Estrogen and progesterone levels at frozen embryo transfer

Frozen Embryo Transfer Using Hormone Replacement: A Step-by-Step Guide

For patients with irregular cycles or ovulation disorders, and for patients who need to plan their therapy around time constraints, we can create an artificial menstrual cycle for FET. This involves treatment with an oral estrogen medication and progesterone (usually administered vaginally). This treatment is well established. Pregnancy rates are equivalent when compared to natural cycle FET. We sometimes recommend a trial (practice) cycle before the actual FET cycle so we can perform an endometrial biopsy to ensure that the medication dosages produce the proper development of the uterine lining. In addition, if you have been pregnant, we recommend a repeat uterine measurement before FET. If you have never had an endometrial biopsy to evaluate the development of the lining of the uterine cavity or if it has been longer than a year or if you have risk factors for uterine structural abnormalities, we will recommend a uterine cavity evaluation prior to FET, either with a saline infusion sonohystogram, office hysteroscopy or a hysterosalpingogram. The steps involved in FET with hormone replacement include:

FET Cycle

1. Hormone therapy (Estrace® and progesterone)
2. Embryo transfer
3. Hormonal studies and pregnancy test
4. Follow-up consultation

Step 1 - Estrogen Therapy

It is important that you start estrogen therapy on the first day of your period. A dose of estrogen is usually administered for 14 days, although shorter or longer cycles may be used, Estrace® is the most common form of estrogen we use. This is a pill containing 2 mg of estradiol, the same hormone produced by the ovaries. We will have you take one pill twice a day for about 14 days. After about 14 days of Estrace®, (your physician may vary the dose or duration of therapy) progesterone is added. This may be administered vaginally or as an intramuscular injection. Estrace® and progesterone are continued until the day of the pregnancy test (usually 12 days after embryo transfer). If the test is positive, these medications may be continued for several weeks. Depending upon the individual physician’s protocol you may also be treated with oral medications such as methylprednisolone and doxycycline prior to the transfer.

Step 2 - Embryo Transfer

Embryo transfer is usually performed on the third to fifth day of progesterone therapy. As with natural cycle FET, embryos are thawed on the morning of the scheduled frozen embryo transfer. In our laboratory, approximately 60-70 percent of embryos survive cryopreservation and thawing. We usually transfer 1 to 2 embryos during each FET cycle. However, this number is flexible, and your physician will discuss this issue with you. Excellent FET pregnancy rates occur in most cases with the transfer of one to two embryos, which also minimizes the risk of multiples. The transfer of more embryos may increase the likelihood of a multiple pregnancy, which increases the pregnancy risks for the woman and the fetuses. The actual embryo transfer itself is identical to the embryo transfer following in vitro fertilization-embryo transfer. Depending upon the physician’s protocol the embryo transfer may be accomplished under ultrasound guidance which will require the bladder to be full. A small plastic catheter is passed gently through the cervix into the uterus. After waiting for 1-2 minutes to allow any mild cramping to resolve, the embryos are deposited into the cavity along with a small amount of fluid. You will be discharged after resting for 20 minutes. No anesthesia is required for the embryo transfer.

Step 3 - Hormonal Studies - Pregnancy Test

We will usually perform a serum pregnancy test 12-14 days after the embryo transfer. If the test is positive, we may also measure serum progesterone. On occasion, we may repeat tests every two or three days. If the test is negative, hormone therapy is discontinued and a period usually begins in a few days. Near the end of that period, your physician may request a vaginal sonogram and/or serum progesterone level.

Step 4 - Follow-up Consultation

If the pregnancy test is positive, we will perform a vaginal sonogram about three weeks later. At this point, we are usually able to identify the number of embryos and can often see a heartbeat. The risk of pregnancy loss is low after this developmental milestone. If the procedure is unsuccessful, you should schedule a consultation with your physician. We will review the procedure and discuss further treatment options.

Journal Article

S Mackens,

1

Centre for Reproductive Medicine

,

Universitair Ziekenhuis Brussel, Vrije Universiteit Brussel

,

Laarbeeklaan 101-1090 Brussels

,

Belgium

Search for other works by this author on:

Revision received:

08 August 2017

Published:

08 September 2017

• PDF
• Split View
• • Article contents
  • Figures & tables
  • Video
  • Audio
  • Supplementary Data

• Cite

  Cite

  S Mackens, S Santos-Ribeiro, A van de Vijver, A Racca, L Van Landuyt, H Tournaye, C Blockeel, Frozen embryo transfer: a review on the optimal endometrial preparation and timing, Human Reproduction, Volume 32, Issue 11, November 2017, Pages 2234–2242, https://doi.org/10.1093/humrep/dex285

  Close

• • Email
  • Twitter
  • Facebook
  • More

Close

Navbar Search Filter Microsite Search Term Search

ABSTRACT

Introduction

More efficient cryopreservation strategies (i.e. vitrification) (Loutradi et al., 2008) and reassuring safety data (Belva et al., 2008; 2016) have progressively increased the use of frozen embryo transfer (FET) (European IVF-Monitoring Consortium (EIM) et al., 2016), namely beyond cases with a surplus amount of good quality embryos following an elective single embryo transfer policy (Peeraer et al., 2014). The use of an antagonist protocol with agonist triggering followed by a ‘freeze-all’ strategy and transfer of the embryo(s) in a subsequent FET cycle is a promising option with high live birth rates (Blockeel et al., 2016). Although elective embryo cryopreservation was mainly developed for patients with an increased risk of developing ovarian hyperstimulation syndrome (Devroey et al., 2011), its use has now been also extended to cycles with pre-implantation genetic diagnosis/screening, late-follicular progesterone elevation (Bosch et al., 2010; Roque et al., 2015; Healy et al., 2016) and embryo-endometrial asynchrony (Shapiro et al., 2008). Moreover, there is an ongoing debate whether frozen embryos transferred in a ‘more physiologic’ non-stimulated endometrium, may not only result in higher pregnancy rates (Shapiro et al., 2011; Roque et al., 2013), but also potentially decrease maternal and neonatal morbidity (Evans et al., 2014; Ishihara et al., 2014).

Materials and Methods

In the following review, we gather the available evidence in search for the best preparation protocol for FET. Literature on the topic was retrieved in PubMed and references from relevant articles were investigated until June 2017.

