Advances in the Clinical Use of Luteal Phase Ovulation Regimens
Since 1998, when Rombauts first reported the success of luteal phase ovulation in obtaining mature oocytes, this protocol has become an important tool in reproductive medicine. Initially, it was used for emergency fertility preservation in patients with malignant tumors, and its rapid oocyte acquisition properties bought valuable time for cancer treatment. In recent years, as the proportion of patients with low ovarian reserve (DOR) and low ovarian response (POR) has risen and the efficacy of traditional ovulation regimens has been limited, luteal phase ovulation has become increasingly advantageous and continues to be used to optimize clinical outcomes through technological innovations.
I. Theoretical basis of luteal phase ovulation induction
According to traditional theory, there is only one follicular recruitment wave in a single menstrual cycle. However, Baerwald et al. revealed that there can be 2-3 follicular waves in a woman’s menstrual cycle, including the follicular ovulation wave and the luteal phase non-ovulation wave. The dominant follicle in the luteal phase is atretic due to inhibition of gonadotropin (Gn) secretion by the hyperestrogenic environment. Application of exogenous follicle stimulating hormone (FSH) reverses this atresia process, while high estrogen levels or exogenous trigger drugs in the luteal phase still induce luteinizing hormone (LH) peaks, which is the core mechanism of ovulation promotion in the luteal phase. The maturity of embryo freezing and thawing technology further guarantees the developmental potential of embryos obtained from this program.
Advantages of Clinical Application for Specific Population Groups
Patients with low ovarian response (POR) and low reserve (DOR)
Comparison of traditional regimens: Li et al. found that the luteal phase ovulation group had a significantly higher number of eggs (3.2±1.5 vs. 2.1±1.2), a higher rate of high-quality embryos (45% vs. 32%) than the microstimulation regimen, and a 40% reduction in cycle cancellation rate.
Breakthrough in dual-stimulation regimen: consecutive follicular phase + luteal phase ovulation induction in a single cycle resulted in a 60% increase in egg acquisition efficiency and an increase in cumulative live birth rate to 28% (vs. 15% in conventional regimen). The Italian Ubaldi team used a synchronized protocol with a GnRH antagonist to achieve an embryo aneuploidy rate of 65% with two ovulation boosts, significantly higher than with a single cycle protocol.
Urgent need for fertility preservation
Egg freezing in oncology patients can be completed in an average of only 9.3 days prior to chemotherapy, 5-7 days shorter than traditional protocols. meta-analysis showed that the luteal phase group had a better egg fertilization rate (78% vs. 70%) and embryo utilization (62% vs. 55%) than the follicular phase regimen, securing a critical window of time for anticancer treatment.
Tapping the Potential of the Normal Ovarian Function Population
Studies in the non-DOR population have shown a 45% improvement in the number of mature eggs per cycle with luteal phase ovulation (12.3±3.1) compared to microstimulation regimen (8.5±2.4), with a simultaneous improvement in the rate of high-quality embryos (58% vs. 49%), suggesting that it could be a strategy to improve the cumulative pregnancy rate.
Special application scenarios for PCOS patients
Despite the risk of ovarian hyperstimulation, the whole-embryo freezing strategy reduced the incidence of OHSS to 1.2% (8.5% in conventional protocols). Case reports have shown that the luteal phase remedial program resulted in 3-5 additional high-quality embryos for those who failed ovulation promotion during the follicular phase.
III. Optimization of key technical parameters
Precision of start-up timing
Studies have confirmed that optimal response is obtained by initiating 1-3 days after ovulation. Follicle diameter screening criteria are gradually refined:
Dominant zone: 82% developmental success rate for 5-12mm follicles, >12mm prone to luteinization, <5mm increased risk of atrophy. Synchronization strategy: synchronization of Gn initiation with follicular wave by ultrasound monitoring of follicular wave dynamics, reducing cycle cancellation rate from 25% to 12%. Drug dosing innovations Letrozole (LE) potentiation mechanism: by inhibiting aromatase, it increases the local androgen concentration in the ovary by 2-3 times and enhances FSH receptor expression in granulosa cells, with a 40% increase in the number of eggs acquired in DOR patients. GnRH antagonist innovation: Comparative studies showed that the incidence of early LH peaks was only 3.8% in the antagonist-naïve group (1.2% in the antagonist group), suggesting that endogenous progesterone (>15ng/ml) is sufficient to maintain pituitary suppression.
Trigger strategy upgrade
Double trigger advantage: the combined GnRH agonist + hCG regimen resulted in an increase in mature egg rate from 75% to 89% and an 18% increase in embryo aneuploidy rate.
Luteolysis prevention and control: Supplementation of dextroprogesterone (20 mg/d) after ovulation promotion in the luteal phase can control the incidence of luteal insufficiency to less than 8%.
IV. Safety and Economics Assessment
Offspring safety: 10-year follow-up data showed that the rate of birth defects in the offspring of luteal phase ovulation (2.1%) was not statistically different from that of natural pregnancy (2.3%), and the main risk factor was maternal age >40 years (OR=3.2).
COST-BENEFIT ANALYSIS: Although the single-cycle cost of the dual-stimulation regimen (8,500) was higher than that of the conventional regimen (6,200), the cumulative cost of live births was reduced by 38%, which is particularly suitable for time-sensitive patients.
V. Future Development Direction
Deepening of molecular mechanisms: single-cell sequencing found that the mitochondrial copy number of oocytes in luteal phase increased by 30% compared with follicular phase, suggesting differences in developmental potential [38].
Artificial intelligence assistance: a prediction model constructed based on clinical data from 1000 cases can predict the optimal timing of initiation 3 days in advance (AUC=0.87).
Novel drug development: a phase II trial of an oral GnRH antagonist (Elagolix) was shown to simplify the dosing regimen and reduce treatment costs by 30%.
Luteal phase ovulation regimens are evolving from complementary to mainstream technologies. With deeper mechanistic studies and the application of precision medicine tools, it is expected to provide a breakthrough solution for 35%-40% of patients with refractory infertility.