Hormonal causes for recurrent pregnancy loss are generally considered luteal phase defects. Luteal phase defects are most often thought to result from inadequate progesterone effect on the uterine endometrial lining. The existing literature on luteal phase defects is inconsistent and many physicians question the significance (or even the existence) of these defects. More often than not, infertility specialists in the USA accept that these luteal phase defects indeed exist and are capable of playing a significant role in a small group of couples (thought to be less than 5% but some supporters claim up to 40%) with recurrent pregnancy loss.
To successfully implant into the uterus the embryo must be available during a window of time limited to a few days per cycle, referred to as the window of uterine receptivity. If this window of uterine receptivity is not properly timed with respect to ovulation then either infertility or pregnancy loss may occur. The primary regulation for this window of receptivity appears to be hormonal (progesterone). Molecular events (currently poorly understood) change in response to hormonal shifts and most likely allow for (and guide) the implantation of a developing embryo (fertilized egg). Research is active in this area. Descriptions of cell adhesion molecules that allow the embryo to adhere to the uterine lining (the molecular glue that sticks the developing embryo to the endometrium) and their hormonal (or other) regulation is just one exciting area of investigation.
Progesterone appears to have a critical role in implantation and the development of a normal pregnancy. Limited exposure to progesterone may result in infertility (severe) or recurrent pregnancy loss (milder). Characteristically, decreased progesterone results in a shortened (less than 11 day) luteal phase (period between ovulation and the onset of the next menses) or a persistently abnormal endometrial biopsy (greater than 2 days out of phase). When these changes are more severe, the impact on reproduction can be greater.
Luteal phase defects can be categorized into classes that guide treatment. The ovary's corpus luteum cyst (that develops following ovulation) produces progesterone. Initially, the stimulus for progesterone production is pituitary LH, which supports progesterone production (by the corpus luteum's granulosa cells) for about 11-14 days. As LH support declines in the presence of a pregnancy progesterone production by the corpus luteum is normally rescued by placental hCG (which is functionally similar to pituitary LH) until about 7-10 weeks gestation. After 8-10 weeks gestation, the primary source of circulating progesterone changes from the ovarian corpus luteum cyst to the uterine placenta.
Available Case Reports:
Three potential causes (classes) of luteal phase defects are:
- Inadequate luteal phase production of progesterone. This may be the result of ovulation from a small ovarian follicle (and thus corpus luteum cyst) which would be lined by fewer hormone producing granulosa cells. There also might be inadequate circulating pituitary LH. This would effect implantation and very early development. Increasing progesterone during this time could be accomplished by direct supplementation (progesterone medication) prior to implantation or promoting increased follicular (and consequently corpus luteal) cyst development (typically with clomiphene citrate).
- Inadequate progesterone production after luteal rescue by the placental hCG. Circulating hCG concentration must increase dramatically until about 10 weeks to adequately support the corpus luteum. Inadequate hCG production might be related to a small (or abnormally growing) placenta due to either a uterus with an inadequate blood supply or an abnormal embryo (fetus). This would affect the embryo from about 4 to 10 weeks gestation. Increasing progesterone during this time could be accomplished by direct supplementation (progesterone medication). Generally, progesterone supplementation is not powerful enough to prevent a miscarriage if there is an abnormal embryo.
- Inadequate placental production of progesterone. This may be due to either a small placental mass or a biosynthetic abnormality in placental progesterone production. This would affect pregnancies primarily after 10 weeks gestation. Increasing progesterone after 8 weeks gestation could be accomplished by direct supplementation (progesterone medication). This appears to be the least common cause for pregnancy loss since most losses occur prior to this time.
Infertility specialists occasionally draw upon a small handful of reports describing women with documented low progesterone concentrations in pregnancies that result in a normal outcome. These reports force one to question the absolute necessity of progesterone, and suggest the possible importance of other nonhormonal regulators of the window of uterine receptivity. These reports include:
- Women with the congenital abnormality known as abetalipoproteinemia have cells that are unable to take up and use VLDL-cholesterol. VLDL-cholesterol is a primary source for cellular cholesterol. Since cholesterol is required for the synthesis of progesterone these women have very low circulating progesterone concentrations. There are reports of women with abetalipoproteinemia who have documented low progesterone concentrations throughout pregnancy and have carried their pregnancy to term
- Fetuses with a rare deficiency in one of the enzymes required for progesterone production, such as 3-beta hydroxysteroid dehydrogenase or the cholesterol side chain cleavage complex, may be delivered at term despite the inability of these fetuses (and presumably also their placentas) to produce adequate progesterone. Prenatal diagnosis of these conditions has never been early enough to actually document low progesterone throughout pregnancy (at least from the time of placental takeover of progesterone production)
- an In Vitro Fertilization patient with a diagnosis of unexplained infertility discontinued her prescribed progesterone when she noted vaginal bleeding at 4-5 weeks gestation (and assumed that she was not pregnant). Bloodwork documented a progesterone concentration of less than 2.0 ng/ml at 5-6 weeks gestation, she did not return to progesterone supplementation and she delivered a normal fetus at term. It is generally accepted that a progesterone concentration of less than 7 ng/ml at the time of hCG rescue (the usual nadir in progesterone concentration which occurs at about 4 weeks gestation) is ominous and predicts spontaneous abortion.
