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Effect of preovulatory progesterone

elevation and duration of
progesterone elevation on the
pregnancy rate of frozen–thawed
embryo transfer in natural cycles
Vivian Chi Yan Lee, M.B.B.S., Raymond Hang Wun Li, M.B.B.S., Joyce Chai, M.B.B.S.,
Tracy Wing Yee Yeung, M.B.B.S., William Shu Biu Yeung, Ph.D., Pak Chung Ho, M.D.,
and Ernest Hung Yu Ng, M.D.
Department of Obstetrics and Gynecology, University of Hong Kong, Hong Kong Special Administrative Region, People's
Republic of China
Objective: To assess the incidence of P elevation (PE) in natural cycles and evaluate its effect on frozen–thawed embryo transfer cycles
performed in natural cycles (FET-NC).
Study Design: Retrospective analysis.
Setting: A tertiary assisted reproductive unit.
Patient(s): Subfertile woman who did not conceive in their stimulated IVF cycle and underwent the first FET-NC cycle.
Intervention(s): Achieved serumsamples were assayed for P concentrations fromthe day of LHsurge up to 3 days before the surge. The
cutoff level of PE was defined as 5 nmol/L.
Main Outcome Measure(s): Clinical and ongoing pregnancy rates.
Result(s): The incidence of PE in natural cycles was 173 of 610 (28.4%). There were no significant differences in both clinical and
ongoing pregnancy rates (39.0% vs. 37.3% and 32.5% vs. 31.7%) between those with vs. without PE on the day of LH surge. If PE lasted
for 2 days or more, there was a significant reduction in the clinical pregnancy rate (39.4%vs. 20.7%). Using multivariate logistic regres-
sion, women's age, PE for 2 days or more, and the number of top-quality embryos were the significant factors for clinical pregnancy
rates in FET-NC.
Conclusion(s): The incidence of PE in FET-NC was similar to that in stimulated cycles. Progesterone elevation for 2 days or more before
the LH surge impaired the clinical pregnancy rate of FET-NC, whereas PE on the day of LHsurge
only did not have such an adverse effect. (Fertil Steril
2014;-:-–-. Ó2014 by American
Society for Reproductive Medicine.)
Key Words: Frozen–thawed embryo transfer, natural cycle, progesterone elevation
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n stimulated IVF cycles it has long
been recognized that a preovulatory
increase in serumP levels sometimes
occurs. With the introduction of GnRH
analogs for pituitary suppression in
IVF, the incidence of premature LHsurge
was significantlyreduced(1). Despite pi-
tuitary down-regulation, P elevation
(PE) was still observed in 12.4%–52.3%
of stimulated IVF cycles (2).
There has been controversy
regarding the effect of PE on the out-
comes of IVF. Many reported adverse
effects on IVF outcomes (3–17),
whereas others reported no such
effects (2, 18–28). Some even reported
a better outcome in specific groups of
patients (29–31). A recent meta-
analysis including more than 60,000
Received December 5, 2013; revised January 16, 2014; accepted January 17, 2014.
V.C.Y.L. has nothing to disclose. R.H.W.L. has nothing to disclose. J.C. has nothing to disclose. T.W.Y.Y.
has nothing to disclose. W.S.B.Y. has nothing to disclose. P.C.H. has nothing to disclose. E.H.Y.N.
has nothing to disclose.
This study was funded by the Department of Obstetrics and Gynecology, University of Hong Kong.
Reprint requests: Vivian Chi Yan Lee, M.B.B.S., Department of Obstetrics and Gynecology, University
of Hong Kong, Queen Mary Hospital, Pokfulam Road, Hong Kong, People's Republic of China
Fertility and Sterility® Vol. -, No. -, -2014 0015-0282/$36.00
Copyright ©2014 American Society for Reproductive Medicine, Published by Elsevier Inc.
VOL. -NO. -/ -2014 1
stimulated IVF cycles confirmed the detrimental effects of PE
on pregnancy rates (32).
