{"paper_id":"02ce4ff3-e5ef-4eac-8dc0-275fb2b70da1","body_text":"In recent decades, the landscape of assisted reproductive technologies (ART) has\nwitnessed significant progress, driven by the refinement of embryo and egg\nvitrification techniques. This progress has prompted the continuous enhancement of\nvarious controlled ovarian stimulation (COS) regimens, a critical aspect influencing\noocyte recovery and overall outcomes ( Hossein\nRashidi  et al. , 2020 ). Despite these advancements, the\npersistent challenge of premature luteinizing hormone (LH) peaks in ovarian\nstimulation protocols remains a focal point in reproductive medicine. Historically,\nup to 30% of controlled ovarian stimulation cycles were at risk of cancellation due\nto premature LH peaks leading to untimely ovulation before oocyte retrieval ( Hossein Rashidi  et al. , 2020 ;\n Iwami  et al. , 2018 ;\n Kuang  et al. , 2015 ).\nAdditionally, while traditional protocols have effectively addressed premature LH\nsurges in  in vitro  fertilization (IVF)/intracytoplasmic sperm\ninjection (ICSI) and oocyte vitrification treatments, they have fallen short in\nmitigating the risk of ovarian hyperstimulation syndrome (OHSS) and managing costs\neffectively. This limitation has sparked continued interest in the exploration of\nnovel treatment regimens ( Xiao  et\nal. , 2014 ;  Zhu  et\nal. , 2017a ).\nDespite being a well-known approach, the use of a GnRH agonist (GnRH-a) for pituitary\ngland desensitization poses challenges such as an extended usage period, high doses,\nand elevated costs. In contrast, GnRH antagonists (GnRH-ant) have demonstrated\neffectiveness in preventing premature LH peaks, offering enhanced safety against\nOHSS, and requiring fewer injections per cycle, while maintaining high treatment\ncosts ( Hossein Rashidi  et al. ,\n2020 ;  Iwami  et al. ,\n2018 ;  Kuang  et al. ,\n2015 ;  Pirard  et al. ,\n2006 ;  Xiao  et al. ,\n2014 ;  Zhu  et al. ,\n2017a ). In response to these challenges, recent years have witnessed the\nemergence of new regimens aiming for improved efficacy and patient convenience.\nNotably, two significant publications in 2016 shed light on the LH-suppressing\neffects of exogenous progestins (PGs), sparking interest in their potential role as\nan alternative to GnRH analogues for preventing premature LH peaks ( Li  et al. , 2016 ;  Wang  et al. , 2016 ). However,\ninitial studies raised concerns about the negative impact of PGs on endometrial\nreceptivity, making their application impractical. With the evolution of\nvitrification techniques and improved oocyte and embryo survival rates, the\nlandscape has shifted, bringing attention back to PGs as a promising option,\nespecially in the context of social fertility cryopreservation and ‘freeze-all’\nprotocols ( La Marca & Capuzzo, 2019 ).\nThe first randomized trial emphasizing Progestin-Primed Ovarian Stimulation (PPOS) in\n2015 evaluated medroxyprogesterone acetate (MPA) due to its mildly androgenic action\n( Kuang  et al. , 2015 ).\nSubsequent studies explored the role of MPA, comparing it with Ganirelix in oocyte\ndonation cycles, while other types of PGs, such as natural micronized progesterone\n(NMP), were still investigated for their effectiveness in preventing premature LH\npeaks ( Beguería  et al. ,\n2019 ;  Zhu  et al. ,\n2015 ).\nBuilding on the efficacy and safety established by MPA and NMP, researchers delved\ninto the potential benefits of DYG, a retroprogesterone with a selective PG receptor\nagonist profile, in the context of COS. Comparative studies, including one by  Zhu  et al.  (2017b) , concluded\nthat DYG effectively blocks premature LH surges, demonstrating similar results in\nembryonic quality and pregnancy rates compared to other PGs.