DUAL-PHASE GNRH-AGONIST STIMULATION IMPROVES OOCYTE YIELD IN POOR RESPONDERS

Patients with diminished ovarian reserve (DOR) represent one of the most challenging populations in assisted reproductive technology (ART).

The DuoStim protocol has emerged as a promising strategy for patients with DOR. Notably, conventional pituitary suppression with GnRH antagonists or progesterone may be insufficient, as these patients remain prone to premature LH surges and ovulation. In such cases, the use of low-dose gonadotropin-releasing hormone (GnRH) agonists can offer more reliable LH suppression.

The aim of our study was to evaluate the efficacy of a modified double-stimulation (duostim) protocol incorporating gonadotropin-releasing hormone (GnRH) agonists in patients with diminished ovarian reserve (DOR), and to compare the rates of mature (MII) oocytes and euploid blastocysts obtained from follicular-phase versus luteal-phase stimulation cycles performed within the same menstrual cycle for preimplantation genetic testing for aneuploidy (PGT-A).

The protocol involves two controlled ovarian stimulations (in the follicular and luteal phases) in patients with diminished ovarian reserve (DOR).
Stimulation is performed using gonadotropins combined with low-dose GnRH agonist (0.03–0.05 mg/mL) beginning on cycle day 2–3.
When follicles reach 18–19 mm, ovulation is triggered with human chorionic gonadotropin (hCG). Oocyte retrieval is performed 36 hours later. Beginning the day after the first retrieval, an identical stimulation protocol is initiated for the luteal phase.
A critical requirement is that follicular diameter at the start of the second stimulation must be <7 mm.

STIMULATION RESPONSE
Follicular-phase stimulation:
➢ Mature oocytes were retrieved in 55/62 patients (89%)
➢ Blastocyst development occurred in 37/55 patients (67%)
➢ Euploid embryos recommended for transfer were obtained in 22/37 cases (59%)
Luteal-phase stimulation:
➢ Mature oocytes were retrieved in 58/62 patients (93%)
➢ Blastocyst development occurred in 49/58 patients (84%)
➢ Euploid embryos recommended for transfer were obtained in 30/49 cases (61%)
OUTCOMES
Embryo transfer was performed in 39 patients (63%).
Clinical pregnancy was achieved in 25 cases (64%), including:
- Early pregnancy loss in 3 cases (12%)
- Ongoing pregnancies in 8 cases (32%)
- Live births in 14 cases (56%)

Patients in Bologna group 3 demonstrated significantly higher numbers of retrieved oocytes, MII oocytes, high-quality embryos, blastocyst formation, implantation rates, and hCG-positive cycles compared with group 4 (p<0.01).

➢The author-modified duostim protocol combined with low-dose GnRH agonists appears to prevent spontaneous ovulation and significantly improve the yield of mature oocytes and blastocysts in women with diminished ovarian reserve. This approach increases the likelihood of generating euploid embryos and achieving pregnancy in patients with a poor prognostic response to conventional stimulation.

➢The use of GnRH agonists in the Duostim protocol has a beneficial effect, potentially by promoting the release of endogenous FSH (a dual flare-up effect)

➢Administration of micro-doses of GnRH agonists mitigates excessive pituitary suppression and reduces their local inhibitory action on the ovaries

➢If no follicles are available for the second stimulation and the patient is under 37 years of age, embryo transfer in the stimulated cycle may be considered

➢This approach may reduce time-to-pregnancy in a challenging population.

➢Poor responders are not poor patients , they require smarter stimulation.