Ever since the first child born in , assisted reproductive technology ART has emerged as one of the most significant and successful medical interventions contributing to approximately 0. Faddy et al. The successful cryopreservation of human embryos was first reported in using slow-cooling technique leading to the first live birth in [ 3 ]. These significant developments changed the course of in vitro fertilization IVF treatment and heralded further developments to follow in ART.
Eventually, the method of rapid cooling and thawing known as vitrification was introduced which bypassed the difficulties and drawbacks associated with slow cooling. A comprehensive world report on ART for by the International Committee for Monitoring Assisted Reproductive Technologies ICMART , noted that the change in clinical practice with reduced number of embryos transferred per attempt yielded favorable outcomes with a considerable decrease in the incidence of multiple births [ 4 ].
Frozen embryo transfer and blastocyst transfer have been performed more often and have been shown to improve the cumulative pregnancy rates for each patient while eliminating multiple pregnancies [ 5 ].
Performance of fresh embryo transfer was seen to decline from Frozen embryo transfer has improved neonatal outcomes and seemed to be associated with reduced ectopic pregnancy risk [ 6 ]. Moreover, with the advancements in vitrification techniques, FET provides temporal flexibility and allows the deferred use of all viable embryos obtained from a single egg collection.
These advancements are quite valuable to those at risk of ovarian hyperstimulation syndrome OHSS and those requiring genetic testing to detect chromosomal abnormalities. As a result of such increasing trends due to a change in clinical practice, the percentage of cycles requiring HRT is expected to be higher. Successful implantation is influenced by the intricate and synchronized crosstalk between good-quality embryos and a receptive endometrium.
This initial process is modulated by the spatial-temporal regulation of different hormones at the uterine and ovarian level [ 14 ], specifically by estrogen and progesterone. Using a mouse model, a study by Ma et al. The regulation of estrogen levels is essential to control uterine receptivity for implantation [ 15 , 16 ]. Endometrial thickness increases throughout the follicular phase under the influence of estrogen [ 17 ]. Following adequate estrogen priming of the endometrium, progesterone prepares the endometrium for implantation [ 18 ].
Estrogen enables contraction of spiral arteries resulting in hypoxia in the functional layers and promotes endometrial proliferation. Since exogenous administration of estrogen is required to increase the serum estrogen within a required range, it is important to be selective and understand the nature of such estrogen interventions.
The pharmacological and clinical similarities or dissimilarities need good quality clinical validations. The common forms in current use are estradiol valerate and micronized estrogens. One of them, estradiol valerate, has been regularly employed in IVF [ 20 , 21 ]. There is not enough literature to ascertain whether the different esters and salts of estradiol act differently and if any such differences translate into valid clinical significance.
Monitoring endometrial thickness in cycles using a HRT protocol provides the best model to study and compare the different estrogen compounds because the endometrium in these cycles is completely under the control of exogenously administered drugs [ 22 , 23 ]. The aim of our study is to analyzeretrospectively if oral estradiol hemihydrate and estradiol valerate are equally efficacious or dissimilar when used in a HRT protocol. Since we are comparing two different estrogen products, the strongest predictors of estrogenic activity, viz.
Secondary outcome measures included in the study are clinical pregnancy rate, abortion rate, live birth rate, and ectopic pregnancy. This study compares the clinical efficacy of two estrogen products in IVF treatment.
This is a retrospective study examining the treatment outcomes of HRT cycles in women during the period from January to December estradiol valerate group and from October to May estradiol hemihydrate group , at Nova IVF Fertility, Ahmedabad, India. Since the study was retrospective in nature, prior ethics approval was not sought.
All the participants had consented written informed to sharing of their treatment records and outcome before initiating treatment at the clinic, and patient data to produce this paper was used only after their consent for use of their data for research purposes was provided. Women suspected or diagnosed to have an endometrial pathology suspected adhesions, polyps, fibroids, or poor endometrium during HRT during endometrial preparation or history of poor endometrium were excluded from the study.
