{"paper_id":"fae8c52e-2f81-4a3a-b790-58344a2debee","body_text":"EDITORIAL\nHas ART Finally Got a Patient-Friendly Progesterone?\nGautam N. Allahbadia 1\nPublished online: 1 July 2015\n/C211Federation of Obstetric & Gynecological Societies of India 2015\nAbout the Author\nIntroduction\nProgesterone prepares the endometrium for pregnancy by\nstimulating proliferation in response to human chorionic\ngonadotropin (hCG), which is produced by the corpus\nluteum. This occurs in the luteal phase of the menstrual\ncycle. In assisted reproduction techniques (ART), the\nprogesterone or hCG levels, or both, are low, and the\nnatural process is insufficient, so the luteal phase is sup-\nported with either progesterone, hCG, or gonadotropin-re-\nleasing hormone (GnRH) agonists. Luteal phase support\nimproves implantation rate and thus pregnancy rates, but\nthe ideal method is still unclear. A large recent Cochrane\nreview showed a significant effect in favor of progesterone\nfor luteal phase support, favoring synthetic progesterone\nover micronized progesterone [ 1]. Overall, the addition of\nother substances such as estrogen or hCG did not seem to\nimprove outcomes. Those authors also found no evidence\nfavoring a specific route or duration of administration of\nprogesterone. They found that hCG, or hCG plus proges-\nterone, was associated with a higher risk of ovarian\nhyperstimulation syndrome (OHSS). The use of hCG\nshould therefore be avoided [ 1]. There were significant\nresults showing beneficial effects from the addition of\nGnRH agonist to progesterone in terms of the outcomes of\nlive birth, clinical pregnancy, and ongoing pregnancy. For\nnow, progesterone seems to be the best option as luteal\nGautam N Allahbadia is the Editor-in-chief of the Journal of\nObstetrics & Gynecology of India as well as the IVF Lite (Journal of\nMinimal Stimulation IVF) and Medical Director at Rotunda—The\nCenter For Human Reproduction, Mumbai, India & New Hope IVF,\nSharjah, UAE.\n& Gautam N. Allahbadia\nivfwaladoc@gmail.com\n1 Rotunda—The Center for Human Reproduction, Mumbai,\nIndia\nGautam N. Allahbadia, MD (Doctor of Medicine), is the Editor-in-chief of the Journal of Obstetrics and Gynecology of\nIndia as well as the IVF Lite (Journal of Minimal Stimulation IVF). He is also the Medical Director of Rotunda—The Center\nfor Human Reproduction, the world-renowned fertility clinic at Bandra, Mumbai, India, as well as the New Hope IVF Clinic\nat Sharjah, UAE. He is a noted world authority on Ultrasound-guided Embryo Transfers and one of the pioneers in Third\nParty Reproduction in South-East Asia. Dr. Allahbadia was responsible for India’s first trans-ethnic surrogate pregnancy\ninvolving a Chinese couple’s baby delivered by an unrelated Indian surrogate mother. He has over 100 peer-reviewed\npublications to his credit and is on the Editorial Board of several international journals. Throughout his career, Dr. Allah-\nbadia has been instrumental in developing new fertility-enhancing protocols and propagating the use of Ultrasound in\nEmbryo Transfer procedures. You can read more about his work at www.gautamallahbadia.com.\nThe Journal of Obstetrics and Gynecology of India (September–October 2015) 65(5):289–292\nDOI 10.1007/s13224-015-0731-8\n123\n\nphase support, with better pregnancy results when synthetic\nprogesterone is used [ 1].\nDiscussion\nProgesterone is a natural steroid hormone controlling\nwomen’s reproductive functions [ 2]. In Donor Egg IVF\nrecipients, exogenous progesterone is used for reproducing\nthe endometrial luteal phase-transformative changes [ 3].