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Primary Amenorrhea in a Teenager

Mar 2011 – by P. Maseelall, MD

Primary amenorrhea (PA) has traditionally been defined as failure to menstruate by age 16. However, an evaluation should be initiated in a 15 year old with normal secondary sexual characteristics, or at age 13 without secondary sexual characteristics who have failed to menstruate. The average age of menarche is 12.5 years of age and usually occurs within 3 years of thelarche.

The initial evaluation includes a careful history, physical exam, exclusion of pregnancy, and appropriate laboratory testing. The history should highlight the patient's medical past including examination of growth charts, exercise habits, nutrition, medicines, family history, and an extensive review of systems. The physical exam should include height, weight, tanner staging, and examination of external genitalia. The goal of the physical exam is to determine whether breast development has occurred, indicative of estrogen stimulation, and to establish the presence or absence of a uterus. Laboratory evaluation should begin with a follicle stimulating hormone (FSH), thyroid stimulating hormone (TSH), and prolactin (PRL) level. The differential diagnosis list is exhaustive and it is helpful to compartmentalize the causes into hypothalamic, pituitary, ovarian and end organ problems.

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 common cause being Turner's syndrome (45X). However, pure gonadal dysgenesis (XX), Noonan's syndrome, Swyer's syndrome (XY) are also causes. Gonadal dysgenesis is the number one cause of primary amenorrhea and must be further evaluated with a karyotype to rule out presence of a Y chromosome. Other causes of hypergonadatropic hypogonadism include but are not limited to, injury or infection to the gonads (chemotherapy, radiation, mumps), resistant ovary syndrome, 17 hydroxylase deficiency, and autoimmune causes.

If breast development is absent and the FSH level is normal or low, the diagnosis is hypogonadotropic hypogonadism (30% of PA). The TSH and PRL levels will rule out thyroid disorders and hyperprolactinemia. The remainder of the differential includes; constitutional delay of puberty, Kallmann syndrome, anorexia nervosa, infiltrative and ischemic causes, exercise, stress, chronic disease, poor nutrition, other pituitary abnormalities, and CNS lesions. In this scenario it is important to rule out the most catastrophic cause, a CNS tumor; therefore, a MRI should be obtained.

The long-term effects of hypogonadism result in lack of breast development and risk for osteoporosis. It is important that the underlying etiology is either corrected, or estrogen replacement therapy is initiated.

If breast development is present, it is important to ascertain whether a uterus is present or absent. If the uterus is absent the physical exam and a testosterone level will be able to decipher between complete androgen insensitivity (5% of PA) and mullerian agenesis (10% of PA). The latter will have a normal hormonal profile and axillary, pubic hair with a normal distribution, and a 46 XX karyotype. The former will have an elevated testosterone level, scant pubic and axillary hair, and a 46 XY karyotype.

If the uterus is present it is important to exclude outlet abnormalities. Patients often present with cyclic abdominal pain and tanner stage V breast development. These include imperforate hymen (1 in 1000) and transverse vaginal septum (1 in 80,000). Surgery is the cure.

At times pubertal development occurs at a normal rate but PA occurs in women with breast development, uterus present, and no evidence of outlet obstruction. Once thyroid disorders and hyperprolactinemia have been excluded one should consider polycystic ovarian syndrome, late onset congenital adrenal hyperplasia, and Cushing's syndrome. These individuals are eugonadal and exhibit signs of hyperandrogenism such as acne and hirsuitism.

In summary it is important to develop an algorithm to help elucidate the cause of primary amenorrhea in an adolescent.