Results

FET preparation methods

FET preparation methods can largely be divided into artificial and natural cycles (NCs). In the artificial cycle, also referred to as a HRT cycle, endometrial proliferation and follicular growth suppression is achieved by estrogen supplementation. Meanwhile, in the NC, solely menstrual cycle monitoring is performed usually without any pharmacological intervention prior to ovulation.

Hormonal replacement treatment

Although originally developed to allow embryo transfers in recipients of donated oocytes, the HRT protocol has proven to be successful in the general population as well (Younis et al., 1996), thus extending its advantages in terms of minimal monitoring and easy scheduling to those performing IVF overall. However, the universal application of HRT cycles may have potential disadvantages including an increased cost, inconvenience and the potential adverse events associated with estrogen supplementation (e.g. increased thrombotic risk).

Estrogen supplementation

Most HRT protocols empirically opt to supplement estrogens for 2 weeks in an attempt to mimic the NC (Lutjen et al., 1984). However, it seems that such an extended period may be unnecessary and that 5–7 days may suffice for adequate endometrial proliferation (Navot et al., 1986). Limiting the length of the estrogen supplementation would be beneficial in terms of cost and time to pregnancy and deserves further attention in upcoming studies. Caution, however, is warranted, given that a higher miscarriage rate with shorter estrogen supplementation has also been previously reported (Borini et al., 2001). Conversely, if necessary, estrogen supplementation may also be safely prolonged if necessary without compromising pregnancy outcome (Soares et al., 2005).

Estrogens may be administered orally, vaginally and parentally (transdermal route) and both natural as well as synthetic estrogens may be used (Scott et al., 1991b). A meta-analysis concluded that the type of estrogen supplementation and route of administration had no effect on the success rates of FETs (Glujovsky et al., 2010). The conversion between different supplementation methods may be estimated as follows: 0.75 mg of micronised estradiol (oral administration) = 1.25 g of estradiol gel (transdermal administration) = 1 mg of estradiol valerate (oral or vaginal adminstration). The standard dose of estradiol valerate is 6 mg daily (Cobo et al., 2012), although different step up protocols—mimicking the rising estradiol levels of a NC—are also frequently used (Soares et al., 2005; Escribá et al., 2006; van de Vijver et al., 2014).

Exogenous mild ovarian stimulation instead of direct estrogen supplementation has been proposed aiming to increase the circulation of serum estrogen and potentially enhance endometrial receptivity. However, a recent systematic review concluded that, when compared to NC, ovarian stimulation with gonadotropins or clomiphene citrate did not seem to enhance live birth pregnancy rates (Yarali et al., 2016). Interestingly, when compared to HRT, gonadotropins or letrozole ovarian stimulation did seem to have a slightly increased chance for live birth. However, until well-designed prospective studies are performed, no definitive recommendation on the use of ovarian stimulation during FET can be made.

Monitoring during estrogen supplementation

In daily clinical practice, an ultrasound scan is usually planned following an initial period of estrogen priming in order to measure endometrial thickness and exclude the presence of a pre-ovulatory follicle, corpus luteum or luteinized endometrium prior to starting progesterone supplementation. The optimal endometrial thickness in HRT FET cycles has been described to be between 9 and 14 mm (El-Toukhy et al., 2008). Conversely, given that a previous meta-analysis has associated endometrial thickness ≤ 7 mm in fresh IVF cycles with a lower chance of pregnancy, this cut-off value is generally extrapolated to FET as well; however, the actual value of this arbitrary cut-off and whether the same limit can be extrapolated to frozen cycles requires further research (Dain et al., 2013; Kasius et al., 2014).

There is limited information available regarding the need for endocrine monitoring during HRT. Specifically, late-follicular serum estradiol and luteinizing hormone (LH) do not seem to predict outcome (Remohi et al., 1997; Banz et al., 2002; Griesinger et al., 2007; Niu et al., 2008; Bocca et al., 2015). Serum progesterone assessments may be used to detect escape ovulation, an event which can be encountered in 1.9–7.4% of HRT FET cycles without pituitary suppression (Dal Prato et al., 2002; van de Vijver et al., 2014). However, given the low incidence, it is questionable whether this measurement significantly improves pregnancy outcome, definitely when additional preventive measures are taken to avoid follicular growth and escape ovulation (e.g. high dose of estrogen supplementation from Day 1 of the cycle onwards).

GnRH agonist

Besides the administration of estrogen, a GnRH agonist can be added to a HRT protocol in order to prevent spontaneous ovulation (Keltz et al., 1995). In one randomized controlled trial (RCT), the use of such an approach was associated with increased clinical pregnancy and live birth rates, mainly due to lower cycle cancellation rates (El-Toukhy et al., 2004). However, endocrine cycle monitoring was not performed in that study, and the incidence of premature ovulation was not reported. The results of this trial are also in contradiction with those of subsequent systematic reviews and meta-analyses, which failed to demonstrate any benefit in terms of clinical pregnancy and cancellation rates (Ghobara and Vandekerckhove, 2008; Glujovsky et al., 2010). More recently, another retrospective study also failed to show any benefit of the use of a GnRH agonist (van de Vijver et al., 2014). Conversely, HRT FET cycles without GnRH agonist co-treatment seem to be more patient-friendly given the avoidance of the cost and potential side effects associated with these drugs.

Progesterone supplementation

Once the proliferation of the endometrium with the administration of estrogens is considered sufficient, progesterone is initiated to promote the final phase of endometrial preparation prior to embryo transfer. An additional injection of hCG on the day of progesterone initiation showed no better implantation or pregnancy rates (Ben-Meir et al., 2010). Regarding progesterone supplementation itself, there is little agreement on the ideal route of administration and dose. Often, micronized progesterone is administered vaginally (Bourgain et al., 1990). When compared to intra-muscular (IM) injections, patients seem to prefer the vaginal route owing to its quick, easy and painless administration (Levine, 2000). However, there is no RCT comparing IM and vaginal routes in HRT FET cycles. Retrospective data are conflicting, being in favor of the IM route (Haddad et al., 2007; Kaser et al., 2012) or showing no significant differences in terms of outcome (Shapiro et al., 2014). A recent double-blinded placebo-controlled RCT demonstrated non-inferiority and a similar safety profile for the oral administration of dydrogesterone in fresh cycles (Tournaye et al., 2017). However, more data are needed to confirm the safety and efficacy of oral dydrogesterone in HRT FET. As for the optimal progesterone dose specifically in HRT FET cycles, one retrospective study concluded that doubling the dose of vaginal progesterone gel in patients with oligomenorrhoea significantly increased live birth rates (Alsbjerg et al., 2013).

