Study question

研究问题

Is there any impact of serum progesterone levels and subcutaneous progesterone supplementation on live birth rate in endometriosis patients undergoing Artificial Cycle-Frozen Embryo Transfer (AC-FET)?

子宫内膜异位症患者接受人工周期冷冻胚胎移植（AC-FET）血清孕酮水平和皮下(注射）孕酮补充对活产率是否有影响？

Summary answer

摘要解答

Endometriosis patients have comparable progesterone levels before transfer to those without endometriosis. Progesterone supplementation results in similar live birth rate (LBR) to the general population.

内异症患者移植前日孕酮水平与非内异症患者相当。孕酮补充会获得与一般人群相似的活产率。

What is known already

已知

Progesterone (P4) resistance is a hallmark of uterine alterations in endometriosis. This disease could disrupt balance between progesterone and estrogen signaling pathways, resulting in estrogen dominance and progesterone resistance at the receptor level, which warrants a deeper exploration for adjusting dosages when performing AC-FET. A recent retrospective study highlights the potential significance of a progesterone threshold when using vaginal and intramuscular progesterone systematically in AC-FET, correlating with a significantly higher LBR for endometriosis-patients. However, no current studies have compared LBR according to P4 the day before blastocyst-transfer and progesterone supplementation in endometriosis versus non-endometriosis-patients undergoing AC-FET with standard vaginal treatment.

孕酮（P4）抵抗是子宫内膜异位症子宫改变的标志。内异症可能破坏孕酮和雌激素信号通路间的平衡，导致受体水平的雌激素优势和孕酮抵抗，因此在进行AC-FET时需要对剂量调整做更深入的探索。最近的一项回顾性研究强调了内异症患者在AC-FET中系统性应用阴道和肌注黄体酮时孕酮阈值的潜在重要性，与显著提高的活产率相关。有关囊胚移植前日孕酮水平及孕酮补充，对于接受AC-FET且应用标准阴道治疗的内异症患者和非内异症患者的活产率差异，目前尚缺乏相关研究。

Study design, size, duration

研究设计、规模及持续时间

This is a retrospective cohort study including 985 cycles undergoing autologous AC-FET with standard vaginal progesterone treatment (600 mg/day) at a university-affiliated fertility center from January 2019 to December 2022. 168 cycles were from patients with confirmed endometriosis. LBR was evaluated in both groups based on P4 levels the day before transfer. Progesterone supplementation via SC injection (25 mg/day) was administered when levels were deemed low (<10.6 ng/mL based on our previously published research).

这是一项回顾性队列研究，纳入了2019年1月至2022年12月在大学附属生殖中心接受自体胚胎AC-FET并应用标准阴道孕激素治疗（600mg/天）的985个周期。其中168个周期为确诊内异症的患者。根据移植前日的孕酮水平评析两组活产率。当孕酮水平较低（据我们此前发表的研究标准为＜10.6ng/mL）时，经由皮下注射补充孕酮25mg/天。

Participants/materials, setting, methods

参与者/材料，设计及方法

Endometrial preparation involved oral estrogens at 6 mg daily from the begging of menstrual cycle. Micronized vaginal progesterone (600 mg/day) was added when thickness reached 7 mm. P4 was measured before embryo transfer; supplementation (25 mg SC injection) was added if < 10.6 ng/mL. FET occurred 6 days after initiating luteal phase support. Treatment continued until the pregnancy test. If pregnant, treatment ceased at 10 weeks of amenorrhea.

子宫内膜准备包括从月经周期开始雌激素口服6mg/日，当内膜厚度达到7mm时加用阴道微粒化黄体酮600mg/日。胚胎移植前日检测孕酮水平，如低于10.6ng/mL，则加用皮下注射黄体酮25mg/日，并于黄体支持第6日行冻胚移植。治疗一直持续到验孕，如妊娠，则在停经10周后停止治疗。

Main results and the role of chance

主要结果及偶然作用

Comparisons between endometriosis and non-endometriosis groups revealed similar baseline characteristics regarding age, BMI, parity, number of embryos transferred, and embryo quality.

The number of cycles with levels ≥10.6 ng/mL before transfer were comparable between patients with and without endometriosis (aOR 0.98, 95% CI 0.65-1.47) according to a multivariable logistic regression analysis adjusting for age, BMI, and prior progesterone levels <10.6ng/mL the day before transfer.

