Subcutaneous progesterone versus vaginal progesterone for luteal-phase support in frozen-thawed embryo transfer: A cross-sectional study

Abstract Background Luteal-phase support is a complex and controversial issue in the field of reproductive management. Objective To compare the safety and efficacy of low-dose subcutaneous progesterone with the vaginal progesterone for luteal-phase support in patients undergoing rozen-thawed embryo transfer. Materials and Methods In this cross-sectional study, information related to 77 women that had frozen-thawed embryo transfer was reviewed. The patients were divided into two groups based on the route of progesterone administration used as a luteal-phase support. When the endometrial thickness reached ≥ 8 mm, in one group progesterone (Prolutex) 25 mg/ daily subcutaneous and in another group, vaginal progesterone (CyclogestⓇ) 400 mg twice or (EndometrinⓇ) 100 mg thrice daily, were administrated and continued until menstruation or in case of clinical pregnancy for 8 wk after the embryo transfer when the fetal heart activity was detected by ultrasonography. Results The patient's characteristics were matched and there was no significant difference. The chemical and clinical pregnancy rate was higher in the vaginal progesterone group compared to the prolutex group, but statistically unnoticeable, (40% vs. 29.6%, p = 0.367) and (28% vs. 22.2%, p = 0.581), respectively. Conclusion The findings of this study demonstrate that the new subcutaneous progesterone can be a good alternative for intramuscular progesterone in women that dislike and do not accept vaginal formulations as luteal-phase support in assisted reproductive technology.


Introduction
Additional embryos obtained through in vitro fertilization (IVF) or intracytoplasmic sperm injection can be stored and transferred in frozen-thawed cycles to prevent the waste of embryo and raises the chance of pregnancy in a single stimulated cycle (1). Oral progesterone has poor bioavailability with limited usage in infertility management due to extensive first-pass metabolism in liver.
Vaginal progesterone notwithstanding lower circulating levels reaches sufficient endometrial concentration and has good efficiency, but a number of side effects such as vaginal discharge or local irritation, discomfort, and doubt about sufficient absorption has reduced its compliance.  In addition, an abortion was defined as the loss of pregnancy before the 20 th wk of gestation while an ongoing pregnancy was considered as a pregnancy continuing beyond the 12 th wk of gestation.

Ethical considerations
This study was approved by the Ethics

Statistical analysis
We analyzed the data by using the statistical package for the social science version 26 for windows (SPSS Inc., Chicago, IL, USA). A student's t test was apply to assess other variables. We used The Chi-square test for comparition the non-continuous variables. A P-value < 0.05 is statistically significant.

Results
This study was conducted on 77 women, of which 27 patients were included in the Prolutex group and 50 in the vaginal progestrone group (Table I). No statistically significant difference was observed between the two groups (

Discussion
The purpose of this study was to evaluate a new progesterone supplementation as LPS in FET cycles, which differs from other available preparations in dosage (25 mg/day) and manner of administration (SC) (4). Our data analysis showed that new SC progesterone resulted in a similar pregnancy outcome when compared with cycles with vaginal progesterone supplementation.
Although, many studies have investigated the effect of different routes of progesterone administration, most of them were directed in fresh IVF cycles. Since there is still no agreement on the method of use, this still remains a controversial issue (7,(9)(10)(11)(12). In some literature, LPS has been continued until 10-12 wk of gestation, however, there is a confirmation about withdrawing P on the day of positive pregnancy test or detection of fetal heart beat without increasing the miscarriage rate (9,10). So, in our study, we administered for 8 wk in pregnant women. Vaisbuch in a web-based universal review showed IM progesterone utilized in 13% of IVF cycles, whereas in North America nearly 60% used alone or with vaginal progesterone (11). Several observational studies showed that the differences in efficacy due to the different forms of progesterone administration in pregnancy likelihood are small (12,13). So the route of progesterone used for LPS did not affect the live birth rate (14).
Lockwood and coworkers have conducted the first large prospective randomized trial 2014 and compared Prolutex (25 mg SC daily) with progesterone gel Crinone (90 mg intravaginal daily) as an LPS, they showed no significant difference in pregnancy outcomes. The ongoing pregnancy rate per protocol in the Prolutex and Crinone groups was 29.2% and 31.2%, respectively (difference -2.00, 95% CI -9.12-5.13) (7).
The results of our study is in line with other investigations showing that the SC aqueous progesterone (Prolutex) 25 mg daily has an equal effect as that of vaginal progesterone. The clinical and ongoing pregnancy rates were 22.2% with Prolutex and 28% with vaginal progesterone (p = 0.581), hence, no significant difference was seen in any of the secondary outcomes, including the implantation rate and abortion.
Although numerous examinations were done for evaluating the reproductive outcomes of all available types of progesterone planning for LPS, limited studies have reflected on patient satisfaction. Only one study has been published so far about the patient's acceptation of SC progesterone with blastocyst transfer in FET cycles; in women that had prior experience of vaginal progesterone, SC progesterone was related with significantly increased receipt, but there was a lack of data about the pregnancy outcomes in this study (5). Vaginal progesterone has different forms, such as capsules, gels, and pessaries. In two studies, patients preferred vaginal gel rather than IM injections as the former is more easier-touse, more contented, and more rapidly used (15). IM progesterone causes a measurable and fixed serum level but due to some adverse reactions which include pain, local irritation, sterile abscess, and limitation on self-administering it has low patient acceptance (3,16). The bioavailability of Prolutex with more rapid absorption is comparable to the IM form in serum level concentration and has higher serum levels than vaginal progesterone (8), however, the endometrial levels are higher when progesterone has been used vaginally (7). Prolutex, as mentioned earlier, can be well-tolerated and is not painful.
Therefore, it can be suggested that for those women who do not accept vaginal preparations and prefer constant LPS or dislike vaginal treatments because of social, personal, or medical causes are also worried about the leakage of drugs and are doubtful about the absorption of sufficient dose. In women with vaginal bleeding, use of a vaginal progesterone can be unpleasant (17). All patients had the experience of SC injection that used gonadotrophins in the hyperstimulation cycle (11).
Finally, we remind that a large number of investigations have been registered in the International clinical trial and there is a lack of information about this SC formulation in the field of oocyte donation and FET cycles. In the near future, we expect to face optimal finding in this context (dose and route) that has not been well-defined, from large, well-designed, and multicenter RCTs.
The limitations of this study are: first, restrictions on access to Prolutex in Iran that led to reducing the study's sample size; second, this survey has been done retrospectively. We assume that the longitudinal time frame between the medication and data record and also negative pregnancy tests may negatively influence women's perception and feelings about the drug; therefore, our patient satisfaction was not considered.

Conclusion
In this study, we attempted to show that the new SC progesterone formulation is comparable with vaginal progesterone for LPS, there was no statistically significant difference in pregnancy outcomes.