Some authors of early reports suggested that the adverse
effects on IVF outcome as a result of PE may be related to its
effect on oocyte quality and/or endometrial receptivity. How-
ever, the hypothesis regarding oocyte quality was proven
otherwise by several studies conducted in oocyte donation
cycles because the pregnancy rate in the recipient cycles
with embryos from those donor cycles with PE was not
decreased (7, 29). Meanwhile, there was evidence from gene
expression studies (33, 34) to show that the main
deleterious effect acts on endometrial receptivity. Some
investigators advocate the cryopreservation of all good-
quality embryos in fresh IVF cycles and replacing them in a
subsequent natural cycle (NC), in which PE was not supposed
to occur, although there seems to be no evidence to prove so
(35). The incidence of PE in NC and its effect on pregnancy
rates could not be found in the literature.
The aims of this retrospective study were to assess the
incidence of PE in NC and to evaluate the effects of PE and
PE duration on the pregnancy outcomes of frozen–thawed
embryo transfer performed in NC (FET-NC). The hypothesis
was that PE impairs the pregnancy rates in FET-NC.
Study Population
All FET-NC treatment cycles carried out between January
2006 and December 2011 were recruited. Subfertile women
who did not conceive in their stimulated IVF cycle and under-
went the first FET-NC with transfer of cleavage-stage em-
bryos during the study period were included. Cases with
incomplete records or data were excluded. Achieved serum
samples were assayed for serum P levels up to 3 days before
the LH surge. Progesterone elevation was defined as serum
P concentration of R5 nmol/L, according to previous studies
(12, 15). The study protocol was approved by the Institutional
Review Board of the University of Hong Kong/Hospital
Authority Hong Kong West Cluster.
Treatment Regimen
The details of the long-protocol ovarian stimulation regimen,
gametes handling, cryopreservation of embryos, and FET
were as previously described (36). During the stimulated IVF
cycle a maximum of two good-quality embryos were trans-
ferred 2 days after oocyte retrieval, whereas surplus good-
quality embryos were cryopreserved in cleavage stage on
the same day. Those who did not get pregnant in the stimu-
lated IVF cycle and had at least one frozen embryo would
undergo FET, at least 2 months after the stimulated cycle.
For women with regular and ovulatory cycles, FET was per-
formed in NC. Blood was taken for serum LH and E
trations 18 days before the next expected period. The LHsurge
was defined as serum LH level >20 IU/L and the LH level
greater than the double of the average value of the previous
3 days' levels. Frozen–thawed embryo transfer was arranged
3 days after the LH surge. The cleavage-stage embryos were
graded by our embryologists as grade 1 to grade 6 according
to the size evenness of the cells and the percentage of frag-
mentation (37). Embryos with grades 1–4, which are available
for transfer or cryopreservation, were regarded as good-
quality embryos in this study. Only embryos with more than
50% of blastomeres present after thawing were transferred
in FET cycles. Again, up to two cleavage-stage embryos
were transferred in each FET cycle.
Outcome Measures
The primary outcome measures of the study were clinical and
ongoing pregnancy rates. Clinical pregnancies were defined
by the presence of one or more gestational sac(s) or the histo-
logic confirmation of gestational product in case of early
pregnancy failures. Ongoing pregnancies were those preg-
nancies beyond 8–10 weeks' gestation, at which stage the
patients were referred for antenatal care. The secondary
outcome measure was the miscarriage rate.
Hormonal Assays
The serum P level was measured by an immunoassay system
from Beckman Coulter. The sensitivity of the assay is
0.25 nmol/L for P, the intra-assay coefficient of variation is
4.4%, and the interassay coefficient of variation is 3.6%.
The intra- and interassay coefficients of variation for serum
level are 4.0% and 7.0% respectively, and the lower limit
of detection is 73 pmol/L.
Statistical Analysis
The Kolmogorov-Smirnov test was used to test the normal
distribution of continuous variables. Results of continuous
variables were given as mean Æ SD if normally distributed
and as median (range) if not normally distributed. Statistical
comparison was carried out by Student's t test, Mann-
Whitney U test, or Wilcoxon signed ranks test for contin-
uous variables, and c
test or Fisher's exact test for categoric
variables, where appropriate. Statistical analysis was per-
formed using the Statistical Package for Social Sciences,
version 20.0 (SPSS). A two-tailed value of P<.05 was
considered statistically significant. Binary logistic regression
using enter method was used to calculate the prediction of
the clinical outcome in FET-NC cycles and the PE in stimu-
lated cycles.
