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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.
Progestin-only pills (POPs) are oral contraceptives without estrogen taken daily to prevent pregnancy. POP formulations are safer than currently available combined hormonal contraceptive (CHC) products due to the lack of estrogen-related thromboembolic risk but are thought to be less effective due to less hypothalamic-pituitary-ovarian (HPO) axis suppression and evidence of ongoing ovulation [
]. However, given the similar real-use effectiveness between CHCs and POPs, progestin-induced cervical mucus changes are thought to be one of the primary mechanisms by which POPs prevent pregnancy [
Cervical mucus thickens under the influence of progesterone from the corpus luteum following ovulation or exogenously administered synthetic progestins; this effect results in decreased sperm penetrability [
]. In contrast, rising estradiol levels during the follicular phase results in increasingly fluid mucus prior to ovulation such that, at ovulatory estradiol levels, mucus facilitates sperm entry into the upper reproductive tract. While progestogen-related mucus changes have been observed consistently with all progestin-containing contraception, prior studies of POPs had either very small sample sizes of 5 or 6 participants or had limited to no monitoring of ovarian activity [
In this study, we describe the cervical mucus effects of a norgestrel 0.075 mg POP during an initial 28-day cycle and evaluate the potential for protection against pregnancy by assessing standardized mucus scores in conjunction with ovulation markers and menstrual cycle serum hormone levels. Norgestrel is a racemic mixture of the active levonorgestrel and inactive dextronorgestrel enantiomers. Therefore, a 0.075 mg norgestrel dose is equivalent to a 0.0375 mg levonorgestrel dose. We hypothesized that use of norgestrel 0.075 mg would result in mucus that did not favor fertility even when ovulation occurred.
2. Methods and Materials
We conducted a prospective, multicenter study at Oregon Health & Science University (OHSU), Portland, Oregon, and the University of California, Davis, Sacramento, California. The results reported in this study represent the “perfect use” initial cycle of a 3-cycle study that also assessed the effects of a missed or delayed pill. The details of the study protocol, including the full inclusion and exclusion criteria, have been previously published [
Assessing the pregnancy protective impact of scheduled nonadherence to a novel progestin-only pill: protocol for a prospective, multicenter, randomized, crossover study.
]. A central institutional review board approved the study for both study sites.
Briefly, we recruited persons 18 to 35 years old with a body mass index (BMI) <32.0 kg/m2, regular menstrual cycles every 21 to 35 days by history, and not using hormonal contraception for at least one or more months prior to enrollment (9 months for injectable contraception). Heterosexually active participants not using a permanent contraception method agreed to use condoms for pregnancy prevention. Screening included progesterone evaluation during the mid-luteal phase to confirm ovulation based on a level >3 ng/mL.
Participants had an enrollment visit within 5 days of the next menses after the screening visit. Participants received one 28-day pack of norgestrel 0.075 mg tablets and took the first pill in the office between 0600 and 1200. Staff instructed participants to choose a time of day within 3 hours of initial pill intake to continue once daily pill intake throughout the cycle. Staff asked participants to then take the study pill no more than 1.5 hours before or 1.5 hours after that chosen time of day. Participants completed a daily text-message based e-diary to document study pill use. If participants did not complete a day in the e-diary, staff asked about pill compliance at the next study encounter. We considered a pill as “missed” if the participant indicated no intake on the e-diary or confirmed no intake during a study encounter.
We scheduled follow-up evaluations every 3 to 4 days for cervical mucus assessments, transvaginal ultrasonography to evaluate follicular development, and phlebotomy for serum estradiol and progesterone levels. Investigators assessed for ovulation using transvaginal ultrasonography and serum progesterone testing. Investigators measured all follicles with a single diameter ≥10 mm in three dimensions to calculate a mean follicular diameter. If an investigator observed a follicle ≥15 mm in one dimension, visit frequency changed to every other day to evaluate for a postovulatory sonographic image. If the investigator did not see a postovulatory image within 3 visits, regular visit frequency resumed.