The use of measuring serum progesterone during the luteal phase in HRT FET cycles requires further investigation as well. The currently available results are contradictory as progesterone levels >20 ng/ml (possibly due to an escape ovulation and subsequent embryo-endometrial asynchrony) on the day of transfer have been associated with decreased ongoing pregnancy and live birth rates (Kofinas et al., 2015), while an optimal mid-luteal progesterone range between 22 and 31 ng/ml has also been proposed (Yovich et al., 2015). The administration route and dose also needs to be taken into account when performing such endocrine monitoring. Furthermore, another potential confounding factor is intercourse during a FET cycle, since it has been shown that it significantly reduces serum progesterone levels in women administering vaginal progesterone gel (Merriam et al., 2015).

No consensus has been reached yet on when to stop progesterone administration following a positive pregnancy test in HRT FET. The estimated onset of placental steroidogenesis, the so-called luteoplacental shift, occurs during the fifth gestational week (Scott et al., 1991a). A meta-analysis has demonstrated that, following a fresh embryo transfer, progesterone can be discontinued once a positive pregnancy test is detected (Liu et al., 2012). However in HRT FET cycles, as no corpus luteum— and, hence, no endogenous progesterone production—is present, the best moment remains to be elucidated.

Natural cycle

In a NC FET, there is no medical intervention, except of endocrine and ultrasound monitoring during the proliferative phase, to schedule the transfer when the endometrium is synchronized to the developmental stage of the embryo. Although the advantage is the absence of estrogen supplementation, this protocol entails more frequent visits to the clinic, less cycle control and flexibility and holds a higher risk of cycle cancellation [up to 6% (Sathanandan et al., 1991)].

Proliferative phase monitoring

The starting point to assess embryo-endometrial synchronization is the ovulation of the dominant follicle, which in a NC can either be triggered exogenously (i.e. modified NC, in which ovulation is triggered by hCG as soon as a dominant follicle of e.g. >16 mm is observed) or by serial blood (or, albeit less accurately, urine) sampling until a LH peak is observed (i.e. true NC, in which ovulation occurs spontaneously). Although the serum hormone levels in such cases are often exhaustively assessed (Casper et al., 2016), the role of such endocrine monitoring in addition to the usual ultrasound monitoring is a subject of much debate in both true and modified NC FETs (Groenewoud et al., 2012, 2017; Lee et al., 2014). Furthermore, the definition of what constitutes an LH surge is not unanimous. Historically, an LH surge has been described as an increase of the level of LH beyond 180% of the mean level observed in the previous 24 h (Frydman et al., 1982). In a clinical setting, however, varying definitions are used, including a concentration of 180% above the latest serum value available in that patient with a continued rise thereafter (Testart et al., 1981) to a level of 10 IU/l or more (Groenewoud et al., 2017).

Regarding endometrial thickness, the optimal threshold for NC FET remains unknown and the extrapolation of findings in fresh and HRT FET cycles should also be approached with caution in this case given the lack of data.

Spontaneous versus triggered ovulation

Two small RCTs revealed conflicting results: while the first (Weissman et al., 2011) did not find any significant differences between spontaneous and exogenously-triggered ovulation cycles, another (Fatemi et al., 2010) was interrupted prematurely due to the fact that an interim analysis revealed remarkably lower pregnancy rates in women who were administered hCG (14.3% versus 31.4%, respectively). One of the posited reasons for this difference was that the research groups had considered different timings to perform the embryo transfer (specifically, a 1-day difference between both studies). Second, it is possible that in the prematurely interrupted study there could have been a higher embryo-endometrial asynchrony in the modified NC study group as FET timing was the same for both arms, despite known differences in the timing of spontaneous versus triggered ovulation (Kosmas et al., 2007). Third, some women from the modified NC group in this same study already had an LH rise on the day of hCG administration which was associated with significantly lower pregnancy rates (suspected to be because of higher grade of embryo-endometrial asynchrony), while serum progesterone >1 ng/ml was an exclusion criterion in the study by Weissman et al. Finally, luteal phase support (LPS) was given only in the RCT performed by Weissman et al.

Three retrospective studies comparing true versus modified NC failed to demonstrate significant differences in clinical outcomes (Weissman et al., 2009; Chang et al., 2011; Tomás et al., 2012), however a recent large retrospective analysis did show a significant difference in clinical pregnancy rate (CPR) in favor of the true NC FET (without LPS) versus the modified NC FET (with LPS) even after adapting the transfer policy to the type of ovulation trigger and excluding patients that administered hCG despite a LH surge (46.9% versus 29.7%, P < 0.001) (Montagut et al., 2016). Thus, until further prospective studies comparing true with modified NC are performed, the question on what seems the best approach remains unanswered.

Progesterone supplementation

The prevalence of a luteal phase defect in NCs in normo-ovulatory subfertility patients has been historically described to be around 8% (Rosenberg et al., 1980), with mid-luteal serum progesterone levels <10 ng/ml being considered to reflect a NC luteal phase defect (Jordan et al., 1994).

The use of LPS in true NC FET is supported by one RCT (Bjuresten et al., 2011) where micronized vaginal progesterone (MVP) was initiated in the evening after FET. Our retrospective analysis (Montagut et al., 2016) did not show a significant difference in CPR when comparing true NC FET with or without MVP; on the contrary, there was a trend favouring one not to supplement (CPR 46.9% versus 39.9%). Here, however, MVP was started sooner, immediately on the day after the LH surge. Hence, the discrepancy between the studies might reflect the importance of the correct timing to start LPS. Another retrospective study investigating true NC FET LPS by two IM injections of hCG (the day of FET and 6 days later) failed to show any difference in outcome (Lee et al., 2013).

For modified NC FET, both prospective (Eftekhar et al., 2013) and retrospective (Kyrou et al., 2010) studies failed to show any difference in terms of pregnancy outcome with or without LPS. Due to prolonged half-life of hCG used as trigger, it makes biological sense that no LPS may be needed, although not all researchers agree (Kim et al., 2014).

Overall, the moment to start LPS in a NC FET is unclear although one may postulate that immediately after the LH surge or hCG trigger may be too soon and affect the window of implantation (WOI). Until further data are accrued on this subject it seems likely that different protocols will continue to be used in daily practice (Weissman et al., 2011; Tomás et al., 2012).

HRT or NC?

