The effect of deliberate non-adherence to a norgestrel progestin-only pill: A randomized, crossover study.

OBJECTIVES: To estimate the effects on cervical mucus, ovarian activity and theoretical contraceptive protection of a 6-hour delay and of missing one norgestrel 0.075 mg progestogen-only pill. STUDY DESIGN: In a prospective, two-site, randomized, crossover study, healthy women aged 18 to 35 with BMI <32.0 kg/m² and regular ovulatory cycles completed a baseline 28-day cycle with correct daily pill use followed by two intervention cycles in which, around mid-cycle, one pill was taken 6 hours late or missed completely. We undertook ovarian ultrasonography, estradiol and progesterone measurement, and cervical mucus assessments every 3 to 4 days (daily around the time of the incorrect use) and based the theoretical contraceptive protection score on ovarian activity status, cervical mucus and their temporal relationship. RESULTS: Of 91 potential participants screened, 52 started the study and 46 provided complete data for each intervention cycle. Fourteen participants (30%) ovulated in each of the two intervention cycles, with four during the delayed pill cycle and two during the missed pill cycle having an abnormal luteal phase. Seven participants in the delayed pill cycle, and six with a missed pill had elevated cervical mucus scores temporally associated with the intervention. However only two women, one in the delayed pill cycle and one in the missed pill cycle, had cervical mucus scores in the range considered favorable for fertility. CONCLUSIONS: Delayed or missed intake of a single norgestrel 0.075 mg progestogen-only pill appears to have little effect on theoretical contraceptive efficacy. IMPLICATIONS: This biomedical study suggests that taking a norgestrel 0.075mg progestogen-only pill 6 hours late or missing one pill have little effect on ovarian activity or cervical mucus and may not jeopardize contraceptive efficacy. Correlation with typical use outcomes is necessary to confirm pregnancy risk with delayed or missed norgestrel intake.

Mechanism of action of a 0.075 mg norgestrel progestogen-only pill 2. Effect on cervical mucus and theoretical risk of conception.

OBJECTIVE: To evaluate the cervical mucus effects of a norgestrel 0.075 mg progestin-only contraceptive pill over a 28-day cycle. STUDY DESIGN: We recruited persons ages 18 to 35 with normal cycles at 2 US academic medical centers. Participants took norgestrel 0.075 mg daily for 28 days at the same time (within a 3 hour window) daily, recorded through a text-message based e-diary. We extracted cervical mucus using a standardized aspiration technique on the day of pill initiation and then at least every 3 to 4 days over the cycle. We monitored subjects for follicular activity with transvaginal ultrasound examination and blood sampling for ovarian hormones and gonadotropins at each visit. We assessed cervical mucus scoring using a 4-category/12-point modified Insler scale (score ≥9 [favoring fertility], 5-8 [intermediate], and ≤4 [unfavorable to fertility]). We stratified cervical mucus scores by serum estradiol levels and ovulatory status based on a modified Hoogland score. RESULTS: Excluding enrollment, we collected and evaluated 413 mucus samples from 51 participants. Participants had a median mucus score of 0 (Interquartile Range 0, 2); most had scores ≤4 (samples = 385, 93%) and none had a score ≥9 favoring fertility. Seventeen (33%) participants ovulated, of which 14 (82%) had unfavorable mucus scores (≤4) at the time of ovulation and 3 (18%) had intermediate scores (5-8). CONCLUSIONS: Norgestrel 0.075 mg daily prevents mucus changes that favor fertility, even during ovulatory cycles. IMPLICATIONS: Daily administration of norgestrel 0.075 mg over an initial 28-day cycle did not result in fertile cervical mucus. Although approximately one-third of users ovulated in this first cycle of pill use, contraceptive efficacy may be maintained by mucus effects.

Mechanism of action of norgestrel 0.075 mg a progestogen-only pill. I. Effect on ovarian activity.

