title: A randomized, controlled trial comparing the efficacy and safety of aqueous subcutaneous progesterone with vaginal progesterone for luteal phase support of in vitro fertilization.
abstract: OBJECTIVE
  Is the ongoing pregnancy rate with a new aqueous formulation of subcutaneous progesterone (Prolutex(®)) non-inferior to vaginal progesterone (Endometrin(®)) when used for luteal phase support of in vitro fertilization?
  
  
  CONCLUSIONS
  In the per-protocol (PP) population, the ongoing pregnancy rates per oocyte retrieval at 12 weeks of gestation were comparable between Prolutex and Endometrin (41.6 versus 44.4%), with a difference between groups of -2.8% (95% confidence interval (CI) -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support.
  
  
  BACKGROUND
  Luteal phase support has been clearly demonstrated to improve pregnancy rates in women undergoing in vitro fertilization (IVF). Because of the increased risk of ovarian hyperstimulation syndrome associated with the use of hCG, progesterone has become the treatment of choice for luteal phase support.
  
  
  METHODS
  This prospective, open-label, randomized, controlled, parallel-group, multicentre, two-arm, non-inferiority study was performed at eight fertility clinics. A total of 800 women, aged 18-42 years, with a BMI of ≤ 30 kg/m(2), with <3 prior completed assisted reproductive technology (ART) cycles, exhibiting baseline (Days 2-3) FSH of ≤ 15 IU/L and undergoing IVF at 8 centres (seven private, one academic) in the USA, were enrolled from January 2009 through June 2011.
  
  
  METHODS
  In total, 800 women undergoing IVF were randomized after retrieval of at least three oocytes to an aqueous preparation of progesterone administered subcutaneously (25 mg daily) or vaginal progesterone (100 mg bid daily). Randomization was performed to enrol 100 patients at each site using a randomization list that was generated with Statistical Analysis Software (SAS(®)). If a viable pregnancy occurred, progesterone treatment was continued up to 12 weeks of gestation.
  
  
  RESULTS
  Using a PP analysis, which included all patients who received an embryo transfer (Prolutex = 392; Endometrin = 390), the ongoing pregnancy rate per retrieval for subcutaneous versus vaginal progesterone was 41.6 versus 44.4%, with a difference between groups of -2.8% (95% CI -9.7, 4.2), consistent with the non-inferiority of subcutaneous progesterone for luteal phase support. In addition, rates of initial positive β-hCG (56.4% subcutaneous versus 59.0% vaginal; 95% CI -9.5, 4.3), clinical intrauterine pregnancy with fetal cardiac activity (42.6 versus 46.4%; 95% CI -10.8, 3.2), implantation defined as number of gestational sacs divided by number of embryos transferred (33.2 versus 35.1%; 95% CI -7.6, 4.0), live birth (41.1 versus 43.1%; 95% CI -8.9, 4.9) and take-home baby (41.1 versus 42.6%; 95% CI -8.4, 5.4) were comparable. Both formulations were well-tolerated, with no difference in serious adverse events. Analysis with the intention-to-treat population also demonstrated no difference for any outcomes between the treatment groups.
  
  
  CONCLUSIONS
  The conclusions are limited to the progesterone dosing regimen studied and duration of treatment for the patient population examined in this study.
  
  
  CONCLUSIONS
  Subcutaneous progesterone represents a novel option for luteal phase support in women undergoing IVF who for personal reasons prefer not to use a vaginal preparation or who wish to avoid the side effects of vaginal or i.m. routes of administration.
  
  
  BACKGROUND
  The study was funded by Institut Biochimique SA (IBSA). CAJ, BC, ST and CJ are employees of IBSA. FH currently consults for IBSA.
  
