Effect of Long-Term Combined Oral

Contraceptive Pill Use on Endometrial

Thickness
Nayana Talukdar, MBBS, MD, Yaakov Bentov, MD, MSc, Paul T. Chang, MD, FRCS(C),
Navid Esfandiari, PhD, Zohreh Nazemian, MD, MSc, and Robert F. Casper, MD, FRCS(C)
OBJECTIVE: To estimate whether there is any association
of long-term use of combined oral contraceptive pills
(OCP) with adverse endometrial growth.
METHODS: We reviewed the charts of 137 patients with
history of OCP use undergoing endometrial preparation
with estrogen for frozen embryo transfer. Endometrial
thickness was measured by transvaginal ultrasonography
on day 10 after menses and patients were divided into
two groups (less than 7 mm and 7 mm or more).
RESULTS: Thirty patients had endometrial thickness less
than 7 mm and 107 had thickness of 7 mm or more. Mean
years of combined OCP use in each group were 9.84.54
and 5.84.52, respectively (P<.001). With 10 years of
combined OCP use as the threshold, the difference
between the two groups (63.35% users in less than 7 mm
group compared with 28.04% in the 7 mm or more
thickness group) was highly significant (P<.001 by Fisher
exact test), with an odds ratio of 4.43 (95% confidence
interval 1.89 10.41). Past use of 5 years of OCPs was also
associated with a significant (P.002) difference in endometrial thickness. The mean endometrial thicknesses on
cycle day 10 in patients using combined OCP for less than
10 years and 10 years or more were 9.541.88 mm and
8.482.33 mm, respectively, with P.007. The mean
endometrial thickness was 9.721.69 mm in less than 5
years and 8.812.23 mm in 5 or more years of use,
respectively (P.008). Cycle cancellation rates in the less
From Reproductive Biology, Toronto Centre for Advanced Reproductive Technology, the Samuel Lunenfeld Research Institute, Mount Sinai Hospital, and the
Department of Obstetrics and Gynecology, the Institute of Medical Sciences, and
the Division of Reproductive Sciences, University of Toronto, Toronto, Canada.
The authors thank Hala Gomaa, MD, for help with data collection.
Corresponding author: Robert Casper, MD, Toronto Centre for Advanced
Reproductive Technology, 150 Bloor Street West, Suite 210, Toronto, Ontario,
Canada, M5S 2X9; e-mail: casper@lunenfeld.
Financial Disclosure
The authors did not report any potential conflicts of interest.
2012 by The American College of Obstetricians and Gynecologists. Published
by Lippincott Williams & Wilkins.
ISSN: 0029-7844/12

348

VOL. 120, NO. 2, PART 1, AUGUST 2012

than 7 mm group and 7 mm or greater endometrial

thickness group were 23% and 4%, respectively (P.002),
but there was no difference in the clinical pregnancy
rates between the two groups (13% compared with 27%,
respectively; P.15).
CONCLUSION: Long-term combined OCP use (5 years
or more) can potentially affect optimal endometrial
growth, leading to a higher cancellation rate and longer
stimulation in frozen embryo transfer cycles. These findings suggest a previously unidentified adverse effect of
long-term combined OCP use in women who are anticipating future fertility.
(Obstet Gynecol 2012;120:34854)
DOI: 10.1097/AOG.0b013e31825ec2ee

LEVEL OF EVIDENCE: II

he combined oral contraceptive pill (OCP) currently being used by more than 100 million
women worldwide1 contains both estrogen and progestin in various combinations. The main mechanism
of action of the steroid is inhibition of follicular
development and prevention of ovulation by pituitary
and hypothalamic suppression of follicle-stimulating
hormone and luteinizing hormone.12 Other secondary
mechanisms of contraceptive activity include progestogenic induction of hostile cervical mucus and of an
endometrial environment that is unfavorable for implantation.3 A predominant progestational effect of
combined OCP on the endometrium includes an
arrest of glandular proliferation, induction of pseudosecretion, and stromal edema followed by decidualized stroma with granulocytes and thin sinusoidal
blood vessels. Prolonged use results in progressive
endometrial atrophy.4 This latter property has been
used for the treatment of dysfunctional uterine bleeding and endometrial hyperplasia. Currently, pretreatment with combined OCPs also is used for diagnostic
and operative hysteroscopy in which the visualization

