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 endo-
metrial 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 Tech-
nology, 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 find-
ings suggest a previously unidentified adverse effect of
long-term combined OCP use in women who are antic-
ipating future fertility.
(Obstet Gynecol 2012;120:34854)
DOI: 10.1097/AOG.0b013e31825ec2ee
LEVEL OF EVIDENCE: II
T he combined oral contraceptive pill (OCP) cur-
rently being used by more than 100 million
women worldwide1 contains both estrogen and pro-
gestin 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 proges-
togenic induction of hostile cervical mucus and of an
endometrial environment that is unfavorable for im-
plantation.3 A predominant progestational effect of
combined OCP on the endometrium includes an
arrest of glandular proliferation, induction of pseu-
dosecretion, and stromal edema followed by decidu-
alized 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 bleed-
ing and endometrial hyperplasia. Currently, pretreat-
ment 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 suc-
cessful implantation of an embryo. Although controver-
sial, it is generally considered that an ultrasonographic
endometrial measurement of 7 mm in cross-section is
the minimum thickness required for successful implan-
tation.6 While monitoring women ultrasonographically
during assisted reproductive techniques, we occasionally
noticed that some women had a persistently thin endo-
metrium 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 prepara-
tion 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. Ul-
trasound monitoring flow sheets of patients undergo-
ing 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 endo-
metrial preparation was used in 295 cycles consisting
of micronized 17 -estradiol (E2) for simulated follic-
ular phase endometrial development. We excluded
cycles in women in whom a different protocol for
frozen embryo transfer was used (natural cycle, estro-
gen 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, intrauter-
ine devices, spermicidal jells, or barrier contracep-
tives were excluded. Patients having other associated
pathology such as uterine fibroids, Asherman syn-
drome, 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 Talukdar et al
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 transvag-
inal 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 trans-
fer was performed either 5 days after starting proges-
terone (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 mea-
sured ultrasonographically using a 5-mHz endovagi-
nal 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 thick-
Frozen 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.
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 com-
bined 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 endo-
metrial 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 can-
celled. 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 soft-
ware and Excel 7. One-sample Kolmogorov-Smirnov
test was conducted for testing normality. For continuous
parameters in both groups that were normally distrib-
uted, 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
Table 1. Comparative Data
Endometrial Thickness
Less Than 7 mm (n30)
Age (y) 36.273.40
BMI (kg/m2) 22.52.57
Age at menarche (y) 12.31.18
Infertility
Primary 16 (53)
Secondary 14 (47)
Duration of infertility (m) 23.011.64
Endometrial thickness (mm) 6.060.62
Combined OCP use (y) 9.84.54
Day of starting progesterone 14.41.62
Cycle cancellation 23 (7/30)
Pregnancy 13 (4/30)
BMI, body mass index; OCP, oral contraceptive pill.
Data are meanstandard deviation, n (%), or % (n/N) unless otherwise specified.
* Mann-Whitney test, unless indicated.
test.
2
Fisher exact test.
350 Talukdar et al Long-Term OCP Use and Endometrial Thickness
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 signif-
icance 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 thick-
ness 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 thick-
ness of less than 7 mm and 7 mm or greater as the two
possible outcomes (dependent variable). Box plots tak-
ing 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
Endometrial Thickness
7 mm or More (n107) P*
36.063.32 .632
22.72.21 .308
11.81.4 .012
66 (62) .410
41 (38)
22.412.08 .725
10.031.45 .001
5.84.52 .001
10.10.29 .001
4 (4/107) .002
27 (29/107) .150
OBSTETRICS & GYNECOLOGY
Table 2. Fisher Exact Test With 10 Years of mary or secondary) and duration of infertility in both
Combined Oral Contraceptive Pill Use groups (as shown in Table 1). However, the age at
as the Threshold menarche was 0.5 years later in the less than 7 mm
Endometrium Endometrium group (P.01; Table 1). The mean years of combined
Less Than 7 mm 7 mm or More Total OCP use in the less than 7 mm endometrial thickness
group was found to be 9.84.54, and in more than or
OCP use less 11 (36.65) 77 (71.96) 88
than 10 y
equal to 7 mm group it was 5.84.52. The difference
OCP use more 19 (63.35) 30 (28.04) 49 in means of duration of combined OCP use was
than 10 y highly significant between the two groups as tested by
Total 30 107 137 Mann-Whitney test by ranks (P.001; Table 1). Tak-
OCP, oral contraceptive pill. ing 10 years of use as a threshold for long-term
Data are n (%) or n. combined OCP use, 63.35% of patients were long-
Two-tailed P.001.
term users in the less than 7 mm endometrial thick-
ness group whereas 28.04% were long-term users in
cycle. These patients comprised the study group with the 7 mm and above endometrial thickness group.
