Clinical Pathology: General Principles, Lab Management, Clinical Chemistry

• Primary amenorrhea is defined as the absence of menarche (first menstruation) by age 15 or16 years in the presence of normal secondary sexual development or within 5 years of normal breast development if breast development occurs before 10 years of age, or lack of initiate breast development by age 13 years.

• The American Society for Reproductive Medicine classification of primary amenorrhea includes three main groups:

1) Primary amenorrhea with normal Tanner stage

2) Primary amenorrhea with low Tanner stage and high follicle-stimulating hormone (FSH) level

3) Primary amenorrhea with low Tanner stage and normal or low FSH level

• In primary amenorrhea with normal Tanner stage, it is important to ascertain whether Müllerian structures (fallopian tubes, uterus, cervix) are present. If the uterus is present, particularly in patients with periodic abdominal pain, outlet abnormalities such as cervical stenosis, vaginal aplasia, vaginal septum, and imperforate hymen are likely. Rarely, primary amenorrhea in a patient with fully developed external female genitalia and normal Müllerian structures with 46, XY karyotype is due to pure gonadal dysgenesis, caused by mutations in genes involved in testis development, including SRY, steroidogenic factor 1 (NR5A1), DAX1 (NR0B1), desert hedgehog (DHH), WT1, WNT4 and SOX9.

• In primary amenorrhea with normal Tanner stage in the absence of Müllerian structures, a karyotype will distinguish the two most common causes:Müllerian agenesis and complete androgen insensitivity. A normal karyotype, and luteinizing hormone (LH) and FSH levels within the reference range indicate Müllerian agenesis. Complete androgen insensitivity (testicular feminization), caused by mutations in the androgen receptor, will present with 46, XY karyotype with an external female phenotype with normal breast development, undescended testis, normal or elevated LH and FSH, and testosterone levels in the normal to high male range.

• Low Tanner staging with elevated LH and FSH indicate delayed puberty caused by hypergonadotropic hypogonadism (gonadal dysgenesis). The most common cause is Turner’s syndrome, defined by a 45, XO karyotype in a female. These patients loose their germ cells during gestation and are at high risk for cardiac, renal, thyroid, and ear abnormalities. Other congenital causes of hypergonadotropic hypogonadism include fragile X, Noonan’s, and Swyer’s syndromes. Causes of acquired primary hypogonadism include premature ovarian failure (idiopathic, trauma, surgery, radiation, chemotherapy, mumps, autoimmune disease); resistant ovary syndrome; and aromatase, 17-hydroxylase, and 17,20-lyase deficiencies.

• Patients with hypogonadotropic hypogonadism present with low levels of FSH, LH, and estradiol. Elevated prolactin suppresses gonadotropin-releasing hormone (GnRH) and can occur with defects in the hypothalamic-pituitary axis, including pituitary adenomas, brain tumors, infections, hemochromatosis, sarcoidosis, aneurysms, trauma, hypothyroidism, and medications. Other causes include Kallmann’s syndrome (congenital GnRH deficiency), thyroid disease, anorexia nervosa, malnutrition, stress, excessive exercise, and several chronic debilitating diseases. Occasionally, early onset of polycystic ovary syndrome (PCOS), Cushing’s syndrome, ovarian or adrenal tumor, or late-onset congenital adrenal hyperplasia can cause primary amenorrhea with signs of hyperandrogenism such as acne and hirsutism. Hypogonadism with low FSH and LH, a family history of delayed puberty, and exclusion of other diseases can be due to constitutional delay of puberty, when puberty occurs later than 2.5 deviations from the population mean.

•Physical examination, patient and family history, and laboratory measurements of FSH, LH, and prolactin can identify the most common causes of primary amenorrhea. Depending on the clinical situation, other useful tests include pelvic ultrasonography, head magnetic resonance imaging (MRI), karyotype, thyroid-stimulating hormone (TSH), testosterone, estradiol, dehydroepiandrosterone sulfate (DHEA-S), androstenedione, and 17-hydroxyprogesterone.

Winter WE, Sokoll LJ, Jialal I: Handbook of Diagnostic Endocrinology.Washington, DC: AACC Press, 2008:211–220.

Practice Committee of the American Society for Reproductive Medicine: Current evaluation of amenorrhea. Fertil Steril 2008;90(5 Suppl):S219–225.

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