Download Preimplantation hormonal differences between the conception and

Human Reproduction vol.12 no.12 pp.2607–2613, 1997
Preimplantation hormonal differences between the
conception and non-conception menstrual cycles of 32
normal women
D.D.Baird1,7, A.J.Wilcox1, C.R.Weinberg2, F.Kamel1,
D.R.McConnaughey3, P.I.Musey4 and D.C.Collins5,6
1Epidemiology
Branch and 2Statistics and Biomathematics Branch,
National Institute of Environmental Health Sciences, Research
Triangle Park, NC 27709, 3Westat Inc., Research Triangle Park,
NC 27709, 4Department of Biology, Clark-Atlanta University,
Atlanta, GA 30314 and 5Veteran’s Administration Medical Center
and Emory University School of Medicine, Decatur, GA 30329,
USA
6Present
address: Veteran’s Administration Medical Center,
Lexington, KY 40511, USA
7To
whom correspondence should be addressed
We compared daily urinary concentrations of oestrogen
and progesterone metabolites in paired menstrual cycles
(conception and non-conception) from 32 women. Volunteers with no known fertility problems were enrolled in
the study at the time they began trying to become pregnant.
They collected first-morning urine specimens and kept
daily records of menstrual bleeding and sexual intercourse
for 6 months or until they became clinically pregnant.
Intercourse in non-conception cycles was close to the time
of ovulation so that failure to conceive was caused by
factors other than poorly timed intercourse. Compared
with non-conception cycles, conception cycles had a steeper
early luteal rise in progesterone and higher mid-luteal
oestrogen and progesterone concentrations. These
hormonal characteristics may be markers of better quality
cycles, but because all these differences were in the luteal
phase, we cannot rule out the possibility that the preimplantation embryo had stimulated early increases in steroid
production. We propose an analysis strategy that could
help support or refute the importance of preimplantation
embryonic signalling, but our small sample size limits our
own conclusions about this mechanism.
Key words: fertility/oestrogen/progesterone/unassisted conception
in fertile women. If a successful pregnancy is conceived in a
given menstrual cycle, then that cycle must have been
hormonally adequate. However, if no recognized pregnancy
occurs, even with well-timed intercourse, inadequate hormonal
conditions may have interfered with fertilization, early development or implantation.
Few data are available on conception cycles from normal
women free of exogenous ovarian stimulation. Lenton et al.
(1982) reported data from 26 conception cycles, but 22 were
from infertility patients, 12 of whom were taking fertility
drugs. Several other publications report measurements from
small samples of women (Branch et al., 1980; Coutts, 1985;
Lenton et al., 1991) or from a small part of the cycle (Irianni
et al., 1992). Two studies provide most of the available
data. Stewart et al. (1993) reported serum oestrogen and
progesterone concentrations from 14 natural conception cycles.
These cycles showed higher luteal oestrogen and progesterone
concentrations compared with non-conception cycles. Lipson
and Ellison (1996) reported salivary oestrogen and progesterone
concentrations in 17 conception cycles. These cycles did
not differ from non-conception cycles in progesterone, but
conception cycles had higher oestrogen throughout, especially
during the mid-follicular phase.
The purpose of this study was to characterize hormonal
patterns associated with successful conception in a larger
sample of natural cycles. We compared daily concentrations
of urinary oestrogen and progesterone metabolites in paired
conception and non-conception cycles from 32 women who
conceived within 6 months of stopping contraception. In
addition, we considered whether hormonal differences between
conception and non-conception cycles after the time of fertilization represented an early response of the ovary to some
signal from the preimplantation conceptus, or whether such
differences reflected a better quality ovarian cycle more able
to support pregnancy.
Materials and methods
Introduction
Amounts of ovarian oestrogen and progesterone production
vary from woman to woman. Variability also occurs from
menstrual cycle to menstrual cycle within individual women.