mean endometrial thickness of 6.060.62 mm. The This difference was also highly significant (P.001) by
control group comprised 107 (78.1%) patients who Fisher exact test (Table 2). The odds ratio was 4.43
had an endometrial thickness of 7 mm or more. The (95% confidence interval 1.89 10.41), indicating that
mean endometrial thickness in this group was those patients with a history of combined OCP use of
10.031.45 mm. The P value for endometrial thick- less than 10 years had 4.43-fold odds of having optimum
ness was highly significant (P.001; Table 1). The endometrium compared with those who had used
mean age in the less than 7 mm endometrial thickness OCPs for 10 years or more.
group was 36.273.40 years, and in the other group it We also analyzed the data taking 5 years of
was 36.063.32 years. Age and body mass index combined OCP use as the threshold based on a
were normally distributed; hence, Student t test was previous study using this definition7 and found that 5
used for comparison. The P values were .63 and .30, years of use also had a significant adverse effect on
respectively (Table 1). Likewise, no significant differ- endometrial thickness. In the 7 mm or greater thick-
ence was observed between degree of infertility (pri- ness 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
16 16
test; Table 3). Alternatively, to consolidate these
14 14 findings further, we calculated the mean endometrial
thickness on cycle day 10 in patients using combined
Endometrial thickness (mm)
Endometrial thickness (mm)

12 12
OCP for less than 10 years and for 10 years or
10 10 more. The mean thickness was 9.541.88 mm and
8.482.33 mm, respectively, with P.007. The mean
8 8
endometrial thickness for those who had used com-
6 6 bined OCP for less than 5 years was 9.721.69 mm,
whereas for those with 5 or more years of use, the
4 4

2 2
Table 3. Fisher Exact Test With 5 Years of
0 0 Combined Oral Contraceptive Pill Use
Oral contraceptive pill Oral contraceptive pill
use for 5 or more years use for fewer than 5 years as the Threshold
Fig. 2. Box plot with 5 years of combined oral contraceptive Endometrium Endometrium
pill (OCP) use as cutoff. The 50th percentile for endometrial Less Than 7 mm 7 mm or More Total
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 OCP use less 4 (13.34) 47 (43.9) 51
thickness was 8.8 mm in the group with 5 or more years of than 5 y
use, and it was 9.72 mm in the group with less than 5 years OCP use 5 y 26 (86.66) 60 (56.1) 86
of use. There were three low outliers and one high outlier in or more
the group with less than 5 years of OCP use. The difference Total 30 107 137
between the two groups was significant (P.008). OCP, oral contraceptive pill.
Talukdar. Long-Term OCP Use and Endometrial Thickness. Data are n (%) or n.
Obstet Gynecol 2012. Two-tailed P.002.

VOL. 120, NO. 2, PART 1, AUGUST 2012 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 de-
spite 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 endome-
trial 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 progester-
one (P.001; Table 1). In the 7 mm or greater
endometrial thickness group, four cycles were can-
celled for various reasons other than thin endome-
trium. The overall cycle cancellation rate was 4% (4 of
107), which is significantly less than the thin endome-
trium 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 progres-
sion by minimizing endometrial proliferation and
menstrual bleeding, thereby improving the chance to
352 Talukdar et al Long-Term OCP Use and Endometrial Thickness
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 endome-
trium.8,9 A later study hypothesized that the 50% 60%
reduced endometrial cancer risk with the use of com-
bined OCP or progestin-releasing intrauterine device
was partly attributable to negative selection for sub-
clinically 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 pro-
tective 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 re-
lated 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. Clomi-
phene citrate, a selective (estrogen) modulator with both
estrogen agonist and antagonist properties, has been
demonstrated to result in an endometrium that is thin-
ner than that seen with other stimulated cycles,13,14 most
likely because of depletion of estrogen receptor levels in
the endometrium. Clomiphene citrate inhibits estrogen-
induced endometrial epithelial cell proliferation and
estrogen response element transactivation, thereby in-
hibiting the recruitment of steroid receptor coactivator-1
to estrogen receptor .15 There may be a similar mech-
anism 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 prefer-
able for successful implantation during fertility treat-
ments.13,16 18 Some studies state that a minimum en-
dometrial thickness of 6 mm18 is acceptable as a
prerequisite for pregnancy, and yet another study
reported pregnancy with endometrium as thin as 4
OBSTETRICS & GYNECOLOGY
mm.19 In a previous study of infertile women receiv-
ing estrogen replacement, an endometrial thickness of
7 mm or more was more likely to have an in phase
endometrium compared with an endometrial thick-
ness of less than 7 mm.20 In our study, we found that
the average endometrial thickness in the thin endo-
metrium 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 post-
menopausal women, also contains clonogenic epithelial
and stromal cells. The endometrium regenerates on
cessation of oral contraceptive therapy and, in post-
menopausal women, when hormone replacement ther-
apy 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 clono-
genic 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 knowl-
edge 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 long-
term use (5 years or more) of combined OCPs and
persisting thin endometrium in women undergoing
frozen embryo transfer cycles demonstrates an un-
usual and, until now, unidentified side effect of com-
VOL. 120, NO. 2, PART 1, AUGUST 2012 Talukdar et al
bined OCPs, leading to a higher cancellation rate and
more days of stimulation. These findings may be of
importance when counseling women considering long-
term contraception.
