studying girls and young women with primary ovarian insufficiency, it has become clear that the menstrual cycle is a marker of general health.6 According to published data, more than 50% of women with primary ovarian insufficiency (also known as premature menopause or premature ovarian failure) saw 3 or more different clinicians before somebody took the condition seriously and performed laboratory testing to make a diagnosis.7 Also, many women delayed seeking evaluation, and most did not consider missing menstrual periods as a significant p roblem. The cost for a delay in diagnosis of an estrogen-deficient state is reduced bone mineral density.8
In this regard, the menstrual cycle can be considered a vital sign of bone health. Teenage girls have an early warning sign of estrogen deficiency: the menstrual cycle. Regular menses are a sign that the ovaries are working normally in their endocrine capacity as a source of estradiol. Estradiol, the major natural human estrogen, plays a critical role in building bone mass. Remarkably, this is true even for men. Men lacking the estradiol alpha receptor or the ability to synthesize estradiol because of aromatase deficiency develop osteoporosis in spite of having normal serum testosterone levels.9 Thus, estradiol is important to achieving peak bone mass for both men and women.
The goal of this article is 2-fold: 1) to advocate for a more aggressive approach to the evaluation of amenorrhea; and 2) to appeal for a comprehensive approach to the management of hypogonadism to optimize bone health and reduce the risk of osteoporosis in later years. To care appropriately for adolescents with hypogonadism, the clinician needs to make the diagnosis in a timely manner, inform the patient (and the parents/guardians, in the case of a minor) of the diagnosis with due care, determine the cause of the condition, and manage the potential emotional and physical sequelae (Table 1).10
|Make the diagnosis|
|Inform patient and parents as appropriate|
|Manage the condition|
The view that anything goes with regard to menstrual cycle regularity during adolescence is an unfortunate misconception that is a major contributor to the delay in diagnosis of hypogonadism in this population. Longitudinal studies of the menstrual cycle in normal girls have demonstrated unequivocally that, even during the first year after menarche, it is statistically unusual for a girl to have more than 90 days between menses.10-12 Therefore, evaluation is indicated for cycle intervals of more than 90 days.
A complete discussion of the evaluation and management of delayed puberty and primary amenorrhea is well beyond the scope of this article. The focus here is on the evaluation of secondary amenorrhea in the adolescent, meaning that the girl has completed normal pubertal development and has experienced at least 1 menses.
Once pregnancy has been ruled out, clinicians need to focus on several aspects of the history (Table 2).13 At a minimum, 3 laboratory tests need to be ordered in the evaluation of secondary amenorrhea. The majority of cases of secondary amenorrhea are caused by one of 4 major conditions: hyperprolactinemia, hypothalamic amenorrhea, primary ovarian insufficiency, and polycystic ovary syndrome. Hyperprolactinemia, hypothalamic amenorrhea, and primary ovarian insufficiency are associated with estradiol deficiency, whereas polycystic ovary syndrome is not.
|Questions to ask|
|Initial tests to runa|
|Major mechanisms to considera|
|Abbreviations: FSH, follicle-stimulating hormone; TSH, thyroid-stimulating hormone.
aInformation from Practice Committee of the American Society for Reproductive Medicine.13
Hyperprolactinemia and hypothalamic amenorrhea
Hyperprolactinemia and hypothalamic amenorrhea in many cases will respond to appropriate management, with return of normal ovarian function and remission of the estradiol deficiency. However, in the case of primary ovarian insufficiency, there are no proven therapies that will restore ovarian endocrine function. Most experts agree that physiologic estrogen and progestin replacement is reasonable in girls and young women with this condition and should be continued until they reach the age at which normal menopause occurs.13,14
In case-controlled studies, transdermal estradiol has a lower risk of venous thromboembolism than oral estrogen and has little effect on hemostatic factors.15,16 The average serum estradiol level across the normal menstrual cycle is approximately 100 pg/mL.17 A dose of 100 mcg of estradiol per day delivered by transdermal patch effectively relieves symptoms and achieves serum estradiol levels in this range.6
Evidence supports the use of cyclic medroxyprogesterone acetate as the preferred progestin. At a dose of 10 mg per day for 12 days each month, this regimen fully induces secretory endometrium and provides protection against endometrial cancer.18,19 Data regarding the endometrial effects of oral micronized progesterone when given along with a full replacement dose of estrogen are not available; the available data evaluated endometrial effects at lower estrogen doses.20
Addressing estrogen deficiency
A recent cross-sectional study examined the risk factors associated with reduced bone density in young women with estrogen deficiency.8 Women who had the onset of menstrual irregularity before the age of 20 years were nearly 3 times as likely to have bone mineral density below normal for their age compared to women who had onset after age 20. Of note, approximately one-half of the patients in this study had vitamin D insufficiency and inadequate calcium intake.