OBSTETRICS & GYNECOLOGY

of the endometrial cavity is facilitated by a thin

endometrium.5
Proper endometrial development is vital for successful implantation of an embryo. Although controversial, it is generally considered that an ultrasonographic
endometrial measurement of 7 mm in cross-section is
the minimum thickness required for successful implantation.6 While monitoring women ultrasonographically
during assisted reproductive techniques, we occasionally
noticed that some women had a persistently thin endometrium with no obvious cause. On closer questioning,
we observed a frequent history of long-term combined
OCP use in the past in many of these women.
The objective of the present study was to estimate
whether there was any association of long-term use of
combined OCPs with adverse endometrial growth.
We performed a study to examine the duration of
combined OCP use and its effect on endometrial
growth and thickness in a group of infertile women all
undergoing the same endometrial estrogen preparation for frozen embryo transfer.

MATERIALS AND METHODS

The present study was performed at the Toronto
Centre for Advanced Reproductive Technology, a
University of Torontoaffiliated infertility center. Ultrasound monitoring flow sheets of patients undergoing frozen embryo transfer were reviewed from 2008
to 2010. The study was approved by the Institutional
Research and Ethics Review Board at Mount Sinai
Hospital, Toronto, Ontario.
A total of 488 frozen embryo transfer cycles was
identified. Patients between 30 and 45 years of age
were included. The same standard protocol for endometrial preparation was used in 295 cycles consisting
of micronized 17 -estradiol (E2) for simulated follicular phase endometrial development. We excluded
cycles in women in whom a different protocol for
frozen embryo transfer was used (natural cycle, estrogen patch) or who were supplemented with low-dose
acetylsalicylic acid. Each patient was accounted for
only once in the first cycle. Thus, we included a total
of 207 single cycles in 207 women. We excluded
patients who had used combined OCPs within the
past 2 years. Patients using contraception other than
combined OCPs, eg, injectable hormones, intrauterine devices, spermicidal jells, or barrier contraceptives were excluded. Patients having other associated
pathology such as uterine fibroids, Asherman syndrome, previous septum resection, endometriosis,
and polycystic ovaries were also excluded. With these
inclusion and exclusion criteria, we had a study group
of 137 patients undergoing frozen embryo transfer

VOL. 120, NO. 2, PART 1, AUGUST 2012

with a history of combined OCP use that was stopped

more than 2 years previously (Fig. 1).
All the patients included in the study used the
described endometrial preparation protocol. Tablets
of micronized E2 (2 mg) were taken orally twice per
day starting from day 3 of the menstrual cycle. Once
vaginal bleeding stopped, the E2 tablets were inserted
vaginally twice daily. On cycle day 8, the E2 dose was
increased to two tablets twice daily, ie, a total daily
dose of 8 mg vaginally. On cycle day 10, a transvaginal ultrasound scan was performed to assess the
endometrial thickness and pattern and was repeated
until the endometrial thickness was at least 8 mm with
a triple line pattern. Progesterone was then added,
200 mg progesterone vaginal suppositories, three
times per day and the E2 dose was reduced to one
tablet twice daily (4 mg) orally. Frozen embryo transfer was performed either 5 days after starting progesterone (D3 cryopreserved embryos) or 7 days later
(blastocyst cryopreservation).
On day 10 of the stimulated cycle, the maximal
endometrial thickness in the sagittal plane was measured ultrasonographically using a 5-mHz endovaginal probe. Endometrial thickness less than 7 mm was
considered thin, and a thickness equal to 7 mm or
more was considered adequate. Thus, we divided the
patients into two groups based on endometrial thickFrozen embryo transfers in
women 3045 years of age,
20082010
N=488

Endometrial preparation
Other protocol
n=93
Standard estrogen protocol
n=295

Second or third cycle of

frozen embryo transfers
n=88

First cycle of frozen

embryo transfers
n=207
Other or no contraceptive
n=60
Combined oral
contraceptive pill
n=147

Other pathology or
incomplete data
n=10

Final study patients

n=137

Fig. 1. Flow chart highlighting patient-selection criteria.

