Double Dosing Levonorgestrel-Based Emergency Contraception for Individuals With Obesity: A Randomized Controlled Trial.

OBJECTIVE: To assess whether dose escalation (ie, doubling the dose) of emergency contraception that contains levonorgestrel (LNG) improves pharmacodynamic outcomes in individuals with obesity. METHODS: We enrolled healthy, reproductive-age individuals with regular menstrual cycles, body mass index (BMI) higher than 30, and weight at least 176 lbs in a randomized pharmacodynamic study. After confirming ovulation (luteal progesterone level greater than 3 ng/mL), we monitored participants with transvaginal ultrasonography and blood sampling for progesterone, luteinizing hormone, and estradiol every other day until a dominant follicle measuring 15 mm or greater was visualized. At that point, participants received either oral emergency contraception with LNG 1.5 mg or 3 mg (double dose) and returned for daily monitoring for up to 7 days. Our primary outcome was the difference in the proportion of participants with no follicle rupture 5 days postdosing (yes or no) between groups. The study had 80% power to detect a 30% difference in the proportion of cycles with at least a 5-day delay in follicle rupture (50% decrease). RESULTS: A total of 70 enrolled and completed study procedures. The two groups had similar baseline demographics (mean age 28 years, BMI 38). We found no difference between groups in the proportion of participants without follicle rupture more than 5 days post-LNG dosing (LNG 1.5 mg: 18/35 [51.4%]; LNG 3.0 mg: 24/35 [68.6%], P=.14). Among participants with follicle rupture before 5 days, the time to rupture did not differ between groups (day at 75% probability of no rupture is day 2 for both groups). CONCLUSION: Individuals with higher BMIs and weights experience a higher risk of failure of emergency contraception with LNG and exhibit an altered pharmacokinetic profile. However, the simple strategy of doubling the dose does not appear to be an effective intervention to improve outcomes. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, 02859337.

Simultaneous assay of segesterone acetate (Nestorone®), estradiol, progesterone, and estrone in human serum by LC-MS/MS.

OBJECTIVE: To develop a method to simultaneously quantify the synthetic contraceptive progestin segesterone acetate (Nestorone®, NES) and the endogenous steroid hormones estradiol (E2), progesterone (P4), and estrone (E1) in human serum samples by liquid chromatography-tandem mass spectrometry (LC-MS/MS). STUDY DESIGN: We analyzed 615 serum samples collected from 67 reproductive-age women actively using a contraceptive vaginal ring (CVR) designed to release NES (200 mcg/d) and E2 (75-200 mcg/d). Samples were taken prior to and up to 30 days after CVR insertion and analyzed for concentrations of NES, E2, P4, and E1 in human serum using a Shimadzu Nexera-LCMS-8050 LC-MS/MS platform. Precision, accuracy, and sensitivity for all analytes were determined across multiple assays. RESULTS: The assay ranges for NES, E2, P4, and E1 in this analytical method were 10 pg/mL to 10 ng/mL with a lower limit of quantification of 10 pg/mL for all targets. Assay precisions were less than or equal to 14.5% and accuracies ranged from 87.0% to 110.8%. When applied to the 615 clinical samples, 550 samples had quantifiable concentrations of NES (value range 0.014-1471 ng/mL). Similarly, 595 samples had quantifiable concentrations of E2 (0.010-0.312 ng/mL), 596 samples had quantifiable concentrations of P4 (0.010-5.791 ng/mL), and 609 samples had quantifiable concentrations of E1 (0.010-0.416 ng/mL). CONCLUSIONS: The LC-MS/MS platform results in a robust, accurate, and sensitive method for the simultaneous quantification of NES and endogenous steroid hormones in human serum. IMPLICATIONS: The analytical method described allows for the simultaneous quantification of NES and endogenous steroids and can be used to monitor NES concentrations during clinical trials and subject adherence to treatment with NES.

Treatment of Unfavorable Bleeding Patterns in Contraceptive Implant Users: A Randomized Controlled Trial.