\nThis comparative study aims to evaluate the effectiveness of DYG in PPOS protocols\nfor IVF/ICSI cycles and oocyte cryopreservation, assessing its capacity to block\npremature LH peaks and its impact on the quality of recovered oocytes.\nWhile estradiol (E2) traditionally plays a predominant role in the feedback\ncontrol of gonadotropin secretion during the follicular phase, some studies in\ncontraceptive research suggest the efficacy of progestins (PGs) in blocking the\nLH surge and preventing ovulation ( Massin,\n2017 ;  Messinis, 2006 ).\nExperiments in monkeys, whose cycle regulation mechanisms are similar to that\noccurring in women, the administration of a progestin (levonorgestrel) from the\nbeginning of the cycle prevents the occurrence of the LH surge despite the\nincrease in circulating E2 levels for as long as its use is continued, being a\ncompletely reversible action with its interruption. The same experiment was\nconducted after previous destruction of the hypothalamus. Under these\nconditions, the administration of E2 valerate induced the LH surge within 24\nhours, proving to be a pituitary action. In contrast, the addition of PG was\nunable to block the E2-induced LH elevation, indicating that PG inhibition of\nthis event occurs at the level of the hypothalamus ( Wildt  et al. , 1981 ).\nSimilarly,  Chabbert-Buffeta  et\nal.  (2000)  described the action of PG in sheep as an\nimportant modulator of LH secretion by reducing the frequency of GnRH pulses\nwhich, in turn, enriches the gonadotropic cells in FSH and prevents a second\npeak of LH. This study demonstrates that changes in PG levels produce dramatic\nneuroendocrine changes in the frequency of GnRH pulses, quickly reversible after\nnormalization of PG ( Chabbert-Buffeta  et\nal. , 2000 ).\nSuch information supports a new aspect in the control of gonadotropin secretion,\nwith the use of PG from the beginning of the follicular growth stimulus. The\ntiming of its onset is important, as some authors investigated whether this\nhormone participates in cooperating with the onset of the E2-induced LH peak in\nthe middle of the cycle ( Hoff  et\nal. , 1979 ). This concept is confirmed by  Zhu  et al.  (2015) , who\ndemonstrated that the pituitary block is efficient after 6 days of PG use.\n\nA retrospective, comparative single-center study was conducted at Fertipraxis - Human\nReproduction Center, a private clinic in the city of Rio de Janeiro, Brazil, from\nJanuary 2018 to December 2020. The study included 550 in vitro fertilization\n(IVF)/intracytoplasmic sperm injection (ICSI) cycles and 186 oocyte cryopreservation\ncycles with LH blockade performed with ant-GnRH or DYG, with no age restrictions.\nThe following exclusion criteria were adopted: patients with endometriosis, previous\novarian surgery, and those with ovarian insufficiency and abnormally high FSH/LH\nlevels. Ethical approval for the study was obtained from the Institutional Review\nBoard (project code 76866123.9.0000.5275), and all participating patients provided\nwritten informed consent before the study was conducted.\nFollicular growth stimulation commenced between the 2 nd  and\n5 th  day of the menstrual cycle. Patients received Follitropin\ndelta (Rekovelle ® , Ferring Pharmaceuticals) or Menotropin\n(Menopur ® , Ferring Pharmaceuticals) with an individualized\ndaily subcutaneous dose, adjusted as needed based on the attending physician›s\nassessment using ultrasound monitoring of follicular growth. Clinical decision\ndetermined the administration of a GnRH-ant (CTA-Cetrorelix acetate,\nCetrotide ® , Merck) at 0.25 mg/day, initiated flexibly when\na follicle reached ≥14 mm and continued throughout the stimulation period\n(326 cycles). Alternatively, dydrogesterone (DYG) at 10 mg every 8 hours\n(Duphaston ® , Abbott) was combined with gonadotrophin from\nthe beginning of stimulation until the day after the trigger (410 cycles). Final\nfollicular maturation occurred with three or more follicles ≥17 mm,\ntriggered by either 250 µg recombinant hCG (Choriogonadotropin alfa,\nOvidrel ® , Merck Serono) or GnRH agonist, 2 ampules\n(triptorelin acetate Gonapeptyl Daily ® , Ferring\nPharmaceuticals). Cancellation criteria included no follicles with a diameter of\n17 mm by day 15, and oocyte retrieval took place 35 hours after triggering.