Certain extreme hormonal conditions reflect impaired fertility,
such as the low luteal progesterone production seen in lactating
women (Diaz et al., 1992). It is not clear to what degree the
variability from cycle to cycle in non-lactating women might
influence the likelihood of successful pregnancy. One way to
study this is to compare conception and non-conception cycles
© European Society for Human Reproduction and Embryology
Women in our sample were participants in a larger study in which
pregnancies were identified at the first detectable rise in urinary human
chorionic gonadotrophin (HCG), measured by a highly sensitive
immunoradiometric assay. The methods employed have been
described in detail elsewhere (Wilcox et al., 1988). Briefly, volunteers
enrolled in the study at or before the time they stopped using
contraception with the intention of becoming pregnant. Women were
excluded from the study if they had any chronic diseases or known
fertility problems, but there were no exclusions based on the length
or regularity of their menstrual cycles. Volunteers collected firstmorning urine specimens each day until they became clinically
pregnant or for 6 months if no clinical pregnancy ensued. Each
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D.D.Baird et al.
morning, participants recorded menstrual bleeding and whether or
not they had had sexual intercourse in the previous 24 h.
First-morning urine specimens were assayed for oestrone-3-glucuronide (E1G) and pregnanediol-3-glucuronide (PdG) by direct radioimmunoassay procedures using highly specific male rabbit antisera
raised against PdG–bovine serum albumin (BSA) and E1G–BSA
respectively (Wright et al., 1978; Samarajeewa et al., 1979). Both
antisera had no cross-reactions to any other urinary steroid conjugates,
except for oestrone sulphate which showed 3.7% cross-reaction with
E1G antiserum. However, each antiserum showed significant crossreaction with its respective unconjugated steroid, pregnanediol and
oestrone. In general, urinary steroids are excreted in the conjugated
form primarily as glucuronides, with unconjugated steroids accounting
for 3–9% (Eren et al., 1967). While unconjugated oestrone is found
in urine, unconjugated pregnanediol is not known to be excreted.
Daily urine specimens were assayed in duplicate or triplicate at 1000and 2000-fold dilutions, thus nullifying interference caused by other
steroids. Intra-and interassay coefficients of variation were 5 and 6%
for E1G, and 9 and 11% for PdG respectively. Because specimens
for a given woman were analysed in the same assay, only the intraassay variability was relevant. Geometric means of daily replicates
were divided by the respective daily creatinine concentration to
correct for variations in the dilution of the urine specimen.
Menstrual cycles were defined by bleeding days, with the first
bleeding day taken as the first day of the cycle. We estimated the
day of ovulation for each cycle (designated luteal day 0) using the
ratio of the urinary steroid metabolites. This method takes advantage
of the drop in oestrogen and rise in progesterone that occurs at around
the time of ovulation. The oestrogen:progesterone ratio drops steeply
as the follicle luteinizes, and remains low through the luteal phase
of an ovulatory cycle. This method was proposed by Baker et al.
(1980), modified by Royston (1983), and further refined and validated
with urinary luteinizing hormone (LH) measurements by Baird et al.
(1991). As a marker of ovulation, it appears to have as little
measurement error as plasma LH (Baird et al., 1995).
Figure 1 shows an example of hormonal and intercourse data for
the paired menstrual cycles from one woman. In each cycle E1G rises
to a peak just prior to luteal day 0, and PdG rises in the luteal phase.
The conception cycle shows the rapid rise of HCG beginning on
luteal day 8.
The sample of women used in our analysis was selected as follows.
In the larger study, 130 of 221 participants conceived a singleton live
birth. Of these, 84 women were in the study for at least one menstrual
cycle before conceiving. Hormone assays were run on all available
daily urine specimens for 65 of these women. Twelve women were
missing ù7 days of hormone data in one of their paired cycles,
leaving 53 women with adequate hormone data.
Frequency and timing of sexual intercourse varied among menstrual
cycles, and conception failed in some cycles simply because there
was no intercourse at around the time of ovulation. To include these
non-conception cycles, which were potentially hormonally adequate,
would reduce our ability to identify endocrine patterns associated
with successful conception. We avoided this problem by excluding
non-conception cycles with poorly timed sexual intercourse. We used
a method of estimating the likelihood of conception for various
patterns of sexual intercourse at around the time of ovulation
(Weinberg et al., 1994) and included only non-conception cycles with
very favourable timing of intercourse, i.e. cycles with intercourse
reported for the estimated day of ovulation or the day before.
