{"paper_id":"5e1577ff-8263-4245-bfab-a9568baa6406","body_text":"Gynecol Obstet, an open access journal\nISSN: 2577-2236\n1 V olume 09; Issue 01\nCase Series\nEffective Luteal Support with Dydrogesterone 30 \nmg SR in Combination with Micronized Vaginal \nProgesterone in Frozen Embryo Transfer and \nSevere Endometriosis: Case Series\nKundan Ingale 1, Kalyani Ingale 2, Gaurav Damdar 3, Anjum Shaikh 4, \nAshutosh Gautam5*\n1Director, Nirmiti Clinic, A Center for Assisted Reproduction and Endoscopy, Pune, India. \n2Consultant and Chief Embryologist, Nirmiti Clinic, A Center for Assisted Reproduction and Endoscopy, Pune, India.\n3Assistant Manager, Medical Affairs, Mankind Pharma Pvt Ltd, New Delhi, India.\n4Junior Consultant, Nirmiti Clinic, Center for Assisted Reproduction and Endoscopy, Pune, India.\n5Assistant Group Lead I Medical Affairs, Mankind Pharma Ltd., 262, Okhla Industrial Estate Phase III, New Delhi, India.\n*Corresponding author: Ashutosh Gautam, Assistant Group Lead I Medical Affairs, Mankind Pharma Ltd., 262, Okhla \nIndustrial Estate Phase III, New Delhi – 20, India.\nCitation: Gautam A, Ingale K,  Damdar G, Shaikh A (2025) Effective luteal support with dydrogesterone 30 mg SR in combination \nwith micronized vaginal progesterone in frozen embryo transfer and severe endometriosis: Case series. Gynecol Obstet Open \nAcc 9: 233. DOI: https://doi.org/10.29011/2577-2236.100233\nReceived Date: 14 March 2025; Accepted Date: 21 March 2025; Published Date: 24 March 2025\nObstetrics & Gynecology: Open Access\nGautham A, et al. Gynecol Obstet Open Acc 9: 233.\nwww.doi.org/10.29011/2577-2236.100233\nwww.gavinpublishers.com\nAbstract\nLuteal phase support is crucial for optimizing outcomes in assisted reproductive technologies, particularly during frozen \nembryo transfer (FET) cycles, where endogenous progesterone production is insufficient for pregnancy maintenance and \nendometrial preparation. This report presents two cases: that of a 32-year-old woman with diminished ovarian reserve and \nthat of a 31-year-old woman with severe endometriosis. Both patients underwent FET and received a combination of vaginal \nmicronized progesterone and oral sustained-release dydrogesterone (30 mg). Both patients achieved pregnancy, indicating the \neffectiveness of combination therapy. The dual regimen may offer a promising approach for enhancing reproductive success \nin patients with complex fertility issues.\nKeywords: Luteal phase support; Progesterone; Dydrogesterone; \nFrozen-embryo transfer; Assisted reproductive technology\nIntroduction\nAssisted reproductive technology has advanced significantly, \nparticularly with the increased use of frozen-thawed embryo \ntransfer (FET) cycles. Key innovations in in-vitro fertilization \n(IVF) include routine blastocyst-stage embryo transfer, greater \nreliance on embryo cryopreservation, preimplantation genetic \nscreening, single embryo transfer, and minimal stimulation \nprotocols [1]. Progesterone plays a crucial role in supporting \nfertility treatments, particularly during FET cycles because of the \ninsufficiency of an endogenous corpus luteum [2]. Progesterone \ndeficiency is commonly seen in conditions such as luteal phase \ndeficiency, threatened abortion, and recurrent pregnancy loss, \noften requiring progesterone supplementation [3].\nDydrogesterone is a stereoisomer of progesterone that has \na metabolically stable chemical structure. It offers several \nadvantages, including high oral bioavailability, specificity for \n\nCitation: Gautam A, Ingale K,  Damdar G, Shaikh A (2025) Effective luteal support with dydrogesterone 30 mg SR in combination with micronized vaginal progesterone \nin frozen embryo transfer and severe endometriosis: Case series. Gynecol Obstet Open Acc 9: 233. DOI: https://doi.org/10.29011/2577-2236.100233\n2\nV olume 09; Issue 01\nGynecol Obstet, an open access journal\nISSN: 2577-2236\nprogesterone receptors, and a favorable tolerability profile \n[2]. Oral dydrogesterone is as effective as vaginal micronized \nprogesterone, but evidence comparing the two in assisted \nreproductive procedures remains inconclusive. The phase 3 Lotus \nI and II trials demonstrated that oral dydrogesterone is non-inferior \nto vaginal micronized progesterone capsules and gel, respectively, \nfor luteal phase support (LPS) in FET cycles [4,5]. A prospective, \nrandomized controlled trial (RCT) in 1373 women undergoing \nIVF showed similar pregnancy (28.7% vs 28.6%) and miscarriage \n(11.6% vs 13.0%) rates with oral dydrogesterone and vaginal \nmicronized progesterone [6]. Another RCT in 150 women with \n≤24 weeks gestation and threatened or recurrent abortion showed \nsignificantly