Talukdar. Long-Term OCP Use and Endometrial Thickness.
Obstet Gynecol 2012.

Talukdar et al

Long-Term OCP Use and Endometrial Thickness

349

ness and then we reviewed the clinical charts of both

the groups and noted past duration of use of combined OCPs. In the literature, Farrow et al7 showed
no adverse effect of more than 5 years of combined
OCP use on womens fertility. Therefore, we initially
defined long-term use as 10 years or more to examine
whether there was any effect of combined OCP use
on the endometrium. However, we also analyzed the
data from 5 years of use. In the women with endometrial thickness less than 7 mm on day 10, we
continued E2 at a dose of 8 mg per day for up to 1
week to estimate whether an increase in endometrial
thickness could be obtained in this group. If the
thickness was still less than 7 mm after another week
of estrogen administration, then the cycle was cancelled. Additional demographic factors that were
noted and later compared in both the groups were
body mass index (calculated as weight (kg)/[height
(m)]2), age at menarche, type of infertility (primary or
secondary), and duration of infertility (Table 1).
All analyses were performed using the Statistical
Package for Social Sciences and GraphPad Prism software and Excel 7. One-sample Kolmogorov-Smirnov
test was conducted for testing normality. For continuous
parameters in both groups that were normally distributed, parametric t tests were performed, whereas the
nonparametric Mann-Whitney test by ranks was used to
analyze the nonnormally distributed data. The 2 and
Fisher exact tests were used for categorical variables. A
significance level of 0.05 was used for all comparisons.
We categorized the patients into four groups: those with
endometrial thickness less than 7 mm and those with
endometrial thickness more than 7 mm, and those

with more than 10 years of combined OCP use or less

than 10 years of use. For this purpose, a twotwo
contingency table was prepared taking endometrial
thickness and years of combined OCP use as binomial
variables. Assuming a null hypothesis of no difference in
the proportion of patients with more than 10 years of
combined OCP use in the two endometrial thickness
groups, we performed Fisher exact tests to assess significance of any difference (Table 2). Similarly, we used the
same strategy to check the significance for 5 years of
combined OCP.
We also calculated the mean endometrial thickness in patients using combined OCPs for more than
10 years and less than 10 years. The difference in the
means and its significance was calculated. Finally,
binary logistic regression was performed and the odds
ratio was calculated, taking the years of combined OCP
use as the independent variable and endometrial thickness of less than 7 mm and 7 mm or greater as the two
possible outcomes (dependent variable). Box plots taking endometrial thickness and years of OCP use were
also drawn, highlighting any outliers (Fig. 2).

RESULTS
Of the 488 patients with frozen embryo transfer
between 2008 and 2010, 137 patients were within the
same age group (30 45 years), had the same protocol
for endometrial preparation before embryo transfer,
and had a history of combined OCP use more than 2
years before treatment (Fig. 1).
As illustrated in Table 1, 30 out of the 137
patients (21.9%) had an endometrial thickness less
than 7 mm on day 10 of the frozen embryo transfer

Table 1. Comparative Data

Age (y)
BMI (kg/m2)
Age at menarche (y)
Infertility
Primary
Secondary
Duration of infertility (m)
Endometrial thickness (mm)
Combined OCP use (y)
Day of starting progesterone
Cycle cancellation
Pregnancy

Endometrial Thickness
Less Than 7 mm (n30)

Endometrial Thickness
7 mm or More (n107)

P*

36.273.40
22.52.57
12.31.18

36.063.32
22.72.21
11.81.4

.632
.308
.012

66 (62)
41 (38)
22.412.08
10.031.45
5.84.52
10.10.29
4 (4/107)
27 (29/107)

.410

16 (53)
14 (47)
23.011.64
6.060.62
9.84.54
14.41.62
23 (7/30)
13 (4/30)

.725
.001
.001
.001
.002
.150

BMI, body mass index; OCP, oral contraceptive pill.

