Effects Of Oral Dydrogesterone Or Intramuscular Progesterone As Luteal Phase Support On Clinical Outcomes In ART Cycles

Effective way to improve the pregnancy rate after embryo transfer has always been the hot issue in ART (assisted reproductive technology) treatment. Normal luteal function is one of the essential preconditions for embryo implantation and maintenance of pregnancy. COS (controlled ovarian stimulation) in IVF-ET (in vitro fertilization and embryo transfer) as well as the use of GnRHa (gonadotropin releasing hormone agonist) and GnRHant (Gonadotropin releasing hormone antagonist) in the pituitary down-regulationcan significantly improve the synchronization of follicular development and avoid the prematurely presence of LH(Luteinizing hormone) peak which brings good affection on ovulation. However, factors including early appearing of endometrial implantation window, the change of endometrial receptivity and LPD (luteal phase defect) during this procedure indicate a negative impact on pregnancy rate in IVF-ET cycles. There are a number of studies demonstrated that appropriate luteal phase support can significantly increase the pregnancy rate in FET cycle. NC-FET(natural cycle of frozen embryo transfer) and HRT-FET (hormone replacement therapy-frozen embryo transfer) are two of the most commonly used procedures in FET (frozen-thawed embryo transfer) treatment.In order to improve the clinical pregnancy rate,appended luteal phase support has been conventional in these two therapeutic schemes. Thus, luteal phase support becomes a routine in ART treatment for better clinical outcome.Making a general survey of studies both domestic and overseas, there is no unified, fixed pattern about luteal phase support. There is still space for further studies to investigate the type of drugs, medication, drug dosage, and best applying time of the drug in luteal phase support. Intramuscular progesterone as luteal phase support is well acceptable for the majority of doctors and patients in our country despite of the inconvenient medication and formation of induration after injection. On the contrary, oral dydrogesterone is easy to take but less research on using dydrogesterone alone, so far, still no literature reports related in domestic.Therefore,used alone dydrogesterone for luteal phase support in clinical remains controversial, can not be widely used in clinical.The aim of our present study was to investigate the clinical outcomes of oral dydrogesterone and intramuscular progesterone as luteal phase support after IVF-ET and FET cycles, so as to provide better option for luteal phase support in routine clinical practice.Part I Effects of oral dydrogesterone or intramuscular progesterone as luteal phase support on clinical outcomes in frozen embryos transfer cycles[Objective]Luteal phase support in FET cycles can improve the clinical outcome by increasing the clinical pregnancy rate and live birth rate. The best pattern of drug use for progesterone including type of drugs, medication, drug dosage, and best applying time are still hanging in doubt. Intramuscular progesterone as luteal phase support is well acceptable for the majority of doctors and patients in our country despite of the inconvenient medication and formation of induration after injection. On the contrary, oral dydrogesterone is easy to take but the concentration can not be detected which may lead the doctors and patients to have doubt in it. Beside the clinical effects of the two preparations are still with controversy.The aim of our present study was to investigate the clinical outcomes of oral dydrogesterone and intramuscular progesterone as luteal phase support after FET cycles, so as to provide better option for luteal phase support in routine clinical practice.[Materials&Methods] (1) Thisstudy was approved by the ethics committee of NanfangHospital. This was a prospective cohort study of all women attending the Center forReproductive Medicine, Department of Gynecology and Obstetrics,NanfangHospital, affiliated with Southern Medical University forFET treatment from January,2010to September,2011. Theinclusion criteria for patients were as follows:(ⅰ) patients with natural cycle of frozen embryo transfer (NC-FET);(ⅱ) patients with hormone replacement therapy-frozen embryo transfer (HRT-FET). Patients with ovulation induction or other therapy were excluded in this study.(2) One thousand six hundred and forty three patients were included in out study. Patients were divided to two groups according to different FET approaches:Group A was natural-cycle FET, Group B was hormone replacement cycle (HRT-FET). Oral dydrogesterone or intramuscular progesterone as luteal phase support were performed in Group A and B, in which Group A Ⅰ used oral dydrogesterone(n=358), in which dydrogesterone tablet was taken orally10mg3/day;Group A Ⅱ used intramuscular progesterone (n=634), in which progesterone was injected intramuscularly60mg1/day;Group B Ⅰ used oral dydrogesterone with progynova (n=185), in which dydrogesterone tablet was taken orally10mg3/day while estradiol valerate was taken orally6-8mg/day; Group BⅡ used intramuscular progesterone with progynova (n=466),in which progesterone was injected intramuscularly60mg1/day while estradiol valerate was taken orally6-8mg/day.The clinical pregnancy rates, implantation rates, early miscarriage rates, ectopic pregnancy rates, ongoing pregnancy rates and delivery rates were compared between the subgroups.(3) Data were analyzed using Student’s t-test andχ2, as appropriate.Non-conditional Logistic regression analysisy were used in describing the relationship between each predictor and the pregnancy outcome. P<0.05was considered statistically significant. Statistical analysis wasperformed with Statistical Package for the Social Sciencesl6.0.[Results](1) In our study, the clinical pregnancy rate is36.0%(591/1643), implantation rate is20.0%(785/3923), early miscarriage rate is14.7%(87/591),ectopic pregnancy rate is4.3%(26/591), ongoing pregnancy rate is29.1%(479/1643). There were no differences in clinical outcomes between dydrogesterone and intramuscular progesterone as luteal phase support in either natural-cycle FET or HRT FET (P>0.05).