Retrospective data have left physicians with conflicting information in terms of clinical outcome (Ghobara and Vandekerckhove, 2008; Givens et al., 2009; Chang et al., 2011; Groenewoud et al., 2013; Guan et al., 2016). Recently, a large, multi-center, non-inferiority trial studying modified NC versus HRT has failed to show any significant difference in live birth, clinical or ongoing pregnancy rates (Groenewoud et al., 2016). Furthermore, the costs of both treatment modalities were comparable. However, this study did not assess the potential benefit of FET performed without exogenous ovulation triggering and concerns were raised due to the overall low success rate reported and the high miscarriage rates (Hreinsson et al., 2016). A previous retrospective analysis has shown a higher miscarriage rate for HRT compared to NC FET, although this could be related to the higher proportion of polycystic ovary syndrome patients in the HRT group (Tomás et al., 2012). Additionally, when comparing HRT FET to fresh embryo transfer, a 1.7-fold higher miscarriage rate has also been described for hormonal substitution FET per se (Veleva et al., 2008) and, in cases of repeated implantation failure endometrial transcriptome analysis favored NC over HRT (Altmäe et al., 2016). Current caution and further research is needed; a RCT comparing true NC versus HRT FET in an unbiased population is warranted.

FET timing

The synchronous interaction between a competent embryo and a receptive endometrium is a complex molecular process indispensable for successful implantation (Tabibzadeh, 1998). It is generally considered that once progesterone levels reach a critical threshold, they set into motion a well-timed and orderly secretory transformation of the endometrium leading to receptivity (Franasiak et al., 2016). This receptiveness for blastocyst attachment only occurs for a short period, the WOI (Psychoyos, 1973; Bergh and Navot, 1992). Decidualization, the secretory transformation that the endometrial stromal compartment undergoes to accommodate pregnancy, plays an important role in receptivity as it is thought to contribute to the active selection of embryos attempting implantation (Brosens et al., 2014). Hence, FET timing should assure that the blastocyst seeking implantation meets the optimal receptive/selective endometrial stage during the WOI. Many efforts have been made to identify biomarkers of endometrial receptivity (Coutifaris et al., 2004; Díaz-Gimeno et al., 2011; Edgell et al., 2013), but, so far, no clinically RCT validated test is available in daily practice.

Hormonal replacement treatment

The optimal duration of exposure to progesterone prior to embryo transfer has remained an elusive topic since the start of ART (Nawroth and Ludwig, 2005). When progesterone supplementation in HRT cycles is initiated 3 days before the cleavage embryo transfer, excellent pregnancy rates of up to 40.5% occur (Givens et al., 2009). A limited amount of evidence indicates that even a very short progesterone exposure may suffice to induce endometrial receptivity (Imbar and Hurwitz, 2004; Theodorou and Forman, 2012). Conversely, a study conducted in oocyte recipients showed a higher biochemical pregnancy rate when progesterone supplementation was longer (i.e. transfer of a Day 3 embryo on the 5th day of progesterone supplementation) (Escribá et al., 2006). In line with this, it has been suggested that the risk of early pregnancy loss increases when implantation takes place later in the WOI (Wilcox et al., 1999). A Cochrane Database Review concluded that starting progesterone at a time equivalent to the day of or the day after oocyte retrieval (OR) results in a significantly higher pregnancy rate than if progesterone is initiated a day earlier than the day equivalent to OR (Glujovsky et al., 2010). A recent RCT compared the outcomes of blastocyst transfer with either 5 or 7 days of progesterone supplementation and CPRs once more tended to be in favor of the shorter protocol, although not statistically significant (32.5% versus 27.6%) (van de Vijver et al., 2017). On the other hand, transferring Day 4 embryos on the third day of progesterone supplementation (a time being equivalent to 2 days after OR) was also deleterious (van de Vijver et al., 2016). Specifically, a higher risk of early pregnancy loss was seen, possibly caused by embryo-endometrial asynchrony or by an insufficient decidualization associated with only 3 days of progesterone administration. Another hypothesis is that, due to a later timing of the WOI, delayed embryos may have a higher chance of encountering a receptive endometrium, allowing them to implant but then being at increased risk for early pregnancy loss.

Taken together, it seems that the starting day of progesterone intake is optimal when equal to the theoretical day of OR or 1 day later (Fig. 1). Given that the WOI is limited in time, this detection of an optimal period is unsurprising and easily understandable; implantation is possible in a quite broad window, but only optimal in a narrower timeframe (Franasiak et al., 2016). Currently, most cleavage stage embryos are transferred around the 4th day of progesterone supplementation, whereas blastocysts are usually transferred on the 6th day of progesterone supplementation. This presumptive embryo transfer timing is in parallel with the timing of fresh embryo transfer after OR: the day of starting progesterone supplementation (considered as P + 0) is set equal to the theoretical day of OR, which is indeed also Day 0 from an embryonic point of view. This should be the preferred terminology as it emphasizes the synchronicity between endometrium and embryo. In a time when embryo transfer may soon become personalized according to a prior diagnostic intervention (e.g. Endometrial Receptivity Array, ERA®, Igenomix) (Díaz-Gimeno et al., 2011), the use of a standardized nomenclature is of utmost importance. Specifically, in repeated implantation failure patients, the WOI is suspected to be narrow and/or displaced (mostly delayed) (Ruiz-Alonso et al., 2013). Meanwhile, even in the general population, delayed endometrial development has been described in up to 25% of the population (Murray et al., 2004) and an increase in pregnancy rates associated with specific histological endometrial dating patterns and corresponding adjustments in progesterone exposure has been shown (Gomaa et al., 2015).

Figure 1

Embryo transfer timing for HRT preparation. tOR, theoretical oocyte retrieval, P, progesterone. In bold: studies with actual comparison of different embryo transfer days.

Natural cycle

In a NC, the WOI is posited to open 6 days after the postovulatory progesterone surge and thought to last ~2–4 days (LH + 7 to LH + 11) (Navot et al., 1991). When using the LH surge to plan embryo transfer one must take into account that the LH surge can occur over a period of 30 h (Acosta et al., 2000). Progesterone rises slightly to 1–3 ng/ml even 12 h to 3 days prior to ovulation, due to the LH-stimulated production by the peripheral granulosa cells (Hoff et al., 1983), with a steep increase in production following ovulation (3–10 ng/ml) due to production by the corpus luteum. The physiological and clinical importance of the pre-ovulatory progesterone elevation is yet to be determined, but is likely to contribute to the induction of the WOI in a NC. However, an accurate mirroring of this finely tuned and tightly regulated molecular system is probably difficult to reproduce artificially and one should acknowledge that all interventions might change the opening, closing, length and functionality of the WOI.

