|Year : 2021 | Volume
| Issue : 1 | Page : 14-26
Comparison of art outcome in frozen embryo transfer cycle using oral estradiol valerate and estradiol transdermal gel
Madhuri Patil, Kavya G Venkatappa, Milind Patil
Dr. Patil’s Fertility and Endoscopy Clinic, No. 1, Uma Admirality, Bannerghatta Road, Bangalore 560029, India
|Date of Submission||08-Jul-2021|
|Date of Acceptance||15-Aug-2021|
|Date of Web Publication||17-Dec-2021|
Dr. Madhuri Patil
Dr. Patil’s Fertility and Endoscopy Clinic, No. 1, Uma Admirality, Bannerghatta Road, Bangalore 560029.
Source of Support: None, Conflict of Interest: None
Aim: Endometrial preparation with exogenous estrogen is a common practice in frozen embryo transfer (FET) cycles. The aim of this study was to compare the clinical outcome of oral estradiol valerate versus transdermal estrogen (17-β estradiol) gel in FET cycles. Materials and Methods: A prospective pilot study was carried out at a tertiary fertility clinic after Ethics Committee approval from January 2018 to December 2018. It included 103 infertile women who underwent FET cycles. Either oral estradiol valerate or transdermal 17-beta estradiol was used for endometrial preparation. Combination was used in case of breakthrough bleeding or if optimal endometrial thickness was not achieved. Baseline demographic parameters and details of the stimulation protocol and embryogenesis in fresh cycle were noted. In the FET cycle, the patient was seen on day 2 of menstrual cycle, where baseline ultrasound (USG), estradiol, and progesterone levels were done. If normal, the patients were given either oral or dermal preparation. The patient was seen again on day 9 for endometrial thickness and if required again after 2 days till endometrial thickness was 9 mm. If optimal endometrial thickness was not achieved or there was breakthrough bleeding, combination of both oral and dermal preparation was used. Once the endometrial thickness was 9 mm or more, progesterone was started, and ET was done on day 5. On the day of progesterone initiation, endometrial thickness, endometrial volume by 3D, and Doppler indices [pulsatility index (PI), resistance index (RI), peak systolic velocity (PSV)] were noted. The primary outcome of the study was clinical pregnancy rate (CPR) and live birth rate (LBR). Results: There was no statistical difference in any of the demographic parameters in groups A and B. In group C, the pregnant patients were younger with higher body mass index and follicle-stimulating hormone and lower anti-Mullerian hormone and antral follicle count when compared with those who did not conceive. Demographics of the fresh cycle did not show any significant difference in dose and duration of stimulation, fertilization, cleavage, and blastulation rate in group A. In group B, the fertilization rate was significantly higher in the pregnant group (0.001), whereas the other parameters were similar. In group C, the pregnant group required more dose and days of stimulation and had lower oocytes retrieved but had a higher blastulation rate. In the hormone replacement therapy (HRT) cycle, there was no difference in the mean duration of HRT in groups A and B but was significantly higher in group C when compared with group A. The CPR with oral estradiol valerate, transdermal gel, and combination therapy was 34.85%, 35%, and 52.94%, respectively. The LBR with oral estradiol valerate, transdermal gel, and combination therapy was 25.76%, 30%, and 47.06%, respectively. Though the CPR and LBR were higher in group C, it did not reach statistical significance and this could be due to small sample size. There was no difference in the abortion rate (oral 7.58%, gel 5%, combination 5.88%) between the three groups. The implantation rate (oral 26%, gel 25.8%, combination 29.03%) in the three groups was also similar. There was also no statistical difference in the endometrial thickness, volume, and blood flow between the three groups. The cut-off values for Doppler indices for a positive pregnancy were as follows: Group A—PSV: >8.7, RI: <0.99, PI: >1.54; Group B—PSV: >5, RI: <0.72, PI: >2.1; Group C—PSV: >5.6, RI: <0.64, PI: >1.29. Conclusion: Both the oral estradiol valerate and transdermal 17-beta estradiol were equally effective for optimal outcome in an FET cycle in HRT. Those not responding to single preparation may benefit from combination therapy. Transdermal 17-beta estradiol gel may be of use in those patients who have breakthrough bleeding with oral preparation which may be due to hepatic bypass effect.
