Category Archives: Gestational Trophoblastic Disease

Gestational Trophoblastic Disease

Four reasons for a positive hCG test in the absence of pregnancy

“Why is the pregnancy test positive if she’s not pregnant?”

This is a question I’ve been asked several times and it’s a good one.  The query usually comes from a nurse, doctor, or other healthcare provider after performing a test for human chorionic gonadotropin (hCG) and getting a positive or elevated result that they did not anticipate.

Because hCG is a hormone normally produced during pregnancy, hCG tests are used to diagnose the pregnant patient.  That makes it easy to think of hCG tests as “pregnancy tests.”  While that’s not an inaccurate label for them, identifying hCG tests as pregnancy tests gives the impression that is all they are supposed to do.  Technically, hCG tests are designed to qualitatively detect and/or measure the hormone in urine or blood and there are other reasons besides being pregnant that can cause hCG to be present.

I can think of four different reasons why hCG could be present in a non-pregnant woman.

  1. Biochemical pregnancy.  A biochemical pregnancy occurs when a woman becomes pregnant yet has a spontaneous loss of the fetus before she even knew she was pregnant.  If hCG testing occurs before all of the hCG has been metabolized out of the body then hCG can be detected by a lab test.  This situation is not as uncommon as one might think for two reasons.  First, hCG tests are frequently performed in healthcare settings in order to identify the pregnant patient in order to avoid any medical interventions that are potentially harmful to a fetus.  Second, hCG tests are capable of detecting very low concentrations of the hormone.  The high frequency of testing combined with the analytical sensitivity of the tests means that biochemical pregnancies are easily detected.
  2. Pituitary hCG.  Although the placenta normally produces hCG during pregnancy, it can be made by the pituitary gland.  The pituitary gland is a small structure in the brain that secretes many different hormones that function to regulate many endocrine organ systems.  Interestingly, three hormones normally produced by the pituitary gland (thyroid stimulating hormone, follicle stimulating hormone, and luteinizing hormone) are structurally similar to hCG.  Pituitary hCG is more commonly detected in women greater than 55 years of age but can be detected in women as young as 41 years.  Non-pregnant women with pituitary hCG usually have low concentrations of hCG present in the blood and urine.  Importantly, concentrations of hCG produced by the pituitary gland don’t show the rapid increases that occur during pregnancy.
  3. Malignancy.  Cancer cells sometimes make hCG.  While many different types of cancer have been shown to make the hormone, it’s most commonly associated with the gestational trophoblastic diseases and certain types of germ cell tumors of the testes.  Because testicular tumors occur only in men, the question of detecting hCG in the absence of pregnancy is clearly not relevant.
  4. Interfering antibodies.  Some women have antibodies in their blood that can interfere with hCG tests and cause a positive or elevated result in the absence of hCG.  Only hCG tests performed on blood can be affected by this problem because the interfering antibody molecules aren’t normally present in the urine.  This can be a serious problem because some women have been mistakenly diagnosed with cancer due to the false-positive hCG test result and have undergone unnecessary treatments for it.  The frequency of this problem is difficult to know but it’s probably very low.  Over the last several years, the manufacturers of hCG tests have worked to minimize possible interference from these antibodies but nothing can be done to completely eliminate the problem.  When alerted, the laboratory can help to determine if an hCG test result is falsely positive due to this issue.

So, just because an hCG test result is interpreted as positive doesn’t automatically mean that a woman is pregnant.  There are very valid reasons for detecting hCG in the absence of pregnancy.  That said, when the hCG test result doesn’t match the clinical picture, the laboratory should still be asked that question!  When alerted to the discrepancy, the lab can help to investigate the problem and perhaps shed some light on the cause.

There is quite a bit more to say on each of those four causes but I’ll save those comments for future posts.


hCG and the thyroid gland

Thyroid tests First things first. The main job of human chorionic gonadotropin (hCG) hormone is to increase the synthesis of progesterone in early pregnancy. Without steadily increasing concentrations of progesterone, an early pregnancy will fail. hCG usually has nothing to do with the thyroid gland.

As a reminder, the thyroid gland, located in the neck in close proximity to the larynx (voice box), is basically responsible for controlling our body's metabolism. It is regulated by a different hormone: thyroid stimulating hormone or TSH.

So hCG maintains pregnancy and TSH regulates the thyroid gland. Sometimes, however, hCG can act like TSH and crank up the function of the thyroid gland. When the thyroid gland is in an over-active state the condition is called hyperthyroidism. Symptoms of hyperthyroidism include weight loss, increased appetite, heat intolerance, hair loss, weakness and fatigue, irritability, and sweating. In extreme cases, hear palpitations, and shortness of breath can occur. How can hCG cause hyperthyroidism? The answer lies in the molecular structure of these two hormones.

As it turns out, hCG and TSH are rather similar to each other. Both are composed of two different protein subunits. One of those protein subunits is called "alpha" and the other "beta." The alpha subunits of hCG and TSH are identical but the beta subunits are a different; but not by much. The beta subunits of hCG and TSH are about 40 percent identical. When present a very high concentrations, hCG can actually stimulate the thyroid gland sending it a message to go into over-drive. In other words, hCG can sometimes act like TSH. Fortunately, this doesn't happen unless the amount of hCG in the blood gets to be very, very elevated.

How elevated? Well, that has been the subject of some recent investigations. Conventional wisdom was that hyperthyroidism could occur in women with an hCG concentration that was greater than 50,000 IU/L. While this hCG concentration may seem very elevated, it's actually quite normal in pregnant women who are in their first trimester. Because the vast majority of pregnant women in early pregnancy do not have symptoms of hyperthyroidism, the 50,000 IU/L threshold didn't seem accurate.

In one study (disclaimer: I participated in that study), an hCG threshold of 400,ooo IU/L was identified as the concentration above which actual symptoms of hyperthyroidism could occur. The lower hCG concentration of 200,000 IU/L was identified as the threshold above which a majority of women demonstrated biochemical signs of hyperthyroidism (i.e. decreased TSH) but they did not have actual symptoms of hyperthyroidism until the hCG increased to twice that amount.

Another study reported that women developed suppressed TSH and/or symptoms of hyperthyroidism only when the hCG concentration was greater than 100,000 IU/L.

A normal, singleton, intrauterine pregnancy doesn't usually produce such sustained elevations of hCG. This means that the vast majority of pregnant women will never have symptoms of hCG-induced hyperthyroidism. However, extreme elevations of hCG can be produced in women with gestational trophoblastic disease (GTD). These are a family of diseases that arise from an abnormal fertilization event so hCG is produced even in the absence of a viable fetus.

The bottom line is that extremely high hCG concentrations can cause biochemial and physical signs of hyperthyroidism but these are rarely the result of the hCG concentrations found in normal pregnancy.