Discussion
Although various strategies have been attempted to improve endometrial
growth in women with thin endometrium, the optimal means of EP in these
women is yet to be determined. The aim of our study was to evaluate the
effect of TAM in patients with a thin endometrium in FET cycles. By
univariate and multivariate analysis, our results found a superior
pregnancy outcome following FET in a TAM ovarian stimulation cycle
compared to HRT cycle
in
women with thin endometrium.
In our study we observed that the durations of endometrium preparation
were 6 day shorter in the TAM FET group (10 days) than in the HRT FET
group (16 days). This
phenomenon
is interesting but hard to explain. We hypothesize that ovarian
stimulation with TAM may stimulate a faster development of the dominant
follicle(s). More prospective studies are needed to explore its clinical
relevance.
The result of this study showed that endometrial lining of the current
HRT cycle differ from prior cycle (8.15±1.11 mm vs <7mm). Different
from previous cycle, prolonged duration, increased dosage and
transvaginal estrogen treatment were used in the present study. The
study of Liu showed that effectiveness of estrogen treatment was
significantly associated with treatment duration (12). Our study was in
line with this study.
Our results showed that endometrium thickness was much more improved in
TAM group than HRT group. TAM has been reported to improve endometrium
thickness while ovulation induction. In the study of Kasey Reynolds,
endometrial thickness was improved when the OI (ovulation induction)
drug been switched from CC to TAM (34).Wang et al compared TAM and CC in
ovarian stimulation cycle in combination with HMG (human menopausal
gonadotrophin) and found that TAM treated patients had a significantly
increased endometrial thickness (28).
The literature on the treatment of thin endometrium with TAM in FET
cycle is rather sparse. Chen X et al used TAM in 3 women who showed a
repeated unresponsive thin endometrium and resulted in endometrium
expansion to at least 7.7mm and conception(29). Soon after, another
study by the same group showed TAM increased the endometrial thickness
from 6.5 to 8.8mm in women with thin endometrium undergoing FET(30).
Ke
H et al explore the effect of TAM in patients with a thin endometrium in
FET cycle. Their study included 226 women who had an EMT of less than
7.5mm in their previous cycles. After the use of TAM, EMTs were
significantly improved. When stratified by different previous
endometrium preparation protocols, EMT increased from 6.11±0.98mm to
7.87±1.48 in NC group, from 6.24±1.01 to 8.22±1.67 in HRT group and from
6.34±1.03 to 8.05±1.58mm in OI group(31). In line with the previous
data, our result showed that the EMT in TAM group was 8.98±2.02mm which
was significantly thicker than the EMT in HRT groups (8.15±1.11mm).
Some authors found that TAM exposure promotes endometrial cell
proliferation through estrogen and non-estrogen pathway. In estrogen
signaling pathway, TAM stimulate the GPER (GPR30 Estrogen Receptor),
which in turn, activates the SF1 (Steroidogenic Factor 1), which is a
transcription factor that induce aromatase expression in endometrial
cells (35). In non-estrogen signaling pathway, a study found that TAM
up-regulates the expression of Ki67 and IGF-1,markers of
proliferation(36).
Although the first studies by Chen X et al only include 3 recurrent thin
endometrium patients who successfully conceived with one miscarriage
after tamoxifen treatment(29), their following studies consisting of
61 thin endometrium women showed that the clinical pregnancy rate, early
miscarriage rate and implantation rate were 44.3%(27/61)、7.4%
(2/27)、24.2%(32/132) respectively. The authors concluded that in
patients of recurrent thin endometrium, tamoxifen treatment may be a
successful alternative approach(30). The study of Ke H et al showed
that when stratified by different etiologies of thin endometrium,
patients with PCOS obtained the highest rate of clinical pregnancy
(60%) and live birth (55.56%) per transfer. The clinical pregnancy
rate and live birth rate in patients with history of intrauterine
adhesion were 6/18(33.33%) and (5/18, 27.78%) respectively, while for
patients with history of uterine curettage, the clinical pregnancy rate
and live birth rate were (39/101, 38.61%) and (32/101,31.68%)
respectively(31). However, there were no control groups in the studies
of Chen X et al and Ke H et al. Furthermore, they are limited by their
small sample size.
Different from the
previous study, our study compared the effect of TAM with the mostly
commonly used protocol- HRT protocol rather than
described
the reproductive outcome only so that this effect can be analyzed
precisely. Overcoming methodological shortcomings in above-mentioned
studies and adjusting for a number of important confounders, our study
demonstrated that not only the clinical pregnancy rate and the
implantation rate but also the ongoing pregnancy rate and live birth
rate of TAM group were significantly higher than HRT group.
Despite the improvement of endometrium thickness, another possible
mechanism for improved reproductive outcomes with the use of TAM during
FET is that TAM might potentially improve corpus luteum function. Wu
reported lower spontaneous abortion rates in patients with luteal-phase
dysfunction treated with TAM as compared with CC(37).
Cost-effectiveness is a major concern for patients during their
infertility treatment. TAM is much cheaper than estrogen agents. In
China, TAM costs $42 for the whole cycle whereas estradiol valerate
costs more than $11 per day supply and cannot be withdrawn until 8-10
weeks gestation. Future studies analyzing cost efficiency of these two
regimens are needed.
Long-term safety of offspring after IVF treatment is of paramount
importance. The short half-life of TAM (86h) and administration of this
agent in the early follicular phase from cycle day 5 to day 10 leave a
sufficient period of time for complete washout before embryo
implantation. Furthermore, previous research suggested that TAM
administration during the first trimester did not increase the risk of
major congenital anomalies (38).
We recognize there are some important limitations of our retrospective
study. First, the retrospective nature of our analysis may subject to
selection bias regarding the type of FET protocol (TAM vs.HRT). In this
regard, we exclude multiple types of FETs following the same fresh
IVF/ICSI cycle. Secondly, endometrial receptivity assay was not
performed on both groups of patients. Further studies on this subject
are needed to investigate the details of the effect of TAM on the
endometrium.
Our study also has some strength. First, our study is the largest in
this area by far with 100% follow-up and provides new insight into
current practice patterns. Secondly, the laboratory conditions and IVF
procedures did not been changed throughout the study period.