Measurement of endometrial thickness was done between the two echogenic borders of endometrium at the midsagittal plane. During the study period Jan 1st—Dec 31st, , all the recruited women were administered estradiol valerate for endometrial preparation. During the study period from 1st October to 31st May , all women were administered estradiol hemihydrate for endometrial preparation during HRT cycle. A transvaginal scan was performed for assessment of endometrial thickness. Once the endometrium was adequately prepared, serum progesterone levels were measured after the endometrial assessment.
A maximum of two blastocysts were transferred after 5 days of progesterone supplementation. Serum beta human chorionic gonadotropin B-hCG levels were measured 14 days after embryo transfer to confirm pregnancy. Since the objective of the study is to see if there were differences between the two estradiol products, 1 endometrial thickness and 2 IR in HRT cycles were chosen as primary outcome measures.
These two measures are directly linked to estrogen activity. Clinical pregnancy rate, abortion rate, ectopic pregnancy rate, and live birth rate were considered as secondary outcome measures. For the descriptive analyses, results were expressed for numerical data as , for categorical variables as number and percentage. The minimum and maximum values are also provided in some cases. The null hypothesis assumed was that the average effect of the two treatments with estradiol valerate or with estradiol hemihydrate is not different.
For the secondary outcome measures, statistical analysis using - test for difference in proportions was used and was significant. The demographic descriptions of treatment groups are given Tables 1 and 2. There were no significant differences between the two treatment groups. Table 2 lists the individual demographic variables for the groups classified based on the embryo transfer cycle. There was no significant difference in the variables among these groups.
A total of 3, embryo transfers using the HRT protocol, corresponding to 2, patients, during the study period were analyzed. Estrogenic preparation of the endometrium was achieved in all the three embryo transfer cycle categories with forms of estradiol formulations Table 1. This is a retrospective study, and the two-sample population were assessed for variability.
Demographic variables including age, partner age, body mass index BMI , and years of infertility were comparable between the two treatment groups receiving either estradiol valerate or estradiol hemihydrate Tables 1 and 2. The HRT treatment regimen was initiated on day 2 of the menstrual cycle by administering oral estrogen in the form of either estrogen valerate or hemihydrate.
In all the treatment groups after estrogen administration, there was an increase in the endometrial thickness Table 3. Irrespective of the different embryo transfer cycles, the two treatment groups receiving either estradiol hemihydrate or estradiol valerate displayed an adequate endometrial line thickness Table 3. The endometrial assessment was first performed after 10 days of estrogen initiation. Implantation rate IR , calculated as the proportion of gestational sacs observed on ultrasonography to the number of transferred embryos, for the two treatment groups is presented in Table 5.
IR for estradiol valerate versus estradiol hemihydrate in the thaw-self category was The statistical analysis of the test of proportions did not indicate any significant difference between the two treatment groups.
The pregnancy outcome was not statistically different between the two groups. Clinical pregnancy rate was comparable between the two groups Clinical abortion rate was about Occurrence of ectopic pregnancy events was negligible with only three in the estradiol valerate-treated frozen-thawed embryo transfer cycle and only one observed in the estradiol hemihydrate frozen-thawed using self-oocyte cycle.
The live birth rate LBR was similar between the two groups Table 6. There was no significant difference in the LBR between estradiol valerate and estradiol hemihydrate treatment groups Overall, the statistical analysis for difference in proportions did not indicate any difference between the two treatment groups irrespective of the embryo transfer protocols.
The advent of technological advancement, especially vitrification and changes implemented in the practice of ART, has seen significant trend towards increasing number of cycles having an embryo transfer using HRT. This also facilitates genetic testing of embryos, assists those at risk of OHSS, and has a role in fertility preservation [ 13 ]. Estrogen supplementation is a crucial and integral part of all HRT protocols. The three common forms of estrogen are estrone E1 , estradiol E2 , and estriol E3 [ 15 , 24 — 27 ].
Estrogen could be administered as natural estrogens, conjugated equine estrogen CEE , or synthetic estrogens. However, estradiol in the natural form has a disadvantage of poor bioavailability [ 28 ].