OBJECTIVE: To evaluate whether a short course of tamoxifen decreases bothersome bleeding in etonogestrel contraceptive implant users. METHODS: In a 90-day, double-blind randomized control trial, we enrolled etonogestrel implant users with frequent or prolonged bleeding or spotting. A sample size of 40 per group (N=80) was planned to compare 10 mg tamoxifen or placebo twice daily for 7 days after 3 consecutive days of bleeding or spotting no more than once per 30 days (maximum three treatments). Participants then entered a 90-day open-label study where all received tamoxifen if needed every 30 days (maximum three treatments). Participants used text messages to record daily bleeding patterns. Our primary outcome was the total number of consecutive amenorrhea days after the first treatment. Secondary outcomes included time to bleeding or spotting cessation and restart after first treatment, overall bleeding patterns, and satisfaction. RESULTS: From January 2017 to November 2018, 112 women enrolled in the study; 88 (79%) completed 90 days, and 79 (71%) completed 180 days. Participant characteristics did not differ between groups; mean age 24, majority identified as white not Hispanic with at least some college education. After the first treatment, the tamoxifen group reported an average of 9.8 (95% CI 4.6-15.0) more consecutive days of amenorrhea and more total days of no bleeding (amenorrhea or spotting) in the first 90 days (median 73.5 [range 24-89] vs 68 [range 11-81], P=.001). The placebo group showed a similar treatment benefit after first active use of tamoxifen in the open-label phase. At the end of the randomized study (first 90 days), women who received tamoxifen reported higher satisfaction (median 62 mm [range 16-100]) than those treated with placebo (46 mm [range 0-100]; P=.023). CONCLUSION: A short course of tamoxifen reduces problematic bleeding and improves satisfaction in users of etonogestrel implants. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, NCT02903121.

Combined oral contraceptive interference with the ability of ulipristal acetate to delay ovulation: A prospective cohort study.

OBJECTIVE: To determine if a combined oral contraceptive (COC) initiated shortly after ulipristal acetate (UPA) administration interferes with its mechanism of action. STUDY DESIGN: Healthy, reproductive-age women of normal BMI with proven ovulation (serum progesterone >3 ng/ml) were enrolled for three cycles (Cycle 1, UPA only; Cycle 2 washout; Cycle 3 UPA plus COC). During Cycles 1 and 3, subjects were monitored with transvaginal ultrasound and blood sampling for progesterone and LH every other day until a dominant follicle measuring >15 mm was visualized. In both treatment cycles, subjects received UPA (30mg) and were followed daily with similar monitoring for up to 7 days. In Cycle 3 only, subjects initiated a daily COC (0.15 mg levonorgestrel/30 µg ethinyl estradiol) 2 days after UPA. The study had 80% power to detect a 15% difference in the proportion of cycles with at least a 5-day delay in follicle rupture. We assessed follicle rupture as >50% decrease in mean size and adjudicated unclear outcomes with serum hormones. RESULTS: A total of 36 women enrolled and 33 completed all study procedures [age 28.4 years (SD 3.9); BMI 23.4 (SD 2.4)]. Compared to Cycle 1, more subjects demonstrated evidence of follicle rupture in <5 days in Cycle 3 [1/33 (3%) vs. 9/33 (27%), p = .008]. We also included data from 2 subjects who experienced rupture prior to COC dosing in the analysis. CONCLUSION: UPA's effectiveness is significantly reduced by administering COCs 2 days later. IMPLICATIONS: This study demonstrates that UPA's efficacy as an emergency contraceptive is reduced with early exposure to COCs.

Tamoxifen for the treatment of breakthrough bleeding with the etonogestrel implant: a randomized controlled trial.