Data are meanstandard deviation, n (%), or % (n/N) unless otherwise specified.
* Mann-Whitney test, unless indicated.
2
test.

Fisher exact test.

350

Talukdar et al

Long-Term OCP Use and Endometrial Thickness

OBSTETRICS & GYNECOLOGY

Table 2. Fisher Exact Test With 10 Years of

Combined Oral Contraceptive Pill Use
as the Threshold

OCP use less

than 10 y
OCP use more
than 10 y
Total

Endometrium
Less Than 7 mm

Endometrium
7 mm or More

Total

11 (36.65)

77 (71.96)

88

19 (63.35)

30 (28.04)

49

30

107

137

OCP, oral contraceptive pill.

Data are n (%) or n.
Two-tailed P.001.

16

16

14

14
Endometrial thickness (mm)

Endometrial thickness (mm)

cycle. These patients comprised the study group with

mean endometrial thickness of 6.060.62 mm. The
control group comprised 107 (78.1%) patients who
had an endometrial thickness of 7 mm or more. The
mean endometrial thickness in this group was
10.031.45 mm. The P value for endometrial thickness was highly significant (P.001; Table 1). The
mean age in the less than 7 mm endometrial thickness
group was 36.273.40 years, and in the other group it
was 36.063.32 years. Age and body mass index
were normally distributed; hence, Student t test was
used for comparison. The P values were .63 and .30,
respectively (Table 1). Likewise, no significant difference was observed between degree of infertility (pri-

12
10
8
6
4

12
10
8
6
4

Oral contraceptive pill

use for 5 or more years

Oral contraceptive pill

use for fewer than 5 years

Fig. 2. Box plot with 5 years of combined oral contraceptive

pill (OCP) use as cutoff. The 50th percentile for endometrial
thickness was 6.710.75 mm for 5 or more years of OCP
use and 8.511 mm for less than 5 years of use. Mean
thickness was 8.8 mm in the group with 5 or more years of
use, and it was 9.72 mm in the group with less than 5 years
of use. There were three low outliers and one high outlier in
the group with less than 5 years of OCP use. The difference
between the two groups was significant (P.008).
Talukdar. Long-Term OCP Use and Endometrial Thickness.
Obstet Gynecol 2012.

VOL. 120, NO. 2, PART 1, AUGUST 2012

mary or secondary) and duration of infertility in both

groups (as shown in Table 1). However, the age at
menarche was 0.5 years later in the less than 7 mm
group (P.01; Table 1). The mean years of combined
OCP use in the less than 7 mm endometrial thickness
group was found to be 9.84.54, and in more than or
equal to 7 mm group it was 5.84.52. The difference
in means of duration of combined OCP use was
highly significant between the two groups as tested by
Mann-Whitney test by ranks (P.001; Table 1). Taking 10 years of use as a threshold for long-term
combined OCP use, 63.35% of patients were longterm users in the less than 7 mm endometrial thickness group whereas 28.04% were long-term users in
the 7 mm and above endometrial thickness group.
This difference was also highly significant (P.001) by
Fisher exact test (Table 2). The odds ratio was 4.43
(95% confidence interval 1.89 10.41), indicating that
those patients with a history of combined OCP use of
less than 10 years had 4.43-fold odds of having optimum
endometrium compared with those who had used
OCPs for 10 years or more.
We also analyzed the data taking 5 years of
combined OCP use as the threshold based on a
previous study using this definition7 and found that 5
years of use also had a significant adverse effect on
endometrial thickness. In the 7 mm or greater thickness group, 56.1% had used the OCP for more than 5
years compared with 86.6% in the less than 7 mm
endometrial thickness group (P.002 by Fisher exact
test; Table 3). Alternatively, to consolidate these
findings further, we calculated the mean endometrial
thickness on cycle day 10 in patients using combined
OCP for less than 10 years and for 10 years or
more. The mean thickness was 9.541.88 mm and
8.482.33 mm, respectively, with P.007. The mean
endometrial thickness for those who had used combined OCP for less than 5 years was 9.721.69 mm,
whereas for those with 5 or more years of use, the
Table 3. Fisher Exact Test With 5 Years of
Combined Oral Contraceptive Pill Use
as the Threshold

