Amenorrhea: A Systematic Approach to Diagnosis and Management
Am Fam Physician. 2019 Jul 1;100(1):39-48.
Patient information: See related handouts on amenorrhea at https://familydoctor.org/condition/amenorrhea/, https://familydoctor.org/condition/female-athlete-triad/, and https://www.aafp.org/afp/2013/0601/p781-s1.html.
Author disclosure: No relevant financial affiliations.
Menstrual patterns can be an indicator of overall health and self-perception of well-being. Primary amenorrhea, defined as the lifelong absence of menses, requires evaluation if menarche has not occurred by 15 years of age or three years post-thelarche. Secondary amenorrhea is characterized by cessation of previously regular menses for three months or previously irregular menses for six months and warrants evaluation. Clinicians may consider etiologies of amenorrhea categorically as outflow tract abnormalities, primary ovarian insufficiency, hypothalamic or pituitary disorders, other endocrine gland disorders, sequelae of chronic disease, physiologic, or induced. The history should include menstrual onset and patterns, eating and exercise habits, presence of psychosocial stressors, body weight changes, medication use, galactorrhea, and chronic illness. Additional questions may target neurologic, vasomotor, hyperandrogenic, or thyroid-related symptoms. The physical examination should identify anthropometric and pubertal development trends. All patients should be offered a pregnancy test and assessment of serum follicle-stimulating hormone, luteinizing hormone, prolactin, and thyroid-stimulating hormone levels. Additional testing, including karyotyping, serum androgen evaluation, and pelvic or brain imaging, should be individualized. Patients with primary ovarian insufficiency can maintain unpredictable ovary function and may require hormone replacement therapy, contraception, or infertility services. Functional hypothalamic amenorrhea may indicate disordered eating and low bone density. Treatment should address the underlying cause. Patients with polycystic ovary syndrome should undergo screening and intervention to attenuate metabolic disease and endometrial cancer risk. Amenorrhea can be associated with clinically challenging pathology and may require lifelong treatment. Patients will benefit from ample time with the clinician, sensitivity, and emotional support.
Menstrual patterns can be an indicator of overall health status and self-perception of well-being.1,2 A broad differential is important to avoid missing rare or emergent pathology because many underlying conditions can present as amenorrhea.3 Primary amenorrhea is the lifelong absence of menses.3 Evaluation should be considered if menarche has not occurred by 15 years of age or three years post-thelarche.1,4 Lack of any pubertal development by 13 years of age should prompt investigation for delayed puberty.4,5
SORT: KEY RECOMMENDATIONS FOR PRACTICE
A = consistent, good-quality patient-oriented evidence; B = inconsistent or limited-quality patient-oriented evidence; C = consensus, disease-oriented evidence, usual practice, expert opinion, or case
Referencesshow all references
1. ACOG Committee opinion no. 651: menstruation in girls and adolescents: using the menstrual cycle as a vital sign. Obstet Gynecol. 2015;126(6):e143–e146....
2. Gordon CM, Ackerman KE, Berga SL, et al. Functional hypothalamic amenorrhea: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2017;102(5):1413–1439.
3. Klein DA, Poth MA. Amenorrhea: an approach to diagnosis and management. Am Fam Physician. 2013;87(11):781–788.
4. Herman-Giddens ME, Slora EJ, Wasserman RC, et al. Secondary sexual characteristics and menses in young girls seen in office practice: a study from the pediatric research in office settings network. Pediatrics. 1997;99(4):505–512.
5. Klein DA, Emerick JE, Sylvester JE, Vogt KS. Disorders of puberty: an approach to diagnosis and management. Am Fam Physician. 2017;96(9):590–599.
6. Practice Committee of American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril. 2008;90(5 suppl):S219–S225.
7. World Health Organization Task Force on Adolescent Reproductive Health. World Health Organization multicenter study on menstrual and ovulatory patterns in adolescent girls. II. Longitudinal study of menstrual patterns in the early postmenarcheal period, duration of bleeding episodes and menstrual cycles. J Adolesc Health Care. 1986;7(4):236–244.
8. Goodman NF, Cobin RH, Futterweit W, Glueck JS, Legro RS, Carmina E. American Association of Clinical Endocrinologists, American College of Endocrinology, and Androgen Excess and PCOS Society disease state clinical review: guide to the best practices in the evaluation and treatment of polycystic ovary syndrome—part 1. Endocr Pract. 2015;21(11):1291–1300.
9. Moglia ML, Nguyen HV, Chyjek K, Chen KT, Castaño PM. Evaluation of smartphone menstrual cycle tracking applications using an adapted APPLICATIONS scoring system. Obstet Gynecol. 2016;127(6):1153–1160.
