Primary amenorrhea (PA) is defined as the absence of menstruation by the age of 15 years in a female with normal secondary sexual characteristics (breasts and pubic / axillary hair), or with 3 years elapsed after thelarche (breast development). A similar evaluation should occur in a female aged 13 years without proper development of secondary sexual characteristics (delayed puberty) and no menstruation. This is distinct from secondary amenorrhea, which is defined as the absence of menstruation for 3 months or longer in a female who previously had regular menstruation for at least 6 months. PA can be classified into several groups based on etiology, with many causes fitting into multiple categories: endocrinologic, anatomic, medication induced, and physiologic. PA occurs in 2% of adolescent females.

The evaluation begins with a comprehensive history and review of systems, including all medications and supplements taken as well as caloric intake and physical activity level. Be sure to ask about a history of head injuries and a history of encephalitis. A complete physical examination should be done, including a pelvic examination if possible, with attention to symptoms such as headaches, vomiting, visual symptoms (pituitary adenomas), hirsutism (increased androgens or adrenal hormones), nipple discharge (prolactinoma / prolactinemia), and cyclic abdominal /pelvic pain (outflow tract obstruction). Laboratory evaluation includes a pregnancy test, hormone testing (luteinizing hormone [LH], ultrasensitive if available, follicle-stimulating hormone [FSH], estrogens, prolactin), thyrotropin (TSH) testing, and possible karyotyping if indicated by history and clinical findings (stigmata of Turner syndrome or other syndrome). Pelvic imaging by ultrasound to evaluate internal pelvic structures and the vagina is recommended. Further imaging of the brain (MRI with pituitary protocol) or genitourinary (GU) tract may be warranted based on initial evaluation and imaging findings.

If a uterus is not present on ultrasound, then testosterone levels as well as a karyotype should be done. A karyotype of 46 XX with normal testosterone indicates Müllerian dysgenesis. A karyotype of 46 XY with high testosterone indicates androgen insensitivity syndrome.

If a normal uterus is found, LH and FSH levels can help determine possible causes of amenorrhea. Low LH and FSH usually indicate constitutional growth delay, functional amenorrhea, or, rarely, primary gonadotropin-releasing hormone (GnRH) deficiency. Elevated LH and FSH indicate primary ovarian failure, which is often seen in Turner syndrome. If LH and FSH levels are normal, consider genital outflow tract obstruction, calorie deficiency / low weight, nonclassical congenital adrenal hyperplasia (CAH), polycystic ovarian syndrome (PCOS), and gonadal tumors.

There are many causes of PA. Endocrinologic causes are the most common, with gonadal dysgenesis accounting for up to 43% of cases. Other causes include functional hypothalamic amenorrhea, inherited deficiency of GnRH, hypopituitarism, PCOS, Cushing disease, nonclassical CAH and other adrenal derangements, thyroid abnormalities, androgen-secreting tumors, hyperprolactinemia, Kallmann syndrome, hypogonadotropic hypogonadism, and hypergonadotropic hypogonadism (gonad failure).

Anatomic causes are the second most common cause, with Müllerian dysgenesis accounting for up to 15% of cases. This is seen in Mayer-Rokitansky-Kuster-Hauser syndrome. Other causes, such as imperforate hymen, transverse vaginal septum, blind vaginal pouch, cervical obstruction, and vaginal agenesis, often present with normal secondary sexual characteristics and cyclic abdominal / pelvic pain.

Other disorders of sexual development include complete androgen insensitivity syndrome and aromatase deficiency.

Autoimmune diseases, including the production of antiovarian antibodies, have been reported but are uncommon.

Medications are an uncommon but possible cause of PA. Culprits include chemotherapeutic medications, previous head or pelvic radiation therapy or exposures, continuous progesterone use, GnRH antagonists, and medications that increase prolactin (ie, antipsychotics, metoclopramide, phenothiazines). Antidepressants and hypertension medications more commonly cause secondary amenorrhea and rarely cause PA.

Physiologic causes are not uncommon and include constitutional growth delay, excessive exercise / physical activity, low body weight (eg, eating disorders, malnutrition), and systemic illnesses (inflammatory bowel disease [IBD], sarcoidosis, galactosemia, thalassemia, etc).