OCP use less

than 5 y
OCP use 5 y
or more
Total

Endometrium
Less Than 7 mm

Endometrium
7 mm or More

Total

4 (13.34)

47 (43.9)

51

26 (86.66)

60 (56.1)

86

30

107

137

OCP, oral contraceptive pill.

Data are n (%) or n.
Two-tailed P.002.

Talukdar et al

Long-Term OCP Use and Endometrial Thickness

351

mean thickness was 8.812.23 mm (P.008). Figure

2 shows the box plot with 5 years of combined OCP
use as the cutoff. The 50th percentile of endometrial
thickness in less than 5 years of use was 8.511 mm,
whereas it was 6.710.75 mm in 5 or more years of
OCP use. There were no outliers in the 5 or more
years of use group. In the less than 5 years group,
there was one high outlier and three low outliers.
As secondary outcome measures, we calculated
cycle cancellation and pregnancy rates. We found
that 7 of 30 cycles (23%) were cancelled in the study
group because of persistently thin endometrium despite continuing estrogen stimulation for 7 more days.
The rest of these women completed the cycle with
prolonged treatment with estrogen. The mean day of
starting progesterone in the 7 mm or greater endometrial thickness group was 10.06, whereas it was 14.43
in the less than 7 mm endometrial thickness group.
Thus, an extra 4 days of estrogen was needed in the
thin endometrium group to reach the required
7-mm-thick endometrium before starting progesterone (P.001; Table 1). In the 7 mm or greater
endometrial thickness group, four cycles were cancelled for various reasons other than thin endometrium. The overall cycle cancellation rate was 4% (4 of
107), which is significantly less than the thin endometrium group in which the cycle cancellation rate was
23% (7 of 30; P.002; Table 1). The pregnancy rate in
the less than 7 mm endometrial thickness group
(including patients in whom up to 7 more days of
estrogen was required to thicken the endometrium)
was 13% (4 of 30 patients), whereas it was 27% (29 of
107 patients) in the 7 mm or greater endometrial
thickness group (P.15; Table 1).

DISCUSSION
In the present study, the endometrial thickness was
recorded in women of similar ages who received the
same endometrial preparation for frozen embryo
transfer. All had a history of combined OCP use of
varying duration, and all had stopped the combined
OCP 2 years before frozen embryo transfer.
The only literature we could find addressing
long-term combined OCP use (defined as 5 years or
more) and fertility suggests that there is no adverse
effect on endometrial growth or pregnancy outcome.7
In fact, the authors observed a reduced time to
pregnancy in women using combined OCPs for 5 or
more years compared with less than 5 years or no use
at all. The authors speculated that the combined OCP
may prevent the possibility of endometriosis progression by minimizing endometrial proliferation and
menstrual bleeding, thereby improving the chance to