OBJECTIVE: The etonogestrel (ENG) subdermal implant can cause frequent breakthrough bleeding in some users. The objective of this study was to evaluate whether a short course of tamoxifen reduces bleeding/spotting days compared to placebo in ENG implant users. STUDY DESIGN: In this double-blind trial, we randomized ENG implant users with frequent or prolonged bleeding or spotting to tamoxifen 10 mg or placebo twice daily for 7 days, to be started after 3 consecutive days of bleeding/spotting. Treatment was repeated as needed up to three times in 180 days. Subjects completed a daily text message bleeding diary. A sample size of 56 provided 80% power to detect a difference of 6 days of bleeding/spotting per 30 days by two-sample t test. Ovulation was monitored by urinary metabolites of progesterone. RESULTS: From March 2014 to February 2015, 56 women enrolled. Fifty-one completed at least 30 days of follow up, and 34 completed 180 days. Compared to women randomized to placebo, women randomized to tamoxifen reported 5 fewer days of bleeding/spotting over 30 days (95% confidence interval [CI] -9.9 to -0.05, p=.05), and 15.2 more continuous bleeding-free days (95% CI 2.8-27.5 days, p=.02) after first use of study drug. Conclusions could not be drawn after 30 days due to higher-than-expected dropout. No ovulation was detected. CONCLUSION: First use of tamoxifen by ENG implant users reduces bleeding/spotting days and provides a longer cessation of bleeding/spotting than placebo, without compromising ovulation suppression. Further study is needed to determine whether this effect is maintained with repeat use. IMPLICATIONS: Women with frequent ENG implant-related breakthrough bleeding may experience a reduction in bleeding/spotting days and an increase in continuous bleeding-free days in the month following first use of tamoxifen. This short course of tamoxifen was well tolerated with bleeding cessation noted within a median of 5 days.

Comparison of interventions for pain control with tenaculum placement: a randomized clinical trial.

OBJECTIVE: Although previous studies have demonstrated that a variety of local anesthetics are effective to decrease pain associated with tenaculum placement, no studies directly compare an injection with a topical anesthetic. The objective of this study was therefore to compare mean pain scores with tenaculum placement after an intracervical lidocaine injection or topical lidocaine gel. STUDY DESIGN: A randomized, single-blinded trial of women presenting for office gynecologic procedures that required a tenaculum. Women aged 18 years or older were randomized to receive either a 1% lidocaine intracervical injection or topical application of 2% lidocaine gel to the cervix immediately prior to tenaculum placement. The primary outcome was pain at the time of tenaculum placement, measured on a 100 mm Visual Analog Scale. Secondary outcomes included pain with the intervention and satisfaction with tenaculum placement. RESULTS: Seventy-four women were enrolled and randomized; 35 subjects in each group met criteria for analysis. The two groups had similar socio-demographic characteristics. Women who received the injection had lower mean pain levels at tenaculum placement [12.3 mm (S.D. 17.4 mm) versus 36.6 mm (S.D. 23.0 mm), p<.001] but higher mean pain levels with study drug application [20.4 mm (S.D. 19.4 mm) versus 5.9 mm (S.D. 8.6 mm), p<.001]. Satisfaction with tenaculum placement was similar for the two groups. CONCLUSION: Mean pain with tenaculum placement is lower after receiving a lidocaine injection than after receiving a topical lidocaine gel. Satisfaction with tenaculum placement is similar with both interventions.

Effect of a combined estrogen and progesterone oral contraceptive on circulating adipocytokines adiponectin, resistin and DLK-1 in normal and obese female rhesus monkeys.

