Más contenido relacionado La actualidad más candente (19) Similar a Jog12130 effect of estradiol valerate on endometrium thickness (20) Más de Luis Carlos Murillo Valencia (20) Jog12130 effect of estradiol valerate on endometrium thickness1. Effect of estradiol valerate on endometrium thickness
during clomiphene citrate-stimulated ovulation
Chonthicha Satirapod1
, Siripen Wingprawat1
, Rattiya Jultanmas2
, Sasivimol Rattanasiri3
,
Siwanon Jirawatnotai4
and Wicharn Choktanasiri1
Departments of 1
Obstetrics and Gynaecology and 2
Nursing, 3
Research Center, Faculty of Medicine, Ramathibodi Hospital, and
4
Department of Pharmacology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand
Abstract
Aim: The aim of this study was to examine the effects of estradiol valerate (EV) on the thickness of clomiphene
citrate (CC)-stimulated endometrium.
Material and Methods: Thirty-four normal ovulatory women were randomized double-blindly into two
groups to receive CC 100 mg/day on day 2–6 of the treatment cycle, and either vitamin B (placebo) or EV
6 mg/day on day 10–14 of the cycle. The endometrial thickness, endometrial pattern, numbers of mature
follicles, and maximal diameters of preovulatory follicles were evaluated by transvaginal sonographic
examination.
Results: Thirty women completed both treatment cycles. Two other participants dropped out during the
treatment due to side-effects (headache). The average endometrial thickness of the group treated with
CC + placebo became slightly thinner when compared to the thickness at the baseline (9.04 vs 9.52 mm;
P = 0.24). The CC + placebo and the CC + EV resulted in similar endometrial pattern, ovulation day, numbers
of mature follicles, and sizes of the leading follicles before ovulation. However, an addition of EV into the CC
cycle significantly increased the average endometrial thickness (10.7 mm vs 9.04 mm; P < 0.001).
Conclusions: We concluded that the addition of 6 mg/day EV following the CC treatment can prevent the
endometrial thinning without perturbing folliculogenesis and ovulation.
Key words: clomiphene citrate, endometrial thickness, estradiol valerate, folliculogenesis, ovarian
stimulation.
Introduction
Clomiphene citrate (CC) is an orally active non-
steroidal estrogen agonist/antagonist that is widely
used as the first-line ovulation inducer in anovulatory
women.1,2
Nowadays, CC is useful in a variety of indi-
cations, such as induction of superovulation in unex-
plained infertility3
and the stimulation protocol for in
vitro fertilization (IVF) cycles.4–6
CC has several marked
advantages for these indications, because it is highly
effective in inducing ovulation, while relatively safe,
inexpensive and can be administered orally.1
However,
despite the fact that CC administration in anovulatory
patients can improve ovulation rate by 60–85%, the
pregnancy rate linked to CC treatment is noticeably
lower than expected (only around 30–40%).4
This dis-
crepancy is believed to result from CC’s negative effect
on the cervical mucus quality7,8
and its anti-estrogenic
activity.9–11
In fact, it has been reported that the anti-
estrogenic activity of CC can cause thinning of
endometrium.9,10,12,13
Normally, endometrial thickness
is a reflection of its ability to proliferate and of the
Received: November 8 2012.
Accepted: March 14 2013.
Reprint request to: Dr Chonthicha Satirapod, Department of Obstetrics and Gynaecology, Faculty of Medicine, Ramathibodi Hospital,
270 Rama 6 Rd., Ratchatawee, Bangkok 10400, Thailand. Email: chonthicha_lek@yahoo.com
bs_bs_banner
doi:10.1111/jog.12130 J. Obstet. Gynaecol. Res. Vol. 40, No. 1: 96–101, January 2014
96 © 2013 The Authors
Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
2. overall intrauterine health.14
Endometrial thickness
was also shown to positively correlate with receptive-
ness. Previous studies reported that thicker endometri-
ums give higher rates for IVF and CC-intrauterine
insemination (IUI) outcome.14–17
Presently, one of the most effective ways to improve
endometrium thinning caused by CC treatment is to
add an exogenous estrogens treatment during the
course of CC stimulation. However, the effectiveness
of exogenous estrogens for the treatment of
endometrium thinning during CC cycle still varies. For
example, several studies showed that the anti-
estrogenic effect of CC on the endometrium might be
overcome by the adjunctive use of exogenous
estrogens,15–18
while other studies showed that the
addition of some types of exogenous estrogens did not
significantly enhance the endometrial thickness.19,20
These different outcomes could be the result of several
factors, such as the type, dosage, and route of admin-
istration of the exogenous estrogens used for the
treatment.16,18,19
Estradiol valerate (EV) is an oral synthetic form of
estradiol. EV is normally used to condition the uterus
for implantation of fertilized ovum, and to promote the
maturation and maintenance of female auxiliary repro-
ductive organs. Because the oral form of estrogen is
more convenient and is relatively safe to use when
compared to the transdermal or the vaginal forms,
many IVF clinics prefer the oral form of EV in several
endometrial preparation procedures.21,22
Here, we
studied the effect of EV on the endometrial thickness
and folliculogenesis when used in conjunction with CC
for ovarian stimulation.