Oral estrogen medications owing to their ease of administration and rapid reversibility are usually preferred in HRT. With a prospect of improving the bioavailability and further enhance the clinical outcomes, alterations of physicochemical characteristics of estradiol have led to the development of varying esters or forms of estradiol.
Therefore, esters of estradiol or other synthetic estrogens with chemical variations having potential to offer pharmacological advantages have been regularly employed for the IVF process. Microcrystalline estradiol offers increased surface area and therefore expected to offer greater bioavailability: the smaller the crystal, the better the absorption. Crystals of estradiol hemihydrate contain minimum water and is a repeated stacked arrangement of two molecules of estradiol associated with one molecule of water.
Following dissolution, the water molecule does not have a pharmacological role. Estradiol hemihydrate is more hydrated than anhydrous estradiol and is more insoluble in water in comparison, which may result in slower absorption rates with specific formulations of the drug such as vaginal tablets.
For estrone, was 6. Estradiol valerate is an ester of the Chydroxy group of estradiol with valeric acid. This formulation prevents the usual metabolism of estradiol to estrone until hydrolysis has taken place.
Upon hydrolysis in the intestines to estradiol and valeric acid, the resulting estradiol is rapidly absorbed. In terms of indication, AUC area under the curve , dosing behavior, and adverse effects, there is no difference between both the molecules [ 32 ].
Accordingly, estradiol hemihydrate and the valerate are dose equivalent [ 33 ]. Although there are clear differences in the physicochemical properties of these formulations of estradiol, whether these translate into a clinically discernible difference is debatable.
A recent study comparing the estradiol levels according to dose and formulation in postmenopausal women using hormonal replacement therapy found similar serum estradiol levels with estradiol valerate and hemihydrate [ 34 ].
Our study, for the first time, compares two oral formulations of estradiol with varying physicochemical characteristics from the standpoint of clinical outcomes up to live birth rates. In this study, we have considered only those cycles with the HRT protocol. Our results indicate that treatments with either estradiol valerate or estradiol hemihydrate improved the endometrial receptivity, indicated by increase in endometrial thickness Tables 3 and 4.
The endometrial thickness achieved by both compounds is adequate though there is a significant increase of 0. Although statistically significant, the difference in endometrial thickness between the two treatment groups is minimal 0.
The implantation rate measured as the proportion of gestational sacs observed on sonography to the number of embryos transferred did not significantly differ between the two treatment groups Table 5. These primary results suggest that estradiol hemihydrate is not inferior to estradiol valerate in terms of efficacy. Recent studies by Vartanyan et al.
They also reported higher implantation rates in the transdermal hemihydrate group [ 36 ]. Further, there was no significant difference between the secondary outcomes including clinical pregnancy rate, abortion rate, and ectopic pregnancy.
Ultimately, the desired clinical outcome for the success of the treatment is the LBR. There was no difference observed in the LBR outcome of the treatments using these two compounds in all the three subgroups studied. We have not observed any adverse symptoms attributable to overdose of estradiol in any of our study subjects.
Although it is a retrospective real-life data analysis of the two different preparations of estradiol, this is the first study where the two oral estradiol compounds have been compared for their clinical effects across various treatments in ART involving HRT cycles. The results of this large study show that there is no significant difference between these two different forms of estradiol in terms of efficacy in endometrial preparation measured as endometrial thickness and the clinical outcomes measured as implantation rates, clinical pregnancy rates, abortion rates, and live birth rates [ 28 , 37 ].
Data is available on request from the authors. Please contact Dr. Parul Arora drparul20arora gmail. What is Known. There has been gradual and sustained increase in assisted reproductive technology ART cycles requiring hormone replacement therapy HRT due to improvements in stimulation protocols, introduction of vitrification, and changes in clinical practice. Estrogens have been used for successful endometrial preparations in HRT.
