Luteal Phase Progesterone |
Progesterone in Pregnancy
37 year old G2 S2 undergoes a basic recurrent pregnancy loss evaluation and finds that an endometrial biopsy is out of phase by 3-4 days. Timing of ovulation was carefully monitored during the biopsy cycle so that the dates were clearly established.
Has the diagnosis of a luteal phase defect been established with certainty for this woman?
Criteria used to diagnose a luteal phase defect are controversial.
The “gold standard” diagnostic test is most often thought to be the endometrial biopsy. However, the ability of an isolated endometrial biopsy to establish the diagnosis has been questioned. There is one clinical trial involving multiple endometrial biopsies from 5 regularly menstruating and fertile women (which is a small sample size) that suggests that there is a high rate of “out of phase” results for a single random biopsy (over 30%) and yet a significantly lower rate of “out of phase” results for two consecutive biopsies (less than 10%). Therefore, in order to establish a diagnosis of a luteal phase defect many reproductive endocrinologists recommend two endometrial biopsies on back to back menstrual cycles when the initial endometrial biopsy is out of phase.
28 year old G2 S2 has a single random serum progesterone concentration in the late luteal phase (of the menstrual cycle) of 5 ng/mL.
Should this woman have additional bloodwork, a luteal phase endometrial biopsy or supplemental natural progesterone?
The diagnostic criteria for a luteal phase defect are controversial.
The serum progesterone concentration in the luteal phase is known to be highly pulsatile, with significant increases and decreases up to every 10-15 minutes. In general, the luteal serum progesterone concentration is greatest in the mid luteal phase.
If a serum progesterone concentration during the luteal phase were reportedly low, I would (minimally) recheck the serum progesterone concentration during the mid luteal phase of a subsequent menstrual cycle. If persistently low, I would consider suggesting supplemental natural progesterone.
I generally do not rely on serum progesterone concentrations to assess a luteal phase defect. I prefer the endometrial biopsy, since the effect of circulating progesterone on the lining of the uterus (endometrium) is the end result that most concerns me and this is dependent on additional variables such as the endometrial progesterone receptor concentrations.
Once a diagnosis of a luteal phase defect is established in a woman with spontaneous pregnancy losses I suggest natural progesterone supplementation.
33 year old G3 S3 with unexplained recurrent pregnancy losses after a thorough basic evaluation now desires progesterone supplementation since “it worked for her girl friend.”
What are the risks and benefits of empiric progesterone supplementation?
The risk of progesterone supplementation in pregnancy is unclear. Progesterone is (generally) thought to be absolutely required in order to maintain a normal pregnancy. Natural progesterone can be administered (by mouth, vaginally or via injection) as a supplement to one’s own progesterone production. The increased risk of birth defects for women who take natural progesterone supplementation in pregnancy is currently thought to be nonexistant or minimal.
The benefit of natural progesterone supplementation in pregnancy is clearest when there is a documented progesterone insufficiency problem (luteal phase defect). The diagnosis of a luteal phase defect is controversial, but once the diagnosis has been made then natural progesterone supplementation should be considered and suggested.
In the absence of a clear diagnosis of a progesterone insufficiency problem, the benefit of supplemental progesterone is controversial.
Some reproductive endocrinologists believe that there may be an important immunologic benefit to supplemental progesterone and that (higher doses of) natural progesterone may prevent some immunological causes of pregnancy loss.
Other reproductive endocrinologists believe that there may be an unrecognized benefit of progesterone supplementation. For these physicians, there is a potential (theoretical) benefit and an absence of a recognized risk so it is given to patients who specifically request the medication.
Yet other reproductive endocrinologists believe that when there is no obvious benefit (such as a diagnosed progesterone insufficiency problem) then the patient should be discouraged from taking any medication. In these situations, there is a focus on the potential (theoretical) unrecognized risk of natural progesterone.
26 year old G3 S2 at 5 weeks gestation (pregnant 5 weeks from the onset of the last menstrual period) with a single random serum progesterone concentration of 6 ng/mL.
Should progesterone supplementation be initiated?
There are 3 different (theoretically defined) time periods of concern with respect to progesterone and pregnancy. Initially, ovarian progesterone production after ovulation is directed by pituitary LH secretion and insufficient progesterone during the luteal phase of the menstrual cycle should effect either embryo implantation and/or very early embryo development. Placental hCG is the hormone that “rescues” ovarian progesterone production if a woman becomes pregnant, and this maintains circulating progesterone concentrations through about 10 weeks gestation. After 10-12 weeks gestation, placental progesterone production becomes the dominant source.
A circulating progesterone concentration of less than 10 ng/mL is thought to be worrisome and a concentration of less than 7 ng/mL at the nadir (when hCG rescues ovarian production at about 4 weeks gestation) is thought to reliably predict a spontaneous loss or ectopic pregnancy. Progesterone concentration in early pregnancy (4-10 weeks gestation) is relatively consistent (not very pulsatile) since it is largely determined by the circulating hCG hormone concentration, which has a steady serum concentration due to a long half life (1-2 days).
There are reported cases when very low progesterone concentrations result in normal pregnancies and deliveries. Different labs may also obtain somewhat different results for the concentration of progesterone in the same serum sample, since the different labs use different hormone assay systems (with different progesterone antibodies, progesterone standards for callibration, and internal reagents) to assess the concentration.
In this situation, if the pregnancy is desired then I would initiate natural progesterone supplementation immediately and recheck the progesterone concentration. I would adjust the supplemental progeseterone to maintain an elevated progesterone concentration. If there were a documented fetal heart beat by 7 weeks gestation (5 weeks after ovulation) then I would continue to observe the pregnancy (as usual). Absence of a fetal heart beat by 5-6 weeks following ovulation (if the time of ovulation is known) is ominous.