Index Stimulated IVF Cycles
Table 1 depicts the demographic data and ovarian response
data of the index stimulated IVF cycle. Women with PE in
FET-NC cycles were significantly younger than those without
PE (P¼.02). There were no significant differences in other
demographic data, including women's weight, duration of
subfertility, and cause of subfertility, between the two groups.
Basal FSH level, antral follicle count, duration and dose of
gonadotropin, endometrial thickness, number of fertilized
oocytes, and total number of top-quality embryos were
comparable for the two groups. Total number of follicles,
number of follicles R16 mm, and number of oocytes were
2 VOL. -NO. -/ -2014
significantly higher in the group with PE than in those
without PE in the FET-NC cycles.
There were significantly more women with PE in stimu-
lated cycles having PE in FET-NC cycles (40.5% vs. 20.0%,
P<.001). The correlation coefficient between PE in stimulated
cycles and in FET-NC was 0.219 (P<.001).
Multivariate logistic regression demonstrated that age of
women and the number of follicles were significant factors for
PE in the index stimulated IVF cycles (Table 2).
Incidence of PE in FET-NC
Between January 2006 and December 2011, 622 FET-NCcycles
were performed. After excluding those FET cycles replacing
blastocysts, 610 FET-NC cycles were included. The incidence
of PE was 28.4% (173 of 610): 144 (83.2%) had 1 day of PE,
22 (12.7%) had 2 days of PE, and 7 (4.1%) had 3 days of PE.
The serum P concentration on the LH surge days in those
women without PE was 3.2 Æ 1.0 nmol/L (0.9–4.9)
[mean Æ SD (range)], whereas in those with PE it was
6.4 Æ 1.7 nmol/L (5.0–15.3); the serum E
concentration was
1,082 Æ 329 pmol/L (376–2,222) and 1,045 Æ 428 pmol/L
(440–2,649), respectively.
Outcomes of FET-NC
There were no significant differences in the clinical preg-
nancy, ongoing pregnancy, and miscarriage rates in women
with or without PE in FET-NC (Table 3A). On further analysis
the clinical pregnancy rate continued to drop with an increase
in duration of PE (39.6%in women with no PE, 38.9%in those
with 1 day of PE, 27.3% in those with 2 days of PE, and 0 in
those with 3 days of PE) (Fig. 1). The clinical pregnancy rate
was significantly lower if PE lasted for 2 or more days
(Table 3B). The ongoing pregnancy rate was also lower if PE
last for 2 or more days, but no significant difference was
found, probably because of the small sample size. The number
of good-quality embryos after thawing replaced in the FET cy-
cles was similar in women with or without PE (0.41 Æ 0.682,
95% confidence interval 0.15–0.67 vs. 0.51 Æ 0.671, 95%
confidence interval 0.45–0.56, respectively, P¼.359).
Age of women, the presence of PE for 2 or more days, and
the number of top-quality embryos were the significant fac-
tors of the clinical pregnancy rates of FET-NC in multivariate
logistic regression analysis (Table 2).
This study tested a novel idea regarding the adverse effect of
preovulatory PE in NCs. To the best of our knowledge this is
Demographic and clinical data of the index stimulated cycle between those with and without PE in FET cycles.
Characteristic P <5 nmol/L (n [449) P R5 nmol/L (n [161) P value
Women's age (y) 36 (22–45) 35 (26–44) .020
Weight (kg) 53.6 (44–77) 54.8 (43–75) .355
Duration of subfertility (y) 4.0 (1–19) 4.0 (1–13) .696
Subfertility cause .052
Tubal factor 81 (18.0) 23 (14.3)
Endometriosis 33 (7.4) 15 (9.3)
Male factor 225 (50.1) 70 (43.5)
Unexplained 57 (12.7) 19 (11.8)
Mixed 53 (11.8) 34 (21.1)
Basal FSH level (IU/L) 8.0 (2.5–13.4) 7.4 (4.8–17.8) .864
Antral follicle count 11 (1–56) 10 (2–55) .498
Gonadotropin duration (d) 11 (8–21) 10 (8–15) .121
Gonadotropin dose (IU) 2,100 (900–5,500) 1,950 (1,075–7,350) .208
Total no. of follicles R10 mm 14 (3–54) 16 (4–42) .019
No. of follicles R16 mm 6 (2–16) 7 (1–15) .003
Endometrial thickness (mm) 12.0 (1–22) 11.8 (6–21) .458
No. of oocytes 9 (3–30) 11 (2–30) .014
No. of oocytes fertilized 6 (1–23) 7 (2–20) .092
Total no. of good-quality embryos 5 (1–23) 6 (2–19) .265
No. of transferred embryos 2 (1–2) 2 (1–2) .793
Note: Continuous variables presented as median (range); categoric variables presented as number (percentage). P ¼ P concentrations on the day of LH surge in FET cycles.
