title: A dose-finding, cross-over study to evaluate the effect of a Nestorone®/Estradiol transdermal gel delivery on ovulation suppression in normal ovulating women.
abstract: OBJECTIVE
  This study aims to determine the lowest effective of three Nestorone (NES)/estradiol (E2) transdermal gel doses to ensure ovulation suppression in 90-95% of cycles.
  
  
  METHODS
  This was a randomized, open-label, three-treatment-period cross-over study to evaluate the effects of NES/E2 transdermal gel on ovulation inhibition, suppression of follicular growth and pharmacokinetic parameters. The doses were low (1.5 mg NES/0.5 mg E2), medium (3.0 mg NES/1.0 mg E2) and high (4.5 mg NES/1.5 mg E2). Participants applied gel daily to a fixed area on the abdomen for 21 consecutive days. They were interviewed regarding their experiences using the gel.
  
  
  RESULTS
  Eighteen participants were randomized; 16 completed the study. Median NES C(max) values for low, medium and high dose groups at day 21 were 318.6 pmol/L, 783.0 pmol/L and 1063.8 pmol/L, respectively. Median maximum follicular diameter was higher with the lowest dose with 16.2 mm versus 10.0 and 10.4 mm with the medium and high doses, respectively. Among adherent participants, ovulation was inhibited in all dose groups, except for one participant in the medium dose (6.7%) that had luteal activity and an ultrasound image suggestive of a luteinized unruptured follicle. There were few reports of unscheduled bleeding, with more episodes reported for the lower dose. Adverse events were mild, and no skin irritation was reported from gel application.
  
  
  CONCLUSIONS
  While all three doses blocked ovulation effectively and were evaluated as safe and acceptable, the medium dose was considered the lowest effective dose based on a more adequate suppression of follicular development. Further development of this novel contraceptive delivering NES and E2 is warranted and has potential for improved safety compared to ethinyl-estradiol-based methods.
authors.affiliation: Profamilia, Santo Domingo 10401, Dominican Republic. Electronic address: vbrache@gmail.com.
authors.forename: Vivian
authors.initials: V
authors.lastname: Brache
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Merkatz
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Narender
authors.initials: N
authors.lastname: Kumar
authors.affiliation: Instituto Chileno de Medicina Reproductiva, Santiago 8320165, Chile.
authors.forename: Cristian
authors.initials: C
authors.lastname: Jesam
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Sussman
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Elena
authors.initials: E
authors.lastname: Hoskin
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Kevin
authors.initials: K
authors.lastname: Roberts
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Mohcine
authors.initials: M
authors.lastname: Alami
authors.affiliation: Department of Obstetrics/Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Deshawn
authors.initials: D
authors.lastname: Taylor
authors.affiliation: Profamilia, Santo Domingo 10401, Dominican Republic.
authors.forename: Aidelis
authors.initials: A
authors.lastname: Jorge
authors.affiliation: Instituto Chileno de Medicina Reproductiva, Santiago 8320165, Chile.
authors.forename: Horacio
authors.initials: H
authors.lastname: Croxatto
authors.affiliation: Wake Forest University School of Medicine, Winston-Salem, NC 27103, USA.
authors.forename: Ellen
authors.initials: E
authors.lastname: Lorange
authors.affiliation: Department of Obstetrics/Gynecology, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Mishell
authors.affiliation: Center for Biomedical Research, Population Council, New York, NY 10065, USA.
authors.forename: Regine
authors.initials: R
authors.lastname: Sitruk-Ware
mesh_terms: D000279:Administration, Cutaneous; D000328:Adult; D003271:Contraceptive Agents, Female / Q000008:administration & dosage* / Q000493:pharmacokinetics; D018592:Cross-Over Studies; D004338:Drug Combinations; D004717:Endometrium / Q000187:drug effects; D004958:Estradiol / Q000008:administration & dosage; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D005782:Gels; D006801:Humans; D055118:Medication Adherence; D008597:Menstrual Cycle / Q000187:drug effects; D009653:Norprogesterones / Q000008:administration & dosage* / Q000493:pharmacokinetics; D010060:Ovulation / Q000187:drug effects*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism
chemical_list: D003271:Contraceptive Agents, Female; D004338:Drug Combinations; D004967:Estrogens; D005782:Gels; D009653:Norprogesterones; D012738:Sex Hormone-Binding Globulin; D004958:Estradiol; C029167:ST 1435
keywords: Contraception; Estradiol; Nestorone; Transdermal gel