We ensured that each site had one or more expert evaluator based on past experience. The lead investigator (LH) performed a central (in-person) training that included 5 of the OHSU investigators and 2 of the UC Davis investigators with standardized patients as well samples from a repository (comprising the full spectrum of the Insler scale) to ensure independent scores matched. Trained investigators performed any further site-specific training for other investigators. During the trial, 5 investigators scored mucus at OHSU and four investigators scored mucus at UC Davis. To collect mucus, we used a speculum to expose the cervix and a synthetic scopette (Puritan Medical Products) to gently cleanse the external os of any debris or vaginal discharge. We inserted a SelectMucus endocervical aspirator [
] (Cooper Surgical) device one centimeter into the external os before retracting the obturator and using negative pressure to obtain a sample. We immediately scored the mucus sample using a modified Insler score of ferning, spinnbarkeit, viscosity, and cellularity based on the World Health Organization (WHO) guidelines (online Appendix Table 1) [
A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
]. We assigned a score of “0” if an investigator could not obtain a mucus sample because it was too thick. We considered a total cervical mucus score of ≥9 as favorable to fertility, scores between 5 and 8 as intermediate, and scores ≤4 as unfavorable to fertility [
]. We scored mucus at all visits; however, we did not obtain a baseline mucus evaluation in actively menstruating participants.
Serum samples were analyzed for estradiol and progesterone. After collection at the study site, staff used a refrigerated centrifuge to separate serum and then stored samples between −70 and −80°C before estradiol and progesterone analysis in laboratories at each respective site. For specimens shipped from the University of California, Davis, staff sent serum containers on dry ice to the central laboratory. We considered a progesterone level >3ng/mL consistent with ovulation and an estradiol >200 pg/mL consistent with a mid-cycle estradiol surge.
An independent adjudication committee evaluated available cervical mucus, ultrasonography and hormone data to assess if ovulation occurred and determine pregnancy risk based on ovulatory and cervical mucus status. The committee categorized ovarian status as quiescent, active without ovulation, or ovulatory based on follicular size, estradiol, and progesterone levels according to the modified Hoogland score [
The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
]. When ovulation occurred, the committee assessed if the luteal phase appeared normal or abnormal. The committee used standardized measures defined in the protocol a priori (online Appendix Table 2). When the ultrasonography and progesterone level results conflicted regarding ovulation, the committee prioritized the progesterone level.
We used descriptive statistics to characterize participant demographics, hormone levels, and mucus scores. We used cross-tabulations to compare hormone levels with mucus scores as well as hormone levels and mucus scores over time. We evaluated theoretical pregnancy risk over the first cycle (28 days) based on ovulatory activity and peri-ovulatory cervical mucus characteristics. We used the findings of the adjudication committee and re-assessed all original data to provide descriptive outcomes. We performed all analyses using SAS (ver. 9.4 or higher) and Microsoft Excel 365.
We enrolled 52 persons, of whom 51 contributed complete data for this analysis. We excluded data from one participant who the investigator withdrew at 2 weeks due to repeated noncompliance. Characteristics of the 51 participants evaluated in this report are presented in Table 1.
Table 1Characteristics of study participants using norgestrel 0.075 mg daily for 28 days (N = 51)
The 51 participants took 1424 (99.7%) of an expected 1428 pills based on subject diaries and visit records, which included 23 missing diary entries for which the participant confirmed pill intake at the next study encounter. Each participant had between 8 and 11 visits during the 28 days of treatment with ultrasonography, cervical mucus, and hormone evaluations completed at all visits except for 3 missing baseline cervical mucus evaluations and one hormone evaluation (participant with quiescent ovarian activity).
At the enrollment visit, 3 participants did not have baseline mucus scores evaluated due to menses. We found a median baseline mucus score in the remaining 48 participants of 1 (Interquartile Range [IQR] 0, 2) with all scores less than four except for one participant (score = 5). Excluding the enrollment visit, 413 cervical mucus evaluations scored an average of 1.1 (95% CI 0.9–1.3) over the 28-day cycle. In the first week of use, excluding the enrollment visit, three subjects had one mucus score >4. Overall, investigators scored 28 (7%) samples >4 and none ≥9 (favoring fertility). Excluding the enrollment visit, 35 (69%) participants had no mucus scores >4 and 16 (31%) participants had a score 5 to 8, of whom seven had such a score only once.
Figure 1 shows the mean estradiol, progesterone, and mucus scores for all participants over the entire 28-day cycle. Mean estradiol levels ranged from 41.4 ± 21.1 pg/mL (cycle day 1) to 403.5 ± 324.2 pg/mL (cycle day 10). Thirty-nine (76%) participants had an estradiol measurement >200 pg/mL during the cycle, and 18 (35%) had progesterone levels >3 ng/mL. We present the relationship between estradiol levels and mucus scores by examining mucus scores stratified by estradiol level in Table 2 and estradiol level stratified by mucus score in Table 3. We found higher median cervical mucus scores (median 0, interquartile range [IQR] 0,2) when estradiol levels exceeded 200 pg/mL as compared to estradiol levels >100 to 200 pg/mL (median 0, IQR [0,0]), p < 0.001or >50 to 100 pg/mL (median 0, IQR [0,1]), p = 0.046. Of the 28 mucus scores >4, 26 (93%) occurred in visits with an estradiol level exceeding 200 pg/mL and 2 (7%) occurred in visits with estradiol levels between 100 and 200 pg/mL.