Unadjusted findings demonstrated equivalent clinical pregnancy, miscarriage, and live birth rates in endometriosis compared to non-endometriosis patients.

A subsequent multivariable logistic regression analysis to analyze LBR was conducted, considering four groups:

Group 1: Endometriosis with progesterone <10.6ng/mL and SC supplementation (51 patients)

Group 2: Endometriosis with progesterone ≥10.6ng/mL (117 patients)

Group 3: Non-endometriosis with progesterone <10.6ng/mL and SC supplementation (274 patients)

Group 4: Non-endometriosis with progesterone ≥10.6ng/mL (543 patients)

Adjusted for age, BMI, and embryo quality, Group 1 was considered as the reference. Results showed comparable live birth rates between the reference group and Group 2 (aOR 0.79, 95% CI 0.36-1.74), Group 3 (aOR 0.91, 95% CI 0.45-1.8), and Group 4 (aOR 1.9, 95% CI 0.71-2.74). Subcutaneous supplementation for endometriosis patients with P4<10.6ng/mL the day before embryo transfer led to similar LBR compared to the other groups.

内异症组和非内异症组相比，在年龄、体重指数、产次、移植胚胎数量及胚胎质量方面，两组基线特征相似。应用logistic多元回归分析，调整年龄、BMI和移植前日孕酮水平＜10.6ng/mL后，内异症患者和非内异症患者移植前日孕酮水平为10.6ng/mL的周期数相当（aOR 0.98,95% CI 0.65-1.47）。未调整的研究结果表明，内异症患者的临床妊娠率、流产率和活产率与非内异症患者相同。随后进行多变量logistic回归分析分为四组分析活产率：组1：内异症伴移植前日孕酮＜10.6ng/mL并皮下注射补充孕酮，共51例；组2：内异症移植前日孕酮水平达到10.6ng/mL，共117例；组3：非内异症伴移植前日孕酮＜10.6ng/mL并皮下注射补充孕酮，共274例；组4：非内异症患者移植前日孕酮达到10.6ng/mL，共543例。经年龄、BMI和胚胎质量调整后，组1被作为参照，结果显示，参照组与组2（aOR 0.79, 95%CI 0.36-1.74）、组3（aOR 0.91, 95%CI 0.45-1.8）和组4（aOR 1.9,95%CI 0.71-2.74）的活产率相当。胚胎移植前日孕酮＜10.6ng/mL时皮下注射补充孕酮的内异症患者的活产率与其他组相似。

Limitations, reasons for caution

局限性，谨慎的理由

The main limitation of this study is the single-center retrospective approach. While the total number of endometriosis patients is 168, the representation of endometriosis patients in group 1 may be a study limitation. Furthermore, all endometriosis stages were analyzed together although this may be clinically distinct entities.

本研究的主要局限性在于采用了单中心回顾的方法。虽然内异症患者总数有168例，但组1内异症患者的代表性可能使研究受到局限。此外，不同临床分期的内异症患者被混在一起进行了研究，而她们的临床表现迥异。

Wider implications of the findings

研究结果的更广泛意义

Endometriosis patients have the same risk to have P4<10.6ng/mL the day before FET as non-endometriosis patients. Vaginal progesterone, with subcutaneous supplementation if necessary, appears user-friendly, leading to a comparable live birth rate to that of patients with normal progesterone levels before transfer, regardless of endometriosis status.

内异症患者与非内异症患者冻胚移植前日孕酮水平＜10.6ng/mL的风险相同。无论是否存在内异症，使用阴道用孕酮制剂必要时联合皮下补充是可行的，最终可让移植前日孕酮低水平患者的活产率与正常孕酮水平的患者相当。

参考文献：N Sachs Guedj, B Coroleu, M Álvarez, S García, N P Polyzos, O-147 Role of serum progesterone levels and subcutaneous progesterone supplementation in endometriosis patients undergoing artificial cycle frozen embryo transfer, Human Reproduction, Volume 39, Issue Supplement_1, July 2024, deae108.166, https://doi.org/10.1093/humrep/deae108.166

Tags： 血清孕酮水平及皮下补充孕酮对内异症患者冻胚移植的作用