Of the 53 women with adequate hormone data, 21 lacked a nonconception cycle with well-timed intercourse. This left 32 women
with paired conception and non-conception cycles. When a woman
had more than one eligible non-conception cycle, the one with the
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Figure 1. An example of the hormonal and intercourse data for the
paired non-conception and conception cycles from a single woman.
The shaded bars show days of menstrual bleeding. The top panel
shows daily creatinine-corrected concentrations of oestrone-3glucuronide (E1G) and pregnanediol-3-glucuronide (PdG). The
second panel shows the ratio of E1G to PdG. Note the vertical
dotted line showing luteal day 0 (the estimated day of ovulation),
when the ratio dropped precipitously. The next panel shows days of
sexual intercourse. The final panel presents concentrations of
human chorionic gonadotrophin (HCG) showing a rapid rise in the
luteal phase of the conception cycle.
most favourable intercourse pattern was chosen. This strategy was
designed to optimize our ability to detect hormonal patterns that
characterize subfertile menstrual cycles.
We plotted the daily steroid metabolite concentrations for conception and non-conception cycles, centred on luteal day 0, to compare
differences in hormonal profiles. SE for each day’s values were
calculated based on within-woman differences (on a logarithmic
scale), thus avoiding any effects of subject-to-subject heterogeneity.
That is, for each day of the cycle, we calculated the difference
between the corresponding values in the two cycles from the same
woman and averaged these differences across women. The SE of this
mean difference for each day is comparable with the measure of
variability used in a paired t-test.
Formal statistical testing of hormone differences between conception and non-conception cycles was conducted with a set of preselected
summary variables. This strategy limited the multiple comparisons
problem that arises when hormonal measurements are compared daily.
In this study we focused on preimplantation hormone patterns because
postimplantation patterns are likely to reflect ovarian response to the
conceptus. Thus, data are presented for ovarian hormones in the
follicular phase and in the luteal phase up to the time of implantation,
specifically through luteal day 6 (one woman showed her first elevated
HCG on luteal day 6, while HCG was first seen on luteal day ù8
for the other 31 women in the sample). Definitions of summary
variables for E1G, PdG and the E1G:PdG ratio are shown in Table I.
Conception versus non-conception menstrual cycle hormonal differences
Table I. Definitions of summary variables used to test for differences between hormone patterns in conception and non-conception cycles
Summary variable
Oestrone-3-glucuronide (E1G)
Early follicular E1G
Mid-follicular E1G
Peak E1G
Definition
Geometric mean of E1G for first 6 days of menstrual cycle
Geometric mean of E1G for the interval starting on day 5 of the cycle and ending 3 days before luteal day 0 (the
estimated day of ovulation)
Geometric mean of E1G for 3 days, centred on the highest mid-cycle E1G (the highest E1G concentration in a 16-day
window ending on luteal day 3)
Slope of 3 days of E1G, ending on the day before the highest mid-cycle concentration
Geometric mean of E1G for luteal days 1–4
Geometric mean of E1G for luteal days 5 and 6
Rate of E1G rise
Early luteal E1G
Mid-luteal E1G
Pregnanediol-3-glucuronide (PdG)
Early follicular PdG
Geometric mean of PdG during the first 6 days of the menstrual cycle
Mid-follicular PdG
Geometric mean of PdG for the interval starting on day 5 of the cycle and ending 3 days before luteal day 0
Early luteal PdG rise
Slope of PdG for luteal days 1–5
Mid-luteal PdG
Geometric mean of PdG for luteal day 5 and 6
Ratio (E1G:PdG)
Ratio descent
The 3-day slope of the ratio values around the estimated day of ovulation [For each cycle, slopes of days –1, 0, 1 and 0, 1,
2 relative to luteal day 0 were calculated, and the more negative (steeper) of the two was chosen to reflect the rapidity of
the mid-cycle transition to the primarily progesterone-producing corpus luteum]
Mid-luteal ratio
Ratio of mid-luteal E1G and mid-luteal PdG
The variables were calculated as mean concentrations or rates of
change over specified intervals in the cycle. We subtracted the value
of each summary variable in the non-conception cycle from the value
in the conception cycle for the same woman. These differences were
tested for statistical significance (α 5 0.05) using Wilcoxon’s signedrank test (Hollander and Wolfe, 1973).