BACKGROUND: Hormonal contraception is the most common medication used by reproductive aged women but there is little understanding of the impact of hormonal contraception on obesity and metabolism. Adipokine levels (adiponectin, resistin) and markers of adipocyte development (DLK-1) are altered in obese animals and humans and are associated with increased cardiovascular risk. We sought to determine the effect of combined hormonal oral contraceptive pills (COCs) on circulating adiponectin, resistin and DLK-1 levels in obese and normal-weight rhesus macaque monkeys. METHODS: Serum adiponectin, resistin and DLK-1 levels in reproductive-age female rhesus macaques of normal (n = 5, mean = 5.76 kg) and inherently obese (n = 5, mean = 8.11 kg) weight were determined before, during and 2 months after cessation of 8 months of continuous treatment with COCs. RESULTS: The obese group alone showed a significant decrease (p<.01) in weight with COC use, which returned to baseline after COC cessation. Baseline adiponectin levels prior to COC treatment were lower in the obese group (p<.05). Adiponectin levels increased from baseline in both groups, but more so in the obese group (p<.05). Resistin levels were similar at baseline, with an increase in both groups following treatment. Circulating resistin remained elevated above baseline levels after COC cessation, particularly in the obese group (p<.05). While DLK-1 levels did not change significantly in either group, a trend for higher levels in obese animals was observed. CONCLUSIONS: COC use may alter metabolic processes via direct (resistin) or indirect (adiponectin) means, while unchanging DLK1 levels suggest they do not affect adipocyte development. COCs may directly increase resistin levels, as observed in both groups. As adiponectin is inversely related to adipocyte mass, increased levels in the obese group are likely attributed to weight loss.

Prolonged monitoring of ethinyl estradiol and levonorgestrel levels confirms an altered pharmacokinetic profile in obese oral contraceptives users.

BACKGROUND: Pharmacokinetic (PK) parameters based on short sampling times (48 h or less) may contain inaccuracies due to their dependency on extrapolated values. This study was designed to measure PK parameters with greater accuracy in obese users of a low-dose oral contraceptive (OC) and to correlate drug levels with assessments of end-organ activity. STUDY DESIGN: Obese [body mass index (BMI) ≥30 kg/m2], ovulatory, otherwise healthy women (n=32) received an OC containing 20 mcg ethinyl estradiol (EE)/100 mcg levonorgestrel (LNG) for two cycles. EE and LNG PK parameters were characterized for 168 h at the end of Cycle 1. During cycle 2, biweekly outpatient visits were performed to assess cervical mucus, monitor ovarian activity with transvaginal ultrasound and obtain serum samples to measure EE, LNG, estradiol and progesterone levels. PK parameters were calculated and correlated with end-organ activity and compared against control samples obtained from normal and obese women sampled up to 48 h in a previous study. Standard determination of PK accuracy was performed, defined by the dependency on extrapolated values ('excess' area under the curve of 25% or less). RESULTS: The mean BMI was 39.4 kg/m2 (SD 6.6) with a range of 30-64 kg/m2. Key LNG PK parameters were as follows: clearance, 0.52 L/h (SD 0.24); half-life, 65 h (SD 40); area under the curve (AUC), 232 h*ng/mL (SD 102); and time to reach steady state, 13.6 days (SD 8.4). The majority of subjects had increased ovarian activity with diameter of follicles ≥8 mm (n=25), but only seven women had follicles ≥10 mm plus cervical mucus scores ≥5. Evidence of poor end-organ suppression did not correlate with the severity of the alterations in PK. As compared to historical normal and obese controls (48-h PK sampling), clearance, half-life, AUC and time to reach steady state were found to be significantly different (p≤.05) in obese women undergoing a longer duration of PK sampling (168 h). Longer sampling also improved PK accuracy for obese women (excess AUC 20%) as compared to both normal and obese controls undergoing shorter sampling times (48 h) with excess AUCs of 25% and 50%, respectively. CONCLUSIONS: Obesity results in significant alterations in OC steroid PK parameters, but the severity of these alterations did not correlate with end-organ suppression. A longer PK sampling interval (168 h vs. 48 h) improved the accuracy of PK testing.

Obesity epidemic: how to make a difference in a busy OB/GYN practice.

