Luteal Phase Support in in vitro Fertilization at 2,800 Meters above Sea Level: Micronized Progesterone versus Combination with Dydrogesterone

Objective: To evaluate the effectiveness of luteal phase support with micronized progesterone alone versus micronized progesterone plus dydrogesterone in patients undergoing in vitro fertilization (IVF) at a human reproduction center located 2,800 meters above sea level.

Methods: Retrospective observational study conducted between July 2021 and January 2025 at Hospital Provida (Latacunga, Ecuador). A total of 113 patients with endometrial thickness ≥ 7 mm and serum progesterone < 1 ng/mL before embryo transfer were included. Group 1 received micronized vaginal progesterone 400 mg every 12 h; Group 2 received the same dose plus oral dydrogesterone 10 mg every 12 h. Primary outcomes were biochemical pregnancy (positive β-hCG, defined as ≥ 5 mIU/mL) and clinical pregnancy (fetal heartbeat).

Results: Of the total, 40 patients were assigned to Group 1 and 73 to Group 2. Mean age was 38.4 vs 37.7 years, with no significant baseline differences. Biochemical pregnancy rates were 62.5% (monotherapy) and 56.2% (combination), while clinical pregnancy rates were 60.0% and 57.5%, respectively (p > 0.05).

Conclusion: Luteal phase support with micronized progesterone alone showed a trend toward higher biochemical and clinical pregnancy rates compared with the combined therapy. These findings support the importance of individualizing luteal phase support strategies in IVF, particularly under physiologically challenging conditions such as high altitude.

Infertility affects a significant proportion of couples of reproductive age, with emotional, social, and economic implications. Common causes include ovulatory disorders, tubal alterations, endometrial dysfunctions, and male-related conditions.

Advances in assisted reproductive technologies over recent decades have allowed many couples to conceive, with in vitro fertilization (IVF) being one of the most effective methods. In IVF, the luteal phase plays a crucial role in embryo implantation and early pregnancy maintenance.

During this phase, progesterone is essential for transforming the endometrium into a receptive state, supporting embryo implantation and pregnancy development. However, in IVF cycles, especially those involving controlled ovarian stimulation, corpus luteum function may be impaired, requiring exogenous progestogen support.

Micronized progesterone, a natural steroid hormone, can be administered orally, vaginally, or intramuscularly. It binds to nuclear progesterone receptors (PR-A and PR-B), regulating gene transcription and inducing endometrial changes that prepare the uterus for implantation. It also exerts rapid non-genomic actions through membrane receptors and influences immune, neurological, and vascular systems.

At the molecular level, it regulates genes such as LIF (Leukemia Inhibitory Factor), VEGFa (angiogenesis), TGF-β (endometrial remodeling), and HOXA-10 (cellular differentiation).

Dydrogesterone, a synthetic progestogen, exhibits pharmacological properties similar to natural progesterone, with good oral tolerance and proven efficacy as luteal phase support. Its molecular structure gives it a high affinity for progesterone receptors, effective at lower doses, improving endometrial receptivity and implantation rates in IVF cycles.

This study aims to compare the effectiveness of luteal phase support with micronized progesterone alone versus its combination with dydrogesterone in IVF patients, contributing evidence to optimize therapeutic strategies toward personalized infertility management.

This retrospective observational study was conducted at Hospital Provida (Latacunga, Ecuador), located 2,800 meters above sea level, between July 2021 and January 2025. The study included women with an endometrial thickness ≥7 mm and serum progesterone <1 ng/mL before embryo transfer.

Group 1: Vaginal micronized progesterone 400 mg every 12 h.

Group 2: Vaginal micronized progesterone 400 mg every 12 h + oral dydrogesterone 10 mg every 12 h.

Embryo transfer was performed after 120 h of hormonal supplementation. Outcomes measured were biochemical pregnancy (β-hCG ≥ 5 mIU/mL) and clinical pregnancy (fetal heartbeat). Sociodemographic and clinical data, such as recipient age, BMI, and source of genetic material (donor oocyte, sperm, or embryo), were also recorded.

Statistical analysis: Continuous variables were expressed as mean ± SD and compared using Welch’s t-test; categorical variables were expressed as n (%) and compared using Pearson’s χ² (or Fisher’s exact test where appropriate). A p < 0.05 was considered statistically significant.

A total of 113 patients were included: 40 received micronized progesterone alone and 73 received the combined regimen. Mean ages were 38.4 vs 37.7 years, with no significant baseline differences. Clinical pregnancy rates were 60.0% vs 57.5%, and biochemical pregnancy rates were 62.5% vs 57.5%, with no statistically significant differences (p > 0.05).

In this high-altitude population, micronized progesterone alone showed pregnancy rates were numerically higher but not statistically significantly compared with the combination regimen. These findings differ from some large studies that reported benefits of adding dydrogesterone, but align with recent evidence showing similar outcomes between regimens.

The choice of luteal phase support should be individualized, considering patient characteristics, tolerability, and clinical context. Limitations of this study include its retrospective design, relatively small sample size, and lack of live birth outcomes.

Nevertheless, this study contributes valuable data from a high-altitude population, an underrepresented setting in current literature.

Luteal phase support with micronized progesterone alone showed slightly higher pregnancy rates compared with the combined regimen, though without statistical significance. The combined approach may still offer physiological advantages by combining local and systemic progestogenic actions. Further randomized multicenter studies are needed to confirm these findings and guide evidence-based protocols in assisted reproduction.

Ethical Considerations

This study was reviewed and approved by the Ethics Committee of Hospital Provida (Latacunga, Ecuador). Due to its retrospective design and anonymized data, informed consent was waived. The research adhered to the principles of the Declaration of Helsinki, ensuring data confidentiality through institutional protocols.

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