Luteal phase ovarian stimulation

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Luteal phase ovarian stimulation is feasible in producing competent oocytes in women undergoing in vitro fertilization/ICSI treatment, with optimal pregnancy outcomes in frozen thawed embryo transfer cycles Kuang, Y Fertility and Sterility 2013

Dr Daiter’s summary of this research article

Target: patients with relative contraindications to follicular phase COH and conventional IVF, including a history of/high risk of premature LH surge or ovarian hyper-stimulation syndrome.

Purpose: prospective cohort study to determine success of luteal phase COH and IVF

Inclusion  criteria included:

(1) women aged 20-38 years,

(2) BMI 18-30 kg/m2,

(3) spontaneous ovulation,

(4) tubal factor, male factor infertility, or unexplained infertility,

(5) already planning to undergo IVF

Spontaneous ovulation was defined by an elevated LH level in the urine, presence of collapsed follicles in an ultrasound exam, or elevated Progesterone concentration in serum to 2.0 ng/mL.

Exclusion criteria included:

(1) clinically significant systemic disease (eg., renal failure),

(2) documented ovarian failure or basal FSH >15 IU/L,

(3) endometriosis grade 3 or higher,

(4) prior unsuccessful IVF/ICSI treatment,

(5) contraindication to COH, and

(6) largest antral follicle with diameter >8mm 1-3 days after ovulation on ultrasound exam

Protocol included:

(1) contracepting during follicular phase of treatment cycle,

(2) detecting ovulation with LH ovulation predictor kit + serum P level + ultrasound,

(3) ultrasound 1-3 days after ovulation and then if antral follicles were all 8mm or less HMG started at 225 IU/day with Letrozole 2.5 mg/day,

(4) monitoring (weekly?) with ultrasound and bloodwork (FSH, LH, E2, P4),

(5) letrozole stopped when follicles reached 12 mm diameter,

(6) medroxyprogesterone acetate (Provera) 10 mg/day started on post ovulation day 12 if follicles were smaller than 14 mm diameter to avoid menstruation at egg retrieval,

(7) ovulation triggered with “triptorelin” (Decapeptyl, Ferring GmbH) 100 mcg when there were 3 x 18 mm follicles or 1 x 20 mm follicle,

(8) egg retrieval 32-26 hours after trigger shot,

(9) highest quality embryos frozen by vitrification on 3rd day after retrieval and others cultured to blastocyst (with only good morphology blastocysts frozen on 5th-6th day after retrieval),

(10) 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),

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

(12) 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 then ET with criteria described above

If endometrial stripe was thin during FET cycle, then oral ethinylestradiol 75 mcg/day from cycle day 3 onward.  Once the endometrial stripe was >8mm Femoston (Solvay Pharmaceuticals B.V.) 8 mg/day was started.  The FET was determined on the third day after Femoston administration and P4 support was continued to 8 weeks EGA.

Adding Letrozole to HMG stimulation shortened the duration of HMG stimulation from 20+ days to 10 +/-2 days.  Mean duration of Letrozole was 8 +/-2 days.  Letrozole may have additional importance since it inhibits aromatization of androgens to estrogens so that there should be little negative estrogenic feedback on the hypothalamus-pituitary and the intraovarian androgens may enhance early follicular development to improve IVF outcomes.

HMG was 225 IU/day, a fairly high dose, since there was a lack of information on the responsiveness of luteal follicles to HMG prior to this study.  Less HMG may be effective in future protocols.

All participants (242 women) succeeded in producing mature eggs, ranging from 1-44, with 94% of women having the highest quality embryos to cryopreserve.  The mean number of antral follicles prior to luteal stimulation was 11 +/- 6 follicles.  The mean number of mature eggs retrieved was 11 +/- 7 mature oocytes.  The clinical pregnancy rate was 56% and the implantation rate was 40%.

No cases of premature LH surge or moderate-severe OHSS were encountered.  No GnRHa was required during stimulation since luteal LH concentrations were very low and apparently there is no/very low risk of a spontaneous luteal LH surge.

Conclusion: ovarian stimulation in the luteal phase seems feasible.

​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 article, 242 women (aged 20-38 years) participated, all women succeeded in producing mature eggs during the luteal phase using both oral and injectable fertility medications (mean number of mature eggs retrieved was 11 +/- 7), the clinical pregnancy rate was 56%, and the implantation rate was 40% per embryo.  There were few complications, with no cases of premature LH surge or moderate-severe ovarian hyperstimulation syndrome.  These cycles cryopreserve via vitrification all embryos and replace the embryos in a subsequent natural cycle.

This study seems to present a very effective protocol for retrieving mature eggs and transferring high quality embryos from women with a high risk for ovarian hyperstimulation syndrome (such as women with PCOS).

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