352

Talukdar et al

conceive. It is known that there are other health

benefits of combined OCP use, such as a reduced risk
of endometrial,8 ovarian,8 and colorectal cancer.9 The
ovarian and endometrial benefits appear to persist for
more than 15 years after stopping OCPs. The reduced
risk of endometrial cancer was attributed to the
antiproliferative actions of progestin on the endometrium.8,9 A later study hypothesized that the 50% 60%
reduced endometrial cancer risk with the use of combined OCP or progestin-releasing intrauterine device
was partly attributable to negative selection for subclinically mutated glands (phosphatase and tensin
homolog mutated glands).10 This mechanism cannot
explain a suppressed endometrial growth in normal
endometrium. However, the observation that the protective effect against endometrial cancer persists for a
long time in combined OCP users might support our
findings that long-term combined OCP use in the past
somehow hampers optimal endometrial growth.
Because most of the effects of estrogen on the
uterus are mediated via estrogen receptors,11 there is a
possibility that there is deficiency of estrogen and
progesterone receptors in a suboptimal endometrium.
However, it also has been established that estrogen or
progesterone receptor concentrations were not related to endometrial thickness and receptivity, and
that the only significant correlation is with the relative
concentrations of these receptors.12 For example, the
ratio of progesterone receptor to estrogen is decreased
in endometrium with a supposedly favorable pattern
for implantation compared with endometrium with a
suspected adverse pattern on ultrasonography. Clomiphene citrate, a selective (estrogen) modulator with both
estrogen agonist and antagonist properties, has been
demonstrated to result in an endometrium that is thinner than that seen with other stimulated cycles,13,14 most
likely because of depletion of estrogen receptor levels in
the endometrium. Clomiphene citrate inhibits estrogeninduced endometrial epithelial cell proliferation and
estrogen response element transactivation, thereby inhibiting the recruitment of steroid receptor coactivator-1
to estrogen receptor .15 There may be a similar mechanism explaining the long-term effects of combined
OCP use, although at present there are insufficient data
to validate this suggestion.
Adequate endometrial growth is important for
embryo implantation. Most investigators suggest that
an endometrial thickness of 7 mm or more is preferable for successful implantation during fertility treatments.13,16 18 Some studies state that a minimum endometrial thickness of 6 mm18 is acceptable as a
prerequisite for pregnancy, and yet another study
reported pregnancy with endometrium as thin as 4

Long-Term OCP Use and Endometrial Thickness

OBSTETRICS & GYNECOLOGY

mm.19 In a previous study of infertile women receiving estrogen replacement, an endometrial thickness of
7 mm or more was more likely to have an in phase
endometrium compared with an endometrial thickness of less than 7 mm.20 In our study, we found that
the average endometrial thickness in the thin endometrium group was 6.060.62 mm, whereas it was
10.031.45 mm in the 7 mm or greater endometrial
thickness group. With longer duration of treatment
with estrogen, the thin endometrium group may catch
up and frozen embryo transfer is possible, although
further along in the cycle. A total of seven cycles had
to be cancelled in the less than7 mm group because of
persistently thin endometrium.
Currently, much focus is on endometrial stem
cells and their important role as the regenerator of
the human endometrium. Although endometrial growth
and differentiation are primarily regulated by estrogen
and progesterone, it is postulated that the clonogenic
activity of the endometrial epithelial and stromal cells is
actually responsible for the remarkable regenerative
capacity of the human endometrium. Several growth
factors have been identified to support clonogenicity.21
Kjiana et al21 demonstrated for the first time to our
knowledge that inactive endometrium, ie, endometrium
of women using oral contraceptive therapy and postmenopausal women, also contains clonogenic epithelial
and stromal cells. The endometrium regenerates on
cessation of oral contraceptive therapy and, in postmenopausal women, when hormone replacement therapy is started. However, they also demonstrated that the
cloning efficiencies were lower in inactive endometrium
than either the proliferative or the secretory phase
endometrium. This suggests that the number of clonogenic cells increases with cycling21 and supports the
possibility that with a prolonged period of inactivity
there is significant suppression of the stem cells, so that
the endometrium fails to recover even with estrogen
stimulation or needs a much prolonged or higher-dose
stimulation for optimal functioning.
We acknowledge that the present study is limited
by several factors. The sample size is small and we
also lack information on the exact composition of
the combined OCP (dose and type of estrogen and
progestin) used. At present, we do not have knowledge of the mechanism of this potential adverse effect
of combined OCPs and a biologic explanation for this
phenomenon awaits further research. However, we
believe our findings of an association between longterm use (5 years or more) of combined OCPs and
persisting thin endometrium in women undergoing
frozen embryo transfer cycles demonstrates an unusual and, until now, unidentified side effect of com-

VOL. 120, NO. 2, PART 1, AUGUST 2012

bined OCPs, leading to a higher cancellation rate and

more days of stimulation. These findings may be of
importance when counseling women considering longterm contraception.
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