At a Glance

Approximately 1% of women of reproductive age experience secondary amenorrhea, cessation of menses. In women who previously experienced regular menstrual cycles, secondary amenorrhea is the absence of menstruation for 6 months. In women who previously experienced irregular menstrual cycles, secondary amenorrhea is the absence of menstruation for 12 months. Secondary amenorrhea is a symptom caused by many pathological states, including pregnancy, polycystic ovary syndrome (PCOS), Cushing’s syndrome, hypopituitarism, hypothyroidism, and hyperprolactinemia. Some patients do not demonstrate an obvious etiology for their amenorrhea; however, the diagnostic evaluation should lead to the correct diagnosis if the problem is approached in a logical, stepwise manner.

What Tests Should I Request to Confirm My Clinical Dx? In addition, what follow-up tests might be useful?

Pregnancy is the most common cause of secondary amenorrhea. Therefore, the first step in the evaluation of secondary amenorrhea is to rule out pregnancy.

Laboratory diagnosis is most frequently performed by human chorionic gonadotropin (hCG) testing. hCG is a glycoprotein hormone produced by the placenta, so it is normally undetectable in nonpregnant, premenopausal women. hCG testing may be qualitative or quantitative. Although quantitative hCG testing is the gold standard test for pregnancy status, qualitative assessments are usually sufficient to confirm pregnancy. Furthermore, the rate of hCG doubling can help assess viability of a pregnancy, so quantitative measurements play an important role in diagnosing suspected ectopic pregnancy or failing pregnancy. Serial measurements should be used to monitor pregnancy.

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Pregnancy is detectable by a serum hCG assay at the time of implantation, or about 7-11 days after ovulation. Production of hCG does not begin until the blastocyst implants in the uterus. According to a study published in the Journal of the American Medical Association (JAMA) in 2001, the highest possible screening sensitivity of an hCG test on the first day of missed menses is 90%. (10% of the pregnancies failed to implant by the first day of missed menses.) Alternatively, a urinary hCG method can detect pregnancy at about the time of the first missed menses, and salivary methods can be used starting 2 weeks after conception.

When serum hCG concentration is at least 6,500 IU/L, an intrauterine pregnancy is identifiable by abdominal ultrasound studies, and it is identifiable by vaginal ultrasound when serum hCG is 1,000-2,000IU/L. An embryo is detectable by ultrasound when serum hCG levels are at 25,000-30,000 IU/L.

Are There Any Factors That Might Affect the Lab Results? In particular, does your patient take any medications – OTC drugs or Herbals – that might affect the lab results?


Testing too early in the pregnancy may lead to false-negative results, because detectable levels of hCG may not yet be present. The concentration of hCG doubles every 2-3 days early in a normal pregnancy.


Very dilute urine can produce false-negative results, so patients should not drink large amounts of fluids before collecting a urine sample. Additionally, blood or protein in the urine can cause false-positive results.


False-negative results can occur in patients who are taking diuretics or promethazine (an antihistamine). False-positive results can occur in patients who are taking anticonvulsants, anti-Parkinson’s drugs, tranquilizers, or hypnotics.

Other Conditions

Trophoblastic tumors and ovarian germ cell tumors can also cause elevated hCG levels.

Pituitary Secretion of hCG

The pituitary is hyperstimulated in peri- and postmenopausal women to produce FSH and LH and may cause low but detectable levels of hCG.


Different hCG assays may use different antibodies with differing specificities, leading to discordant results. Additionally, patients may have circulating heterophilic antibodies, resulting in false-positive results in some serum assays. In these cases, analysis by a urine method can confirm results (serum positive and does not dilute linearly while urine assay is negative). Finally, hCG variants, particularly β-core fragment (urine only), can cause false-negative results.