\nAvailable progesterone preparations include oral-, vaginal-,\noil-based intramuscular (IM) formulations and now aque-\nous subcutaneous (SC) Progesterone [ 4–8]. Oral prepara-\ntions, however, are of limited use in fertility management\nbecause of poor bioavailability [ 7]. Vaginal progesterone\nachieves adequate endometrial transformation, despite\nlower circulating levels of progesterone, but is associated\nwith side effects, e.g., vaginal discharge and/or local irri-\ntation [ 9, 10]. The parenteral intramuscular route reliably\nachieves serum levels of progesterone encountered in the\nnatural luteal phase but can cause severe discomfort and\npain at the injection site [ 11]. A new aqueous progesterone\npreparation for subcutaneous (SC) administration, aimed at\nproviding the advantages of existing parenteral prepara-\ntions without their local tolerability issues, has recently\nbeen developed [ 12, 13]. Considering the advantages given\nby the possibility of self-medication, the SC aqueous for-\nmulation could offer a convenient alternative for patients\non ART treatments.\nWhen GnRH analogs are used for pituitary down regu-\nlation, LH secretion is inhibited, and its effect will be\ncontinued in the luteal phase [ 14]. Abysmally low levels of\nluteal phase LH may be insufficient to promote endometrial\nmaturation to support an early pregnancy. Endogenous LH\nsecretion can be suppressed for as long as 10 days after\nGnRH agonist treatment [ 15, 16]. In order to compensate\nthe low levels, progesterone gel, intramuscular proges-\nterone, and suppository forms of this steroid are used by\nclinicians. Numerous studies have shown that supplemen-\ntary hCG increases the risk of OHSS, and therefore, pro-\ngesterone seems to be the preferred drug [ 17, 18].\nIntramuscular oil-based injections are obviously painful\nand have side effects like abscess formation. On the other\nhand, progesterone suppository may cause lower serum\nlevels which may result in poor implantation; however,\nnumerous clinical trials in this field have had paradoxical\nresults [ 19–21]. Research to find a patient-compliant and\npatient-preferred progesterone protocol in IVF has been\nongoing for the last five decades. In a prospective study of\n206 IVF cases in Texas in 1999, intramuscular proges-\nterone (50 mg daily) and Crinone gel 8 % were compared\n[22]. Vaginal bleeding (11–12 days after ovum pick up)\nwas more frequent in the Crinone gel group; however,\nserum progesterone in the intramuscular group was higher.\nAnother randomized study from Italy comparing intra-\nmuscular and vaginal progesterone showed that proges-\nterone level by using vaginal gel was more stable and gel\nwas comfortably used by the patients [ 23]. In 2013, a novel\naqueous progesterone formulation was developed with\nthree studies published as part of one research paper [ 24].\nThe first study was a three-way cross-over, open-label\nstudy in 24 postmenopausal women. Comparison of the\npharmacokinetic profiles of a single 100-mg dose of\naqueous test product administered by subcutaneous (s.c.)\nand intramuscular (i.m.) injection and an i.m. reference oily\nproduct. The second study was a three-way cross-over open\nlabel study of 25, 50, and 100 mg s.c. single doses of the\naqueous formulation in 12 post-menopausal women. The\nthird study was a Parallel group, observer-blinded study in\n25 fertile women administered multiple s.c. 25 and 50 mg\ndoses of the aqueous formulation once daily for 11 days.\nBaseline-corrected pharmacokinetic parameters were\nevaluated. Aqueous formulation (100 mg) was promptly\nabsorbed, achieving progesterone peak serum levels at an\nearlier time than the reference (1 h vs 7 h; p \\ 0.0001).\nTest and reference were bioequivalent in the extent of\nexposure: confidence intervals for AUC0-t geometric\nmeans ratios were within the prespecified 80–125 % limits.\nPharmacokinetics was linear over the range of doses\nstudied. Steady state was reached within 4 days of multiple\ndose treatment. Sator et al. concluded that the novel pro-\ngesterone aqueous formulation showed similar bioavail-\nability as the reference oil-based product [ 24]. In these\npreliminary studies, it was demonstrated that the serum\nlevels of P achieved with 25 mg were above the threshold\nnecessary for pre-decidualization to occur [ 25, 26]. In\naddition, an earlier phase II study [ 27] performed in 24\nhealthy subjects provided evidence that this aqueous pro-\ngesterone administered SC at a daily dose of 25 or 50 mg\nwas effective at priming the endometrial changes seen in\nthe menstrual cycle in the absence of endogenous P.