\nThe procedure was performed with the patient sedated, using a single-gauge\n17-needle (Wallace ONS1733), properly adapted to the vaginal transducer.\nAspiration was conducted in a closed-circuit system using an aspiration pump\n(Pioneer Pro-Pump OS 483) under a pressure of 90-100 mmHg.\nThe primary outcome was the incidence of premature LH surge. Secondary outcomes\nincluded metaphase II oocytes, follicles ≥15 mm and <18 mm and\n≥18 mm on trigger day and ovarian hyperstimulation syndrome (OHSS)\nsymptoms.\nSix analyses of covariance (ANCOVAs) were performed to assess statistically\nsignificant differences in scores (LH at trigger, MII, MI, or germinal vesicle\n(GV) oocytes, follicles ≥18 mm, and follicles ≥15 mm and <18\nmm) between two groups, after controlling for age, anti-Mullerian hormone (AMH),\nantral follicle count (AFC), and body mass index (BMI). Partial squared Eta was\nused as the effect size index.\nResampling procedures (bootstrapping; 1000 resamplings, with 99% confidence\ninterval) were implemented for group comparison analyses to enhance result\nreliability and present a 99% confidence interval for means and standard\ndeviations ( Haukoos & Lewis, 2005 ).\nThe analyses were conducted using SPSS software for Windows version 23. Data\nwere expressed as mean ± standard deviation (SD), and a\n p -value ≤ 0.05 was considered statistically\nsignificant.\n\nA total of 736 cycles were distributed into two groups: 326 in the GnRH antagonist\ngroup (Ant) and 410 in the Dydrogesterone group (Dyd). Demographic and descriptive\ncharacteristics are summarized in  Table\n1 .\nDemographic and treatment characteristics.\nIn 2 cases in group 1 (Ant) and in 3 cases in group 2 (DYG), a premature LH surge\nwith early follicular rupture were observed, which did not represent a statistical\ndifference ( p =1.00). The serum LH levels of these patients were\nexcluded from the analysis to avoid skewing the mean value and standard deviation.\nAccording to  Table 2 , the analysis of LH\nlevels on the trigger day revealed no statistical difference between the groups\n(Ant: Average (Ave) = 2.63, Standard Deviation (SD) = 1.15; DYG: Ave = 2.47, SD =\n1.22,  p =0.19). Controlling for control variables, including age,\nAMH, AFC, and BMI, we identified no interferences in the evaluated outcomes.\nAnalysis of difference between LH scores on trigger in the antagonist and\ndydrogesterone groups.\nIn  Table 3 , after controlling for the\nmentioned covariates, there was no statistically significant difference in the\nnumber of metaphase II (MII) oocytes. The analysis demonstrated that the Antagonist\ngroup presented Ave = 6.28 and SD = 4.72 of MII oocytes, while the Dydrogesterone\ngroup presented Ave = 6.71 and SD = 4.53, with no significant difference between the\ngroups ( p =0.15).\nAnalysis of difference between MII, MI and GV scores between the antagonist\nand dydrogesterone groups.\n= partial squared Eta.\nSimilarly, concerning the analysis of metaphase I (MI) and germinal vesicle (GV)\noocytes, after controlling, no statistically significant differences were observed\nbetween the groups ( Table 3 ).\nRegarding the number of follicles ≥ 18 mm and 15 to 17 mm, which was not the\nprimary outcome of the study but a possible indication of the quality of stimulation\nwith different protocols, the analysis demonstrated that the Antagonist group showed\nlower rates of follicles ≥ 18 mm (Ave = 3.33, SD = 2.06) than the\nDydrogesterone group (Ave = 4.19, SD = 2.53) -  p =0.001.