Progesterone: The Most Misunderstood Hormone
Progesterone levels have been measurable in the blood since the 1970s. This test is now easily and inexpensively run, with results often available on the day of blood draw. Progesterone serves a number of functions in the body. For this hormone to produce an effect it needs to bind to a receptor within a cell. Therefore, certain body cells with no progesterone receptors will not be impacted by this hormone. Progesterone in the uterus will change a lining (primed by estrogen) to prepare it to accept an embryo for implantation and pregnancy.
Without progesterone the uterus has an extremely difficult time supporting a pregnancy. Very old studies showed that the removal of the ovary that is making progesterone early in pregnancy, results in a miscarriage. Replacing progesterone prevented that loss. Because of its importance in pregnancy, treatment of a "low" progesterone has excited our expectations for a long time. Unfortunately, many of these hopes have proven unrealistic and/or unproven.
MEASURING PROGESTERONE IN THE SECOND HALF OF THE MENSTRUAL CYCLE (LUTEAL PHASE).
A progesterone level of less than 1 ng/mL is generally felt to be associated with lack of evidence of ovulation. This level, however, does not indicate a progesterone "deficiency," as this low level is perfectly normal during the first 2 weeks of the menstrual cycle and again just prior to the initiation of the period. After a surge of a hormone called LH (that induces ovulation), the small cyst in the ovary (the follicle that holds the egg) then begins producing progesterone to support the pregnancy that the uterus is innocently expecting every month. Progesterone levels rise and peak about 1 week after ovulation (i.e., 1 week before the next menstrual period if pregnancy does not occur).
Unfortunately, measuring progesterone in the luteal phase is highly variable, as the day on which the progesterone is drawn may not always be at the time of peak production (7 days prior to the next menstrual period). In addition, progesterone is released in pulses. One study during the midluteal phase (second half of the menstrual cycle) showed values ranging from 5 to 35 ng/mL in a single day. It is no wonder that there is no such thing as a "normal" progesterone in the luteal phase. We use this hormone measurement simply to tell us whether an LH surge has occurred and whether the ovary has responded to this surge.
PROGESTERONE TO SUPPORT PREGNANCY.
A second major misconception involves the use of progesterone to support pregnancy. We physicians are often as or more confused than our patients. In a study that evaluated physicians' self-reported practices in 2016, progesterone was given by many doctors for a wide range of proven or presumed defects of ovulation and infertility. For example, 70% of doctors gave progesterone for prevention of miscarriage and 24% of physicians "always" used progesterone in patients who were receiving medicines (clomiphene or letrozole) to induce ovulation. Despite the frequency of prescription writing, it has been difficult to scientifically justify these practices. In an excellent report in the New England Journal of Medicine this past year, progesterone supplementation was found to be ineffective in preventing miscarriages. It has also long been known that giving progesterone after a pregnancy test is positive does not alter the subsequent miscarriage rate.
THEN WHY DO SO MANY PHYSICIANS PRESCRIBE PROGESTERONE FOR WOMEN WITH THREATENED MISCARRIAGES?
The answer is complicated. The first reason is that an abnormal pregnancy will often be associated with a low progesterone. The reason is not that the ovary is unable to produce progesterone but that the pregnancy itself (that is, the placenta) is not asking the ovary to produce higher progesterone levels when the pregnancy is failing. It is therefore no wonder that adding progesterone is of no benefit, as we are treating the messenger and not the actual cause of the problem. Nonetheless, both patients and physicians focus on the actual level of progesterone, and both are desperate to do something that might help support their pregnancy.
WHERE IS PROGESTERONE HELPFUL?
Progesterone may be of some use in patients with a very short second half of the cycle. However, we will often treat this condition (called "short luteal phase") by helping ovulation start out correctly in the first place. Progesterone also may help in patients with uterine abnormalities, such as uterine septation or a bicornuate (double) uterus. Later in pregnancy, progesterone is used to reduce preterm birth in women with either a history of preterm births or women with a short cervix an ultrasound scan after 18 weeks gestation. Progesterone is given in virtually all in vitro fertilization (IVF) cycles prior to implantation and continued into early pregnancy.