OBJECTIVE: To explore the effect on ovarian activity and ovulation of 28 days of correct daily use of a progestogen-only pill containing norgestrel 0.075 mg. STUDY DESIGN: We performed a prospective, randomized, crossover study at 2 US sites, recruiting healthy women of reproductive age to use norgestrel 0.075 mg daily for three 28-day treatment cycles. We monitored ovarian activity every 3 to 4 days with reproductive hormone measurements and ovarian ultrasonography. Participants recorded pill use in daily diaries. An adjudication committee independent of the research sites assessed ovarian activity using a modified Hoogland score combining hormone concentrations and follicle diameter and appearance (quiescence 1-3, ovarian activity without ovulation 4-5, and ovulatory/postovulatory 6-7). RESULTS: We report here the findings of the initial 28-day treatment cycle in which 51 of 52 recruited participants provided data sufficient for analysis. Two thirds of subjects had no evidence of ovulation (34/51, 66.6%); eight of these (15.7%) had quiescent ovaries (follicle <13 mm diameter) and 26 (51%) had follicular development (follicle >13 mm diameter) without ovulation. Seventeen participants ovulated, of whom 12 (23.5%) had a normal, and 5 (9.8%) an abnormal luteal phase. Persistent ovarian follicles were common among women who had ovarian activity without ovulation, 17 of 26 participants (65.4%) had a large follicle which persisted beyond 28 days. CONCLUSION: During 28 days of exposure to a norgestrel 0.075 mg progestogen-only pill, most women had no evidence of ovulation. IMPLICATIONS: Ovulation inhibition and follicle growth disturbance are important in the mechanism of action of a progestogen-only pill containing norgestrel 0.075 mg.

Assessing the Pregnancy Protective Impact of Scheduled Nonadherence to a Novel Progestin-Only Pill: Protocol for a Prospective, Multicenter, Randomized, Crossover Study.

BACKGROUND: Progestin-only contraceptive pills (POP) are commonly reserved for women with medical comorbidities but in actuality, POPs can be safely used by anyone wanting to prevent pregnancy. This wide safety profile makes them an ideal candidate for being available over the counter without a prescription, but adherence issues may be more common with over-the-counter use. We need a better understanding of the ability of POPs to prevent pregnancy when adherence issues occur in the form of a missed or delayed pill. OBJECTIVE: This study aims to determine cervical mucus characteristics following a 6-hour delayed pill intake or after one missed pill as compared to typical daily use of norgestrel 75 mcg. METHODS: This prospective, multicenter, randomized, crossover study assesses the effect of norgestrel 75 mcg (Opill) on cervical mucus and ovarian activity during reported compliant daily use, after a 6-hour delayed intake mid cycle, and after a mid-cycle missed pill. Subject participation will last approximately 4.5 months. We will recruit at 2 US sites: Oregon Health & Science University, Portland, Oregon and University of California Davis Health, Sacramento, California. Reproductive-aged subjects with regular menstrual cycles (21-35 days), BMI <32 kg/m2, and proven ovulation (screening luteal phase progesterone >3 ng/mL [>10 nmol/L]) are eligible to enroll. Participants cannot be at risk for pregnancy during the study period and not use other hormonal methods. Norgestrel 75 mcg will be taken at the same time daily except for one day in each of treatment periods 2 and 3, when the pill will be taken either 6 hours late (delayed pill) or omitted completely (missed pill). Every 3-4 days, we will monitor subjects for follicular activity with transvaginal ultrasound (TVUS) examination, cervical mucus, and blood sampling for ovarian hormones and gonadotropins. Subjects will undergo serial cervical mucus sampling on the days with missed and delayed pill intake at 8 hours after pill intake on the day before the delayed or missed pill, 3 hours following the scheduled time of pill intake if intake was delayed, 6 hours after the scheduled time if intake was omitted, and on the next day 30 minutes before the time of scheduled pill intake. The primary objective of the study is to determine the effect of a delayed or omitted pill intake on cervical mucus characteristics based on a modified Insler score compared to reported daily use. RESULTS: Our protocol was successfully approved by a central institutional review board (Advarra, Columbia, MD), received ethical approval on March 23, 2018, and was registered with ClinicalTrials.gov (NCT03585712). As of January 2020, the study completed enrollment of 52 subjects. Analyses are pending. CONCLUSIONS: Our protocol was approved by a central review board, and study procedures were successfully executed with completed proposed enrollment. TRIAL REGISTRATION: ClinicalTrials.gov NCT03585712; https://clinicaltrials.gov/ct2/show/NCT03585712. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/29208.