\nBecause of no difference in the endometrial biopsies hav-\ning been shown between the two doses tested, the lowest\ndose (25 mg/days, which corresponds to the physiologic\namount produced by the ovary in the midluteal phase [ 28]\nwas selected for the phase III trials of LPS in assisted\nreproduction technologies (ART).\nGiven the reluctance of some patients to use vaginal\npreparations owing to the messy administration, vaginal\ndischarge, and, rarely, intolerability, as well as the incon-\nvenience and discomfort associated with prolonged IM\nadministration of P in oil (castor or sesame oil), a water-\nsoluble injectable P has been developed that may be\nadministered by subcutaneous (SC) injection [ 12, 13, 24].\nThis injection is a complex of P and hydroxypropyl-\nb-cyclodextrin in water [ 13] which has been demonstrated\n123\nAllahbadia The Journal of Obstetrics and Gynecology of India (September–October 2015) 65(5):289–292\n290\n\nto produce adequate endometrial decidualization at a daily\ndose of 25 or 50 mg in a dose-finding study [ 27].\nLockwood et al. compared the safety, efficacy, and tol-\nerability of subcutaneous progesterone (Prolutex, 25 mg;\nIBSA Institut Biochimique SA) with vaginal progesterone\ngel (Crinone, 8 %; Merck Serono) for patients subjected to\nluteal phase support (LPS) in assisted reproduction tech-\nnologies (ART) [ 8]. A total of 683 ART patients were ran-\ndomized into two groups: Prolutex, 25 mg subcutaneously\ndaily ( n = 339); and Crinone, 90 mg 8 % gel daily\n(n = 344). On the day of oocyte retrieval, Prolutex or Cri-\nnone gel was begun for LPS and continued for up to\n10 weeks. The nonsignificant difference between the groups\nwas -3.09 % (95 % confidence interval [CI] -9.91 to 3.73),\nindicating noninferiority of Prolutex to Crinone. Delivery,\nand live birth rates resulted to be equivalent between the two\ntreatments (26.8 vs. 29.9 % in the Prolutex and Crinone\ngroups, respectively [ITT]; difference -3.10 [95 % CI\n-9.87 to 3.68]). No statistically significant differences were\nreported for any of the other secondary efficacy endpoints,\nincluding comfort of usage and overall satisfaction. The\nstudy summarized that implantation rate, pregnancy rate,\nlive birth rate, and early miscarriage rate for Prolutex were\nsimilar to those for Crinone. The adverse event profiles were\nsimilar, and Prolutex was safe and well tolerated [ 8].\nA prospective, open-label, randomized, controlled, par-\nallel-group, multicenter, two-arm, non-inferiority study\nwas performed at eight fertility clinics [ 29]. A total of 800\nwomen, aged 18-42 years, with a BMI of B30 kg/m [ 2],\nwith \\3 prior completed assisted reproductive technology\n(ART) cycles, exhibiting baseline (Days 2–3) FSH of\nB15 IU/L, and undergoing IVF at eight centers (seven\nprivate, one academic) in the USA, were enrolled from\nJanuary 2009 through June 2011. In total, 800 women\nundergoing IVF were randomized after retrieval of at least\nthree oocytes to an aqueous preparation of progesterone\nadministered subcutaneously (25 mg daily) or vaginal\nprogesterone (100 mg bid daily). If a viable pregnancy\noccurred, progesterone treatment was continued up to\n12 weeks of gestation. Using a PP analysis, which included\nall patients who received an embryo transfer (Prolu-\ntex = 392; Endometrin = 390), the ongoing pregnancy\nrate per retrieval for subcutaneous versus vaginal proges-\nterone was 41.6 versus 44.4 %, with a difference between\ngroups of -2.8 % (95 % CI -9.7, 4.2), consistent with the\nnon-inferiority of subcutaneous progesterone for luteal\nphase support. In addition, rates of initial positive b-hCG\n(56.4 % subcutaneous vs. 59.0 % vaginal; 95 % CI -9.5,\n4.3), clinical intrauterine pregnancy with fetal cardiac\nactivity (42.6 vs. 46.4 %; 95 % CI -10.8, 3.2), implanta-\ntion defined as number of gestational sacs divided by\nnumber of embryos transferred (33.2 vs. 35.1 %; 95 % CI\n-7.6, 4.0), live birth (41.1 vs. 43.1 %; 95 % CI -8.9, 4.9),\nand take-home baby (41.1 vs. 42.6 %; 95 % CI -8.4, 5.4)\nwere comparable. Both formulations were well tolerated,\nwith no difference in serious adverse events. Analysis with\nthe intention-to-treat population also demonstrated no dif-\nference for any outcomes between the treatment groups.