Primary Amenorrhea in a Teenager
Primary amenorrhea (PA) has traditionally been defined as failure to menstruate by age 15. An evaluation should be initiated if a 15-year-old with normal secondary sexual characteristics or a 13-year-old without secondary sexual characteristics has failed to menstruate. The average age of menarche is 12.5 years and usually occurs within 2-3 years of thelarche.
The history should evaluate habits (such as extreme athletics), nutrition, medicines, and assessment for anorexia and bulimia.
The physical exam should include height, weight, Tanner staging, and examination of external genitalia. Growth should be charted. The goal is to determine whether there are estrogen effects such as breast development and hymeneal thickening and determine external patency of the vaginal opening. An internal pelvic or recto-abdominal exam is not necessary.
Initial laboratory evaluation should include follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), hCG, and prolactin (PRL) levels. Internal anatomy should be defined with transabdominal pelvic ultrasound.
The differential diagnosis should include constitutional delay, anomalies of the outflow tract, enzyme deficiencies & receptor abnormalities, gonadal dysgenesis, central CNS anomalies, and other endocrinopathies (such as PCOS, thyroid, adrenal, Cushing’s, and diabetes). With this broad differential, it is helpful to compartmentalize causes based on physical exam findings and hormonal evaluation results.
If breast development is absent and the FSH level is high, the diagnosis is hypergonadotropic hypogonadism (40% of PA). This is primarily caused by gonadal dysgenesis, the most frequent cause of primary amenorrhea. The most common cause is Turner’s syndrome (45X). Pure gonadal dysgenesis (XX) and Swyer’s syndrome (XY) are other causes. Karyotype including microanalysis for Y chromosome material should be performed. Other causes of hypergonadatropic hypogonadism include gonadal injury (chemotherapy, radiation), infection (mumps), resistant ovary syndrome, 17a hydroxylase deficiency, and autoimmune causes.
If breast development is absent and the FSH level is normal or low, hypogonadotropic hypogonadism (30% of PA) is present. Normal TSH and PRL levels rule out thyroid disorders and hyperprolactinemia. The remainder of the differential includes constitutional delay (most common), exercise, stress, chronic disease, poor nutrition, anorexia nervosa, infiltrative and ischemic causes, other pituitary abnormalities, Kallmann syndrome, and CNS lesions. A MRI should be obtained to rule out CNS tumor.
The long-term effects of hypogonadism include lack of breast development and osteoporosis. The underlying etiology should be corrected to allow normal pubertal development, or low estrogen replacement therapy initiated with gradual increase over a 2-year period to promote puberty.
If breast development is present, an ultrasound should be performed to determine if a uterus is present. If the uterus is absent, the physical exam, ultrasound findings and testosterone level will differentiate between complete androgen insensitivity (5% of PA) and Mullerian agenesis (10% of PA). Androgen insensitivity has an elevated testosterone level, scant pubic and axillary hair, and a 46 XY karyotype. Mullerian agenesis has a normal hormonal profile, normal distribution of axillary and pubic hair, and a 46 XX karyotype.
At times, PA occurs in women with an otherwise normal pubertal progression, with breast development, uterus present, and no evidence of outlet obstruction. Polycystic ovarian syndrome, late onset congenital adrenal hyperplasia, and Cushing’s syndrome are possible in women where hyperprolactinemia and thyroid disorders have been excluded. These individuals are eugonadal and exhibit signs of hyperandrogenism such as acne and hirsutism. Less severe forms of poor nutrition, eating disorders, chronic medical disorders, and exercise can also present this way.
American College of Obstetricians and Gynecologists, Committee opinion no. 605: primary ovarian insufficiency in adolescents and young women. Obstet Gynecol. 2014 Jul;124(1):193-7. doi: 10.1097/01.AOG.0000451757.51964.98.
Yoon JY, Cheon CK. Evaluation and management of amenorrhea related to congenital sex hormonal disorders. Ann Pediatr Endocrinol Metab. 2019 Sep;24(3):149-157. doi: 10.6065/apem.2019.24.3.149. Epub 2019 Sep 30. PMID: 31607107; PMCID: PMC6790874.
Initial Approval March 2011. Revised September 2016. Reaffirmed September 2019; Minor Revision May 2021
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