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
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 implantation of the 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 the 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.
Three potential causes (classes) of luteal phase defects
- 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 preimplantation direct supplementation (progesterone medication)
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
effect 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 effect 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
Infertility specialists occasionally draw upon a small handful
of reports describing women with documented low progesterone concentrations
in pregnancies resulting in normal outcomes. 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 of 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 detect 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
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
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