(2) Women aged under35years old who had oral dydrogesterone for luteal phase support, their clinical pregnancy rate is35.7%undergoing NC-FET, while in the HRT FET group, the pregnancy rate is higher than40.0%, the ongoing pregnancy rate is35.7%[Conclusions](1) In the FET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes compared with intramuscular progesterone, especially in HRT-FET therapy.(2) Age is one independent predictor of ART clinical outcome. We divided patients who took oral dydrogesterone tablets for luteal support into groups according to age. Thus, our study showed that Women aged under35years old who had oral dydrogesterone for luteal phase support, their clinical pregnancy rate is35.7%undergoing N-C FET, while in the HRT FET group, the pregnancy rate is higher than40.0%, the ongoing pregnancy rate is35.7%(3) In the FET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes compared with intramuscular progesterone. And we recommend oral dydrogesterone as an alternative to intramuscular progesterone for luteal phase support in clinical practice.Part II Effects of oral dydrogesterone or intramuscular progesterone as luteal phase support on clinical outcomes in IVF-ET cycles[Objective]COS in IVF-ET as well as the use of GnRHa and GnRHant in the pituitary down-regulationcan significantly improve the synchronization of follicular development and avoid the prematurely presence of LH peak, which brings good affection on ovulation.However, factors including early appearing of endometrial implantation window, the change of endometrial receptivity and LPD (luteal phase defect) during this procedure indicate a negative impact on pregnancy rate in IVF-ET cycles.The aim of our present study was to investigate the clinical outcomes of oral dydrogesterone and intramuscular progesterone as luteal phase support after IVF-ET cycles, so as to provide better option for luteal phase support in routine clinical practice.[Materials&Methods](1) Thisstudy was approved by the ethics committee of NanfangHospitaland written informed consent was obtained from each participant. This was a randomized controlled clinical study of all women attending the Center forReproductive Medicine, Department of Gynecology and Obstetrics,NanfangHospital, affiliated with Southern Medical University forIVF-ET treatment from June22,2012toNovember27,2011. Theinclusion criteria for patients were as follows:(ⅰ) age<38years old;(ⅱ) no previous hydrosalpix history;(ⅲ) less than three embryo transfer attempts (including the study attempt);(ⅳ) GnRHa (1.875mg) pituitary down regulation;(ⅴ) the initial dosage of150-300iuexogenous Gn (gonadotropin) daily owing to age;(ⅵ) level of serumprogesterone (P)<1.5ng/ml on HCG day;(ⅶ) number of retrieved follicles≥5. exclusion criteria:(ⅰ) number of retrieved follicles<5;(ⅱ) level of serumP≥1.5ng/ml on HCG day;(ⅲ) moderate and severe hydrosalpix history;(iv) luteal phase support by hCG after OPU. Rejection criteria:(ⅰ) backward flow of hydrosalpix was detected by ultrasound on embryo transfer day;(ⅱ) endometrial thickness<8mm;(ⅲ) embryo transferred5days’after OPU or canceled embryo transfer. Eighty seven patients were enrolled.(2) All patients in our study received long protocol. GnRHa (1.875mg) was taken for pituitary down regulation and the initial dosage of150～300iuexogenous Gn was injected daily owing to age. If there presented≥3follicles≥17mm in average diameter or≥2follicles≥18mm with the combination of serum hormone level, the patient would be triggered with hCG at10pm. (3) All patients in our study have luteal phase support from OPU (ovum pick up) day and were divided into two groups according to different luteal phase support. Group A:dydrogesterone was taken orally10mg4/day; Group B: progesterone was injected intramuscularly60mg1/day. Ultrasound guided embryo transfer was performed3days after retrieval. Serum hCG test was preformed13-15days’after embryo transfer. Luteal phase support was continued until a negative pregnancy test or a10-12-week gestation. The clinical pregnancy rates, implantation rates, early miscarriage rates, ectopic pregnancy rates, ongoing pregnancy rates and delivery rates were compared between the two groups.(4) Data were analyzed using Student’s t-test andχ2, as appropriate.Non-conditional Logistic regression analysisy were used in describing the relationship between each predictor and the pregnancy outcome. P<0.05was considered statistically significant. Statistical analysis wasperformed with Statistical Package for the Social Sciences16.0.[Results](1) Among the IVF-ET cycles (n=87), the clinical pregnancy rate was56.3%(49/87), the embryo implantation rate was37.4%(67/179), the early miscarriage rate was4.1%(2/49), the ectopic pregnancy rate was4.1%(2/49) and the ongoing pregnancy rate was51.7%(45/87).(2) Among the oral dydrogesterone group (n=44), the clinical pregnancy rate was59.1%(26/44), the embryo implantation rate was37.0%(34/92), the early miscarriage rate was7.7%(2/26), the ectopic pregnancy rate was7.7%(2/26) and the ongoing pregnancy rate was50.0%(22/44). Among the intramuscular progesterone group (n=43), the clinical pregnancy rate was53.5%(23/43), the embryo implantation rate was37.9%(33/87), the early miscarriage rate was0%(0/23), the ectopic pregnancy rate was0%(0/23) and the ongoing pregnancy rate was53.5%(23/43).There was no statistically significant difference in the clinical pregnancy rate, the embryo implantation rate, the early miscarriage rate, the ectopic pregnancy rate and the ongoing pregnancy ratein fresh cycle between the oral dydrogesterone group intramuscular progesterone group(P>0.05).[Conclusions](1) In the IVF-ET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes compared with intramuscular progesterone. Compared with intramuscular progesterone, oral dydrogesterone tablets is more convience for administration which provides better patients compliance and avoid the trouble of intramuscular injection.(2) In the IVF-ET cycles, oral dydrogesterone tablets for luteal support can achieve good clinical outcomes compared with intramuscular progesterone. Oral dydrogesterone is alternative to intramuscular progesterone for luteal phase support in clinical practice.Limitation:our study had a relatively small sample capacity. Thus, whether our conclusions from this present study can guide the clinical applications should be further verified by enlarging the sample capacity.