Table 1. Differential Diagnosis of Amenorrhea
Disease Present in Primary Present in Secondary
Amenorrhea? Amenorrhea? LH FSH E2 Notes
Hypothalamus
Hypothalamic amenorrhea Yes Yes ↓or normal ↓or normal ↓ Exercise, weight loss, stress, chronic illness
Hypogonadotropic
hypogonadism Yes Yes ↓or normal ↓ or normal ↓ Anosmia may be present Hypothalamic tumors Yes Yes ↓or normal ↓or normal ↓ Brain imaging necessary
Pituitary
Hypogonadotropic
hypogonadism Yes Yes ↓or normal ↓ or normal ↓
Pituitary tumors
(e.g., prolactinoma) Yes Yes ↓or normal ↓or normal ↓ Brain imaging; prolactin may
Pituitary infection or infiltration Yes Yes ↓or normal ↓or normal ↓
Sheehan's syndrome No Yes ↓or normal ↓or normal ↓ After delivery; can be acute or insidious
Ovary
Gonadal dysgenesis Yes Yes ↓ 45,XO = Turner's syndrome Pure gonadal dysgenesis Yes Yes ↓ Karyotype either 46,XX or
46,XY
Premature ovarian failure No Yes ↓ Autoimmune syndromes Polycystic ovary syndrome Yes Yes or normal Normal Normal Hyperandrogenism;
oligomenorrhea since menarche
Ovarian tumors No Yes ↓ ↓ or normal Look for acute virilization 17␣-hydroxylase deficiency Yes No ↓ Sexual infantilism
Uterus
Müllerian agenesis Yes No Normal Normal Normal May have cyclical pelvic pain Asherman's syndrome No Yes Normal Normal Normal History dilation and curettage (uterine synechiae)
Other
Adrenal tumors No Yes ↓ ↓ or Normal Hyperandrogenism Thyroid disease Yes Yes Normal Normal Normal
Testicular feminization Yes No or normal XY karyotype
DHEAS = dehydroepiandrosterone sulfate; E2= estradiol; FSH = follicle-stimulating hormone; LH = luteinizing hormone; T3= triiodothyronine; T4= thyroxine.
↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓ ↓
Disorders of Menstruation and Menopause • 125
Table 2. Laboratory and Other Studies for Amenorrhea
Test Notes
-HCG Use to confirm or exclude pregnancy.
FSH Hypergonadotropism (ovarian failure, menopause) is present when levels are >20 IU/mL. Use to rule out ovarian failure. Perform karyotyping in all patients <30 years with elevated FSH levels.
Prolactin Because prolactin levels can be elevated by stress, breast exam, and food intake, repeat analysis on a fasting morning sample before performing cranial imaging. Hypothyroidism can also cause elevations in serum prolactin level. Phenothiazine, tricyclic antidepressants, metoclopramide, reserpine and methyldopa, can cause hyperprolactinemia. Values >100 ng/mL suggest pituitary tumor.
TSH Hypothyroidism and, less commonly, hyperthyroidism are associated with menstrual cycle abnormalities and infertility.
Testosterone, DHEAS Serum androgens may be helpful in the setting of hirsutism and acne; total testosterone >200 µg/dL and DHEAS >3ǂ upper limit of normal may suggest tumor (although no tumor will be found on most occasions).
17-hydroxyprogesterone Beneficial in screening for congenital adrenal hyperplasia.
Estradiol Decreased in hypothalamic and pituitary amenorrhea, and in ovarian failure; should always be assessed with FSH. Very limited use in clinical practice unless evaluating primary amenorrhea.
Luteinizing hormone Normal levels are 5-20 IU/mL, with midcycle peak three times the base level. In hypogonadotropic states (hypothalamic or pituitary dysfunction), the level is <5 IU/mL. In hypergonadotropic states (postmenopausal or ovarian failure), the level is >20-40 IU/mL. Not needed to diagnose PCOS.
Bone density test (DEXA) May be required in a patient with amenorrhea who is estrogen deficient.
Brain MRI Necessary to rule out a hypothalamic or pituitary mass, infection, or infiltration; critical to consider in the setting of primary amenorrhea with hypogonadotropic hypogonadism.
-HCG =  human chorionic gonadotropin; DEXA = dual-energy X-ray absorptiometry; DHEAS = dehydroepiandrosterone sulfate; FSH = follicle-stimulating hormone; IU = international units; LH = luteinizing hormone; MRI = magnetic resonance imaging; PCOS = polycystic ovary syndrome; TSH = thyroid-stimulating hormone.
production, which then causes a surge of LH secretion 34-36 hours before follicle rupture and ovulation. Once this occurs, progesterone is produced by ovarian granulose cells (the corpus luteum) for approximately 14 days, which then involutes unless pregnancy is established. Estrogen functions physiologically to increase the thickness and vascularity of the endometrial lining whereas progesterone increases its glandular secretion and vessel tortuosity. The cyclical withdrawal of estrogen and progesterone results in endometrial sloughing and menstrual bleeding.