Keywords: Estradiol valerate, frozen embryo transfer (FET) cycle, hormone replacement therapy (HRT), live birth rate, transdermal 17-beta estradiol
|How to cite this article:|
Patil M, Venkatappa KG, Patil M. Comparison of art outcome in frozen embryo transfer cycle using oral estradiol valerate and estradiol transdermal gel. Onco Fertil J 2021;4:14-26
|How to cite this URL:|
Patil M, Venkatappa KG, Patil M. Comparison of art outcome in frozen embryo transfer cycle using oral estradiol valerate and estradiol transdermal gel. Onco Fertil J [serial online] 2021 [cited 2022 Jun 26];4:14-26. Available from: https://www.tofjonline.org/text.asp?2021/4/1/14/332640
| Introduction|| |
More efficient cryopreservation and reassuring safety data, have progressively increased the use of frozen embryo transfer (FET). Since the first successful pregnancy after FET in 1983, FET has been designated as a principal component of assisted reproductive technology (ART). Initially, cryopreservation of embryos was done only for surplus embryos after FET. Today, the scope of cryopreservation is widened and is done to prevent ovarian hyperstimulation syndrome, especially when GnRH agonist is administered for trigger, increased use of preimplantation genetic testing, progesterone (P4) elevation on day of human chorionic gonadotropin, slow developing blastocysts, when random start or double stimulation is used, in poor responders with embryo pooling, personalized ET after endometrial receptivity array in women with recurrent implantation failure, fertility preservation in cancer patients and thin endometrium. It is also thought that FET for all can achieve higher PRs, although this remains a matter of debate.
The pregnancy outcome of FET is dependent on some clinical and embryological features such as the age of woman at the time of cryopreservation, cause of infertility, the technique of oocyte fertilization, the developmental phase of embryos at freezing, the embryo quality before and after freezing, the level of estradiol (E2) and endometrial thickness at the time of transfer, the degree of embryo damage after thawing, and the resumption of post-thaw blastomere divisions and blastocyst expansion. The recent data from USA have shown that live birth rates (LBRs) following FET are comparable and sometimes better than fresh cycles.
Adequate hormonal preparation of the endometrium is of utmost importance in frozen embryo replacement cycles to provide the optimal chances of pregnancy. FET can be performed in a natural cycle, a modified natural cycle (with ovulation triggering), a stimulated cycle using exogenous gonadotrophins or oral ovulation induction agents, and artificial or hormone replacement treatment (HRT) cycle using treatment with exogenous estrogen (E2) and progesterone (P4).,,, The disadvantage of natural cycle and modified natural cycle is that scheduling of the cycle is not possible as the transfer date is dictated by the patient’s ovulation and also cannot be offered to women with irregular cycles. Stimulated cycles are associated with a higher cost and more treatment-related side effects, especially with gonadotropins, and are usually offered as second line and in specific cases. HRT cycles are most commonly used in FET cycles worldwide as it allows easy scheduling. The overall PRs and LBRs are comparable with all protocols used for FET.,
Estrogens can be administered orally, vaginally, or by transdermal application. The oral route of estrogen is simple and well-tolerated, but the transdermal and vaginal route offers several advantages. With transdermal and vaginal route, there is a higher bioavailability as it bypasses the intestinal and hepatic metabolism, thus decreasing the risk of conversion of estradiol to estrone (E1) and estrone sulfate (E1S), with a more stable plasma concentration of estradiol.,,, The transdermal route is easy and more patient-compliant with low side effects. In addition, the transdermal route yields a most steady level of estrogen with physiological estradiol–estrone ratio, as it bypasses intestinal and biliary tracts., A good endometrial thickness and morphology with transdermal route confers a better endometrial receptivity compared with oral preparation. Earlier, the transdermal route was used extensively in HRT in menopausal patients.