- A mouse with a knockout mutation involving the gene encoding the progesterone receptor has recently been described. These mice appear to be incapable of ovulation. Future experiments with these mice may reveal important aspects of the role of progesterone in reproduction, including implantation.
The endometrial biopsy is the gold standard diagnostic test for luteal phase defects. It only detects defects that are due to inadequate luteal phase progesterone production. The other hCG or placental progesterone defects are not determined. Pregnancies lost due to early hormonal defects occur throughout the first trimester suggesting abnormal embryogenesis (embryo development) rather than an immediate uterine rejection.
The reliability of the endometrial biopsy has been questioned. Research on the biopsy includes
- Introduction of histologic criteria for dating endometrium in 1951, with a stated mean error in dating of 1.8 days.
- More than 60 luteal biopsy specimens were examined by the same experienced pathologist at two different times to compare the assigned dates and only 24% (about 1 in 4) were read as the same day and in 10% of specimens there was a greater than 2 day discrepancy in dating (which would change the diagnosis of LPD).
- More than 60 luteal phase biopsy specimens were read by 5 different pathologists and in about one third of the specimens there was a difference in dating of 2 days or more.
- When multiple methods of ovulation detection were compared head to head in the assessment of greater than 25 biopsy specimens it was demonstrated that the percentage of out of phase biopsies is related to the method of ovulation detection used. The percent of out of phase biopsies was 4% with ultrasonography, 15% with ovulation predictor kits, 23% with basal body temperatures and 30% with next menstrual period.
- A total of 39 luteal phase biopsies were performed in repeated months in 5 regularly menstruating fertile women with normal circulating thyroid hormone and prolactin concentrations. Using the usual criterion of a greater than 2 day discrepancy to define an out of phase biopsy it was determined that 31% of random single biopsies and 6-7% of (two) consecutive biopsies were out of phase.
These studies emphasize the importance of attention to detail in timing and performing endometrial biopsies. In particular, an experienced pathologist or infertility specialist trained to assign dates to these tissues should be sought, there should be use of multiple ovulation detection techniques (I typically use a combination of the next menstrual period, the basal body temperatures and the ovulation predictor kits), and ideally an abnormal result should be repeated prior to diagnosing a LPD (most fertility specialists define the LPD as two consecutive out of phase biopsies) since there is a high background rate of abnormality in single random biopsies.
If an inadequate progesterone effect is documented or believed to exist during the luteal phase of the menstrual cycle then either supplemental progesterone (either as oral micronized progesterone, vaginal suppositories in a gel, or by injection in an oil base), supplemental hCG (as injections every few days following ovulation to enhance the ovary's own progesterone production) or clomiphene citrate in the follicular phase (to increase the final follicular size, number of granulosa cells and luteal progesterone production) are treatment options. Supplemental progesterone medication is usually administered until about 10 weeks gestation (after the placenta takes over progesterone production).
Reports of treatment success with progesterone supplementation for LPD often lack appropriate controls (such as a similar group of women who did not receive progesterone treatment). However, existing reports taken together support the use of progesterone supplementation in documented cases of LPD.
Claims of progesterone teratogenicity (cause of fetal malformations) are unproven. A Collaborative Perinatal Project report in 1977 suggested an association between fetal cardiac defects and first trimester exposure to female hormones or birth control pills. The data in this study was reevaluated (published in 1984), revealing that the timing of the hormonal drug exposure was inconsistent with the cardiac effects suggested and that if the examined pregnancies which involved Down's syndrome were removed from the data then there was no increased risk of cardiac anomalies.
In a report (published in 1985) of women who were given progesterone supplementation for prevention of spontaneous abortion (upon presentation with a threatened abortion) over 2,700 infants were examined and did not have an increased number of anomalies compared to the general population.
Overall, there seems to be no known significant increased risk of fetal anomalies in taking natural progesterone supplementation during pregnancy. However, the couple taking the medication should be aware of this potential for risk and the data that addresses this risk.