lower serum progesterone (21.3 vs 24.1 ng/mL, \np=0.001), reduced spotting/bleeding episodes (4.0 vs 7.2, p<0.001), \nand a lower rate of miscarriage (8.0% vs 20.0%, p=0.034) with oral \ndydrogesterone compared to vaginal micronized progesterone [7]. \nOral dydrogesterone can reduce vaginal irritation and discharge \nwhile enhancing patient compliance [6]. Moreover, some studies \nhave highlighted the benefit of combining oral dydrogesterone \nwith vaginal progesterone. A single-center, retrospective cohort \nstudy of 391 women undergoing FET (2013–2019) showed \nthat the addition of oral dydrogesterone to vaginal micronized \nprogesterone gel in LPS during artificial FET cycles was associated \nwith significantly higher clinical birth rates than when vaginal \nprogesterone was used alone [8]. The MIDRONE study compared \nvaginal micronized progesterone and its combination with oral \ndydrogesterone for LPS in 1364 women undergoing IVF with FET \n[9]. Although there was no significant increase in live birth rates \n(41.3% vs 46.3%, p=0.06), miscarriage rates were significantly \nreduced with the combination therapy (6.6% vs 3.4%, p=0.009). \nThe findings indicate that oral dydrogesterone supplementation \nmay enhance the efficacy of vaginal progesterone in reducing \nmiscarriage rates and improving live birth rates during FET cycles \n[9]. While both treatments are individually well-studied and \neffective, the potential synergistic benefits of their combined use \nremain largely unexplored. However, there is a critical need for \nmore comprehensive studies focusing on the combination therapy \nof vaginal progesterone and oral dydrogesterone for LPS.\nThis report presents two clinical cases illustrating the effectiveness \nof a combination of vaginal micronized progesterone and \ndydrogesterone sustained release (SR) 30 mg in improving \npregnancy outcomes during FET. The first case involves a patient \nwith poor ovarian reserve, and the second case focuses on a patient \nwith grade 4 endometriosis.\nCase Series\nCase 1: LPS in FET despite poor ovarian reserve\nA 32-year-old woman, married for 5 years, presented with a \nhistory of obstetric complications, including an intrauterine \ndeath at 33 gestation weeks 5 years ago. This complication was \nattributed to severe pregnancy-induced hypertension and abruptio \nplacenta. During the initial assessment in December 2023, she was \nfound to have endometrial polyps with eumenorrhea and optimal \nendometrial thickness. Hysterolaparoscopy conducted in January \n2024 revealed a right hydrosalpinx, for which salpingectomy was \nperformed, along with excision of endometrial polyps.\nGiven her poor ovarian reserve, with an antral follicle count \nof seven, she was counseled for IVF. In March 2024, ovarian \nstimulation was initiated with human menopausal gonadotropins \n(HMG) 450 IU. Seven mature metaphase II oocytes were retrieved, \nof which six were fertilized, resulting in two blastocysts: one fully \nexpanded blastocyst (grade AA) and one early blastocyst (grade \nBB). FET was planned, and hormone replacement therapy was \nstarted. A single depot intramuscular injection of gonadotropin-\nreleasing hormone (GnRH) agonist (3.75 mg) was administered on \nday 2 of the patient’s menstrual cycle, followed by confirmation of \novarian downregulation, with reduction in estradiol (<100 pg/mL) \nand luteinizing hormone (LH, <5 mIU/mL) levels. Transvaginal \nultrasound revealed an absence of endometrial growth.\nThe endometrial thickness during ovarian stimulation was 7 mm. \nTherefore, estradiol hemihydrate was administered in incremental \ndoses ranging from 4–24 mg/day over a prolonged period of 40 \ndays, helping to achieve an endometrial thickness of 10.2 mm. \nSub-endometrial blood flow was assessed, with a peak systolic \nvelocity of 17.91 cm/s indicating favorable conditions for embryo \ntransfer.\nLPS was provided using a combination of vaginal micronized \nprogesterone capsule (400 µg, thrice daily), oral dydrogesterone \nSR (30 mg; Dydroboon 30 SR, once daily), and intramuscular \nprogesterone (100 mg for 6 days). On day 7 of progesterone \nsupplementation (June 2024), a single-thawed blastocyst was \ntransferred. Thirteen days post-transfer, the serum beta-human \nchorionic gonadotropin (beta-hCG) level was 764 IU/L, and it \nincreased to 2100 IU/L after 4 days. Transvaginal ultrasound at 7 \nweeks of gestation confirmed a single live intrauterine pregnancy.\nAdministration of vaginal micronized progesterone capsule and \noral dydrogesterone was continued until week 10 (12 weeks of \ngestation). There has been no episode of threatened abortion, \nindicating that progesterone levels were adequately maintained. \nThe most recent follow-up in August 2024 revealed ongoing \npregnancy.