Several drugs and various protocols of administration have been tried by several investigators in order to optimize implantation rate and consequently improve the success rates of FET procedures, but the best regimen is not known yet. Studies assessing different routes and compounds of estradiol in FET have been published already, but literature lacks enough surveys on transdermal estrogen application in reproductive medicine. With this background, the present prospective study was conducted to compare the clinical outcome of oral estrogen (oral estradiol valerate) and transdermal estrogen gel (transdermal 17-beta estradiol) in FET cycles. The main objective of the study was to determine whether there is any difference in the clinical pregnancy rate (CPR) or LBR between the oral and transdermal route. The secondary objective was to determine whether there is any difference in the outcome related to endometrial thickness, endometrial volume, blood flow, and Doppler indices and its correlation with pregnancy.
| Materials and methods|| |
A prospective study was carried at a tertiary fertility clinic after Ethics Committee approval from January 2018 to December 2018. It included 103 infertile women who underwent FET cycles in an HRT cycle and had given consent to participate in the study. FET cycles in natural cycle, modified natural cycles, and oocyte donation cycles were excluded. Either oral estradiol valerate or transdermal 17-beta estradiol was used for endometrial preparation. Combination was used in case of breakthrough bleeding or if optimal endometrial thickness is not achieved [Figure 1].
Participants have been allocated by a nurse to use either estradiol valerate tablet (group A, n = 81) or transdermal gel (group B, n = 22) according to a computer-generated randomization list. Those cases in which optimal endometrial thickness was not achieved or had breakthrough bleeding (group A 15/81 and group B 2/22), a combination of estradiol valerate tablet and transdermal gel was used (group C = A + B, n = 17) [Figure 1]. Once the patient was assigned to one of the two treatments, it was not blinded for either the doctors or patients. Patients have participated in the study once only. The inclusion and exclusion criteria were as follows.
Women attending tertiary care clinic for a frozen embryo replacement cycle in HRT cycle;
Willing and able to give informed consent for participation in the study;
Age at original fresh IVF cycle <37 years;
At least two embryos frozen in storage;
First or second FET cycle.
Women with endometrial pathology such as intrauterine adhesions and sub-mucous myoma;
Women with history of endometritis or genital tuberculosis;
Coexisting medical illness including renal, cardiac, and liver disease;
Women for whom the study medication(s) is contraindicated or who have known allergic reactions to study medication(s);
Women who do not volunteer to participate in the study.
Baseline demographic parameters [Table 1] and details of the stimulation protocol and embryogenesis in fresh cycle [Table 2] were noted. In the FET cycle, the patient was seen on day 2 of menstrual cycle, where baseline ultrasound (USG), E2, and P4 levels were done. On day 2, if there was no cyst and E2< 50 pg/mL and P4 < 1 ng/mL, either oral estradiol valerate (Bayer Zydus Pharma) in the dose of 2 mg three times a day or transdermal 17-beta estradiol (gel) (Abbott) in the dose of 2.5 g gel containing 1.5 mg estradiol twice a day was given. We did not use GnRH agonist for downregulation of the cycles. The patient was seen again on day 9 for endometrial thickness and if required again after 2 days till endometrial thickness was 9 mm. In case of breakthrough bleeding or if optimal endometrial thickness is not achieved by day 11 or 12 of HRT, either estradiol valerate tablet or transdermal gel was added to the original medication given. Once the endometrial thickness was 9 mm or more, progesterone 100 mg (Gestone, Ferring Pharmaceutical Ltd) intramuscular was started, and ET was done on day 5. The day on which progesterone was started was considered as day 0. On the day of P4 initiation, endometrial thickness, endometrial volume by 3D, blood flow in endometrial zones, and Doppler indices [resistance index (RI), pulsatility index (PI), peak systolic velocity (PSV)] were taken. The ET was performed in operation room with cook catheter (COOK Medical, Ltd, Australia) under sterile conditions. The embryos were thawed depending on the stage of vitrification: if frozen at cleavage stage on day 3, they were cultured further to day 5 and if frozen on day 5, the embryos were thawed and cultured further for 6–8 h before ET to verify its survival and expansion. All ETS were performed by a single operator under USG guidance.
The primary outcome was CPR and LBR. Biochemical pregnancies were not included in the analysis. The secondary outcome parameters that were correlated with pregnancy outcome were endometrial thickness, endometrial volume by 3D, blood flow in endometrial zones, and Doppler indices in the three groups.