  
  BACKGROUND
  NCT00828191.
authors.affiliation: Department of Obstetrics and Gynecology, Stanford University School of Medicine, Palo Alto, CA, USA vlbaker@stanford.edu.
authors.forename: Valerie L
authors.initials: VL
authors.lastname: Baker
authors.affiliation: IBSA-US Operations, Thousand Oaks, CA, USA.
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Jones
authors.affiliation: Center for Assisted Reproduction, Bedford, TX, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Doody
authors.affiliation: Idaho Center for Reproductive Medicine, Boise, ID, USA.
authors.forename: Russell
authors.initials: R
authors.lastname: Foulk
authors.affiliation: Reproductive Partners Medical Group, Redondo Beach, CA, USA.
authors.forename: Bill
authors.initials: B
authors.lastname: Yee
authors.affiliation: Fertility Physicians of Northern California, San Jose, CA, USA.
authors.forename: G David
authors.initials: GD
authors.lastname: Adamson
authors.affiliation: IBSA, Pambio-Noranco, CH, Switzerland.
authors.forename: Barbara
authors.initials: B
authors.lastname: Cometti
authors.affiliation: Center for Reproductive Medicine, Orlando, FL, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: DeVane
authors.affiliation: Fertility and Surgical Associates, Thousand Oaks, CA, USA.
authors.forename: Gary
authors.initials: G
authors.lastname: Hubert
authors.affiliation: IBSA, Pambio-Noranco, CH, Switzerland.
authors.forename: Silvia
authors.initials: S
authors.lastname: Trevisan
authors.affiliation: Data Management Center, Orange, CA, USA.
authors.forename: Fred
authors.initials: F
authors.lastname: Hoehler
authors.affiliation: IBSA-US Operations, Thousand Oaks, CA, USA.
authors.forename: Clarence
authors.initials: C
authors.lastname: Jones
authors.affiliation: Seattle Reproductive Medicine, Seattle, WA, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Soules
mesh_terms: D000282:Administration, Intravaginal; D000328:Adult; D006063:Chorionic Gonadotropin / Q000097:blood; D004624:Embryo Transfer; D005260:Female; D005307:Fertilization in Vitro; D006801:Humans; D007279:Injections, Subcutaneous; D008183:Luteal Phase / Q000187:drug effects*; D011247:Pregnancy; D011256:Pregnancy Outcome; D011374:Progesterone / Q000008:administration & dosage* / Q000494:pharmacology; D011372:Progestins / Q000008:administration & dosage* / Q000494:pharmacology; D016216:Ultrasonography, Prenatal
chemical_list: D006063:Chorionic Gonadotropin; D011372:Progestins; D011374:Progesterone
keywords: RCT; in vitro fertilization; luteal phase support; progesterone
references.citation: J Assist Reprod Genet. 2003 Dec;20(12):517-20
references.pmid: 15035552
references.citation: Fertil Steril. 2010 Feb;93(2):554-69
references.pmid: 19362305
references.citation: Cochrane Database Syst Rev. 2011 Oct 05;(10):CD009154
references.pmid: 21975790
references.citation: Hum Reprod. 2006 Apr;21(4):905-8
references.pmid: 16373409
references.citation: Fertil Steril. 2014 Jan;101(1):112-119.e3
references.pmid: 24140033
references.citation: Reprod Biol Endocrinol. 2012 Dec 13;10:107
references.pmid: 23237065
references.citation: Fertil Steril. 2012 Feb;97(2):344-8
references.pmid: 22188983
references.citation: Fertil Steril. 2011 Sep;96(3):530-5
references.pmid: 21880274
references.citation: Fertil Steril. 2009 Apr;91(4):1012-7
references.pmid: 18371963
references.citation: Hum Reprod. 2008 Apr;23(4):857-62
references.pmid: 18270182
references.citation: Fertil Steril. 2011 May;95(6):1961-5
references.pmid: 21333984
references.citation: Fertil Steril. 2013 Sep;100(3):860-6
references.pmid: 23806850
references.citation: Fertil Steril. 2009 Jun;91(6):2445-50
references.pmid: 18555224
references.citation: Fertil Steril. 2010 Dec;94(7):2596-9
references.pmid: 20347079
references.citation: Fertil Steril. 2012 Oct;98(4):858-62
references.pmid: 22749223
references.citation: Reprod Biomed Online. 2012 Aug;25(2):139-45
references.pmid: 22683150
references.citation: Fertil Steril. 2013 May;99(6):1543-9
references.pmid: 23465817
references.citation: Gynecol Endocrinol. 2013 Mar;29(3):205-8
references.pmid: 23127204