Methods
Volunteers
Thirty-four healthy women aged 20–39 years with
regular menstrual cycles of 26–35 days and normal
pelvic examinations were recruited in this study. The
inclusion criteria were: body mass index 18–25 kg/m2
,
day-3 follicle-stimulating hormone (FSH) < 10 IU/L,
normal ovulatory cycle which was documented by
cycle regularity of previous 3 months, existence of
dominant follicle, mid-luteal progesterone Ն4 ng/ml
in the recent cycle, and no pregnancy desired. They
were advised to use barrier contraception during the
study periods, if tubal resection had not been per-
formed. Participants were excluded if they had pre-
existing ovarian cysts, or had used oral contraceptive
pills, gonadotrophin-releasing hormone (GnRH) ago-
nists, or depot medroxyprogesterone acetate/GnRH
agonist depots within 1, 3 or 6 months of enrollment,
respectively.
Study design
This study was designed as a crossover study, in which
the same group of participants would receive the same
treatments. Participants were asked for consent and
screened for eligibility. The study was involved in four
consecutive menstrual cycles. During the first natural
cycle, all participants had to be verified to undergo a
normal cycle in order to proceed to the next step. Blood
samples were taken from all participants for day-3 FSH
levels during the first cycle. If the day-3 FSH level of a
participant was within the normal range, she would
then undergo transvaginal sonographic examination
using a 7.5-mHz transducer. The transvaginal sono-
graphic examination began on day 12 of the first cycle
onwards to determine the ovulation. After 1 week of
ovulation, progesterone levels were confirmed. These
data were used as the baseline value.
After the inclusion and exclusion criteria, all partici-
pants were randomly assigned into two groups, based
on numbers randomly generated by computers. One
group received CC + placebo (vitamin B complex),
while the other group received CC + EV in their second
cycle. The randomization of group assignment was per-
formed by an independent research assistant. The
CC + placebo group was treated with CC (100 mg/day)
on day 2 to day 6 and then with placebo (vitamin B
complex) three tablets/day on day 10 to day 14. The
CC + EV group was treated with CC (100 mg/day) on
day 2 to day 6 and then with EV (2 mg/tab) three
tablets/day on day 10 to day 14. During the second
cycle, transvaginal ultrasonography was performed
from day 12 until ovulation to document the numbers
and sizes of developing follicles, the presence of tri-
laminar layer, and the thickness of endometrium. The
study was conducted in a double-blinded way so that
both the investigator and the participants were
unaware of the participants’ group assignment.
The third cycle was used as a washout period. The
cycle interval was monitored during this period. In
the last cycle, both groups were treated again with the
same protocols used during the second cycle. Failure to
ovulate during any treatment cycle was diagnosed if
no leading follicle was larger than 12 mm on day 16 of
the cycle, and/or the leading follicle was smaller than
18 mm and was not progressing for at least 3 days.
This study was approved by the ethical committee of
Ramathibodi Hospital (MURA2007/169).
EV improves endometrium on CC cycles
© 2013 The Authors 97
Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
3. Transvaginal sonographic examination
After aligning the uterus along with the central longi-
tudinal axis, the endometrial thickness was mea-
sured from the echogenic interface between the
endometrium and myometrium to the opposite inter-
face at the point of maximal thickness.23
The follicular
diameter was determined by calculating the mean of
the two perpendicular diameters measured at the
greatest plane of the follicle. An ovulation was con-
firmed by documenting at least two of the following
four parameters: a decrease in follicular diameter, blur-
ring of the follicular border, the presence of internal
echoes, and free fluid in the cul-de-sac.24
Statistical analysis
All of the outcomes were analyzed by using stata
version 9. The results of descriptive characteristics of
the study population are expressed as mean Ϯ
standard deviation (SD) for normally distributed data
while median and range were used for non-parametric
data. The statistical analysis was performed by the Wil-
coxon signed rank test for non-parametric data and
paired t-test for normally distributed data. P < 0.05 was
considered statistically significant.