Statistical analys is was done using SPSS software (Statistical Package for the Social Sciences, version 19.0, SPSS Inc., Chicago, IL, USA). For descriptive statistics with a normal distribution, mean, frequency, percentage, and standard deviation were used. In inferential statistics, namely, independent t-test, correlation was used to compare and to correlate variables between the three groups. The level of significance used was P < 0.05.
| Results|| |
A total of 103 patients were included in the study. Eighty-one patients were randomized to the oral administration (pills) group and 22 to the transdermal administration (gel) group. Fifteen patients in the oral estradiol valerate group and two patients in the transdermal 17-beta estradiol (gel) group either had breakthrough bleeding or the endometrial response was not optimal. Breakthrough bleeding was more common in the oral estradiol valerate group and stopped after addition of 17-beta estradiol gel. In the primary 17-beta estradiol gel group, out of the 22 patients, only 2 had inadequate development of the endometrium and required addition of oral estradiol valerate.
There was no statistical difference in any of the demographic parameters in groups A and B [Table 1]. In group C, pregnant patients were younger with higher body mass index (BMI) and follicle-stimulating hormone (FSH) and lower anti-Mullerian hormone (AMH) and antral follicle count (AFC) compared with those who did not conceive [Table 1]. Demographics of the fresh cycle did not show any significant difference in dose and duration of stimulation, fertilization, cleavage, and blastulation rates in group A [Table 2]. In group B, the fertilization rate was significantly higher in the pregnant group (0.001), whereas the other parameters (dose and duration of stimulation, cleavage, and blastulation rates) did not show any difference. In group C, the pregnant group required more dose and days of stimulation, had lower oocytes retrieved but had a higher blastulation rate. In the HRT cycle, there was no difference in the mean duration of hormone replacement when group A was compared with B and group B was compared with group C [Table 3]. When group A was compared with C for the number of days HRT was administered, it was significantly higher in group C compared with group A in the non-pregnant group but not in the pregnant group [Table 3]. In the oral estradiol group (group A), 15 out of the 81 (18.52%) patients required addition of dermal preparation for breakthrough bleeding or thin endometrium of which 53.33% conceived. In contrast, in group B, only 2 out of 22 (9.09%) required addition of oral preparation and one patient conceived. Thus, the number of patients requiring addition of another route of administration was higher in the oral group when compared with the dermal group. In the oral estradiol valerate group, single embryo transfer (SET) was done in 32 (48%) patients and double embryo transfer (DET) in 34 (52%) patients. In the 17-beta estradiol gel group, SET was performed in 9 (45%) and DET in 11 (55%) patients, whereas in the combination group, SET was done in 3 (18%) and DET in 14 (72%) patients [Table 3]. There was no difference between the three groups with regard to PR when SET or DET was done [Table 3]. There was also no difference in the PR when SET was compared with DET, with P-value being 0.553 for group A and 1 for both groups B and C.
The CPR with oral estradiol valerate, transdermal gel, and combination therapy was 34.85%, 35%, and 52.94%, respectively. The LBR with oral estradiol valerate, transdermal gel, and combination therapy was 25.76%, 30%, and 47.06%, respectively. Though the CPR and LBR were higher in group C, it did not reach statistical significance and this could be due to small sample size. There was no statistically significant difference in the CPR and abortion rate between the three groups [Figure 2]. There was only one ectopic pregnancy and that was in group A. Although the implantation rate was higher in group C (A—26%, B—25.8%, and C—29.03%), it did not reach statistical significance.
There was no statistical difference in the endometrial thickness and volume between the three groups [Table 4] and [Table 5]. Maximum patients had an endometrial thickness between 8 and 12 mm and a volume between 2.5 and 5 mm3 [Tables 4] and . When the blood flow in three zones using 2D power Doppler was compared with PR for oral and dermal preparation, there was no statistical difference found [Table 6]. The sensitivity and specificity for the endometrial blood flow indices for the three groups are seen in[Figure 3]. The cut-off values for Doppler indices for a positive pregnancy were as follows: group A—PSV: >8.7, RI: <0.99, PI: >1.54; group B—PSV: >5, RI: <0.72, PI: >2.1; group C—PSV: >5.6, RI: <0.64, PI: >1.29 [Figure 3]. The cut-off value for PSV in the pregnant group was highest in group A and lowest in group B but did not reach statistical significance. In non-pregnant women of group C, the PSV was significantly lower when compared with group A but not with group B. There was also no statistical difference in PI between the three groups. When all three groups were compared for RI, group B had a significantly lower RI when compared with group A but no difference was seen in the values of RI when groups A and B were compared with group C [Table 7].