Statistically significant.
Yan Lee. Progesterone elevation in FET reduces PR. Fertil Steril 2014.
Multivariate logistic regression.
Factor B
value 95% CI
Stimulated IVF cycles
PE in stimulated IVF cycles
Women's age (y) 0.228 1.256 .007 1.066–1.482
No. of follicles 0.082 1.086 .007 1.023–1.153
FET cycles
Clinical pregnancy rate
Women's age (y) À0.168 0.845 <.001 0.795–0.900
PE for 2 d À1.101 0.333 .040 0.117–0.949
No. of top-quality
0.369 1.446 .010 1.090–1.918
Note: CI ¼ confidence interval.
Yan Lee. Progesterone elevation in FET reduces PR. Fertil Steril 2014.
VOL. -NO. -/ -2014 3
Fertility and Sterility®
the first study to demonstrate the detrimental effects of PE
and duration of PE on the pregnancy outcomes of FET-NC.
Our results showed that PE was found in 28.4% of FET-NC
and may not adversely affect the clinical pregnancy rate of
FET-NC unless PE was present for 2 or more days before the
LH surge. Because we proved previously that the use of
luteal-phase support in FET-NC did not improve pregnancy
rates, we did not use luteal-phase support routinely in FET
cycles (38).
Although early studies and meta-analyses revealed con-
tradictory effects on pregnancy rates by PE in stimulated
IVF cycles, more recent published data rather confirmed the
detrimental effects on pregnancy rates by PE (12, 39–41)
when 1.5 ng/mL was used as their cutoff value for PE. The
different cutoff values used in earlier studies, ranging from
0.9 ng/mL to 2.0 ng/mL, may probably be the reason for the
inconsistent results and also the failure of producing a
meaningful result from earlier meta-analyses. It was clear in
the most recent meta-analysis including more than 60,000
stimulated IVF cycles, when they used different cutoff values,
from 0.8 to 1.1 ng/mL (2.54–3.50 nmol/mL) onward, there
were significantly lower clinical and ongoing pregnancy rates
in stimulated IVF cycles when the P levels increased (32).
One of the hypotheses regarding the deleterious effects of
PE in stimulated IVF cycles was the action on the oocyte and
embryo quality. However, studies in oocyte donation cycles
indicated that embryo quality was not affected by PE in the
donor stimulated cycles because the pregnancy rate was not
decreased in the recipient cycles (26, 32, 42). Another
plausible mechanism of the deleterious effect is on
endometrial receptivity. Gene expression was anomalously
altered in the endometrium when exposed to a high P level
on hCG day (33, 34). If the altered gene expression and the
deleterious effects are related to the high circulating P level,
PE in NC would have a similar detrimental effect on the
pregnancy rate. However, our study failed to show the
adverse effect of PE on a single day of LH surge; rather, the
pregnancy rates continued to drop with the increase in the
duration of PE on or before the day of LH surge. The similar
adverse effect of the longer duration of exposure of the
endometrium to high P concentrations was said to be more
detrimental than a single value of P concentration in
stimulated IVF cycles (43). Our data confirmed such a
detrimental effect of PE on pregnancy rates in FET-NC cycles.
Because the surplus embryos were cryopreserved 3 days after
LHsurge in the fresh cycles, the endometriumwas asynchron-
ized if exposed to high P concentrations 2 days or more before
the LH surge. However, in both stimulated cycles and FET
cycles, P concentration may not be regularly checked, and
so the length of exposure to PE may not be recognized by
the clinicians. As shown in our study, even in FET-NC cycles,
P concentration should be checked before the LH surge.
