Luteal phase ovarian stimulation following oocyte retrieval: is it helpful for poor responders?

Luteal phase ovarian stimulation following oocyte retrieval: is it helpful for poor responders?  John Zhang (New Hope Fertility Center) Reprod Biol Endocrinol 2015

Dr. Daiter’s summary of this research article

Target: patients with poor ovarian response to COH with no oocytes retrieved at conventional IVF

Purpose: to report the social and scientific rationale for luteal phase ovarian stimulation following oocyte retrieval in the same cycle (double stimulation)

In cycles with very little follicular development, no oocytes are often retrieved despite apparently good follicle development on ultrasound exam, rise in estradiol concentration, and meticulous follicle aspiration with flushing.  The reasons may include poor ovarian response, ovulation disorders, errors in HCG administration, or premature ovulation.  Patient usually has tremendous stress when no eggs are retrieved.

Human folliculogenesis is not well understood, theories include

(1) traditional view: antral follicles are recruited only once per menstrual cycle during the late luteal phase (at luteal regression) of the prior cycle;

(2) antral follicles are continuously recruited to grow following ovulation and one follicle is generally selected to become the dominant follicle possible “by chance” following luteal regression; and

(3) multiple (two or more) waves of antral follicles develop during each menstrual cycle with only the final wave’s maturing follicles leading to ovulation during a natural cycle.

The wave theory is the basis for COH during the luteal phase of the cycle.  The reproductive quality of eggs retrieved during the luteal phase is undetermined, but some pregnancies have resulted.

Typical COH protocol for double stimulation cycle:

(1) cycle day 3-10 start and continue Clomiphene Citrate or Letrozole,

(2) cycle day 5-10 start and continue FSH/LH,

(3) cycle day 11 GnRHa or HCG trigger of ovulation (if/when lead follicle is 18mm),

(4) cycle day 13 egg retrieval #1,

(5) cycle day 20-25 (start 2-7 days after ER #1: when the lead follicle measures less than 13mm) restart and continue Clomiphene Citrate (25-100 mg/day) or Letrozole (2.5-5 mg/day),

(6) cycle day 22-25 (start 2 days after Clomid) restart and continue FSH/LH (75-150 IU/day),

(7) after 5 days of luteal stimulation, ultrasounds and BW to monitor egg development resumes,

(8) cycle day 26 (if/when lead follicle is 18mm) GnRHa (0.1 mg) or HCG trigger (5,000 IU) of ovulation,

(9) cycle day 28 egg retrieval #2,

(10) since endometrium is out of phase and medications likely result in poor uterine receptivity, all embryos are frozen for subsequent transfer

Conclusion: Double stimulation is promising for patients with poor ovarian response especially when conventional IVF has failed and time is of the essence.  Large cohort studies and CRTs are needed to further understand the benefits.

​​Dr. Daiter’s review of this research article
John J. Zhang is a pioneer in Reproductive Endocrinology and Infertility, including but not limited to the field of mini IVF and natural cycle IVF.
This article is theoretical, since no actual clinical study data is presented and discussed.  It does bring to our attention the potential utility of luteal phase ovarian stimulation using a protocol largely developed in Shanghai by Dr. Kuang (some of his work is presented in this collection of scholarly articles).  As Dr. Zhang notes, luteal phase stimulation may be particularly helpful with patients for which no eggs were retrieved following follicular phase stimulation and women where time is “of the essence.”


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