|Figure 3: Sensitivity and specificity of Doppler indices in the three groups|
Click here to view
| Discussion|| |
With the use of vitrification technique for cryopreservation, the number of FET IVF cycles is growing. Natural cycle has an advantage of using the endogenous steroids for endometrial preparation without exposing to the risks of exogenous hormones. But use of HRT for FET gives more flexibility and requires less monitoring compared with natural, modified natural, and stimulated cycles without compromising the reproductive outcome. HRT can be used with or without the use of GnRH agonists for downregulation and with similar results. Moreover, with the use of HRT, there is a significant reduction in the cancellation rates. However, the superiority of HRT cycle over natural cycles in terms of reproductive outcome has not been confirmed.
Estradiol for HRT can be administered via many routes: oral, transdermal, intramuscular, and vaginal. The oral route of administration is simple, well-tolerated, and has been extensively used and studied. Despite the oral route being extensively used, we are aware that oral estradiol valerate is metabolized both in the intestine and in the liver and is converted to estrone (E1) and estrone sulfate (E1S), which is a weaker estrogen when compared with E2, with lower binding affinity for estrogen receptors. With oral administration, the E1 levels are three to six times higher than those of E2. The serum estradiol levels decreased by 30% after oral estrogen supplementation due to first liver bypass, but this effect was not seen with transdermal preparations., One can circumvent first-pass hepatic metabolism by administration of estrogens via transdermal, intramuscular (IM), or vaginal route. The transdermal route gives stable steady-state levels of E2 and less of the transdermal-absorbed E2 is converted into E1, with E1/E2 ratios of 1–2. As transdermal absorption of E2 can be variable, it may be useful to monitor serum E2 levels, especially if an appropriate endometrial response is not achieved. Vaginal E2 administration results in high serum and endometrial levels of E2, and only a small fraction of the absorbed E2 is converted to E1.,,,, This gives both higher serum E2 levels and even higher (supraphysiologic) endometrial tissue levels, which can affect the endometrial receptivity. Therefore, in most cases, either the oral or transdermal route is used in a HRT cycle to achieve adequate endometrial proliferation and development. The vaginal E2 may be reserved for those cases in which optimal development of endometrium is not achieved with either oral or dermal preparation.
In our present study, we compared the oral versus transdermal route of estrogen administration. We used the transdermal gel and not the patches, which are not readily available in our country. The two groups A and B were similar in demographic factors (BMI, age, cause of infertility, basal FSH, luteinizing hormone, AMH, and AFC). In group C, the pregnant patients were younger with higher BMI and FSH and lower AMH and AFC when compared with groups A and B. Our results showed that there is no difference in the CPR and LBR when oral and transdermal preparations were compared for endometrial preparation for FET cycles. The CPR and LBR were higher in group C than in groups A and B. There was also no difference seen for the secondary outcome parameters, which included endometrial thickness and volume, blood flow in the endometrium, and blood flow indices except for RI.
Adequate hormonal preparation of the endometrium is of utmost importance in frozen embryo replacement cycles to provide an optimal chance of pregnancy. An endometrial thickness of more than 8 mm gives optimal outcome. In our study, neither of the three groups had any patient with endometrial thickness of less than 8 mm. El-Toukhy et al. reported significantly higher LBRs in cycles with an endometrial thickness between 9 and 14 mm when compared with 7–8 mm in FET cycles. The large retrospective cohort study of the Canadian ART registry included 18,942 FET cycles and found that CPR and LBR declined with each millimeter decrease below 7 mm. However, no comparisons were made between thicknesses ≥ 8 mm. In our study, maximum pregnancies in all three groups were achieved with an endometrial thickness of 8–12 mm. In our study, about 22.72% of the patients in group A had endometrial thickness between 12 and 14 mm and 4.5% in the same group had an endometrial thickness more than 14 mm. The PRs were not compromised in all three groups and were not statistically different from patients who had an endometrial thickness between 8 and 12 mm. More number of patients (18.52%) in the oral group needed addition of dermal preparation when compared with group B (9.09%), who required addition of oral preparation. None of the patients in group B or C had endometrial thickness greater than 12 mm. One randomized controlled trial (RCT) found that endometrial thickness was significantly higher with the use of transdermal estrogen when compared with oral treatment, whereas two other RCTs failed to find any significant difference in endometrial thickness between the two routes., Our study also did not find any difference in the endometrial thickness and volume between the three groups, although the endometrial thickness in 18 patients in the oral estradiol group was > 12 mm.