Amenorrhea
Primary amenorrhea is the failure of menstruation in girls 16 years of age or older, while secondary amenorrhea is the absence of menstruation for 3 cycle intervals or 6 consecutive months in women with prior menstrual flow. Table 2 lists common tests used in the evaluation of primary and secondary amenorrhea. Approximately 50% of primary amenorrhea is caused by chromo- somal disorders, which cause gonadal dysgenesis and depletion of ovarian follicles. Turner’s syndrome is the most common in this category and is classically associated with a 45 XO genotype. It is characterized by a lack of secondary sexual characteristics, growth retardation, webbed neck, and frequent skeletal abnormalities. Hypothalamic hypoandrogenism accounts for approximately 20% of causes and includes both functional and structural hypothala- mic disorders, such as developmental defects of cranial midline structures, tumors, or infiltrative disorders.
Less common etiologies of primary amenorrhea include devel- opmental disorders, such as mullerian agenesis, imperforate hymen, and defects of the cervix or vagina. Such patients have normal secondary sexual characteristics. Patients with androgen- resistance syndromes (XY karyotype) have some female secondary
sexual characteristics, but absence of or minimal pubic and axillary hair, a shallow vagina, and often a labial mass (testes). Endocrine abnormalities such as prolactin excess, thyroid disease, or poly- cystic ovary syndrome (PCOS), while more commonly associat- ed with secondary amenorrhea, also cause primary amenorrhea. Patients with primary amenorrhea should be examined for the presence of an intact uterus and vaginal outflow tract, secondary sexual characteristics, and signs of hyperandrogenism. If evidence of characteristic developmental disorders is present, karyotype test- ing should be considered. Primary ovarian failure of any etiology can be diagnosed by an elevated follicle-stimulating hormone (FSH). If the FSH is low or normal, testing of prolactin and thy- roid-stimulating hormone (TSH) is warranted as well as head imaging to exclude structural disease.
Secondary amenorrhea is much more common. All previous- ly menstruating women who present with amenorrhea should be tested for pregnancy, the most common etiology. Premature ovarian failure may occur as a result of surgical oophorectomy, chemotherapy, radiation, or autoimmune destruction of ovarian tissue. Diagnosis of secondary ovarian failure is also made by an elevated FSH. In such patients, vaginal bleeding will not occur with a progesterone challenge because estrogen levels are low, but will occur after estrogen priming followed by a progesterone challenge, demonstrating the integrity of the uterine lining and outflow tract.
Polycystic ovary syndrome (PCOS) affects 6% of women of child-bearing age and typically presents with oligomenorrhea and signs of androgen excess (hirsutism, acne, and occasionally alope- cia). The cause is not fully understood, but there is abnormal gonadotropin regulation, with subsequent overactivity of the ovarian androgen pathway. Insulin resistance is an important fea- ture of the disorder, as is overweight/obesity, though only 50%
of affected women are obese. Other forms of androgen excess (androgen-producing tumor, congenital adrenal hyperplasia, Cushing’s syndrome) should be excluded. Typically there is a mild elevation in testosterone and DHEA-S (dehydroepiandrosterone sulfate) levels and a luteinizing hormone (LH)/FSH ratio greater than 2:1. Diagnosis requires two out of three of the following: ovulatory dysfunction, laboratory or clinical evidence of hyperan- drogenism, and ultrasonographic evidence of polycystic ovaries.
Hyperprolactinemia is a frequent cause of secondary amenor- rhea and is commonly related to medications. Drugs that reduce central catecholamine and dopamine production or release can cause hyperprolactinemia. Among the most common are tricyclic antidepressants, phenothiazines, and metoclopramide. Primary hypothyroidism reduces negative feedback on the production of hypothalamic thyrotropin-releasing hormone, which stimulates prolactin production. Tumors that secrete prolactin or compress the pituitary stalk will lead to hyperprolactinemia. If the prolactin level is elevated and medication and hypothyroidism are exclud- ed, imaging of the head is warranted.
Hypothalamic amenorrhea involves disordered gonadotropin release. It may be a result of a tumor or infiltrative lesion (e.g. lym- phoma, sarcoidosis) but more commonly is functional. The usual etiologic factors are stress, excessive loss of body weight or fat, excessive exercise, or some combination thereof. Diagnosis is one of exclusion.
When amenorrhea with low or inappropriately normal FSH level is present, secondary causes (PCOS, androgen or prolactin excess, hypothyroidism) must be ruled out. If a functional etiolo- gy is suspected, reduction in exercise, improvement in nutrition, and attention to emotional needs are helpful adjuncts. Because lack of adequate estrogen predisposes to osteoporosis, it is very important to initiate adequate estrogen and progesterone replace- ment until etiologic factors are resolved and menstruation can return to normal.