Results
Demographic and menstrual cycle characteristics of the 32
women in our sample are shown in Table II. They ranged in
age from 23 to 39 years, with a mean of 29 years. All but one
of the women were Caucasian, and 91% had better than a high
school education. In all, 10 of the women had never been
pregnant before. The length of the non-conception menstrual
cycle varied from 25 to 39 days, with an average of 30 days.
In these characteristics the women were similar to the total
sample of 221 women from the larger study. The time to
achieve a pregnancy averaged four menstrual cycles.
The length of the follicular phase varied from 9 to 33 days
and was similar in the conception and non-conception cycles
within women (correlation coefficient 5 0.50 for the pairs).
Non-conception cycles were not more likely to have very short
or very long follicular phases (Figure 2), nor was the average
paired difference in follicular phase length between conception
and non-conception cycles significantly different from zero.
The hormonal profiles for the conception and non-conception
cycles were similar during the follicular phase (Figure 3).
However, in the luteal phase, conception cycles showed somewhat higher concentrations of both E1G and PdG. Examining
our a-priori summary measures, there was a significantly
steeper early luteal rise in PdG and higher mid-luteal E1G
and PdG concentrations in conception cycles (Table III). In
addition, the falling slope of the ratio of E1G:PdG (ratio
descent) at the time of ovulation was steeper (more negative)
in conception cycles.
About two-thirds of the pairs had higher E1G concentrations
in the conception cycles, and about two-thirds had higher PdG
concentrations, but these were not the same two-thirds. A
Table II. Demographic and menstrual cycle characteristics of the 32 women
with both non-conception and conception cycles
Number
(%)
Age (years)
20–24
3
(9)
25–29
16
(50)
30–34
10
(31)
35–39
3
(9)
Prior pregnancies (n)
0
10
(31)
1
12
(38)
2
8
(25)
ù3
2
(6)
Smoking status
Never
19
(59)
Past
10
(31)
Current
3
(9)
Menstrual cycle length (non-conception cycle) (days)
25–26
3
(9)
27–28
13
(41)
29–30
3
(9)
31–32
8
(25)
ù33
5
(16)
Number of menstrual cycles to conception (n)
2
4
(12)
3
9
(28)
4
6
(19)
5
8
(25)
ù6
5
(16)
First day of human chorionic gonadotrophin rise (conception cycle)
Luteal day 6
1
(3)
Luteal day 7
0
(0)
Luteal day 8
7
(23)
Luteal day 9
10
(32)
Luteal day 10
8
(26)
Luteal day 11
4
(13)
Luteal day 12
1
(3)
higher mid-luteal E1G concentration was not closely associated
with a higher mid-luteal PdG concentration, a stronger rise in
PdG or a steeper ratio descent (Spearman r , 0.15 and P .
0.40 for all three Spearman correlations between difference
variables). However, the differences between conception and
non-conception cycles for the two progesterone measures were
2609
D.D.Baird et al.
Figure 2. The distribution of follicular phase lengths in nonconception (top panel) and conception cycles (bottom panel) from
32 women.
highly correlated (r 5 0.68) and they were weakly correlated
with the difference in ratio descent (r 5 –0.20 and –0.24 for
Spearman correlations with differences in the mid-luteal PdG
and the early luteal PdG rise respectively). Non-conception
cycles did not tend to have short luteal phases. Only three of
the 32 luteal phases were ,12 days in length, and these did
not differ much in the concentration of mid-luteal PdG from
their respective conception cycles (mean of 2.7 versus 3.0 µg/
mg creatinine).
