Double Stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes

Double Stimulations during the follicular and luteal phases of poor responders in IVF/ICSI programmes (Shanghai protocol) Kuang,Y; Reprod Biomed Online: 2014

Dr. Daiter’s summary of this research article
Target: women with poor ovarian response to COH for IVF, defined (Bologna Criteria, ESHRE) as at least 2 of the following 3 features (1) advanced maternal age or any other risk factor for poor ovarian response, (2) previous poor ovarian response, (3) abnormal ovarian reserve test.

Purpose: to examine the efficacy of luteal phase ovarian stimulation in patients with poor ovarian response after follicular phase stimulation

Study included women with at least 2 of the following criteria:

(1) aged >40 years or with a history of ovarian surgery;

(2) conventional COH and IVF with <3 oocytes retrieved;

(3) antral follicle count of <5 on CD 2-3 or basal FSH concentration between 10-19 IU/L

Exclusion criteria included:

(1) documented ovarian failure (basal FSH >20 IU/L) or no antral follicles;

(2) endometriosis grade 3 or higher;

(3) any contraindication to COH

Protocol included:

(1) CD 3  ultrasound and serum FSH;

(2) Clomiphene Citrate 25 mg/day cotreatment with Letrozole 2.5 mg/day starting on CD 3- Clomiphene Citrate was continued until the day prior to ovulation trigger and Letrozole was continued for only 4 days;

(3) HMG 150 IU every 2 days beginning on CD 6 (Fig  1 has HMG starting on day 6 of Clomiphene = CD 8);

(4) cycle monitoring with ultrasound and serum FSH, LH, E2, P4 starting CD 10 every 2-4 days;

(5) ovulation trigger with Triptorelin (Decapeptyl; Ferring GmbH Germany) 100 mcg along with a 2 day course of Ibuprofen Sustained Release Capsules (600 mg/day, Tianjin Glaxo Smith Kline Pharm, China) to prevent early ovulation when 1-2 x 18mm diameter follicles were present;

(6) oocyte retrieval 32-36 hours after GnRHa administration SPARING any 10mm follicles to be left for luteal stimulation;

(7) all highest quality 8 cell embryos (grade 1-2 using Cummins criteria) were cryopreserved by vitrification (cryotop carrier system used for vitrification and 15% (v/v) ethylene glycol, 15% (v/v) Dimethlysulphoxide, and 0.5M sucrose as cryoprotectant; for warming 1M, 0.5M and 0M sucrose solutions were used as cryoprotectants dilution step by step with all warming steps at room temperature except the initial warming step at 37C) on 3rd post retrieval day, other embryos were cultured to blastocyst, and only good quality blastocysts were cryopreserved by vitrification on 5th-6th post retrieval day;

(8) on day of retrieval or 1st post retrieval day an ultrasound is performed to determine if minimal criteria (at least 2 x 2-8mm antral follicles) for luteal stimulation is met and if so, then start HMG 225 IU/day with Letrozole 2.5 mg /day;

(9) monitoring with ultrasound and serum FSH, LH, E2, P4 starting 5-7 days after luteal stimulation start and continuing every 2-4 days;

(10) Letrozole discontinued when follicles reached 12mm diameter (given that large follicles have redundant FSH and LH receptors and good response to exogenous HMG);

(11) medroxyprogesterone acetate 10 mg/day started on stimulation day 12 if follicle size <14mm diameter to avoid menstruation at time of oocyte retrieval;

(12) when 3 x 18mm follicles or 1 x 20mm follicle present then ovulation triggered with Triptorelin 100 mcg along with a 2 day course of Ibuprofen (600mg/day);

(13) egg retrieval 36-38 hours after GnRHa trigger and embryos treated (cryopreserved by vitrification) using same criteria as described for follicular phase embryos;

(14) endometrial preparation as described in Kuang et al, 2013:

(15) embryo transfer in subsequent natural cycle with monitoring of follicle growth by ultrasound and bloodwork from CD 10 and when dominant follicle >16 mm + endometrial stipe >8 mm + E2 >150 pg/mL + P4 <1.0 ng/mL then (a) if LH <20 IU/L then HCG 10,000 IU at 21:00 with ET of 3 day old embryos arranged 5 days later (blastocysts transferred 7 days later), or (b) if LH >20 IU/L then HCG 10,000 in the same afternoon and the ET of 3 day old embryos arranged 4 days later (blastocysts transferred 6 days later),

(16) luteal support with Duphaston (Abbott Biologicals B.V., America) 40 mg/day beginning on 3rd day after HCG injection,

(17) if irregular menstrual cycles then (to stimulate mono-follicular growth) letrozole (2.5-5 mg/day) +/- HMG (75 IU/day) from CD 3-7, with monitoring using ultrasound and blood starting CD 10 and HCG (10,000 IU) then ET with criteria described above

If endometrial stripe was thin during FET cycle, then oral ethinylestradiol 75 mcg/day (25 mcg TID) from cycle day 3 onward.  Once the endometrial stripe was >8mm Femoston (Solvay Pharmaceuticals B.V.) 8 mg/day (2 yellow tablets twice a day, each tablet containing 2mg estradiol and 10mg dydrogesterone) along with vaginal progesterone capsules (200 mg twice a day) was started.  The FET (with maximum number of embryos transferred being 2 per patient) was determined on the third day after Femoston administration and P4 support was continued to 10 weeks EGA.

Of 38 women enrolled, 6 women did not complete luteal phase stimulation due to low antral follicle count or poor luteal response and 2 additional women dropped out of the study, 37/38 women had eggs retrieved in stage 1 and 29/30 had eggs retrieved in stage 2, cancellation rate (no embryos to freeze) was 20/38 (53%) in stage 1 and 13/30 (43%) in stage 2, 19/30 stage 2 women used Provera to postpone menstruation, 26 women had 1-6 viable embryos after double stimulation, no significant differences found in rate of mature eggs or fertilization rates or cleavage rates, or top quality embryos to freeze between stage 1 and stage 2, and no patients with moderate to severe OHSS, 21 women completed 23 FETs with an implantation rate of 37% (15/41) and a clinical pregnancy rate of 56%/FET (13/23) with similar implantation rates of embryos derived from stage 1 and stage 2.

Conclusion: double stimulation in the same menstrual cycle provided more opportunities to retrieve oocytes in poor responders, with the resulting embryos having similar developmental potential.

Dr. Daiter’s review of this research article
Dr. Yanping Kuang is the main founder and current (2016) director of the Department of Assisted Reproductive Medicine of Shanghai Nineth People’s Hospital affiliated with Shanghai Jiaotong University School of Medicine.  Dr. Kuang is a pioneer in mild stimulation and natural cycle IVF and he established a new approach of performing luteal-phase ovarian stimulation.

In this pilot study, 38 women at high risk for poor ovarian response to conventional controlled ovarian hyperstimulation (using high doses of gonadotropins) for IVF had their ovaries stimulated with a “milder” combination of oral and injectable fertility medications during the follicular phase of the cycle, eggs were retrieved, and then these women underwent a 2nd ovarian stimulation during the luteal phase of this same cycle with similar “mild” doses of medications and a second egg retrieval was performed.  All good quality embryos that resulted from this IVF cycle were cryopreserved  by vitrification and these embryos were transferred in a subsequent menstrual cycle.
It appears that most women were able to complete egg retrievals in both the follicular and the luteal phases of the cycle, but only 53% of the follicular phase embryos and 43% of the luteal phase embryos were of high enough quality to freeze.  21 of the 38 women (55%) were able to complete at least one frozen embryo transfer cycle with an implantation rate of 37% per embryo and a clinical pregnancy rate of 56% per transfer. Since the embryos derived from the two different phases of the menstrual cycle appeared to have very similar reproductive potential, then one can reasonably conclude that double stimulation within the same menstrual cycle should provide more reproductively competent embryos per cycle.  This is particularly valuable for “poor responders” where time is an important consideration.


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