Due to the major concern with lower bioavailability, several formulations of estrogens have been developed. What is New. While there are esters and salt formulations of estrogen with varying physicochemical properties, this large-scale retrospective analysis reviews for the first time to our knowledge any potential clinical advantages of one over the other.
Specifically, we have compared for the first time oral estrogen valerate and estrogen hemihydrate in the context of endometrial preparation for various HRT treatment groups in in vitro fertilization IVF treatment.
We report that these two estradiol preparations are similar in our study. The authors declare that they have no conflict of interest. All authors declare no support, either financial or other activities, from any organization that could appear to have influenced the submitted work.
All the four authors contributed to the concept and design of the study, interpretation of the data, critical revision of the manuscript, and approval of the manuscript. Manish Banker and Dr. Parul Arora were involved in the data acquisition. Manish Banker, Dr. Parul Arora, and Dr. Jwal Banker were involved in the statistical analysis and drafting the manuscript.
This is an open access article distributed under the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Article of the Year Award: Outstanding research contributions of , as selected by our Chief Editors. Then, clinicians can do upward titration based on clinical response 3 , For a long time, CE 0. Generally, CE 0. However, 0. In addition to serum estradiol level, serum FSH level also has been used to address the relative potencies of estrogens. In the present study, however, serum FSH level did not differ significantly between 1 and 2 mg doses of estradiol Of interest, whereas the serum estradiol level was similar, serum FSH level was significantly higher in CE 0.
Since CE is a mixture of estrogens, effects of CE on serum FSH level might be different compared with estradiol, even in the similar serum estradiol level. Considering that associations between serum FSH levels and surrogate markers or clinical outcomes of several diseases have been demonstrated recently, further investigation might be needed to explain the difference in responses to MHT for serum FSH level and serum estradiol level.
Although EV 1 mg is equivalent to estradiol 0. It might result from a small number of subjects, and a further large-scale study is warranted to draw a clear conclusion. The present study has several strengths. First, this study was performed in a single center, and serum estradiol level was measured using the same kit. This allowed for direct comparisons of serum estradiol levels with different doses and formulations of estrogens.
Second, the present study included only young healthy postmenopausal women who are the main candidates for MHT. Pharmacokinetics of oral estrogens may differ between younger and older postmenopausal women due to decrease in liver and kidney function, cardiac output, pulmonary function, muscle mass, and body composition associated with aging 19 , Finally, we considered many variables that could affect serum estradiol level.
Age and body mass index were addressed, and women with a history of bilateral oophorectomy, premature ovarian insufficiency, known liver or kidney disease, or malignancy were excluded. Current smokers, heavy alcohol drinkers, and users of any medication that could affect serum estradiol level were also excluded from analyses.
However, our findings should be interpreted with caution. First, mass spectrometry, which can determine serum estradiol level more accurately, was not used in our study.
However, the aim of this study was to compare relative potencies of various regimens based on the same method for measurement, not to determine estradiol concentration exactly. Second, differences in serum estradiol level do not directly reflect differences in the effects of MHT. Indeed, potency of hormones is determined by interactions with receptors and response elements on the DNA and by intracellular concentration 23 , not solely by serum estradiol level.
Third, effects of CE might not absolutely depend on serum estradiol level, because CE is a mixture of estrogens and major components of CE are estrone sulfate and equilin sulfate. It also might be difficult to measure serum estradiol concentrations in CE users.
Fourth, pharmacokinetics of MHTs such as maximal peak or h change of serum estradiol concentrations are unknown, and serum estradiol level was measured at a single time point. In addition, only drugs available in our country were included, and our results could not be extrapolated to other doses, formulations, or administration routes of estrogens.
Finally, we did not consider type or dose of progestogen. However, progestogens do not affect the serum estradiol level This study suggests that mean serum estradiol level is not directly proportional to estrogen dose, and CE 0.
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The authors wish to gratefully acknowledge the biostatistics team of Samsung Biomedical Research Institute, Seoul, Korea, for assistance in the preparation of the article.
You can also search for this author in PubMed Google Scholar. Correspondence to Dong-Yun Lee.
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