10. Nelson LM. Clinical practice. Primary ovarian insufficiency. N Engl JMed. 2009;360(6):606–614.
11. Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014;124(1):193–197.
12. ACOG Practice Bulletin no. 194: polycystic ovary syndrome. Obstet Gynecol. 2018;131(6):e157–e171.
13. Molitch ME. Diagnosis and treatment of pituitary adenomas: a review. JAMA. 2017;317(5):516–524.
14. Melmed S, Casanueva FF, Hoffman AR, et al.; Endocrine Society. Diagnosis and treatment of hyperprolactinemia: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2011;96(2):273–288.
15. Martin KA, Anderson RR, Chang RJ, et al. Evaluation and treatment of hirsutism in premenopausal women: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(4):1233–1257.
16. Committee on Adolescent Health Care. ACOG Committee opinion no. 728: Müllerian agenesis: diagnosis, management, and treatment. Obstet Gynecol. 2018;131(1):e35–e42.
17. Rebar RW, Connolly HV. Clinical features of young women with hyper-gonadotropic amenorrhea. Fertil Steril. 1990;53(5):804–810.
18. Nelson SM. Biomarkers of ovarian response: current and future applications. Fertil Steril. 2013;99(4):963–969.
19. Tosi F, Fiers T, Kaufman JM, et al. Implications of androgen assay accuracy in the phenotyping of women with polycystic ovary syndrome. J Clin Endocrinol Metab. 2016;101(2):610–618.
20. Gravholt CH, Andersen NH, Conway GS, et al.; International Turner Syndrome Consensus Group. Clinical practice guidelines for the care of girls and women with Turner syndrome: proceedings from the 2016 Cincinnati International Turner Syndrome Meeting. Eur J Endocrinol. 2017;177(3):G1–G70.
21. Geckinli BB, Toksoy G, Sayar C, et al. Prevalence of X-aneuploidies, X-structural abnormalities and 46,XY sex reversal in Turkish women with primary amenorrhea or premature ovarian insufficiency. Eur J Obstet Gynecol Reprod Biol. 2014;182:211–215.
22. De Souza MJ, Nattiv A, Joy E, et al.; Expert Panel. 2014 female athlete triad coalition consensus statement on treatment and return to play of the female athlete triad: 1st international conference held in San Francisco, California, May 2012 and 2nd international conference held in Indianapolis, Indiana, May 2013. Br J Sports Med. 2014;48(4):289.
23. Rarick LD, Shangold MM, Ahmed SW. Cervical mucus and serum estradiol as predictors of response to progestin challenge. Fertil Steril. 1990;54(2):353–355.
24. Nakamura S, Douchi T, Oki T, Ijuin H, Yamamoto S, Nagata Y. Relationship between sonographic endometrial thickness and progestin-induced withdrawal bleeding. Obstet Gynecol. 1996;87(5 pt 1):722–725.
25. Fontana L, Gentilin B, Fedele L, Gervasini C, Miozzo M. Genetics of Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome. Clin Genet. 2017;91(2):233–246.
26. Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecol. 1981;140(4):371–380.
27. Khan Z, Goldberg JM. Hysteroscopic management of Asherman's syndrome. J Minim Invasive Gynecol. 2018;25(2):218–228.
28. Mendoza N, Motos MA. Androgen insensitivity syndrome. Gynecol Endocrinol. 2013;29(1):1–5.
29. Berglund A, Johannsen TH, Stochholm K, et al. Incidence, prevalence, diagnostic delay, and clinical presentation of female 46,XY disorders of sex development. J Clin Endocrinol Metab. 2016;101(12):4532–4540.
30. Boehmer AL, Brinkmann O, Brüggenwirth H, et al. Genotype versus phenotype in families with androgen insensitivity syndrome [published correction appears in J Clin Endocrinol Metab. 2002;87(7):3109]. J Clin Endocrinol Metab. 2001;86(9):4151–4160.
31. Witchel SF. Disorders of sex development. Best Pract Res Clin Obstet Gynaecol. 2018;48:90–102.
32. Coulam CB, Adamson SC, Annegers JF. Incidence of premature ovarian failure. Obstet Gynecol. 1986;67(4):604–606.
33. Committee on Genetics. Committee opinion no. 691: carrier screening for genetic conditions. Obstet Gynecol. 2017;129(3):e41–e55.