A difference in the timing of FET in true versus modified NC could be considered, as ovulation occurs 36–48 h after hCG administration but varies from 24 to 56 h after a spontaneous LH surge (Kosmas et al., 2007). For intra-uterine insemination, it has been shown that pregnancy rates are higher when it was performed 36–42 h after hCG trigger, but 18–24 h after spontaneous LH surge (Fuh et al., 1997; Robb et al., 2004). One could draw the parallel to FET and transfer 1-day earlier when a spontaneous LH surge is detected in the serum compared to when ovulation is triggered with hCG. When using urinary LH measurement, this difference in timing might not be beneficial, since a 1-day delay for the detection of peak hormone levels in the urine has been described (Cekan et al., 1986).

We suggest not to administer hCG when a spontaneous LH surge is detected, given the previously noted potential association with a detrimental outcome (Fatemi et al., 2010), even though it has not been confirmed in a recent post hoc analysis of the ANTARCTICA trial (Groenewoud et al., 2017). We hypothesize that hCG trigger, as well as additional LPS may impact on the natural course of the endometrium towards receptivity and might cause a shift in the WOI, leading to a more pronounced embryo-endometrial asynchrony. Further research is needed to test this hypothesis and to clearly state what should be the preferred policy in clinical practice.

FET timing proposal

We have observed that in studies assessing the optimal preparation for FET, embryo transfer timing is often described vaguely or confusingly. However, when there was no optimal synchronization, incorrect conclusions on how to best prepare FET could be drawn. We propose the following FET timing strategy and terminology, which could assist in the harmonization and comparability of clinical practice and future trials (Fig. 2):

• − In HRT:

  • On day (embryonic age + 1) of progesterone administration, annotated as P+ embryonic age (e.g. a Day 5 embryo on the 6th day of progesterone administration, annotated as P + 5).

• − In a modified NC (with hCG trigger):

  • On day (embryonic age + 2) after hCG injection (e.g. a Day 5 embryo on hCG + 7).

• − In a true NC (with spontaneous LH surge):

  • On day (embryonic age + 1) after LH surge (e.g. a Day 5 embryo on LH + 6).

Figure 2

Clinical practice proposal for embryo transfer timing in the different preparation methods. tOR, theoretical oocyte retrieval, E2, estradiol, P, progesterone, NC, natural cycle.

Specific attention is warranted in situations where embryo thawing is followed by further in vitro culture and embryonic development prior to transfer. In such cases, it is likely better to take into account the expected embryonic stage at the moment of transfer instead of the stage in which the embryo was cryopreserved (Cercas et al., 2012; Jin et al., 2013; van de Vijver et al., 2016). No studies have investigated whether the timing of FET should be different for embryos cryopreserved by slow-freezing or vitrification. However, an impact has been described of the method of freezing on post-thaw embryo development and metabolism (Balaban et al., 2008; Cercas et al., 2012) and further research into the potential clinical effects of such differences might optimize embryo-endometrial synchrony.

Conclusion and future perspectives

Although FET is increasingly used for multiple indications, the optimal preparation protocol is yet to be determined. At the basic research level, the evidence points toward the NC being superior to HRT. Hence, future research should compare both the pregnancy and neonatal outcomes between HRT and true NC FET. Furthermore, caution when using HRT is warranted since the rate of early pregnancy loss is alarmingly high in some reports.

In terms of embryo transfer timing, we propose to start progesterone intake on the theoretical day of oocyte retrieval in HRT and to perform blastocyst transfer at hCG + 7 or LH + 6 in modified or true NC, respectively. As individual timing of the WOI becomes increasingly substantiated by diagnostics tools, subsequent time corrections might offer further opportunities to increase FET success rates.

Authors’ roles

S.M. wrote the manuscript. S.S-.R. participated in the writing of the manuscript. A.V.D.V., A.R., L.V.L. and H.T. contributed to the interpretation and editing of the manuscript. C.B. is responsible for the concept and final revision of the manuscript.

Funding

S.M. is funded by the Research Fund of Flanders (FWO).

Conflict of interest

H.T. and C.B. report grants from Merck, Goodlife, Besins and Abbott during the conduct of the study.

References

Acosta

AA

Endometrial dating and determination of the window of implantation in healthy fertile women

.

Fertil Steril

2000

;

73

:

788

–

798

.

Alsbjerg

B

Increasing vaginal progesterone gel supplementation after frozen-thawed embryo transfer significantly increases the delivery rate

.

Reprod Biomed Online

2013

;

26

:

133

–

137

.

Altmäe

S

Endometrial transcriptome analysis indicates superiority of natural over artificial cycles in recurrent implantation failure patients undergoing frozen embryo transfer

.

Reprod Biomed Online

2016

;

32

:

597

–

613

.

Balaban

B

A randomized controlled study of human Day 3 embryo cryopreservation by slow freezing or vitrification: vitrification is associated with higher survival, metabolism and blastocyst formation

.

Hum Reprod

2008

;

23

:

1976

–

1982

.

Banz

C

Preparation of cycles for cryopreservation transfers using estradiol patches and Crinone 8% vaginal gel is effective and does not need any monitoring

.

Eur J Obstet Gynecol Reprod Biol

2002

;

103

:

43

–

47

.

Belva

F

Neonatal health including congenital malformation risk of 1072 children born after vitrified embryo transfer

.

Hum Reprod

2016

;

31

:

1610

–

1620

.

Belva

F

Neonatal outcome of 937 children born after transfer of cryopreserved embryos obtained by ICSI and IVF and comparison with outcome data of fresh ICSI and IVF cycles

.

Hum Reprod

2008

;

23

:

2227

–

2238

.

Ben-Meir

A

The benefit of human chorionic gonadotropin supplementation throughout the secretory phase of frozen-thawed embryo transfer cycles

.

Fertil Steril

2010

;

93

:

351

–

354

.

Bergh

PA

The impact of embryonic development and endometrial maturity on the timing of implantation

.

Fertil Steril

1992

;

58

:

537

–

542

.

Bjuresten

K

Luteal phase progesterone increases live birth rate after frozen embryo transfer

.

Fertil Steril

2011

;

95

:

534

–

537

.

Blockeel

C

A fresh look at the freeze-all protocol: a SWOT analysis

.

Hum Reprod

2016

;

31

:

491

–

497

.

