A convenient endometrium is required for the implantation of the blastocyst and the maintenance of the pregnancy. Proper preparation of the endometrium occurs with the effect of estrogen in the follicular phase and progesterone in the luteal phase (8). In stimulated cycles in which GnRH antagonists are used, it has been shown that progesterone production is impaired and LH pulsatility is suppressed with the loss of corpus luteum support (9,10). Low sex steroids in the luteal phase have been associated with inadequate implantation and pregnancy rates (11). With these data, luteal phase support has become a routine practice associated with IVF cycles. When using progesterone for luteal phase support, the most convenient and tolerable mode of administration for the patient should be used. Our aim should be to provide a high implantation and pregnancy rate. In reviewing the literature, it can be seen that quite a number of studies have mainly compared vaginal progesterone with intramuscular progesterone. In Lotus I and Lotus II studies, vaginal progesterone and oral progesterone were compared. Lotus I is a randomized, multicenter controlled phase III clinical trial that provides evidence that oral dydrogesterone is as effective as current treatments in luteal phase support for women undergoing IVF (12,13). In this study, 1,031 patients undergoing IVF or intracytoplasmic sperm injection with a fresh single or double embryo transfer after controlled ovarian stimulation were randomized to one of the two treatment arms on the day of oocyte retrieval. MVP 200 mg capsules were administered three times a day to the experimental group patients. Oral dydrogesterone was administered to the control group as 10 mg tablets three times a day. The treatment was initiated on the evening of the oocyte retrieval day, and this was continued until the 12th gestational week if pregnancy was observed on the 12th day of β-hCG. Considering the data collected in this study, dydrogesterone showed a positive benefit/risk profile. The mean age of women in the LOTUS I study was 32.5 years. The mean body mass index was 23 kg/m2, and 43% of the patients had a single embryo transfer. The LOTUS I trial has conclusively proven that oral dydrogesterone is not inferior to micronized vaginal progesterone. In our study, there was no significant difference between the oral dydrogesterone and vaginal progesterone groups in terms of the male age, female age, and BMI variables. The number and quality of embryos transferred are similar. According to the Lotus I study, the primary purpose of progesterone supplementation given in the luteal phase was to maintain the fetal heartbeat of the 12-week old embryo. The Lotus I study demonstrated that the impact of oral dydrogesterone and micronized vaginal progesterone were similar in terms of fetal heart rate. Continued pregnancy rates were 37.6% and 33.1% (difference is 4.7%; 95% CI: −1.2–10.6%) in the oral and vaginal treatment groups, respectively. Similar results were observed for the live birth rates of 34.6% and 29.9% (difference 4.9%; 95% CI: −0.8–10.7%) for the oral and vaginal treatment groups, respectively (13). Once again, according to this study, data on neonatal safety collected at birth were similar between groups. In other words, in the Lotus I study, the dydrogesterone and micronized vaginal progesterone used to support the luteal phase in IVF for both mother and fetus had similar safety and side-effect profiles (13). Within the scope of our study, oral dydrogesterone and vaginal progesterone groups with β-hCG positive or negative rates on the 12th day after embryo transfer were similar. When the progesterone
groups are compared in terms of the clinical status of their pregnancies, no significant differency is observed in terms of biochemical pregnancy, clinical abortion, and ongoing pregnancy rates (p > 0.05).