\nCase 2: LPS in FET despite operated grade 4 endometriosis\nA 31-year-old female, married for 1.5 years, with a 2-year history \nof endometriosis presented with primary infertility. In January \n2022, she received a depot intramuscular injection of leuprolide \n(11.25 mg) for ovarian downregulation. Although her menstrual \ncycle was regular, she experienced prolonged bleeding (8–10 \ndays) and severe dysmenorrhea. In June 2022, she underwent \n\nCitation: Gautam A, Ingale K,  Damdar G, Shaikh A (2025) Effective luteal support with dydrogesterone 30 mg SR in combination with micronized vaginal progesterone \nin frozen embryo transfer and severe endometriosis: Case series. Gynecol Obstet Open Acc 9: 233. DOI: https://doi.org/10.29011/2577-2236.100233\n3\nV olume 09; Issue 01\nGynecol Obstet, an open access journal\nISSN: 2577-2236\nlaparoscopic excision of a 4–5 cm endometriotic cyst in the left \novary. However, during her visit in March 2023, both ovaries were \ndeemed non-approachable due to recurrent endometriosis, and an \nendometriotic cyst (6 cm) was detected in the left ovary.\nOwing to the challenging position of the ovaries for oocyte \nretrieval, a second laparoscopic surgery was performed in \nMarch 2023 to facilitate ovarian mobilization. Intraoperative \nfindings included left hydrosalpinx (which was managed with \nsalpingectomy), recurrence of extensive endometriosis, and a \nnodule on the sigmoid colon, which was excised. The ovaries were \nthen mobilized and placed appropriately in the pelvic cavity for \noocyte retrieval.\nFor ovarian stimulation, HMG 450 IU was initiated in antagonist \nprotocol in September 2023. Eleven cumulus-oocyte complexes \nwere retrieved, yielding eight mature metaphase-2 oocytes. Two \nblastocysts (grade AA and BB) were obtained after 5 days of \nculture and vitrified for future FET.\nThe first FET, using a hormone replacement protocol, resulted \nin a negative beta-hCG test. The patient underwent a second \novarian stimulation cycle in March 2024, yielding 12 cumulus-\noocyte complexes, eight mature oocytes, and two blastocysts. \nLPS was administered using a combination of vaginal micronized \nprogesterone capsule (400 mg thrice daily), oral dydrogesterone \nSR (30 mg; Dydroboon 30 SR once daily), and intramuscular \ninjection of progesterone (100 mg for 6 days). A single blastocyst \nwas transferred, resulting in a positive beta-hCG test 13 days \npost-transfer. Subsequently, ultrasonography confirmed a single \nuterine pregnancy at 7 weeks. LPS was continued until week 10 \n(12 weeks of gestation), with no episode of threatened abortion. \nUltrasound examination showed good sub-endometrial blood flow \nwith adequate endometrial growth (Figure 1). As of September \n2024, the pregnancy had completed 24 weeks of gestation.\nFigure 1: Ultrasound (Color Doppler) examination showed good \nsub-endometrial blood flow with adequate endometrial growth\nDiscussion\nThis report presents two cases where the addition of oral \ndydrogesterone SR 30 mg to vaginal micronized progesterone \nled to successful pregnancies in patients with a challenging \nreproductive history – one patient had a poor ovarian reserve and \nanother had grade 4 endometriosis.\nThe outcomes in Case 1 offer initial evidence to support \nthe combination vaginal micronized progesterone and oral \ndydrogesterone as a viable option for patients with significant \nreproductive challenges. The patient had a history of obstetric \ncomplications and a low ovarian reserve. In IVF cycles, retrieving \n15–20 oocytes is recommended to achieve a 70–80% chance of \nhaving at least one baby in women younger than 38 years [10,11]. \nIn this case, FET was planned following endometrial preparation \ncycle with hormone replacement therapy. A successful pregnancy \ndepends on two key factors: a high-quality, chromosomally normal \nblastocyst and a receptive uterine endometrium [12]. The timing \nof embryo implantation must be synchronized with the optimal \nwindow of endometrial receptivity. Ovarian response is typically \nassessed based on antral follicle count, anti-mullerian hormone \nlevel, and basal follicle-stimulating hormone level [13]. The \nestradiol and LH levels of patient 1 were reduced after 11 days \nafter an intramuscular injection of a GnRH agonist depot 3.75 mg.\nCombined therapy with vaginal micronized progesterone and \ndydrogesterone SR was effective in this case in achieving and \nmaintaining an ongoing pregnancy post-FET. The hormonal regimen \neffectively supported endometrial thickening and satisfactory beta-\nhCG levels without a threatened abortion, indicating adequate \nprogesterone levels during LPS. This case highlights the potential \nfor successful pregnancy outcomes in women with low ovarian \nreserve on using the described combination therapy.