Causes of primary amenorrhea
- Corrine K Welt, MD
Corrine K Welt, MD
- Professor of Medicine
- University of Utah School of Medicine
- Robert L Barbieri, MD
Robert L Barbieri, MD
- Editor-in-Chief — Obstetrics, Gynecology and Women's Health
- Section Editor — General Gynecology and Female Reproductive Endocrinology
- Kate Macy Ladd Professor of Obstetrics, Gynecology and Reproductive Biology
- Harvard Medical School
- Section Editors
- William F Crowley, Jr, MD
William F Crowley, Jr, MD
- Section Editor — Female Reproductive Endocrinology
- Daniel K Podolsky Professor of Medicine
- Harvard Medical School
- Mitchell E Geffner, MD
Mitchell E Geffner, MD
- Section Editor — Pediatric Endocrinology
- Professor of Pediatrics
- Keck School of Medicine, University of Southern California
Amenorrhea (absence of menses) can be a transient, intermittent, or permanent condition resulting from dysfunction of the hypothalamus, pituitary, ovaries, uterus, or vagina (table 1 and table 2). It is often classified as either primary (absence of menarche by age 15 years) or secondary (absence of menses for more than three cycle intervals or six months in women who were previously menstruating). Primary amenorrhea should prompt a thorough evaluation to identify the cause.
The causes and diagnosis of primary amenorrhea are reviewed here. The diagnostic evaluation and treatment options for primary amenorrhea and the etiology, diagnosis, and treatment of secondary amenorrhea are discussed separately. (See "Evaluation and management of primary amenorrhea" and "Epidemiology and causes of secondary amenorrhea" and "Evaluation and management of secondary amenorrhea".)
Primary amenorrhea is defined as the absence of menses at age 15 years in the presence of normal growth and secondary sexual characteristics. The identification of primary amenorrhea should always prompt a thorough evaluation to identify a cause . At age 13 years, if no menses have occurred and there is a complete absence of secondary sexual characteristics such as breast development, evaluation for primary amenorrhea should begin. In addition, some girls with secondary sexual characteristics may present before age 15 years with amenorrhea and cyclic pelvic pain. These girls should be evaluated for possible outflow tract obstruction.
Primary amenorrhea is usually the result of a genetic or anatomical abnormality. However, all causes of secondary amenorrhea can also present as primary amenorrhea. In a large case series of primary amenorrhea, the most common etiologies were :
●Gonadal dysgenesis, including Turner syndrome – 43 percentTo continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Practice Committee of the American Society for Reproductive Medicine. Current evaluation of amenorrhea. Fertil Steril 2006; 86:S148.
- Reindollar RH, Byrd JR, McDonough PG. Delayed sexual development: a study of 252 patients. Am J Obstet Gynecol 1981; 140:371.
- Laitinen EM, Vaaralahti K, Tommiska J, et al. Incidence, phenotypic features and molecular genetics of Kallmann syndrome in Finland. Orphanet J Rare Dis 2011; 6:41.
- Santoro N, Filicori M, Crowley WF Jr. Hypogonadotropic disorders in men and women: diagnosis and therapy with pulsatile gonadotropin-releasing hormone. Endocr Rev 1986; 7:11.
- Crowley WF Jr, Jameson JL. Clinical counterpoint: gonadotropin-releasing hormone deficiency: perspectives from clinical investigation. Endocr Rev 1992; 13:635.
- Saenger P. Turner's syndrome. N Engl J Med 1996; 335:1749.
- Massarano AA, Adams JA, Preece MA, Brook CG. Ovarian ultrasound appearances in Turner syndrome. J Pediatr 1989; 114:568.
- Zhong Q, Layman LC. Genetic considerations in the patient with Turner syndrome--45,X with or without mosaicism. Fertil Steril 2012; 98:775.
- Portuondo JA, Neyro JL, Benito JA, et al. Familial 46,XX gonadal dysgenesis. Int J Fertil 1987; 32:56.
- Kohmanaee S, Dalili S, Rad AH. Pure gonadal dysgenesis (46 XX type) with a familial pattern. Adv Biomed Res 2015; 4:162.
- de Vries L, Behar DM, Smirin-Yosef P, et al. Exome sequencing reveals SYCE1 mutation associated with autosomal recessive primary ovarian insufficiency. J Clin Endocrinol Metab 2014; 99:E2129.
- Caburet S, Arboleda VA, Llano E, et al. Mutant cohesin in premature ovarian failure. N Engl J Med 2014; 370:943.
- Wood-Trageser MA, Gurbuz F, Yatsenko SA, et al. MCM9 mutations are associated with ovarian failure, short stature, and chromosomal instability. Am J Hum Genet 2014; 95:754.
- AlAsiri S, Basit S, Wood-Trageser MA, et al. Exome sequencing reveals MCM8 mutation underlies ovarian failure and chromosomal instability. J Clin Invest 2015; 125:258.
- Smirin-Yosef P, Zuckerman-Levin N, Tzur S, et al. A Biallelic Mutation in the Homologous Recombination Repair Gene SPIDR Is Associated With Human Gonadal Dysgenesis. J Clin Endocrinol Metab 2017; 102:681.
- Zangen D, Kaufman Y, Zeligson S, et al. XX ovarian dysgenesis is caused by a PSMC3IP/HOP2 mutation that abolishes coactivation of estrogen-driven transcription. Am J Hum Genet 2011; 89:572.
- Bastian C, Muller JB, Lortat-Jacob S, et al. Genetic mutations and somatic anomalies in association with 46,XY gonadal dysgenesis. Fertil Steril 2015; 103:1297.
- Rachmiel M, Kives S, Atenafu E, Hamilton J. Primary amenorrhea as a manifestation of polycystic ovarian syndrome in adolescents: a unique subgroup? Arch Pediatr Adolesc Med 2008; 162:521.
- 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; 98:4565.
- Cama A, Sierra ML, Kadowaki T, et al. Two mutant alleles of the insulin receptor gene in a family with a genetic form of insulin resistance: a 10 base pair deletion in exon 1 and a mutation substituting serine for asparagine-462. Hum Genet 1995; 95:174.
- Taylor SI, Dons RF, Hernandez E, et al. Insulin resistance associated with androgen excess in women with autoantibodies to the insulin receptor. Ann Intern Med 1982; 97:851.
- Oral EA, Ruiz E, Andewelt A, et al. Effect of leptin replacement on pituitary hormone regulation in patients with severe lipodystrophy. J Clin Endocrinol Metab 2002; 87:3110.
- Quaynor SD, Stradtman EW Jr, Kim HG, et al. Delayed puberty and estrogen resistance in a woman with estrogen receptor α variant. N Engl J Med 2013; 369:164.
- Hypothalamic and pituitary disease
- - Functional hypothalamic amenorrhea
- - Isolated GnRH deficiency
- - Constitutional delay of puberty
- - Hyperprolactinemia
- - Other
- Gonadal dysgenesis/primary ovarian insufficiency
- - Turner syndrome
- - 46,XY gonadal dysgenesis
- - Primary ovarian insufficiency (POI)
- Polycystic ovary syndrome
- Outflow tract disorders
- - Imperforate hymen
- - Transverse vaginal septum
- - Müllerian agenesis
- Receptor abnormalities and enzyme deficiencies
- - Complete androgen insensitivity syndrome
- - 5-alpha-reductase deficiency
- - 17-alpha-hydroxylase deficiency
- - P450 oxidoreductase deficiency
- - Estrogen resistance
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