Lotus II was a randomized, multicenter Phase III study conducted from August 2015 to May 2017 at 37 IVF centers in 10 countries worldwide (14). A total of 1,034 premenopausal women (>18 to <42 years of age) were randomized into two groups to receive 30 mg oral dydrogesterone or 8% MVP gel 90 mg daily. Subjects received oral dydrogesterone (n = 520) or MVP gel (n = 514) on the day of oocyte retrieval. Luteal phase support continued until the 12th gestational week. The primary measure of success was the presence of fetal heartbeats at the 12th week of pregnancy. Pregnancy rates at the 12th gestational week in the oral dydrogesterone and MVP gel groups were 38.7% (191/494) and 35.0% (171/489), respectively (adjusted difference is recorded as 3.7%; 95% CI: −2.3 to 9.7). However, when secondary target analysis was performed for the oral dydrogesterone and MVP gel groups, live birth rates of 34.4% (170/494) and 32.5% (159/489) were obtained, respectively (adjusted difference 1.9%; 95% CI: -4.0 to 7.8). Accordingly, when compared to MVP, the success of oral dydrogesterone was not lower than that of vaginal progesterone. Miscarriage rates were similar in the two treatment groups, although this was not directly and explicitly investigated in the study. Overall, these findings were consistent with the results of the Lotus I study (13). Results from Lotus I and Lotus II, two multicentric studies in IVF, indicate that oral dydrogesterone is a viable alternative to micronized vaginal progesterone gel for luteal phase support. A prospective clinical study conducted by Kahraman S. et al. compared the effectiveness of vaginal progesterone gel versus intramuscular progesterone for luteal phase support, and it was assumed that a relationship existed between endometrial thickness and pregnancy rates (15). In another study investigating the effects of vaginal progesterone on post-transfer hormonal parameters and endometrial thickness , patients were compared (16) and the endometrial thickness was found to be higher in patients receiving vaginal progesterone than in patients who were not receiving (p < 0.01). These findings suggest that progesterone supplementation affects pregnancy rates by increasing endometrial thickness, thus increasing endometrial receptivity. In our study, no significant difference was observed between the oral dydrogesterone and vaginal progesterone groups with respect to endometrial thickness on the day of embryo transfer (p > 0.05). However, the progesterone level measured on the 12th day after embryo transfer was higher in the vaginal progesterone group (p < 0.05). A number of studies in the literature reveal that female age is one of the most effective predictors of ART success (17). In general, the highest pregnancy rates in these studies were obtained in cases where the female age was below 35 years. The most likely explanation for this is that age is a direct indicator of oocyte quality. With advancing age, the number of follicles, granulosa function, oocyte quality, and endometrial receptivity decrease in women. In our study, IVF was performed on patients between the ages of 18–44. The mean age in the oral dydrogesterone group was 31.5 ± 5.5, and the mean age in the micronized vaginal progesterone group was 32.5 ± 5.3. No statistically significant difference was found between the groups. In another randomized controlled study, the effect on IVF results was compared by examining sperm parameters in patients who underwent ICSI. Consequently, it was observed that sperm parameters did not correlate with ICSI results (18). In our study, spermiogram results were similar between the progesterone groups (p > 0.05). The most important advantage of vaginal progesterone is its local endometrial effect, also known as the uterine first pass effect. Due to direct transport from the vagina to the uterus, high endometrial concentrations are achieved despite low circulating progesterone levels. Since vaginal use allows targeted drug delivery to the uterus (19), it is expected to be more effective in supporting the luteal phase with ART. However, the results of the Lotus I study showed that dydrogesterone had similar success with micronized vaginal progesterone gel (13). On the other hand, luteal phase support with the use of progesterone is usually initiated after oocyte pick-up. As such, there is a risk of exposure of progesterone and its excipients into the uterine cavity when the embryo transfer catheter is passed through the cervical canal. Moreover, supraphysiological progesterone concentrations in the vagina can alter the local microbiome, and this has recently become the focus of attention in the IVF context (20). Tomic et al. (21) reported that the instances of perineal irritation, vaginal bleeding, vaginal discharge, and/or interference with sexual activity were significantly higher in patients receiving vaginal progesterone gel compared to those who were receiving oral dydrogesterone. The most important tolerability issue with vaginal progesterone is discharge and irritation. In our study, the rate of vaginal discharge or irritation was higher in the micronized vaginal progesterone group (13.6%) than in the oral dydrogesterone group (1.9%). This finding is statistically significant (p < 0.05).