Prolonged PE may cause an inappropriately advanced
endometrium, leading to an early closure of the implantation
window and therefore significantly decreased clinical and
ongoing pregnancy rates (43). Histologic dating of endome-
trium revealed a prematurely secretory transformation on
the day of oocyte retrieval, which may be less receptive to
slower-developing embryos (44). If this is the culprit of the
deleterious effects of PE in stimulated cycles, PE in FET-NC
would have similar adverse effects, which can explain the
significantly lower pregnancy rates when PE was present
for 2 or more days in our study.
Several studies suggested that the elevated P level is
caused by the physiologic accumulation from multiple folli-
cles during the late follicular phase, and P levels were found
to be consistently positively correlated to higher E
tration on the day of hCG administration and the number of
retrieved oocytes in the stimulated cycles (2, 39, 43). Our
study showed that women with PE in FET-NC had also better
ovarian response in the index stimulated cycles with higher E
level and more oocytes retrieved. Because PE tends to recur in
NC, we postulated that there would be some intrinsic factors
affecting PE. However, in our study, the only demographic
factor that was different between the two groups was
women's age. A prospective, well-designed study would be
needed to explore the risk factors for PE in both stimulated
cycles and NCs.
A. Pregnancy and miscarriage rates in FET cycles, according to
P level on LH surge day.
Variable P <5 nmol/L P R5 nmol/L P value
Clinical pregnancy rate 175/449 (39.0) 60/161 (37.3) .702
Ongoing pregnancy rate 146/449 (32.5) 51/161 (31.7) .845
Miscarriage rate 27/175 (15.4) 8/60 (13.3) .694
Ectopic pregnancy rate 2/175 (1.1) 1/60 (1.7) .785
B. Pregnancy and miscarriage rates in FET cycles, according to
duration of PE.
Variable PE <2 d PE R2 d P value
Clinical pregnancy rate 229/581 (39.4) 6/29 (20.7) .043
Ongoing pregnancy rate 192/581 (33.0) 5/29 (17.2) .076
Miscarriage rate 34/229 (14.8) 1/6 (16.7) .902
Ectopic pregnancy rate 3/229 (1.3) 0 .698
Note: Values are number (percentage).
Statistically significant.
Yan Lee. Progesterone elevation in FET reduces PR. Fertil Steril 2014.
Clinical and ongoing pregnancy rates of subjects with no P rise, or
2 day, 2 days, and 3 days of P rise. CPR ¼ clinical pregnancy rate;
OPR ¼ ongoing pregnancy rate; P4 ¼ progesterone.
Yan Lee. Progesterone elevation in FET reduces PR. Fertil Steril 2014.
4 VOL. -NO. -/ -2014
The management to improve the outcome in case of PE in
stimulated IVF cycles lacks consensus. Some authors suggest
freezing all embryos in stimulated cycles and replacing the
cryopreserved embryos in NC cycles (11) because the preg-
nancy rate in the subsequent FET cycles was not adversely
affected by PE in the fresh cycles. It was presumed that the
P level was normal in NC, without any measurement (17,
45). As shown in the present study, PE also occurs in NC,
and 17% of these cycles had PE for 2 or more days. Women
with PE in stimulated IVF cycles tended to have PE in NC as
well. Another strategy is to replace blastocysts instead of
cleavage-stage embryos, because one prospective study re-
vealed that the pregnancy rate was not affected if blastocysts
were replaced instead of cleavage-stage embryos in cycles
with PE (12). However, subsequent retrospective studies
showed contradictory results from blastocyst transfers (46,
47). Another possible strategy is to use hormonal
replacement therapy for FET cycles, to avoid the detrimental
effects of PE. Further prospective studies would be required
to answer all these questions.
The limitation of our study is its retrospective nature:
there may be some confounding factors that could not be
totally controlled in our data analysis. Our limited sample
size did not allow us to show a significant difference in the
ongoing pregnancy rates. Further larger prospective studies
are needed to confirm our findings.
In conclusion, PE for 2 or more days in NC has an adverse
effect on the clinical pregnancy rates in FET, similar to stim-
ulated IVF cycles.
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