I would like to know the best preparation protocol of endometrium for frozen embryo transfer in normally ovulating women and women with irregular cycle.
Mohamed Farouk el Agamy, M.D.
Consultant of obstetric and gynecology
Mansoura General Hospital in Egypt.
Answer by Ariel Weissman
In normally ovulating women the protocol of choice should be based on detection of ovulation during a natural cycle. This can be done using US combined with blood (E2+P+/-LH) monitoring. The day of ovulation corresponds to the day of egg retrieval. If embryos were frozen at 72h, ovulation day+3 is the right time to transfer. It is questionable if luteal phase support (vaginal P) should be given, but it is usually given, starting from ovulation day. It is possible to shorten the monitoring by 1-2 day with the administration of hCG if the patient is ready (large follicle, good lining and bloods indicating that ovulation has not started yet). We published this method recently in RBM Online.
In patients with irregular cycles HRT is best used. Oral E2 (progynova or estrofem/estrace) is given 4-6 mg/day. Once the lining is greater than 7 mm vaginal P can be started. The day P is started is considered ovulation/opu day, and the time of thaw/transfer is determined accordingly.
If oral E2 is not sufficient, E2 can also be given through the vaginal or transdermal routes.
Rarely, ovulation induction can be used to build the lining by either clomiphene or gonadotropins.
Ariel Weissman, MD
Answer by Yanping Kuang
In patients with irregular cycles Letrozole is the first choice for endometrium preparation for FET in our unit. we used letrozole 2.5mg-5mg on cycle day 3 to cycle 7, in order to promote monofollicular development. then monitor the follicle growth by ultrosound and serum hormones, when the follicles reach the criteria of mature, hCG 10000IU is injected to triggering ovulation, then the embryos transfer are performed after 4 or 5 days if embryos were frozen at 72h. Blastocyst transfer is performed after 7 days. if the follicles growth is not ideal, mild stimulation (such as HMG 150 IU qod) is added when necessary.
our experiences are, for the patients with menstrual cycle more than 40 days, the dose of letrozole is 5mg qd for 5 days. for the patients with cycle 35-40 days, the dose of letrozole commonly use 5mg for 3 days. for the patients with cycle less than 28 days, the dose of letrozole is recommended 2.5mg for 3-5 days.
for the patients with thin endometrium or multiple ET failures, HRT is best used. Oral E2 (ethinyloestradiol) is given 75ug/day for 14-28 days. Once the lining is greater than 8 mm, Femonston (estace and dydrogesterone) 8mg/d can be started. The day femonston is started is considered ovulation/opu day, and the time of thaw/transfer is determined accordingly. If oral E2 is not sufficient, E2 can also be given through vaginal routes. Femonston (estrace) 1mg/d by vaginal route has good effects for the patients with thin endometrium.
for the patients can not bulid the lining with the above methods, we advise patients to perform office hysterscopy before FET. if the endometrium is present pale mucous and insufficiency bloold flow, docotors will scissor endometrium gently. Intrauterine scar tissue can be removed with hysteroscopy, intrauterine device will be placed for a few months to prevent further adhesion formation when necessary.
With the above methods, our FET have good clinical effects. the clinical pregnancy rate is always 50%, and the average implaning rate is 25-35%.
professor Yanping Kuang
Answer by Yanping Kuang
There are three keypoints in performing FET：
1. selecting proper embryos used for FET
which embryos are suitable for freezing ? the cleavaged embryos with grade I or II, and present more than 6 blastomeres at day 3 are the right kind. for the embryos with 4 blastomere, we would like to continue in vitro culture to reach the stage of 8 blastomere then perform vitrification cryopreservation. for the non-high quality embryos, we continue to culture them into blasocyst and select the valid blastocyst for cryopreservation. this step is important for settling the appropriate time for embryo transfer.
2. accurate synchronization of endometrium and embyos
Accurate synchronization of embryos and endometrium is the key of performing FET. we perform the synchronizing stratery of \"hCG priming\" rather than based on ovulation time. for the ovulation time calculated on LH level has a large margin of about 24 hours, while hCG injection time is easy to control when the dominant follicles reach the criteria of mature. our clinical data confirm the superiority of HCG priming than ovulation time. the commonly method is , when the follicle reach mature, hCG injection at 21:00 then after 5 days to transfer embryos of day 3. for the patients with the presence of spontanous LH surge, time of hCG injection advanced into afternoon then transfer embryos after 4 days.
3. sufficient luteal support
sufficient luteal support is a precondition for successful FET. for the patients with ovulation, luteal support is sufficient by oral Duphaston (40mg/d) and vaginal progesterone. progesterone injection 40mg/d or 60mg/d is used when necessary. for the patients with HRT, Femoston and vaginal progesterone both used for luteal support. progesterone injection 40mg/d or 60mg/d is used when necessary.
Answer by Qiuju Chen
Good endometrial lining is the ideal signs of sufficient estrogen in natural cycle. so if it is absent, we try to stimulate follicular growth mildly with letrozole (2.5-5mg for cycle day 3 to day 7) for the patients with regular cycles, then monitor the follicle and endometrium from day 10 onwards. If the follicles growth is not ideal, low dose of HMG is useful. when the follicular reach mature, it is better to schedule the ovulation time using hCG triggering than waiting spontaneous LH surge. The time of FET will calculate according to the embryos and ovulation time. most patients can have good endometrial lining using the mild stimulation methods. HRT is useful for patients with advanced age, no irregular menses or recurrent IVF failures. Hysteroscopy is recommended for the patients with intrauterine adhesion or other abnormal.
Dr. Qiuju Chen
Shanghai Ninth People's Hospital, Shanghai, China
Answer by Lois A. Salamonsen
I would urge all clinicians to consider the very detrimental effects of ovulation induction on the endometrium (see Review, Evans et al, Fresh vs Frozen embryo Transfer: Backing clinical decisions with scientific and clinical evidence. Human Reprod Update, December 2014. This review covers a lot of basic data. As a result of this I would urge that a fully natural cycle is considered first - over-stimulation with hormones, particularly the initial estrogen can result in too much proliferation and enhanced fluid in the cavity, with at present unknown effects on the differentiation stimulated by progesterone, that drives development of receptivity. Providing hCG prior to transfer makes the endometrium non-receptive to blastocyst hCG a few days later by down-regulation of the hCG receptor (Evans et al, Human Reproduction 2013, Too much of a good thing: experimental evidence suggests prolonged exposure to hCG is detrimental to endometrial receptivity.
Professor Lois A. Salamonsen PhD, FRANZCO(hon)
Head, Centre for Reproductive Health
MIMR-PHI Institute of Medical Research , Melbourne Australia