\nAdditionally, the Antagonist group exhibited higher rates of 15 to 17 mm follicles\n(Ave = 6.25, SD = 3.75) compared to the Dydrogesterone group (Ave = 5.16, SD = 4.66)\n-  p =0.024 ( Table 4 ).\nAnalysis of difference between ≥ 18 mm and 15 to 18 mm follicles\nscores between antagonist and Dyd groups.\n\nThe evaluation of progestins (PG) as alternatives to GnRH agonists and antagonists in\npreventing the luteinizing hormone (LH) surge during ovarian stimulation cycles has\ngained attention due to ease of use and potential cost savings.  Kuang  et al.  (2015)  conducted\na prospective controlled study assessing the efficacy of medroxyprogesterone acetate\n(MPA) since the day 3 of the PPOS cycles, comparing this protocol with conventional\nshort a-GnRH protocol. The study showed a longer stimulation by 1 day and a lower\ntotal gonadotropin dose in the MPA group, around 400 IU, compared to the a-GnRH\nprotocol. Despite these differences, the number of mature oocytes was similar in\nboth groups of normal responders ( Kuang  et\nal. , 2015 ).  Wang  et\nal.  (2016)  still evaluating the effects of MPA, this time in\npatients with polycystic ovary syndrome (PCOS), reported in a randomized controlled\nstudy that MPA reduces the incidence of premature LH surge without interfering with\npregnancy outcomes in IVF/ICSI cycles. More, the data also indicated a reduction in\nthe risks of OHSS in these patients ( Wang  et\nal. , 2016 ). Similarly, our study found no statistical\ndifference in the number of mature oocytes between Dydrogesterone and ant-GnRH\ngroups. Even evaluating another type of progestin, Dydrogesterone, our results also\nshowed no statistical difference in the number of mature oocytes, as well as in the\nLH peak on the day of the trigger. Despite similar results in stimulus duration, AMH\nand AFC, after controlling for all variables, more favorable distribution was\nobserved, with a higher number of follicles ≥ 18 mm in favor of the\nDydrogesterone group, which may suggest potential benefits in terms of ovarian\nresponse.\nPatients with polycystic ovary syndrome (PCOS) represent a challenge group due to LH\nhypersecretion, hyperandrogenism, and increased intrafollicular androgen levels,\nwhich can affect oocyte quality, lead to lower fertilization rates, higher abortion\nrates, and increased risk of ovarian hyperstimulation syndrome (OHSS) ( Delvigne  et al. , 1993 ;  Wang  et al. , 2016 ). While GnRH\nantagonists are known to reduce the incidence of moderate and severe OHSS, our study\ndid not observe cases of moderate or severe OHSS in either group. This is consistent\nwith findings by  Pundir et al. (2012) , who\nhighlighted the high risks in PCOS patients even with GnRH antagonists. Another\ndownside for women with PCOS is their increased cycle cancellation rates for IVF\ncompared to women without PCOS ( Heijnen  et\nal. , 2006 ). Although we have not separately evaluated\npatients with PCOS, we did not observe cases of moderate or severe OHSS, as well as\nof cycle cancellation in any of the groups.\nBeguería  et al.  (2019) \nstudied the effects of MPA with a focus on the assessment of non-inferiority,\ncompared to ganirelix with regard to the number of mature oocytes (MII) in egg\ndonation programs. In a randomized clinical trial, 173 donors were divided into 2\ncomparison groups and the results were comparable both in the amount of recovered\nMII and in the pregnancy rates of these eggs ( Beguería  et al. , 2019 ).