Several studies have already shown that the type of estrogen treatment does not influence the pregnancy outcomes in HRT FET cycles, although the quality of evidence is very low.,,,,,, Our study also did not show any difference in the CPR and LBR between oral and dermal use of estrogen for endometrial preparation in FET cycles. Thus different administration routes of estrogens could be used without significant differences in the reproductive outcomes. There was one study which also looked at the reproductive outcome when increasing or constant dose of estrogen was used. This study concluded that use of different doses of estrogen did not influence the outcome and patients preferred a constant dose as it involved simpler administration regimens and was less stressful. In our study, we kept the dose of estrogen constant to prevent any confounding factor from influencing the results, though in routine practice we do increase the dose of oral estradiol valerate from 6 to 8 mg in case optimal endometrial thickness is not obtained by day 12 of HRT.
Contart et al. demonstrated similar implantation and PRs with endometrial vascularity in four different zones as visualized by two power Doppler and concluded that the power Doppler grading system did not have any predictive value for occurrence of pregnancy. In our study also, we did not find any difference in the PRs when blood flow in the three zones was compared in each group as well as between the three groups.
As endometrial perfusion may be related to endometrial receptivity, monitoring the Doppler indices may be useful in making decisions about the timing of ER or cancellation of cycle. We conclude that Doppler USG may be useful in monitoring artificial cycles and in predicting uterine receptivity. There are not many studies that looked into the endometrial blood flow indices. Most studies published have studied uterine artery doppler dynamics. In a study by Ghosh et al., they found no difference in the blood flow parameters of RI, PSV, and PI. In our study, there was no difference in the RI, PI, and PSV between pregnant and non-pregnant women in groups A and C. In group B, there was no difference seen in PI and PSV, but RI was significantly lower in the pregnant group. There was no difference seen in RI, PI, and PSV between the three groups in women who did not conceive. In the pregnant group, there was no difference in PI and PSV when group A was compared with groups B and C and group B was compared with group C. RI was lower in group B when compared with group A but not group C in women who conceived. Today, the role of endometrial and sub-endometrial vascularity assessed by power Doppler USG in predicting pregnancy is still controversial and thus requires large RCTs. In our study, cut-off scores for PSV and PI for a positive pregnancy were similar, but RI was lowest in group B when compared with group A but no difference was seen when groups A and B were compared with group C.
Successful human reproduction is dependent on endometrial receptivity, which can be induced with exogenously administered E2 and P4 in a FET cycle apart from natural, modified natural, and stimulated cycles. One could use a variety of estrogen and progesterone regimens, doses, and routes of administration to achieve optimal endometrial thickness and receptivity. The estrogen is essential for both endometrial proliferation and the induction of P4 receptors. Initiation of progesterone results in architectural, morphological, cytochemical, molecular, and genetic changes in the endometrium to open the window of implantation. Thus appropriate endometrial preparation is of utmost importance in FET cycles for optimal reproductive outcome. For this choosing the appropriate estrogen preparation, its dose and route of administration are essential.
| Limitations and strengths|| |
The sample size could also be a limitation, because this is a small series of patients. Moreover, the number of patients in the dermal estrogen group was much less compared to the oral route of administration. Maybe, a larger sample size could show differences among pregnancy, miscarriage, and LBRs. Moreover, we did not evaluate the estrogen and progesterone levels in the two groups, which can influence the results.
Our clinical trial could be interesting for clinical practice: if response is not seen to one route of administration, one could combine two routes for optimal reproductive outcome without cancellation of cycle. We followed all patients until they gave birth, which enabled us to assess LBR as well as implantation and CPR.
| Conclusion|| |
Both the oral estradiol valerate and transdermal 17-beta estradiol were equally effective in our study for optimal endometrial development and FET outcome in HRT cycle. Patients not responding to single preparation may benefit from combination therapy. Transdermal 17-beta estradiol gel may be of use in those patients who have breakthrough bleeding with oral preparation which may be due to hepatic bypass effect.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
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[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7]