Fig. 1Serum estradiol (pg/mL), progesterone (ng/mL), and cervical mucus scores in all participants using norgestrel 0.075 mg daily for 28 days (N = 51).
Table 3Serum estradiol levels of all visits excluding enrollment, stratified by mucus scores in study participants using norgestrel 0.075 mg daily for 28 days (N = 413)
Estradiol (pg/mL)
Mucus scores
0
1–4
5–8
9
Total
<50
2 (0.5)
0
0
0
2 (0.5)
50–100
21 (5.1)
8 (1.9)
0
0
29 (7.0)
>100–200
64 (15.5)
16 (3.9)
2 (0.5)
0
82 (19.9)
>200
173 (41.9)
101 (24.5)
26 (6.3)
0
300 (72.6)
Total
260 (63.0)
125 (30.3)
28 (6.8)
0
413 (100.0)
Data presented as n (%).
Mucus score ≤4: unfavorable to fertility; 5–8: indeterminate; ≥9: favorable to fertility.
Thirty-four (67%, 95% CI 54%–80%) participants had no ovulatory activity and 34 (67%, 95% CI 54%–80%) had mucus evaluations with all scores considered unfavorable to fertility. Based on modified Hoogland scoring, we determined 17 (33%) participants ovulated. Of those ovulatory cycles, 6 (35%) had mucus scores at some time during the 28 days between 5 to 8 and 11 (65%) had scores ≤4. Overall, 48 (94%, 95% CI 88%–100%) participants had full protection against pregnancy with either no ovulation or ovulatory activity with unfavorable cervical mucus (Table 4). The other three participants ovulated with a normal luteal phase but given intermediate mucus scores, the adjudication committee scored them as having “moderate protection.” The details of these three participants clarify the potential pregnancy prevention. One had a single mucus score of 5 on day 12 with a 22.4 mm follicle and a progesterone of 0.5 ng/mL; the highest recorded progesterone level occurred seven days later at 10.9 ng/mL. The second participant had a single mucus score of 5 on day 10 with a 21.3 mm follicle and a progesterone of 0.2 ng/mL; the highest recorded progesterone level occurred eight days later at 5 ng/mL. The third participant had mucus scores of 6 on days 9 and 11 with a 19.8 mm follicle on day 9 and 6.6 mm follicle on day 11. The highest recorded progesterone level occurred on day 18 at 6.6 ng/mL.
Table 4Ovulation status based on modified Hoogland Score and categorized cervical mucus score in participants using norgestrel 0.075 mg daily for 28 days (N = 51)
Ovarian status
Cervical mucus status
Fully protective(Insler score ≤4)
Moderately protective (Insler score 5-8)
No protection(Insler score ≥9)
Ovulation, normal luteal phase
9
3
0
Ovulation, abnormal luteal phase
5
0
0
No Ovulation
17
9
0
Quiescent
8
0
0
Insler score: see online Appendix Table 1 (WHO)].
Cervical mucus scores assessed peri-ovulatory in participants who ovulated; for participants who did not ovulate, scores represent highest score reported during cycle days 8–21.
During the first 28 days of use, persons using a norgestrel 0.075 mg POP are likely protected against pregnancy through a combination of ovulatory and cervical mucus effects. We found that cervical mucus changes were unfavorable even within the first week of pill start and did not demonstrate fertility-favoring characteristics at any point during the cycle. This finding remained consistent even though 75% of participants had serum estradiol measurements at or above ovulatory levels (>200 pg/mL) [
] (1971) evaluated 6 women taking norgestrel 0.075 mcg for a single 28-day cycle and found low mucus and poor sperm penetration throughout the cycle, despite ovulation occurring in three women. In 1968, Roland et al. [
] reported primarily descriptive outcomes from 60 women who used norgestrel 0.050 or 0.075 mg daily for 2 consecutive 30-day cycles following a control (no treatment) cycle. The authors reported that no active sperm could be recovered from the endometrial cavity of participants despite high concentrations of sperm found in the mucus itself. In contrast, the investigators recovered active, motile sperm from the cavity in all untreated cycles. However, this study does not evaluate the mucus itself or ovarian activity/ovulation. Neither of the aforementioned studies report any statistics (i.e., means, variances) or use statistical testing in their manuscripts and we know no information about the subjects other than they were “healthy.” Of note, no prior studies evaluated progestin-dose dependent cervical mucus changes or compared mucus changes in POPs to CHCs [
]. In other studies of progestin containing pills, implants, and IUDs, mucus became more unfavorable after initiating the progestin containing contraceptive. However, comparison across studies is difficult as studies utilized different methods and endpoints for evaluating mucus effects.