REFERENCES
1. Trussel J. Contraceptive efficacy. In: Hatcher RA, editor.
Contraceptive technology. 19th revised ed. New York (NY):
Ardent-Media; 2007.
2. Speroff L, Darney PD. Oral contraception. In: A clinical guide
for contraception. 4th ed. Philadelphia (PA): Lippincott Wil-
liams & Wilkins; 2005. p. 21138.
3. Rivera R, Yacobson I, Grimes D. The mechanism of action of
hormonal contraceptives and intrauterine contraceptive devices.
Am J Obstet Gynecol 1999;181:12639.
4. Deligdisch L. Hormonal pathology of the endometrium. Mod
Pathol 2000;13:28594.
5. Grow DR, Iromloo K. Oral contraceptives maintain a very
thin endometrium before operative hysteroscopy. Fertil Steril
2006;85:204 7.
6. Oliveira JB, Baruffi RL, Mauri AL, Petersen CG, Borges MC,
Franco JG Jr. Endometrial ultrasonography as a predictor of
pregnancy in an in-vitro fertilization programme after ovarian
stimulation and gonadotrophin-releasing hormone and gonad-
otrophins. Hum Reprod 1997;12:2515 8.
7. Farrow A, Hull MG, Northstone K, Taylor H, Ford WC, Golding
J. Prolonged use of oral contraception before a planned preg-
nancy is associated with a decreased risk of delayed conception.
Hum Reprod 2002;17:2754 61.
8. Collaborative Group on Epidemiological Studies of Ovarian
Cancer, Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian
cancer and oral contraceptives: Collaborative reanalysis of data
from 45 epidemiological studies including 23,257 women with
ovarian cancer and 87,303 controls. Lancet 2008;371:30314.
9. Cogliano V, Grosse Y, Baan R, Straif K, Secretan B, El Ghissassi
F, et al. Carcinogenicity of combined oestrogen-progestagen
contraceptives and menopausal treatment. Lancet Oncol 2005;6:
5523.
10. Lin MC, Burkholder KA, Viswanathan AN, Neuberg D, Mutter
GL. Involution of latent endometrial precancers by hormonal and
nonhormonal mechanisms. Cancer 2009;115:2111 8.
11. Weihua Z, Saji S, Makinen S, Cheng G, Jensen EV, Warner M,
et al. Estrogen receptor (ER) beta, a modulator of ERalpha in
the uterus. Proc Natl Acad Sci U S A 2000;97:5936 41.
12. Ohno Y, Fujimoto Y. Endometrial oestrogen and progesterone
receptors and their relationship to sonographic appearance of
the endometrium. Hum Reprod Update 1998;4:560 4.
13. Randall JM, Templeton A. Transvaginal sonographic assess-
ment of follicular and endometrial growth in spontaneous and
clomiphene citrate cycles. Fertil Steril 1991;56:208 12.
14. Gonen Y, Casper RF. Prediction of implantation by the
sonographic appearance of the endometrium during controlled
ovarian stimulation for in vitro fertilization (IVF). J In Vitro
Fert Embryo Transf 1990;7:146 52.
15. Amita M, Takahashi T, Tsutsumi S, Ohta T, Takata K, Henmi
N, et al. Molecular mechanism of the inhibition of estradiol-
induced endometrial epithelial cell proliferation by clomi-
phene citrate. Endocrinology 2010;151:394 405.
16. Friedler S, Schenker JG, Herman A, Lewin A. The role of
ultrasonography in the evaluation of endometrial receptivity
following assisted reproductive treatments: A critical review.
Hum Reprod Update 1996;2:32335.
Long-Term OCP Use and Endometrial Thickness 353
17. Kovacs P, Matyas S, Boda K, Kaali SG. The effect of endometrial
thickness on IVF/ICSI outcome. Hum Reprod 2003;18:233741.
18. Coulam CB, Bustillo M, Soenksen DM, Britten S. Ultrasono-
graphic predictors of implantation after assisted reproduction.
Fertil Steril 1994;62:1004 10.
19. Sundstrom P. Establishment of a successful pregnancy follow-
ing in-vitro fertilization with an endometrial thickness of no
more than 4 mm. Hum Reprod 1998;13:1550 2.
20. Hofmann GE, Thie J, Scott RT Jr, Navot D. Endometrial
thickness is predictive of histologic endometrial maturation in
women undergoing hormone replacement for ovum donation.
Fertil Steril 1996;66:380 3.
21. Kjiana E, Schwab R, Wah SC, Gargett CE. Putative stem
cell activity of human endometrial epithelial and stromal
cells during the menstrual cycle. Fertil Steril 2005;84(Suppl
2):1124.

354 Talukdar et al Long-Term OCP Use and Endometrial Thickness OBSTETRICS & GYNECOLOGY