\nWith the discussed reduction of endometrial receptivity in cycles of controlled\novarian stimulation and the improved results of the vitrification technique in the\nlast decade, new stimulation regimens have emerged. Indeed, transfer of frozen\nembryos in freeze-all protocols has been followed by encouraging results in\npregnancy and birth rates ( Devroey  et\nal. , 2011 ;  Doody,\n2014 ;  Wong  et al. ,\n2014 ). In our experience, we have observed an increasing number of older\npatients and a consequent increase in the performance of embryonic genetic studies,\nas well as in the preservation of fertility in younger women. For such cases, a\nprotocol with PG is suitable for blocking the LH peak, with a relevant cost\nreduction.\nSeveral recent studies highlight the effectiveness of natural micronized progesterone\n(NMP), both in supporting the luteal phase and blocking the LH surge.  Zhu  et al.  (2015)  demonstrated\nan efficient block of pituitary LH levels after 6 days of using\nUtrogestan ® , with similar results, with no case of premature\nLH elevation being observed in COH cycles ( Zhu\n et al. , 2015 ).\nTaking into account only the cost-effectiveness of Dydrogesterone, given the\ndifferent treatment models, recent data from 2019 show that the use of progestin was\nnot cost effective compared to GnRH analogues when compared to fresh embryo transfer\ncycles. However, in freeze-all cycles, progestins were clearly superior in terms of\ncost-effectiveness. In the same sense, also in relation to the rates of premature\nbirths, newborn weight and malformation, no differences were demonstrated between\nDydrogesterone and GnRH agonists ( Evans  et\nal. , 2019 ). Our work did not cover obstetric outcomes, but\nthey are in frank agreement with respect to cost-effectiveness.\nMotaref  et al.  (2020) \ncompared Dydrogesterone and ant-GnRH and their effects on the quality of oocytes and\nembryos in women undergoing ICSI, highlighting the qualities of PG, not only in\npreventing the LH surge but also for its supposed ability to improve the number of\nretrieved oocytes. Although we identified similar results between the protocols,\nwith regard to costs, it seems to us that the choice of Dydrogesterone is fully\njustified, whenever the planned treatment allows it. Additionally, this work has\ndemonstrated a higher rate of follicles > 18 mm in the Dydrogesterone group,\nwhich can be understood as a positive differential of this protocol.\nConsidering effectiveness, convenience and tolerability,  Griesinger  et al.  (2018)  emphasized the use of\nNMP by vaginal route, as the oral route has low bioavailability and is associated\nwith more frequent systemic adverse events. In a large multi-center randomized\nstudy, they compared NMP with Dydrogesterone, reporting favorable results to\nDydrogesterone which, although not statistically significant, confirm the importance\nof the drug in the current context. In a randomized controlled trial (RCT),  Hossein Rashidi  et al.  (2020) ,\nbased on the low cost, efficacy and greater practicality of oral presentation,\naffirm the tenability of using Dydrogesterone as an alternative to GnRH antagonists\nfor the prevention of LH peaks. Likewise, our results were similar to these and\nother recent studies that compared Dydrogesterone with GnRH antagonists, either for\nluteal phase support or for PPOS cycles, highlighting its favorable\ncost-effectiveness, greater convenience of the oral use, lower androgenic activity,\nadverse effects and good tolerability when compared to other progestins ( Hossein Rashidi  et al. , 2020 ;\n Zhu  et al. , 2017b ).\nWe recognize its retrospective design as the main weakness, which leads to future\nprospective studies. However, our data revealed similar results with respect to\npremature LH peak, LH level, number of oocytes in metaphase II of Dydrogesterone\ngroup compared to GnRH antagonists, making this synthetic PG a cost-effective tool\nin IVF/ICSI cycles for freeze-all / PGT-A and oocyte preservation. It can also be\nconsidered in egg/embryo bank programs or as prevention of OHSS in patients with\nhigh levels of AMH.","source_license":"public-domain-us","license_restricted":false}