\nBaker et al. concluded that subcutaneous progesterone\nrepresents a novel option for luteal phase support in women\nundergoing IVF who for personal reasons prefer not to use\na vaginal preparation or who wish to avoid the side effects\nof vaginal or IM routes of administration [ 29].\nConclusion\nLevine [30] and later Yanushpolsky et al. [31]c o n fi r m e dt h a t\npatients prefer vaginal over intramuscular progesterone, and\nthis was clearly related to the pain and inconvenience asso-\nciated with IM injections, which are difficult to self-admin-\nister and are painful, even when the injection is administered\nby a nurse. Contemporary IVF, however, relies otherwise\nalmost entirely on subcutaneous injections for agonist,\nantagonist, and gonadotropin therapies, and women feel\ncomfortable in self-administering these injections. Also, some\nwomen because of cultural and religious beliefs, particularly\nonce a pregnancy has been confirmed, are uneasy and reluc-\ntant to insert medication vaginally and are very concerned\nabout the leakage associated with gels and pessaries, fearing\nthat they might have not absorbed completely, and insertion of\na vaginal preparation in case of spotting or vaginal bleeding\ncan be unpleasant. In addition, the vaginal manipulation when\nperformed in a not properly clean environment may increase\nthe risk of genital tract infections, which have been shown to\nbe one of the causes of spontaneous abortion [ 32], preterm\nbirths, and poor pregnancy outcome [ 33] if not treated\nimmediately. This new product may therefore be a patient-\nfriendly alternative for these patients. The option of admin-\nistering progesterone SC for LPS in ART will broaden the\nspectrum of available treatments, an advantage for women\nneeding sustained LPS [34] or disliking vaginal treatments for\ncultural, personal, or medical reasons.\nConflict of interest None.\nReferences\n1. van der Linden M, Buckingham K, Farquhar C, et al. Luteal\nphase support for assisted reproduction cycles. Cochrane Data-\nbase Syst Rev. 20115;(10):CD009154. doi: 10.1002/14651858.\nCD009154.pub2.\n2. Warren MP, Shantha S. Uses of progesterone in clinical practice.\nInt J Fertil Womens Med. 1999;44:96–103.\n3. Gibbons WE, Toner JP, Hamacher P, et al. Experience with a\nnovel vaginal progesterone preparation in a donor oocyte pro-\ngram. Fertil Steril. 1998;69:96–101.\n123\nThe Journal of Obstetrics and Gynecology of India (September–October 2015) 65(5):289–292 Has ART Finally Got a Patient-Friendly Progesterone?\n291\n\n4. Stanczyk FZ. 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HornsteinM.\nCrinone vaginal gel is equally effective and better tolerated than\nintramuscular progesterone for luteal phase support in in vitro\nfertilization-embryo transfer cycles: a prospective randomized\nstudy. Fertil Steril. 2010;94:2596–9.\n32. Donders GG, Van Bulck B, Caudron J, et al. Relationship of\nbacterial vaginosis and mycoplasmas to the risk of spontaneous\nabortion. Am J Obstet Gynecol. 2000;183:431–7.\n33. Flynn CA, Helwig AL, Meurer LN. Bacterial vaginosis in pregnancy\nLockwood G, Griesinger G, Cometti B; 13 European Centers.\nSubcutaneous progesterone versus vaginal progesterone gel for\nluteal phase support in in vitro fertilization: a noninferiority ran-\ndomized controlled study. Fertil Steril. 2014;101(1):112.e3–119.e3.\ndoi: 10.1016/j.fertnstert.2013.09.010.E p u b2 0 1 3O c t1 7\n34. Engmann L, Benadiva C. Agonist trigger: what is the best\napproach? Agonist trigger with aggressive luteal support. Fertil\nSteril. 2012;97:531–3.\n123\nAllahbadia The Journal of Obstetrics and Gynecology of India (September–October 2015) 65(5):289–292\n292","source_license":"CC0","license_restricted":false}