At just one-third of the American population, those with a normal body mass index are now in the minority in the United States, whereas 68% are overweight or obese. The key to reducing the prevalence of obesity and improving the health of our population is, of course, screening and prevention. Screening (as simple as a weight and height) is effective, inexpensive, and already part of the routine vital signs taken at every visit. However, providers often avoid tackling the issue of weight due to a misperception that treatment is not effective, or from fear of causing offense or compromising rapport. However, clearly more harm is done by not discussing this important health issue. Cardiovascular disease remains the number 1 killer of women, and obesity is the leading modifiable risk factor. Beyond heart disease, obesity has implications for every visit type seen in the OB/GYN office, from contraception to pregnancy to abnormal bleeding to cancer. In addition, maternal obesity adversely affects future generations, making the impact of obesity a never-ending cycle. OB/GYNs are often the only physicians that reproductive-aged women see, and, thus, OB/GYNs have the opportunity to provide a potentially life-altering intervention. Effective treatment is available and includes lifestyle changes, behavioral counseling, medication, and bariatric surgery. Time is always a limitation in a busy practice but becoming more comfortable with how to approach patients, the language to use and tailoring counseling can save time increase impact.

Pain experienced using two different methods of endometrial biopsy: a randomized controlled trial.

OBJECTIVE: To compare patient-reported pain, provider- reported ease of use, and tissue sampling adequacy between endometrial biopsy instruments. METHODS: Women presenting for endometrial biopsy were randomized to either Pipelle or Explora curette. The primary outcome was patient-reported pain with biopsy as measured by a 100-mm visual analog scale. Secondary outcomes included the adequacy of biopsy sample and provider-reported ease of instrument use. RESULTS: Groups were similar in respect to age, parity, ethnicity, level of dysmenorrhea, menopausal status, and biopsy indication. The most common indication for biopsy was abnormal uterine bleeding. Subject reported pain with biopsy was similar between groups (Pipelle, 6.21 ± 2.41 cm; Explora, 6.91 ± 2.88 cm; P=.14), as was provider-reported ease of use. Although procedure length was significantly shorter for patients in the Pipelle group (4.05 ± 1.48 minutes compared with 5.27 ± 2.53 minutes; P=.007), 38% of Pipelle procedures required two or more passes to obtain a sample compared with only 9% using the Explora (P=.004). The Explora group had a higher proportion of adequate samples (97% compared with 91%; P=.33). CONCLUSION: Women's pain during endometrial biopsy does not differ by type of biopsy instrument used. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov NCT00613925.

A nonhormonal model for emergency contraception: prostaglandin synthesis inhibitor effects on luteal function and lifespan, a pilot study.

OBJECTIVES: The purpose of this study is to determine if the use of a specific prostaglandin endoperoxide-2 inhibitor will prevent luteal development in women. STUDY DESIGN: Ovulatory reproductive-aged women not using or needing hormonal contraception were prospectively followed for three menstrual cycles. Women were randomized into two groups using a crossover design [Group 1: control cycle, placebo cycle, active drug (celecoxib 400 mg orally) cycle; Group 2: control cycle, celecoxib cycle, placebo cycle]. Study drug was dosed daily until the onset of the next menses. Demographics, menstrual cycle length and twice-weekly progesterone (P) levels during the placebo and active drug cycles were recorded. End points included the change in luteal phase P levels and menstrual cycle length (days) during active drug exposure. RESULTS: A total of 11 women completed the study (Group 1, n=7; Group 2, n=4). No demographic differences were found between groups [age, race, body mass index (BMI), control cycle length]. A comparison of the control and active drug cycles for all participants demonstrated a trend toward a longer menstrual cycle with active drug exposure [control, 27.2 days (SD, 2.4); study drug, 28.5 days (SD, 2.5), p=.09]. Five women had a delay in the rise of their luteal phase P levels, two women had lower peak P levels and two women had no elevation of luteal phase P levels during active drug cycle as compared to placebo cycle. CONCLUSION: Daily administration of a prostaglandin synthesis inhibitor may delay the timing of luteal events and, therefore, fertility in women. PTGS2 inhibitors may hold potential as an emergency contraceptive.

Impact of obesity on oral contraceptive pharmacokinetics and hypothalamic-pituitary-ovarian activity.