Norgestrel 0.075 mg has not been available in the United States since 2005 and is currently under development to be re-introduced as an over-the-counter product. Over the past two decades, newer POPs have been introduced containing higher progestin doses with the ability to suppress ovulation, including desogestrel 0.075 mg and drospirenone 4 mg [
A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen.
]. However, the desogestrel POP is not available in the US and the drospirenone POP is a new prescription-only pill without a low-cost generic option at this time. Although the ovulation rates may be slightly higher with norgestrel POPs than COCs, drospirenone POP, or desogestrel POP, the secondary effects on cervical mucus likely provides high contraceptive protection with consistent use. The most recent Cochrane review found that no firm conclusion is possible concerning the comparative efficacy of POPs or whether such pills are as effective as COCs [
As with other studies of contraceptive mechanisms, our study uses surrogate endpoints for fertility (mucus scores, ovulation) and does not provide direct evidence of contraceptive efficacy. Insler mucus scores are currently the most widely accepted method for appraising cervical mucus and correlate with fertility [
]. However, we lack evidence that mucus changes alone prevent pregnancy as mucus characteristics are directly related to the ovarian and hormonal status of users. This analysis did not evaluate other mechanisms by which POPs may be contraceptive [
]. While there may be unmeasured confounding due to inter-rater variability in both mucus collection and mucus scoring, we tried to minimize this effect by using limited study staff trained in a uniform manner prior to the study start to standardize score interpretation. Although study staff were not blinded to treatment when assessing mucus, they did not know the hormone levels at the time of mucus appraisal and reported consistently low mucus scores across variable estradiol levels such that a small detection bias would not have changed the overall outcome. Although we included women with BMI <32.0 kg/m2, our mean BMI was only 24 kg/m2. Previous studies have found that levonorgestrel levels are lower in obese women compared to non-obese users [
]. However, unlike ovulation, serum progestin levels have not been directly studied with respect to cervical mucus changes. In one study of NORETHINDRONE 0.35 mg, cervical mucus is altered at very low serum NORETHINDRONE levels even while estradiol levels are elevated [
This study examining cervical mucus changes supports the theoretical efficacy of a norgestrel 0.075 mg POP even when ovulation occurs. However, some participants only had “moderate protection” based on intermediate mucus scores, possibly reflecting biological variability in both pharmacodynamic and pharmacokinetic responses to progestins. Additional studies examining duration of cervical mucus effects after delayed or missed pill would further inform clinicians about pill efficacy.
Funding
The study was funded by HRA Pharma. Part of this work was supported by NIH Grant P51OD011092.
Assessing the pregnancy protective impact of scheduled nonadherence to a novel progestin-only pill: protocol for a prospective, multicenter, randomized, crossover study.
A prospective, randomized, pharmacodynamic study of quick-starting a desogestrel progestin-only pill following ulipristal acetate for emergency contraception.
The effects on ovarian activity of delaying versus immediately restarting combined oral contraception after missing three pills and taking ulipristal acetate 30 mg.
A randomised study comparing the effect on ovarian activity of a progestogen-only pill (POP) containing desogestrel and a new POP containing drospirenone in a 24/4 regimen.
Declaration of Competing Interest: LH has no conflicts to declare. MDC has received speaking honorarium from Gedeon Richter, serves on an Advisory Board for Merck, and is a consultant for Estetra, Mayne, Medicines360, and Merck. The Department of Obstetrics and Gynecology, University of California, Davis, receives contraceptive research funding for Dr. Creinin from Chemo Research SL, Evofem, HRA Pharma, Medicines360, Merck, and Sebela. AH is an employee of HRA Pharma. AG acts as an independent, paid, medical consultant to HRA Pharma. MJC is a speaker for Mayne Pharma. AE receives royalties from Up to Date, Inc. Oregon Health & Science University receives research funding from OHSU Foundation, Merck, HRA Pharma, and NIH where AE is the principal investigator. All authors were involved in design, analysis and manuscript preparation. Data acquisition was performed by LH, MC, MC, AE.
p-value represents comparison to estradiol>200 pg/mL group using Wilcoxon rank sum test.IQR: interquartile range (1st and 3rd quartile)
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