Bocca

S

Impact of serum estradiol levels on the implantation rate of cleavage stage cryopreserved-thawed embryos transferred in programmed cycles with exogenous hormonal replacement

.

J Assist Reprod Genet

2015

;

32

:

395

–

400

.

Borini

A

Effect of duration of estradiol replacement on the outcome of oocyte donation

.

J Assist Reprod Genet

2001

;

18

:

185

–

190

.

Bosch

E

Circulating progesterone levels and ongoing pregnancy rates in controlled ovarian stimulation cycles for in vitro fertilization: analysis of over 4000 cycles

.

Hum Reprod

2010

;

25

:

2092

–

2100

.

Bourgain

C

Effects of natural progesterone on the morphology of the endometrium in patients with primary ovarian failure

.

Hum Reprod

1990

;

5

:

537

–

543

.

Brosens

JJ

Uterine selection of human embryos at implantation

.

Sci Rep

2014

;

4

:

3894

.

Casper

RF

Optimal endometrial preparation for frozen embryo transfer cycles: window of implantation and progesterone support

.

Fertil Steril

2016

;

105

:

867

–

872

.

Cekan

SZ

The prediction and/or detection of ovulation by means of urinary steroid assays

.

Contraception

1986

;

33

:

327

–

345

.

Cercas

R

Vitrification can modify embryo cleavage stage after warming. Should we change endometrial preparation?

J Assist Reprod Genet

2012

;

29

:

1363

–

1368

.

Chang

EM

Use of the natural cycle and vitrification thawed blastocyst transfer results in better in-vitro fertilization outcomes: cycle regimens of vitrification thawed blastocyst transfer

.

J Assist Reprod Genet

2011

;

28

:

369

–

374

.

Cobo

A

Outcomes of vitrified early cleavage-stage and blastocyst-stage embryos in a cryopreservation program: evaluation of 3,150 warming cycles

.

Fertil Steril

2012

;

98

:

1138

–

46.e1

.

Coutifaris

C

Histological dating of timed endometrial biopsy tissue is not related to fertility status

.

Fertil Steril

2004

;

82

:

1264

–

1272

.

Dain

L

Thin endometrium in donor oocyte recipients: enigma or obstacle for implantation?

Fertil Steril

2013

;

100

:

1289

–

1295

.

Dal Prato

L

Endometrial preparation for frozen-thawed embryo transfer with or without pretreatment with gonadotropin-releasing hormone agonist

.

Fertil Steril

2002

;

77

:

956

–

960

.

Devroey

P

An OHSS-Free Clinic by segmentation of IVF treatment

.

Hum Reprod

2011

;

26

:

2593

–

2597

.

Díaz-Gimeno

P

A genomic diagnostic tool for human endometrial receptivity based on the transcriptomic signature

.

Fertil Steril

2011

;

95

:

50–60–60.e1

–

15

.

Edgell

TA

Assessing receptivity in the endometrium: the need for a rapid, non-invasive test

.

Reprod Biomed Online

2013

;

27

:

486

–

496

.

Eftekhar

M

Effect of progesterone supplementation on natural frozen-thawed embryo transfer cycles: a randomized controlled trial

.

Int J Fertil Steril

2013

;

7

:

13

–

20

.

El-Toukhy

T

The relationship between endometrial thickness and outcome of medicated frozen embryo replacement cycles

.

Fertil Steril

2008

;

89

:

832

–

839

.

El-Toukhy

T

Pituitary suppression in ultrasound-monitored frozen embryo replacement cycles. A randomised study

.

Hum Reprod

2004

;

19

:

874

–

879

.

Escribá

M-J

Delaying the initiation of progesterone supplementation until the day of fertilization does not compromise cycle outcome in patients receiving donated oocytes: a randomized study

.

Fertil Steril

2006

;

86

:

92

–

97

.

European IVF-Monitoring Consortium (EIM), European Society of Human Reproduction and Embryology (ESHRE)

Assisted reproductive technology in Europe, 2011: results generated from European registers by ESHRE

.

Hum Reprod

2016

;

31

:

233

–

248

.

Evans

J

Fresh versus frozen embryo transfer: backing clinical decisions with scientific and clinical evidence

.

Hum Reprod Update

2014

;

20

:

808

–

821

.

Fatemi

HM

Cryopreserved-thawed human embryo transfer: spontaneous natural cycle is superior to human chorionic gonadotropin-induced natural cycle

.

Fertil Steril

2010

;

94

:

2054

–

2058

.

Franasiak

JM

Both slowly developing embryos and a variable pace of luteal endometrial progression may conspire to prevent normal birth in spite of a capable embryo

.

Fertil Steril

2016

;

105

:

861

–

866

.

Frydman

R

[Prediction of ovulation]

.

J Gynecol Obstet Biol Reprod (Paris)

1982

;

11

:

793

–

799

.

Fuh

KW

Intrauterine insemination: effect of the temporal relationship between the luteinizing hormone surge, human chorionic gonadotrophin administration and insemination on pregnancy rates

.

Hum Reprod

1997

;

12

:

2162

–

2166

.

Ghobara

T

Cycle regimens for frozen-thawed embryo transfer

.

Cochrane Database Syst Rev

2008

;1:art. no. CD003414.

Givens

CR

Outcomes of natural cycles versus programmed cycles for 1677 frozen-thawed embryo transfers

.

Reprod Biomed Online

2009

;

19

:

380

–

384

.

Glujovsky

D

Endometrial preparation for women undergoing embryo transfer with frozen embryos or embryos derived from donor oocytes

.

Cochrane Database Syst Rev

2010

;1:art. no. CD006359.

Gomaa

H

Non-synchronized endometrium and its correction in non-ovulatory cryopreserved embryo transfer cycles

.

Reprod Biomed Online

2015

;

30

:

378

–

384

.

Griesinger

G

Mid-cycle serum levels of endogenous LH are not associated with the likelihood of pregnancy in artificial frozen-thawed embryo transfer cycles without pituitary suppression

.

Hum Reprod

2007

;

22

:

2589

–

2593

.

Groenewoud

ER

What is the optimal means of preparing the endometrium in frozen-thawed embryo transfer cycles? A systematic review and meta-analysis

.

Hum Reprod Update

2013

;

19

:

458

–

470

.

Groenewoud

ER

A randomized controlled, non-inferiority trial of modified natural versus artificial cycle for cryo-thawed embryo transfer

.