Researchers also found that delayed diagnosis, nonadherence to estrogen replacementtherapy,andlackofregularexercise were also risk factors for reduced bone density (Table 3).8 Taken together, these findings stress the need for early diagnosis, estrogen replacement adherence, counseling about calcium and vitamin D, and a regular weight-bearing exercise program.
|Information from US Department of Health and Human Services.21,22|
The US Department of Health and Human Services recommends a calcium intake of at least 1,300 mg every day.21 They also recommend for adolescents a minimum of 1 hour or more of moderate or vigorous aerobic physical activity every day, along with muscle-strengthening and bone-strengthening activities at least 3 days a week (Table 4).22
At every medical encounter involving adolescent girls, 2 questions need to be asked: 1) "When was your last menstrual period?" and 2) "Are your periods coming regularly?" The answers merit inclusion on the vital-sign line, along with temperature, pulse, respiration, and blood pressure. Abnormalities in the menstrual cycle deserve serious attention. View the menstrual cycle as a vital sign in order to make the diagnosis of estrogen deficiency in a timely manner. Inform the family and patient of the diagnosis with due care. Then provide a base for ongoing integrated and multidisciplinary care.
- Buckley T, Gottlieb A, eds. Blood Magic: The Anthropology of Menstruation. Berkeley, CA: University of California Press; 1988.
- Markstrom CA. Empowerment of North American Indian Girls: Ritual Expressions at Puberty. Lincoln, NB: University of Nebraska Press; 2008.
- Stubbs ML. Cultural perceptions and practices around menarche and adolescent menstruation in the United States. Ann N Y Acad Sci. 2008;1135:58-66.
- Henry yM, Fatayerji D, Eastell R. Attainment of peak bone mass at the lumbar spine, femoral neck and radius in men and women: relative contributions of bone size and volumetric bone mineral density. Osteoporos Int. 2004;15(4):263-273.
- Chesnut CH 3rd. Is osteoporosis a pediatric disease? Peak bone mass attainment in the adolescent female. Public Health Rep. 1989;104(suppl):50-54.
- Nelson LM. Primary ovarian insufficiency. N Engl J Med. 2009;360(6):606-614.
- Alzubaidi NH, Chapin HL, Vanderhoof VH, Calis KA, Nelson LM. Meeting the needs of young women with secondary amenorrhea and spontaneous premature ovarian failure. Obstet Gynecol. 2002;99(5):720-725.
- Popat VB, Calis KA, Vanderhoof VH, et al. Bone mineral density in estrogen-deficient young women. J Clin Endocrinol Metab. 2009;94(7):2277-2283.
- Khosla S. Estrogen and bone: insights from estrogen-resistant, aromatase-deficient, and normal men. Bone. 2008;43(3):414-417.
- American Academy of Pediatrics Committee on Adolescence; American College of Obstetricians and Gynecologists; Committee on Adolescent Health Care, Diaz A, Laufer MR, Breech LL. Menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Pediatrics. 118(5):2245-2250.
- Treloar AE, Boynton RE, Behn BG, Brown BW. Variation of the human menstrual cycle through reproductive life. Int J Fertil. 1967;12(1 pt 2):77-126.
- Flug D, Largo RH, Prader A. Menstrual patterns in adolescent Swiss girls: a longitudinal study. Ann Hum Biol. 1984;11(6):495-508.
- Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2004;82(suppl 1):S33-S39.
- Board of the International Menopause Society, Pines A, Sturdee DW, et al. IMS updated recommendations on postmenopausal hormone therapy. Climacteric. 2007;10(3):181194.
- Scarabin Py, Alhenc-Gelas M, Plu-Bureau G, Taisne P, Agher R, Aiach M. Effects of oral and transdermal estrogen/ progesterone regimens on blood coagulation and fibrinolysis in postmenopausal women. A randomized controlled trial. Arterioscler Thromb Vasc Biol. 1997;17(11):3071-3078.
- Canonico M, Oger E, Plu-Bureau G, et al; Estrogen and Thromboembolism Risk (ESTHER) Study Group. Hormone therapy and venous thromboembolism among postmenopausal women: impact of the route of estrogen administration and progestogens: the ESTHER study. Circulation. 2007;115(7):840-845.
- Mishell DR Jr, Nakamura RM, Crosignani PG, et al. Serum gonadotropin and steroid patterns during the normal menstrual cycle. Am J Obstet Gynecol. 1971;111(1):60-65.
- Gibbons WE, Moyer DL, Lobo RA, Roy S, Mishell DR Jr. Biochemical and histologic effects of sequential estrogen/ progestin therapy on the endometrium of postmenopausal women. Am J Obstet Gynecol. 1986;154(2):456-461.
- Bjarnason K, Cerin A, Lindgren R, Weber T. Adverse endometrial effects during long cycle hormone replacement therapy. Scandinavian Long Cycle Study Group. Maturitas. 1999;32(3):161-170.
- Effects of estrogen or estrogen/progestin regimens on heart disease risk factors in postmenopausal women. The Postmenopausal Estrogen/Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA. 1995;273(3):199208. Erratum in: JAMA. 1995;274(21):1676.
- US Department of Health and Human Services. Office on Women's Health. Best Bones Forever! www.bestbonesforever. gov/whatsbest/calcium/index.cfm. Accessed January 13, 2010.
- US Department of Health and Human Services. Office of Disease Prevention and Health Promotion. Physical Activity Guidelines for Americans. At-a-glace: a fact sheet for professionals. www.health.gov/paguidelines/factsheetprof.aspx. Accessed January 13, 2010.
About the Author
Dr. Nelson is a medical officer in the United States Public Health Service, Integrative Reproductive Medicine Unit, Intramural Research Program on Reproductive and Adult Endocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland. He is supported by the Intramural Research Program of the National Institute of Child Health and Human Development, National Institutes of Health.
© Reprinted from Contemporary OBGYN, March 2010. An Advanstar Publication. Printed in USA.