Original research article| Volume 108, P61-64, April 2022

The use of serum segesterone acetate levels to assess adherence of trial participants with a contraceptive vaginal ring



      To determine the incidence of out-of-range segesterone acetate (NES) concentrations in participants of a pharmacokinetic/pharmacodynamic trial of a continuous use contraceptive vaginal ring (CVR) releasing NES and estradiol (E2). We hypothesized that out-of-range concentrations reflect nonadherent ring use and predict ovulation risk.

      Study Design

      We conducted a secondary analysis of data from a prospective, multi-centered, randomized, Phase IIa dose-finding trial for a CVR releasing NES and E2. Our primary outcome was the risk of ovulation associated with out-of-range NES events. We calculated the 5th and 95th percentile NES concentrations of subjects at steady state to determine high and low cutoffs. We used a Fisher's exact test to determine group differences, and calculated the relative risk of ovulation for each group.


      We analyzed available serum NES data from cycles 2 (n = 172), 3 (n = 156) and 7 (n = 115) to determine the 5th and 95th percentile of all NES concentrations (64, 296 pg/mL). In the 443 cycles of observation, no ovulations occurred in participants with NES concentrations within the expected range. In contrast, we found ovulatory elevations of progesterone in 21 cycles with out-of-range values. Of these, 15 (71%) cycles had evidence of one or more nonadherent low and 6 (29%) one or more unexpected peak. The relative risk of ovulation increased with evidence of multiple non-adherent levels.


      We found out-of-range NES concentrations, suggestive of improper use of a CVR associated with an increased risk of ovulation, with a direct relationship between the number of out-of-range events and the relative risk.


      The results of this study support the use of out-of-range serum NES values as a marker of adherence in contraceptive clinical trials of continuous vaginal rings, and suggest that nonadherence occurs even in early phase clinical trials with close monitoring.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Contraception
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • Lessard LN
        • Karasek D
        • Ma S
        • et al.
        Contraceptive features preferred by women at high risk of unintended pregnancy.
        Perspect Sex Reprod Health. 2012; 44: 194-200
        • Madden T
        • Secura GM
        • Nease RF
        • Politi MC
        • Peipert JF.
        The role of contraceptive attributes in women's contraceptive decision making.
        Am J Obstet Gynecol. 2015; 213: 46.e1-46.e6
        • Walker AW
        • Stern L
        • Cipres D
        • Rodriguez A
        • Alvarez J
        • Seidman D.
        Do adolescent women's contraceptive preferences predict method use and satisfaction? A survey of Northern California family planning clients.
        J Adolesc Health. 2019; 64: 640-647
        • Mcnicholas C
        • Madden T
        • Secura G
        • Peipert JF.
        The contraceptive CHOICE project round up: what we did and what we learned.
        Clin Obstet Gynecol. 2014; 57: 635-643
        • Peipert JF
        • Zhao Q
        • Allsworth JE
        • et al.
        Continuation and satisfaction of reversible contraception.
        Obstet Gynecol. 2011; 117: 1105-1113
        • Trussell J
        • Portman D.
        The creeping Pearl: why has the rate of contraceptive failure increased in clinical trials of combined hormonal contraceptive pills?.
        Contraception. 2013; 88: 604-610
        • Kaunitz AM
        • Portman D
        • Westhoff CL
        • Archer DF
        • Mishell DR
        • Foegh M.
        Self-reported and verified compliance in a phase 3 clinical trial of a novel low-dose contraceptive patch and pill.
        Contraception. 2015; 91: 204-210
        • Westhoff CL
        • Torgal AT
        • Mayeda ER
        • Shimoni N
        • Stanczyk FZ
        • Pike MC
        Predictors of noncompliance in an oral contraceptive clinical trial.
        Contraception. 2012; 85: 465-469
        • Westhoff CL
        • Petrie KA
        • Cremers S.
        Using changes in binding globulins to assess oral contraceptive compliance.
        Contraception. 2013; 87: 176-181
        • Haaland RE
        • Holder A
        • Evans-strickfaden T
        • et al.
        Residual hormone levels in used contraceptive rings as a measurement of adherence to vaginal ring use.
        Contraception. 2017; 95: 602-604
        • Fraser IS
        • Weisberg E
        • Brache V
        • et al.
        Serum Nestorone and ethinyl estradiol levels, and ovulation inhibition in women using three different dosage combinations of a Nestorone progestogen-ethinyl estradiol contraceptive vaginal ring on a bleeding-signaled regimen.
        Contraception. 2005; 72: 40-45
        • Jensen JT
        • Edelman AB
        • Chen BA
        • et al.
        Continuous dosing of a novel contraceptive vaginal ring releasing Nestorone® and estradiol: pharmacokinetics from a dose-finding study.
        Contraception. 2018; 97: 422-427
        • Edelman AB
        • Cherala G
        • Blue SW
        • Erikson DW
        • Jensen JT.
        Impact of obesity on the pharmacokinetics of levonorgestrel-based emergency contraception: single and double dosing.
        Contraception. 2016; 94: 52-57
        • He YL
        • Sabo R
        • Campestrini J
        • et al.
        The effect of age, gender, and body mass index on the pharmacokinetics and pharmacodynamics of vildagliptin in healthy volunteers.
        Br J Clin Pharmacol. 2008; 65: 338-346