Hum Reprod

2016

;

31

:

1483

–

1492

.

Groenewoud

ER

Spontaneous LH surges prior to HCG administration in unstimulated-cycle frozen-thawed embryo transfer do not influence pregnancy rates

.

Reprod Biomed Online

2012

;

24

:

191

–

196

.

Groenewoud

ER

ANTARCTICA Study Group

The effect of elevated progesterone levels before HCG triggering in modified natural cycle frozen-thawed embryo transfer cycles

.

Reprod Biomed Online

2017

;

34

:

546

–

554

.

Guan

Y

A modified natural cycle results in higher live birth rate in vitrified-thawed embryo transfer for women with regular menstruation

.

Syst Biol Reprod Med

2016

;

62

:

335

–

342

.

Haddad

G

Intramuscular route of progesterone administration increases pregnancy rates during non-downregulated frozen embryo transfer cycles

.

J Assist Reprod Genet

2007

;

24

:

467

–

470

.

Healy

MW

Does a frozen embryo transfer ameliorate the effect of elevated progesterone seen in fresh transfer cycles?

Fertil Steril

2016

;

105

:

93

–

9.e1

.

Hoff

JD

Hormonal dynamics at midcycle: a reevaluation

.

J Clin Endocrinol Metab

1983

;

57

:

792

–

796

.

Hreinsson

J

Perspectives on results from cryopreservation/thawing cycles

.

Hum Reprod

2016

;

31

:

2894

–

2894

.

Imbar

T

Synchronization between endometrial and embryonic age is not absolutely crucial for implantation

.

Fertil Steril

2004

;

82

:

472

–

474

.

Ishihara

O

Impact of frozen-thawed single-blastocyst transfer on maternal and neonatal outcome: an analysis of 277,042 single-embryo transfer cycles from 2008 to 2010 in Japan

.

Fertil Steril

2014

;

101

:

128

–

133

.

Jin

R

Extended culture of vitrified-warmed embryos in day-3 embryo transfer cycles: a randomized controlled pilot study

.

Reprod Biomed Online

2013

;

26

:

384

–

392

.

Jordan

J

Luteal phase defect: the sensitivity and specificity of diagnostic methods in common clinical use

.

Fertil Steril

1994

;

62

:

54

–

62

.

Kaser

DJ

Intramuscular progesterone versus 8% Crinone vaginal gel for luteal phase support for day 3 cryopreserved embryo transfer

.

Fertil Steril

2012

;

98

:

1464

–

1469

.

Kasius

A

Endometrial thickness and pregnancy rates after IVF: a systematic review and meta-analysis

.

Hum Reprod Update

2014

;

20

:

530

–

541

.

Keltz

MD

Baseline cyst formation after luteal phase gonadotropin-releasing hormone agonist administration is linked to poor in vitro fertilization outcome

.

Fertil Steril

1995

;

64

:

568

–

572

.

Kim

C-H

The effect of luteal phase progesterone supplementation on natural frozen-thawed embryo transfer cycles

.

Obstet Gynecol Sci

2014

;

57

:

291

–

296

.

Kofinas

JD

Serum progesterone levels greater than 20 ng/dl on day of embryo transfer are associated with lower live birth and higher pregnancy loss rates

.

J Assist Reprod Genet

2015

;

32

:

1395

–

1399

.

Kosmas

IP

Human chorionic gonadotropin administration vs. luteinizing monitoring for intrauterine insemination timing, after administration of clomiphene citrate: a meta-analysis

.

Fertil Steril

2007

;

87

:

607

–

612

.

Kyrou

D

Vaginal progesterone supplementation has no effect on ongoing pregnancy rate in hCG-induced natural frozen–thawed embryo transfer cycles

.

EJOG

2010

;

150

:

175

–

179

. Elsevier.

Lee

VCY

Effect of preovulatory progesterone elevation and duration of progesterone elevation on the pregnancy rate of frozen-thawed embryo transfer in natural cycles

.

Fertil Steril

2014

;

101

:

1288

–

1293

.

Lee

VCY

Luteal phase support does not improve the clinical pregnancy rate of natural cycle frozen-thawed embryo transfer: a retrospective analysis

.

Eur J Obstet Gynecol Reprod Biol

2013

;

169

:

50

–

53

.

Levine

H

Luteal support in IVF using the novel vaginal progesterone gel Crinone 8%: results of an open-label trial in 1184 women from 16 US centers

.

Fertil Steril

2000

;

74

:

836

–

837

.

Liu

X-R

The optimal duration of progesterone supplementation in pregnant women after IVF/ICSI: a meta-analysis

.

Reprod Biol Endocrinol

2012

;

10

:

107

.

Loutradi

KE

Cryopreservation of human embryos by vitrification or slow freezing: a systematic review and meta-analysis

.

Fertil Steril

2008

;

90

:

186

–

193

.

Lutjen

P

The establishment and maintenance of pregnancy using in vitro fertilization and embryo donation in a patient with primary ovarian failure

.

Nature

1984

;

307

:

174

–

175

.

Merriam

KS

Sexual absorption of vaginal progesterone: a randomized control trial

.

Int J Endocrinol

2015

;

2015

:

685281

–

685285

.

Montagut

M

Frozen-thawed embryo transfers in natural cycles with spontaneous or induced ovulation: the search for the best protocol continues

.

Hum Reprod

2016

;

31

:

2803

–

2810

.

Murray

MJ

A critical analysis of the accuracy, reproducibility, and clinical utility of histologic endometrial dating in fertile women

.

Fertil Steril

2004

;

81

:

1333

–

1343

.

Navot

D

Artificially induced endometrial cycles and establishment of pregnancies in the absence of ovaries

.

N Engl J Med

1986

;

314

:

806

–

811

.

Navot

D

The window of embryo transfer and the efficiency of human conception in vitro

.

Fertil Steril

1991

;

55

:

114

–

118

.

Nawroth

F

What is the ‘ideal’ duration of progesterone supplementation before the transfer of cryopreserved-thawed embryos in estrogen/progesterone replacement protocols?

Hum Reprod

2005

;

20

:

1127

–

1134

.

Niu

Z

Estrogen level monitoring in artificial frozen-thawed embryo transfer cycles using step-up regime without pituitary suppression: is it necessary?

J Exp Clin Assist Reprod

2008

;

5

:

4

.

Peeraer

K

The impact of legally restricted embryo transfer and reimbursement policy on cumulative delivery rate after treatment with assisted reproduction technology

.