\nIn Case 2, the patient had severe (grade 4) endometriosis, which \nis known to significantly and adversely impact fertility [14]. \nMore than 10% of women of reproductive age are diagnosed \nwith endometriosis, and more than 38%–50% of infertility cases \namong women are due to endometriosis [15,16]. A systematic \nliterature review of 19 studies suggests that dydrogesterone is \na safer alternative to gestrinone for managing pelvic pain and \ndysmenorrhea in women of reproductive age, with improved \npregnancy rates and potentially fewer side effects. The review \nsupported the favorable therapeutic profile of dydrogesterone \ncompared to that of gestrinone, GnRH agonists, and other treatments \nin managing endometriosis [17]. However, the difference was not \nstatistically significant. Moreover, few studies have examined the \nefficacy of combining vaginal micronized progesterone with oral \ndydrogesterone in patients with severe endometriosis.\nBefore her successful FET pregnancy, the patient in our second \ncase underwent multiple surgeries, including salpingectomy and \n\nCitation: Gautam A, Ingale K,  Damdar G, Shaikh A (2025) Effective luteal support with dydrogesterone 30 mg SR in combination with micronized vaginal progesterone \nin frozen embryo transfer and severe endometriosis: Case series. Gynecol Obstet Open Acc 9: 233. DOI: https://doi.org/10.29011/2577-2236.100233\n4\nV olume 09; Issue 01\nGynecol Obstet, an open access journal\nISSN: 2577-2236\nlaparoscopic excision of recurrent endometriotic cysts. Ovarian \nstripping and surgical excision of endometriotic cysts can \ncompromise ovarian vascularity and result in local inflammation \nand thermal damage, thereby reducing the ovarian reserve [15]. \nAlthough the number of antral follicles in the second case are \nunknown, combining vaginal micronized progesterone and oral \ndydrogesterone led to a successful intrauterine singleton pregnancy.\nManaging LPS in endometriosis can be challenging due to the \ncomplex nature of the disorder, often involving inflammation \nand reduced endometrial receptivity [15]. Reduced endometrial \nreceptivity, can be treated through prolonged progesterone \nsupplementation and/or increasing serum progesterone levels \n[18]. Substantial variability has been reported in the amount \nof progesterone absorbed through the vagina [19]. Vaginal \nprogesterone administration may have local adverse effects, such \nas vaginal bleeding, irritation, and discharge, potentially impacting \npatient comfort and sexual function [2]. Therefore, increasing the \nduration of progesterone administration using vaginal progesterone \nalone may not be practical from a patient’s perspective [18]. In this \ncontext, combining oral dydrogesterone with vaginal progesterone \nseems promising. Moreover, women with endometriosis often \nrequire multiple daily doses of dydrogesterone, which can be \ninconvenient. Oral dydrogesterone 30 mg SR tablets offer a more \nconvenient treatment option with once-daily dosing, reducing pill \nburden and improving treatment adherence.\nConclusion\nThe two cases presented herein highlight the effectiveness \nof combining vaginal micronized progesterone with oral \ndydrogesterone 30 mg SR in fertility treatments. This approach \nhas shown promise in providing adequate LPS and improving \npregnancy outcomes for patients with poor ovarian reserve \nundergoing FET and those with severe endometriosis.\nAcknowledgements\nThe authors acknowledge Dr. Salini Asok, Dr. Ashwini Maratha, \nand Dr. Sonal Nafade from Neovation Consultancy Services Pvt. \nLtd. for medical writing and editorial support. This research did \nnot receive any specific grant from funding agencies in the public, \ncommercial, or not-for-profit sectors.\nEthical considerations\nBoth patients provided informed consent for the use of anonymized \nimages from their diagnosis and treatment for research purposes, \nensuring that all identifying information would be removed. \nWritten informed consent was obtained from both the patients \ndescribed in this case series.\nConflict of interest\nThe authors declare no conflicts of interest.\nReferences\n1. 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(2024) Is \noral dydrogesterone equivalent to vaginal micronized progesterone for \nluteal phase support in women receiving oocyte donation? Reprod Biol \nEndocrinol 22: 154.","source_license":"CC0","license_restricted":false}