34. Allen EG, Grus WE, Narayan S, Espinel W, Sherman SL. Approaches to identify genetic variants that influence the risk for onset of fragile X-associated primary ovarian insufficiency (FXPOI): a preliminary study. Front Genet. 2014;5:260.
35. Bakalov VK, Vanderhoof VH, Bondy CA, Nelson LM. Adrenal antibodies detect asymptomatic auto-immune adrenal insufficiency in young women with spontaneous premature ovarian failure. Hum Reprod. 2002;17(8):2096–2100.
36. Christ JP, Gunning MN, Palla G, et al. Estrogen deprivation and cardiovascular disease risk in primary ovarian insufficiency. Fertil Steril. 2018;109(4):594–600.e1.
37. Popat VB, Calis KA, Kalantaridou SN, et al. Bone mineral density in young women with primary ovarian insufficiency: results of a three-year randomized controlled trial of physiological transdermal estradiol and testosterone replacement. J Clin Endocrinol Metab. 2014;99(9):3418–3426.
38. Committee on Gynecologic Practice. Committee opinion no. 698: hormone therapy in primary ovarian insufficiency. Obstet Gynecol. 2017;129(5):e134–e141.
39. Burgos N, Cintron D, Latortue-Albino P, et al. Estrogen-based hormone therapy in women with primary ovarian insufficiency: a systematic review. Endocrine. 2017;58(3):413–425.
40. 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.
41. Camacho PM, Petak SM, Binkley N, et al. American Association of Clinical Endocrinologists and American College of Endocrinology clinical practice guidelines for the diagnosis and treatment of postmenopausal osteoporosis - 2016. Endocr Pract. 2016;22(suppl 4):1–42.
42. Alper MM, Jolly EE, Garner PR. Pregnancies after premature ovarian failure. Obstet Gynecol. 1986;67(3 suppl):59S–62S.
43. Rovinski D, Ramos RB, Fighera TM, Casanova GK, Spritzer PM. Risk of venous thromboembolism events in postmenopausal women using oral versus non-oral hormone therapy: A systematic review and meta-analysis. Thromb Res. 2018;168:83–95.
44. Gibbs JC, Nattiv A, Barrack MT, et al. Low bone density risk is higher in exercising women with multiple triad risk factors. Med Sci Sports Exerc. 2014;46(1):167–176.
45. Kandemir N, Slattery M, Ackerman KE, et al. Bone parameters in anorexia nervosa and athletic amenorrhea: comparison of two hypothalamic amenorrhea states. J Clin Endocrinol Metab. 2018;103(6):2392–2402.
46. Chamberlain R. The female athlete triad: recommendations for management. Am Fam Physician. 2018;97(8):499–502.
47. Misra M, Katzman D, Miller KK, et al. Physiologic estrogen replacement increases bone density in adolescent girls with anorexia nervosa. J Bone Miner Res. 2011;26(10):2430–2438.
48. Altayar O, Al Nofal A, Carranza Leon BG, Prokop LJ, Wang Z, Murad MH. Treatments to prevent bone loss in functional hypothalamic amenorrhea: a systematic review and meta-analysis. J Endocr Soc. 2017;1(5):500–511.
49. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–4592.
50. Teede HJ, Misso ML, Costello MF, et al.; International PCOS Network. Recommendations from the international evidence-based guideline for the assessment and management of polycystic ovary syndrome. Hum Reprod. 2018;33(9):1602–1618.
51. Jellinger PS, Handelsman Y, Rosenblit PD, et al. American Association of Clinical Endocrinologists and American College of Endocrinology guidelines for management of dyslipidemia and prevention of cardiovascular disease. Endocr Pract. 2017;23(suppl 2):1–87.
52. Hu S, Yu Q, Wang Y, Wang M, Xia W, Zhu C. Letrozole versus clomiphene citrate in polycystic ovary syndrome: a meta-analysis of randomized controlled trials. Arch Gynecol Obstet. 2018;297(5):1081–1088.
53. Hannah-Shmouni F, Morissette R, Sinaii N, et al. Revisiting the prevalence of nonclassic congenital adrenal hyperplasia in US Ashkenazi Jews and Caucasians. Genet Med. 2017;19(11):1276–1279.
54. Chaudhry S, Tadokoro-Cuccaro R, Hannema SE, Acerini CL, Hughes IA. Frequency of gonadal tumours in complete androgen insensitivity syndrome (CAIS): a retrospective case-series analysis. J Pediatr Urol. 2017;13(5):498.e1–498.e6.
55. Master-Hunter T, Heiman DL. Amenorrhea: evaluation and treatment. Am Fam Physician. 2006;73(8):1374–1382.
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