Hum Reprod

2014

;

29

:

267

–

275

.

Psychoyos

A

Hormonal control of ovoimplantation

.

Vitam Horm

1973

;

31

:

201

–

256

.

Remohi

J

Endometrial thickness and serum oestradiol concentrations as predictors of outcome in oocyte donation

.

Hum Reprod

1997

;

12

:

2271

–

2276

.

Robb

PA

Timing of hCG administration does not affect pregnancy rates in couples undergoing intrauterine insemination using clomiphene citrate

.

J Natl Med Assoc

2004

;

96

:

1431

–

1433

.

Roque

M

Fresh embryo transfer versus frozen embryo transfer in in vitro fertilization cycles: a systematic review and meta-analysis

.

Fertil Steril

2013

;

99

:

156

–

162

.

Roque

M

Freeze-all policy: fresh vs. frozen-thawed embryo transfer

.

Fertil Steril

2015

;

103

:

1190

–

1193

.

Rosenberg

SM

The luteal phase defect: the relative frequency of, and encouraging response to, treatment with vaginal progesterone

.

Fertil Steril

1980

;

34

:

17

–

20

.

Ruiz-Alonso

M

The endometrial receptivity array for diagnosis and personalized embryo transfer as a treatment for patients with repeated implantation failure

.

Fertil Steril

2013

;

100

:

818

–

824

.

Sathanandan

M

Replacement of frozen - thawed embryos in artificial and natural cycles: a prospective semi-randomized study

.

Hum Reprod

1991

;

6

:

685

–

687

.

Scott

R

A human in vivo model for the luteoplacental shift

.

Fertil Steril

1991

a;

56

:

481

–

484

.

Scott

RT

Pharmacokinetics of percutaneous estradiol: a crossover study using a gel and a transdermal system in comparison with oral micronized estradiol

.

Obstet Gynecol

1991

b;

77

:

758

–

764

.

Shapiro

BS

Evidence of impaired endometrial receptivity after ovarian stimulation for in vitro fertilization: a prospective randomized trial comparing fresh and frozen-thawed embryo transfer in normal responders

.

Fertil Steril

2011

;

96

:

344

–

348

.

Shapiro

BS

Contrasting patterns in in vitro fertilization pregnancy rates among fresh autologous, fresh oocyte donor, and cryopreserved cycles with the use of day 5 or day 6 blastocysts may reflect differences in embryo-endometrium synchrony

.

Fertil Steril

2008

;

89

:

20

–

26

.

Shapiro

DB

Progesterone replacement with vaginal gel versus i.m. injection: cycle and pregnancy outcomes in IVF patients receiving vitrified blastocysts

.

Hum Reprod

2014

;

29

:

1706

–

1711

.

Soares

SR

Age and uterine receptiveness: predicting the outcome of oocyte donation cycles

.

J Clin Endocrinol Metab

2005

;

90

:

4399

–

4404

.

Tabibzadeh

S

Molecular control of the implantation window

.

Hum Reprod Update

1998

;

4

:

465

–

471

.

Testart

J

Interpretation of plasma luteinizing hormone assay for the collection of mature oocytes from women: definition of a luteinizing hormone surge-initiating rise

.

Fertil Steril

1981

;

36

:

50

–

54

.

Theodorou

E

Live birth after blastocyst transfer following only 2 days of progesterone administration in an agonadal oocyte recipient

.

Reprod Biomed Online

2012

;

25

:

355

–

357

.

Tomás

C

Pregnancy loss after frozen-embryo transfer--a comparison of three protocols

.

Fertil Steril

2012

;

98

:

1165

–

1169

.

Tournaye

H

A Phase III randomized controlled trial comparing the efficacy, safety and tolerability of oral dydrogesterone versus micronized vaginal progesterone for luteal support in in vitro fertilization

.

Hum Reprod

2017

;

32

:

1019

–

1027

.

van de Vijver

A

Vitrified-warmed blastocyst transfer on the 5th or 7th day of progesterone supplementation in an artificial cycle: a randomised controlled trial

.

Gynecol Endocrinol

2017

:

1

–

4

.

. [Epub ahead of print].

van de Vijver

A

Cryopreserved embryo transfer in an artificial cycle: is GnRH agonist down-regulation necessary?

Reprod Biomed Online

2014

;

29

:

588

–

594

.

van de Vijver

A

What is the optimal duration of progesterone administration before transferring a vitrified-warmed cleavage stage embryo? A randomized controlled trial

.

Hum Reprod

2016

;

31

:

1097

–

1104

.

Veleva

Z

High and low BMI increase the risk of miscarriage after IVF/ICSI and FET

.

Hum Reprod

2008

;

23

:

878

–

884

.

Weissman

A

Spontaneous ovulation versus HCG triggering for timing natural-cycle frozen-thawed embryo transfer: a randomized study

.

Reprod Biomed Online

2011

;

23

:

484

–

489

.

Weissman

A

What is the preferred method for timing natural cycle frozen-thawed embryo transfer?

Reprod Biomed Online

2009

;

19

:

66

–

71

.

Wilcox

AJ

Time of implantation of the conceptus and loss of pregnancy

.

N Engl J Med

1999

;

340

:

1796

–

1799

.

Yarali

H

Preparation of endometrium for frozen embryo replacement cycles: a systematic review and meta-analysis

.

J Assist Reprod Genet

2016

;

33

:

1287

–

1304

.

Younis

JS

Endometrial preparation: lessons from oocyte donation

.

Fertil Steril

1996

;

66

:

873

–

884

.

Yovich

JL

Mid-luteal serum progesterone concentrations govern implantation rates for cryopreserved embryo transfers conducted under hormone replacement

.

Reprod Biomed Online

2015

;

31

:

180

–

191

.

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail:

© The Author 2017. Published by Oxford University Press on behalf of the European Society of Human Reproduction and Embryology. All rights reserved. For Permissions, please e-mail:

Topic:

• pregnancy
• estrogen
• chorionic gonadotropin
• embryo stage 3
• embryo transfer
• newborn
• social role
• progesterone
• early stage of pregnancy
• funding
• oocyte retrieval
• transfer technique
• research funding

Citations

Views

Altmetric

Email alerts

More on this topic

Related articles in PubMed

Citing articles via

• Most Read

• Most Cited

More from Oxford Academic

What is a good progesterone level for frozen embryo transfer?

What is the ideal estrogen level for FET?

Can estrogen be too high for FET?

What should estradiol levels be for IVF transfer?