Case Summary: Luteal-Phase Stimulation (LPS) in a Patient with Diminished Ovarian Reserve (DOR)

Patient Profile

A 43-year-old female (G1P0AB1) with diminished ovarian reserve underwent controlled ovarian stimulation (COS) using a long luteal-phase GnRH agonist protocol.

Treatment Protocol:

• Stimulation Protocol: Long luteal-phase GnRH agonist protocol.
• Downregulation: Achieved using the GnRH agonist, followed by controlled ovarian stimulation starting on day 3 of menstruation.
• Medications:
• 450 IU of highly purified human menopausal gonadotropin (HP-HMG) daily
• Synarel nasal spray

Treatment Progress:

• Day 5 of Stimulation: A single dominant follicle measuring 23 mm developed, followed by spontaneous ovulation (serum progesterone: 7 nmol/L).
• Ultrasound Findings: Small antral follicles visible.
• Decision to Proceed: The patient was counseled about continuing ovarian stimulation into the luteal phase, with all resulting embryos to be cryopreserved. She opted to proceed.

Ongoing Stimulation:

• The same medication regimen continued.
• Estradiol and progesterone levels progressively increased (see chart for detailed levels).
• Oocyte Maturation: Triggered with 250 mcg of recombinant hCG.
• Estradiol: 7429 pmol/L
• LH: 0.34 IU/L
• Progesterone: 10.8 nmol/L

Oocyte Retrieval:

• Performed 36 hours post-trigger, yielding 8 oocytes.
• 6 mature (MII) oocytes, 5 fertilized via ICSI.
• 3 good-quality embryos cryopreserved.

In summary:

A 43-year-old woman with DOR underwent controlled ovarian stimulation using a long luteal-phase GnRH agonist protocol. After early spontaneous ovulation during stimulation, she chose to continue with LPS. Eight oocytes were retrieved, six were mature, five fertilized via ICSI, and three good-quality embryos were cryopreserved. This case illustrates the feasibility of luteal-phase stimulation in long GnRH agonist protocols and supports the concept of multiple follicular waves within a single cycle.

 Discussion

Luteal-Phase Stimulation in GnRH Agonist Protocols

LPS traditionally used in GnRH antagonist protocols, is feasible in long GnRH agonist protocols. Initiating COS during the luteal phase leverages multiple follicular waves, optimizing oocyte yield in patients with DOR (Baerwald & Pierson, 2020; Sighinolfi et al., 2018; Vaiarelli et al., 2020). This case illustrates successful LPS following spontaneous ovulation.

Multiple Follicular Waves

Multiple follicular waves two in approximately two-thirds of women and three in one-third, challenge the traditional view of a single follicular cohort per cycle (Baerwald et al., 2003). This physiological pattern enables flexible stimulation timing, as seen in this case, where luteal-phase stimulation maximized oocyte retrieval in a poor responder (Baerwald & Pierson, 2020; Sighinolfi et al., 2018).

Clinical Validation

The patient’s response was monitored via ultrasound (23 mm dominant follicle, small antral follicles) and hormonal profiling (estradiol: 7429 pmol/L; progesterone: 10.8 nmol/L; LH: 0.34 IU/L). The retrieval of 8 oocytes, with 6 mature and 3 embryos cryopreserved, aligns with studies supporting LPS efficacy in DOR patients (Cimadomo et al., 2018; Vaiarelli et al., 2020).

Generalizability

While this case is specific to a 43-year-old with DOR, LPS is particularly relevant for poor responders and patients requiring urgent fertility preservation. Studies show LPS improves oocyte yield and live birth rates in DOR patients (Huang et al., 2018; Vaiarelli et al., 2020). Earlier gonadotropin initiation in LPS shortens stimulation duration and reduces gonadotropin use without compromising outcomes (Huang et al., 2022).

Success Rates and Long-Term Outcomes

LPS yields clinical pregnancy and live birth rates comparable to follicular phase stimulation (FPS) (Lu et al., 2021; Martinez et al., 2022; Wang et al., 2016). A meta-analysis found no significant differences in outcomes between LPS and FPS across 4,433 patients (Lu et al., 2021). LPS also produces a comparable or higher number of oocytes and blastocysts without compromising quality (Cimadomo et al., 2018; Martinez et al., 2022).

Protocol Optimization

Flexible stimulation timing and GnRH agonist luteal support optimize outcomes in poor responders. Double stimulation (follicular and luteal) increases cumulative live birth rates (Vaiarelli et al., 2020).

Patient Populations Benefiting from LPS

LPS benefits:

• Poor Responders: Higher oocyte yield and live birth rates (Cimadomo et al., 2018; Vaiarelli et al., 2020).
• Oncological Patients: Enables random-start stimulation for fertility preservation (Cimadomo et al., 2018).
• Normal Ovarian Reserve: Comparable outcomes to FPS (Wang et al., 2016).

Cost Implications

LPS requires higher gonadotropin doses (mean difference: 817 IU) and longer stimulation (1.1 days) than FPS (Boots et al., 2016). However, total costs are comparable to other protocols due to fewer cycle cancellations and similar outcomes (Zhao et al., 2023).

Conclusion

This case supports LPS as a viable strategy for DOR patients, leveraging multiple follicular waves to optimize oocyte yield. LPS offers comparable outcomes to FPS and is particularly beneficial for poor responders and oncological patients. Further studies are needed to validate these findings in larger cohorts.

References

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• Baerwald A, Pierson R. Ovarian follicular waves during the menstrual cycle: physiologic insights into novel approaches for ovarian stimulation. Fertil Steril. 2020;114(3):443-457. doi:10.1016/j.fertnstert.2020.07.008.
• Boots CE, Meister M, Cooper AR, Hardi A, Jungheim ES. Ovarian stimulation in the luteal phase: systematic review and meta-analysis. J Assist Reprod Genet. 2016;33(8):971-980. doi:10.1007/s10815-016-0721-5.
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