Results
Among the 34 women recruited for this study, 32
women met the inclusion criteria. Thirty out of 32
women completed the study, because two women
dropped out due to unpleasant side-effects (headache)
during the course of CC treatment and thus were
excluded from the study.
The characteristics of the 30 participants completing
the study were as follows: average age 32 Ϯ 4.6 years
(range 21–39 years), body mass index 20.4 Ϯ 2.3 kg/m2
(range 15.2–24.1 kg/m2
), 30 Ϯ 1.5 days of cycle inter-
val (range 26–34 days), and the median parity was 1.5
(range 0–3). All participants had normal range of day-3
FSH serum levels with an average at 5.9 Ϯ 1.8 IU/L
(range 3.1–8.9 IU/L). The mean mid-luteal progester-
one serum level was 14.4 Ϯ 6.2 ng/ml (range 6.2–
27 ng/ml). Table 1 showed the baseline of endometrial
thickness in natural cycles was 9.52 Ϯ 1.33 mm, and
all of the endometrial patterns were triple layer.
The ovulation day was in day 16 (range 13–18) with
only one mature follicle in each person per cycle and
the maximum follicular diameter was 20.8 Ϯ 1.5 mm.
In the first and third cycles, we found that the
day of ovulation, the number of mature follicles, the
maximum follicle diameter, and the endometrial thick-
ness were not different between the groups (data not
shown).
Consistent with a previous report, CC treatment
slightly reduced the endometrial thickness when com-
pared with that during the natural cycle (baseline value)
(9.04 Ϯ 1.78 mm vs 9.52 Ϯ 1.33 mm, respectively).
Notably, EV treatment together with CC significantly
enhanced endometrial thickness when compared to
that in participants receiving CC + placebo (10.77 Ϯ
1.65 mm vs 9.04 Ϯ 1.78 mm, P < 0.001). We found that,
although statistically significant, EV only mildly
increased the thickness of endometrium. However,
when we categorized the participants who received CC
treatment into two groups consisting of the first group,
those whose endometrium suffered the endometrium
thinning by the CC treatment (endometrium thickness
Յ8 mm [n = 12, the average endometrium thickness =
7.4 Ϯ 0.25 mm]), and the second group, those whose
endometrium thickness was not affected by the CC
(endometrium thickness >8 mm [n = 18, the average
endometrium thickness = 10.13 mm Ϯ 1.34]), we found
that EV greatly improved those whose endometrium
thinned by CC (the average thickness increased
from 7.4 Ϯ 0.25 mm to 10.48 Ϯ 0.43 mm, P < 0.0001)
(Table 2). On the other hand, EV did not increase
endometrium thickness of the second group
(10.13 Ϯ 1.34 mm vs 10.97 Ϯ 1.76 mm, P = 0.118). This
data suggest that EV treatment is especially beneficial to
those who suffer from CC treatment, but may have only
a small effect on those with normal endometrium thick-
ness. When compared to the baseline endometrium
thickness, that of the EV + CC-treated group was
slightly thicker (9.52 Ϯ 1.33 mm vs 10.77 Ϯ 1.65, respec-
tively, P < 0.001).
The endometrial patterns after CC + EV cycles were
similar to that after CC + placebo cycles (data not
shown). In addition, days of ovulation, numbers of
intermediate follicles, numbers of mature follicles, and
Table 1 Baseline outcome in natural cycles
Outcome Natural cycle
Day of ovulation (cycle day)† 16 (13–18)
Number of follicles >18 mm 1
Maximum follicle diameter (mm)‡ 20.8 Ϯ 1.5
Endometrial thickness (mm)‡ 9.52 Ϯ 1.33
Endometrial pattern
Triple layer 30 (100%)
Non-triple layer 0
†Values are given as mean (range). ‡Values are given as
mean Ϯ standard deviation.
C. Satirapod et al.
98 © 2013 The Authors
Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
4. the maximum follicular diameters were comparable in
both placebo and EV added groups in CC-stimulated
cycles (Table 3).
Adverse effects
We found a few mild adverse effects from participants
in the CC + placebo cycles; two dropped out because of
headache and one had minimal headache, two partici-
pants had dizziness, and two participants had breast
tenderness. In the CC + EV cycles, we also observed
some mild adverse effects; two participants had dizzi-
ness, and three participants had breast tenderness. The
rates of adverse effects from both groups were not
significantly different (data not shown). No other
serious adverse effects were found. Almost all partici-
pants with mild adverse effects could tolerate them
and completed the study protocol.