The higher luteal hormone concentration in conception
cycles is open to two alternative interpretations: (i) higher
luteal hormone concentrations reflect an inherently better
quality cycle for conception, or (ii) the early conceptus can
stimulate hormone production. To pursue this question, we
expanded our analysis to examine the hormone patterns from
a subset of the women we had previously excluded.
Of the 20 women who failed to have well-timed sexual
intercourse during their non-conception cycle, we chose the
eight pairs with relatively poorly timed intercourse in the nonconception cycle. The closest intercourse was ù3 days before
the estimated day of ovulation, so the probability of conception
was low, even if the cycle was adequate in other ways (Wilcox
et al., 1995). The timing of the rise in HCG for the group of
eight conceptions showed the same distribution as that for the
group of 32, and all eight pregnancies led to full-term births.
We postulated that if the higher luteal hormonal concentrations
we had observed in the 32 pairs were a result of stimulation
from the embryo, then the same hormonal differences should
be apparent in these eight pairs as well. On the other hand, if
the higher luteal hormone concentrations we saw in conception
cycles from the 32 women reflect inherently better quality
cycles, we would expect the differences between conception
and non-conception cycles to be blunted in the group of eight.
This is because many of the eight cycles would be expected
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Figure 3. Daily geometric means of oestrone-3-glucuronide (E1G;
top panel) and pregnanediol-3-glucuronide (PdG; lower panel) for
the paired conception (s) and non-conception (d) cycles from 32
women whose non-conception cycles had well-timed sexual
intercourse. Data are centred on luteal day 0, the estimated day of
ovulation (vertical dotted line). The SEs (shown by a single dotted
line for each day) are based on within-woman differences between
the two cycles, i.e. the difference between the corresponding daily
values in the two cycles for each woman is calculated, these
differences are averaged across women and the SE of the resultant
mean difference is determined.
to be hormonally adequate but to have failed just because of
poorly timed intercourse, whereas the group of 32 were selected
to include non-conception cycles which failed for some reason
other than poorly timed intercourse.
Figure 4 shows the daily profiles of oestrogen and progesterone metabolites in the paired cycles from the group of eight
women. In contrast to the original 32 paired cycles, the
luteal progesterone metabolite profiles in conception and nonconception cycles appeared similar, and the luteal oestrogen
profiles appeared higher in the conception cycles only on luteal
day 6. However, as in the previously described 32 pairs, the
analysis of the mid-luteal E1G variable tended to be somewhat
higher in the conception cycles (Table IV). Six of eight
Conception versus non-conception menstrual cycle hormonal differences
Table III. Testing for differences in oestrone-3-glucuronide (E1G) and
pregnanediol-3-glucuronide (PdG) between 32 paired conception and nonconception cycles (non-conception cycles had sexual intercourse close to
estimated day of ovulation so that poor timing of intercourse was unlikely
to account for the failure to conceive)
Summary variable
Oestrone-3-glucuronide (E1G)
Early follicular E1G
Mid-follicular E1G
Peak E1G
Rate of E1G rise
Early luteal E1G
Mid-luteal E1G
Pregnanediol-3-glucuronide
Early follicular PdG
Mid-follicular PdG
Early luteal PdG rise
Mid-luteal PdG
Ratio (E1G/PdG)
Ratio descent
Mid-luteal ratio
n
Differencea (SE)
P valueb
29
31
30
30
29
31
1.79
1.04
4.51
0.31
4.24
7.13
(1.33)
(1.70)
(3.99)
(2.10)
(2.51)
(2.44)
0.27
0.37
0.36
0.58
0.39
,0.01
29
31
31
31
0.05
0.01
0.21
0.60
(0.07)
(0.02)
(0.09)
(0.32)
0.99
0.55
,0.01
0.04
–11.58 (5.77)
0.72 (2.67)
0.08
0.72
32
31
aThe
value for the non-conception cycle was subtracted from the value for
the conception cycle.
bP values were based on the Wilcoxon signed-rank procedure.
conception cycles had higher mid-luteal E1G concentrations
than the respective non-conception cycle, but the difference
was not statistically significant in this small group of eight pairs.