Discussion
Several studies have demonstrated the benefits of
adding exogenous estrogen treatment into the
CC-stimulated cycle.16–18
These benefits include
increased endometrial thickness, improved pregnancy
rate, and reduced miscarriage rate.16
Here, we show
that administration of EV, an oral form of estradiol,
relieved the endometrial thinning effect of CC. Our
data suggested that the 6 mg daily regimen of EV for 5
days was sufficient to increase the endometrial thick-
ness after CC treatment in normal ovulatory women.
Moreover, EV can overcome the effect of CC on the
endometrial thickness, especially in patients who have
a thin endometrium (below 8 mm). An addition of EV
into the CC cycle did not alter the overall pattern of
endometrium and yielded the similar tri-laminar
pattern observed from the CC + placebo group,
therefore retaining the desirable pattern that favors
pregnancy.25–27
Exogenous estrogen exerts its positive effect on
endometrium by binding to estrogen receptors in
endometrium and facilitates endometrium develop-
ment.27
It is known that the exogenous estrogen can
antagonize the negative effects of CC on endometrial
glandular-stromal tissue.17
It has also been shown that
0.05 mg/day18
or 0.02 mg/day17
of oral ethinyl estra-
diol for at least 5 days/cycle can prevent the loss of
glandular density and increase vacuolated cells during
CC stimulation.16–18
We found that the oral form of EV treatment signifi-
cantly improved the thickness of the CC-stimulated
cycle without interfering with the CC-stimulated tri-
laminar pattern, folliculogenesis, and ovulation. Of
note, in our protocol, EV was designed to be given on
day 10 to day 14 of the cycle, which should not interfere
with the effect of CC on FSH levels.
The adverse effects found during the CC stimulation
were minor and well tolerated. An addition of EV into
the CC cycle did not increase any of these adverse
Table 2 Effects of subgroup of endometrium thickness between CC and CC + EV
Outcome CC + placebo CC + EV P
Endometrial thickness†
Յ8 mm (n = 12)
7.4 Ϯ 0.25 10.48 Ϯ 0.43 <0.0001
Endometrial thickness†
>8 mm (n = 18)
10.13 Ϯ 1.34 10.97 Ϯ 1.76 0.118
†Values are given as mean Ϯ standard deviation. CC, clomiphene citrate; EV, estradiol
valerate.
Table 3 Effects of ovarian stimulation between CC and CC + EV
Outcome CC + Placebo
(n = 30)
CC + EV
(n = 30)
P
Day of ovulation (cycle day)† 15 (13–18) 16 (13–19) 0.66
Number of follicles Ն18 mm‡ 2.5 Ϯ 1.3 2.2 Ϯ 1.0 0.25
Number of intermediate follicles‡ 2.1 Ϯ 1.2 2.3 Ϯ 1.1 0.37
Maximum follicle diameter‡ 24.9 Ϯ 2.8 25.0 Ϯ 3.7 0.92
Endometrial thickness‡ 9.04 Ϯ 1.78 10.77 Ϯ 1.65 <0.001
Endometrial pattern§ 22 (73.37%) 20 (66.67%) 0.3
†Values are given as mean (range). ‡Values are given as mean Ϯ standard deviation. §Values
are given as number (percentage). CC, clomiphene citrate; EV, estradiol valerate.
EV improves endometrium on CC cycles
© 2013 The Authors 99
Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology
5. effects, or produce new adverse effects that were not
observed in CC stimulation alone.
Therefore, adding the oral form of estradiol, EV, to
CC cycles could be an effective way to prevent
CC-related endometrium thinning with minimum
adverse effects. Because of its efficacy and safety, we
propose that EV could be used as the estrogen form of
choice to prevent endometrium thinning caused by CC
stimulation. However, a limitation of this study is that
we are only able to show the benefit of EV in normo-
ovulatory women and the endometrial thickness is our
main outcome. Although, the endometrium thickness
is generally well accepted as one of the strong indica-
tive parameters for fertility, other parameters should
also be investigated. Hence, we suggest that future
study may be evaluated in the infertile patient and mea-
sured final outcome (pregnancy rate or live birth rate).
Given that the thinning endometrium is a major side-
effect of CC treatment,9,14,28,29
we envision that EV
would enhance pregnancy rate in CC-IUI cycles.
We concluded that the addition of EV at 6 mg/day to
the CC-stimulated ovulation regimen can significantly
improve endometrial thickness in normo-ovulatory
women and does not interfere with folliculogenesis.
Acknowledgment
This study was supported by a Research Grant (No.
50048) from the Faculty of Medicine, Ramathibodi Hos-
pital, Mahidol University.
Disclosure
No author has any potential conflict of interest.
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EV improves endometrium on CC cycles
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Journal of Obstetrics and Gynaecology Research © 2013 Japan Society of Obstetrics and Gynecology