Discussion
To characterize hormonal patterns predictive of conception,
we excluded from our initial comparisons non-conception
cycles that were likely to have failed due to poorly timed
sexual intercourse. Conception cycles in the group of 32
women with well-timed intercourse in their non-conception
cycles showed a significantly stronger early luteal rise in PdG
and higher mid-luteal E1G and PdG concentrations compared
with non-conception cycles from the same women. Conception
cycles also tended to have a more rapid mid-cycle transition
from follicular production of oestrogen to luteal production of
progesterone (i.e. a more rapid luteinization reflected in a
steeper descent of the E1G:PdG ratio), but this difference was
not statistically significant. No differences were found in preovulatory concentrations of urinary oestrogen and progesterone
metabolites.
These differences cannot be explained by errors in our
estimated day of ovulation. The E1G peak occurred on the day
before our estimated day of ovulation in approximately half of
both conception and non-conception cycles, and the remaining
distribution of the number of days between the E1G peak
and our estimated day of ovulation was nearly identical
for conception and non-conception cycles. Nor can these
differences be explained by changes over time, a concern
because the non-conception cycle always preceded the conception cycle for each participant. When non-conception cycles
from early in participation were compared with non-conception
cycles late in participation for the 80 women in the North
Carolina Early Pregnancy Study with such data, none of the
observed differences between conception and non-conception
cycles were seen.
Figure 4. Daily geometric means of oestrone-3-glucuronide (E1G;
top panel) and pregnanediol-3-glucuronide (PdG; lower panel) for
paired conception (s) and non-conception (d) cycles from eight
women whose non-conception cycle had poorly timed sexual
intercourse. Data are centred on luteal day 0, the estimated day of
ovulation (vertical dotted line). The SEs (shown by a single dotted
line for each day) are based on within-woman differences between
the two cycles, i.e. the difference between the corresponding daily
values in the two cycles for each woman is calculated, these
differences are averaged across women and the SE of the resultant
mean difference is determined.
The hormonal patterns associated with conception in our
urine-based data are remarkably similar to those reported
by Stewart et al. (1993) based on plasma oestrogen and
progesterone measures. As in our study, the women in their
study had no known fertility problems and were trying to
conceive. Furthermore, the non-conception cycles were similarly selected for well-timed intercourse [Stewart et al. (1993)
studied unsuccessful artificial insemination cycles during which
inseminations were clinically timed to coincide with ovulation].
Our results differ somewhat from those reported by Lipson
and Ellison (1996) for salivary oestrogen and progesterone
concentrations in 17 conception cycles. They found no differences in progesterone concentrations, and higher oestrogen
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D.D.Baird et al.
Table IV. Testing for differences in luteal oestrone-3-glucuronide (E1G) and
pregnanediol-3-glucuronide (PdG) between eight paired conception and nonconception cycles (non-conception cycles had poorly timed sexual
intercourse so that poor timing of intercourse might account for the failure
to conceive)
Summary variable
Oestrone-3-glucuronide (E1G)
Early luteal E1G
Mid-luteal E1G
Pregnanediol-3-glucuronide (PdG)
Early luteal PdG rise
Mid-luteal PdG
Ratio (E1G/PdG)
Ratio descent
Mid-luteal ratio
n
Differencea (SE)
P valueb
8
8
0.38 (2.17)
8.25 (6.76)
0.84
0.25
8
8
–0.08 (0.13)
–0.14 (0.42)
0.95
0.84
8
8
3.52 (13.43)
0.51 (1.64)
0.64
0.74
aThe
value for the non-conception cycle was subtracted from the value for
the conception cycle.
bP values were based on the Wilcoxon signed-rank procedure.
throughout the conception cycle, especially at the time of midfollicular development.
Stewart et al. (1993) argued that the higher hormone concentrations in conception cycles are probably a response of the
ovary to a preimplantation embryonic signal, which they
suggested could be early HCG secretion at concentrations too
low to be detected in peripheral blood or urine. Preimplantation
embryonic HCG production has been reported (Lopata and
Hay, 1989), and tubal tissue expresses HCG receptors that
could be responsive to early preimplantation signals (Lei
et al., 1993).
If the differences seen by Stewart et al. (1993) and also
reported here were due to the influence of the conceptus, then
we should see similarly higher hormone concentrations in
conception cycles whether or not sexual intercourse was well
timed in the paired non-conception cycles. Therefore we
examined eight pairs with poorly timed intercourse in the nonconception cycle (chosen to optimize the number of hormonally
adequate cycles among the non-conception cycles as these
cycles may have failed just because of poorly timed intercourse). Among the eight cycles we found no evidence of
higher luteal progesterone concentrations in the conception
cycles. There was still a suggestion of higher mid-luteal
oestrogen concentrations, though the difference was not statistically significant in this small sample.
Our progesterone data are more consistent with the hypothesis that higher luteal progesterone concentrations in conception cycles reflect inherently better quality cycles that enhance
the likelihood of conception, rather than the hypothesis that
signals from the early embryo stimulate enhanced progesterone
production by the ovary. The findings of more rapid luteinization and higher mid-luteal progesterone concentrations are
consistent with the well-known need for luteal progesterone
to prepare the oestrogen-primed endometrium for implantation
(Li et al., 1991). Basal body temperature data also support an
association between slow luteinization, reflected in a slow
temperature rise, and subfertile cycles (Ishimaru et al., 1992).
It may also be that the higher progesterone metabolite concentrations associated with conception in our data are not of direct
importance for fertility, but rather are markers of a healthy
2612
egg (Jones, 1990) and well-functioning hormonal regulation.
Lower progesterone concentrations in the luteal phase have
been observed in women with unexplained infertility and may
be secondary to temporary luteal cyst formation (Coutts, 1985;
Hamilton et al., 1990) or failure of the follicle to rupture,
despite an LH surge (Kugu et al., 1991). None of the women
in our analysis was clinically infertile, but fertile women
may also have occasional low-fertility cycles with impaired
luteinization and a lower mid-luteal progesterone concentration.
Higher mid-luteal oestrogen metabolite concentrations were
strongly related to conception in the group of 32 women
selected for well-timed intercourse in their non-conception
cycles, and a fairly similar pattern was seen in the group of
eight with poorly timed intercourse in the non-conception
cycles. So the possibility that the preimplantation embryo can
stimulate increased mid-luteal oestrogen production cannot be
ruled out. The importance of luteal oestrogen for endometrial
preparation and implantation in humans and other primates is
controversial (Moudgal and Ravindranath, 1989; Moudgal,
1991; Ghosh et al., 1994; Yoshinaga, 1994; Younis et al., 1994;
de Ziegler, 1995; Edgar, 1995; Ghosh and Sengupta, 1995),
but may be critical in suppressing gonadotrophin concentrations
and thus suppressing the development of the next cohort of
follicles (Zeleznik et al., 1987; Nippoldt et al., 1989; de
Ziegler et al., 1992). Whether this suppression is important
for successful implantation and early development is unclear.
In summary, we observed evidence of more rapid luteinization and higher luteal oestrogen and progesterone concentrations in conception cycles compared with non-conception
cycles that were selected to include hormonally inadequate
cycles (sexual intercourse was well timed but no pregnancy
ensued). Higher fertility associated with rapid luteinization
and high progesterone production is not surprising, but any
benefit associated with elevated luteal oestrogen requires
further investigations. Although we described an analysis
designed to support or refute the importance of preimplantation
embryonic signalling as a cause for higher luteal hormone
concentrations in conception cycles, our sample size was
insufficient to provide convincing evidence on either side.
Preimplantation embryo signalling could not be ruled out.
Acknowledgements
Joy Pierce managed the field study of women attempting pregnancy
and, assisted by Francis Patterson and Irene Gunter, managed urine
storage and shipment. Robin Randall, Michelle Mason-Woodard and
Robin King conducted laboratory assays. Drs Bill Lasley, James
Kesner, Elizabeth Lenton, Sioban Harlow, Gary Hodgen, Ronald
Gray, Beth Gladen and Walter Rogan reviewed an earlier draft of
this manuscript.
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Received on August 11, 1997; accepted on September 24, 1997
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