BACKGROUND: This study was conducted to determine whether increased body mass index (BMI) affects oral contraceptive (OC) pharmacokinetics and suppression of hypothalamic-pituitary-ovarian (HPO) axis activity. STUDY DESIGN: Ovulatory reproductive-age women with normal weight (BMI <25 kg/m(2); n=10) and with obesity (BMI >30 kg/m(2); n=10) received OCs for two cycles (prospective cohort). Subjects were admitted for two 48-h inpatient stays at the beginning and end of the hormone-free interval. Ethinyl estradiol and levonorgestrel (LNG) levels were evaluated during both inpatient stays. Gonadotropin pulsatility (follicle-stimulating hormone and luteinizing hormone) was measured during the second inpatient stay. Estradiol (E(2)) and progesterone (P) were measured daily during inpatient stays and twice per week in Cycle 2. RESULTS: BMI was greater in the obese compared to the normal-BMI group [37.3 kg/m(2) (SD, 6.0) vs. 21.9 kg/m(2) (SD, 1.6); p<.05]. The LNG half-life was significantly longer in the obese group (52.1+/-29.4 vs. 25.6+/-9.3 h, p<.05), which correlated with a lower maximum LNG concentration on Cycle 2, Day 1 [1.9 ng/mL (SD, 0.5) vs. 2.5 ng/mL (SD, 0.7)] and a longer time to reach steady state (10 vs. 5 days) in obese women. There were no significant differences in volume of distribution between groups. LH pulse parameters did not differ statistically between groups but trended toward greater HPO activity in the obese group. Additionally, more obese (6/10 vs. 3/10 normal BMI, p>.05) women exhibited E(2) levels consistent with development of a dominant follicle and P levels consistent with ovulation (2/10 vs. 1/10) during Cycle 2. CONCLUSIONS: Compared to women with normal BMI, obese women exhibit differences in OC pharmacokinetics that are associated with greater HPO activity.

Continuous oral contraceptives: are bleeding patterns dependent on the hormones given?

OBJECTIVE: To estimate whether progestin type or estrogen dose influences bleeding patterns, adverse effects, or satisfaction with combined oral contraceptives dosed continuously. METHODS: This was a randomized, double blind, 4-arm active treatment study. Subjects received either 100 microg levonorgestrel/20 microg ethinyl estradiol (E2) (20LNG group), 100 microg levonorgestrel/30 microg ethinyl E2 (30LNG group), 1,000 microg norethindrone acetate/20 microg ethinyl E2 (20NETA group), or 1,000 microg norethindrone acetate/30 microg ethinyl E2 (30NETA group) for 180 days. Subjects logged bleeding events and adverse effects on a daily menstrual calendar. An exit survey measured satisfaction with bleeding patterns. RESULTS: One hundred thirty-nine women were enrolled. Patients in the 20NETA and 30NETA arms had significantly more days of amenorrhea than the 30LNG arm in the second 90 days (P < .008). The 30LNG group reported more spotting days than the 20NETA group over the entire study period (P < .008) and the 30NETA group for the second 90 days (P < .008). Only a small number of bleeding days were reported with no differences between groups. No differences in adverse effects between groups were found. Women in the 30LNG arm reported lower levels of satisfaction with their bleeding patterns than the other groups (30LNG compared with 20NETA, P = .01; 30LNG compared with 30NETA, P = .001). CONCLUSION: The addition of 10 microg of ethinyl E2 to a 20 microg ethinyl E2 pill containing levonorgestrel or norethindrone acetate did not improve bleeding patterns. During continuous dosing, the use of oral contraceptives containing 1,000 microg norethindrone acetate resulted in more days of amenorrhea and fewer days of spotting than preparations containing 100 microg levonorgestrel. LEVEL OF EVIDENCE: I.

Successful medical abortion of a pregnancy within a noncommunicating rudimentary uterine horn.

In asymptomatic patients with an early gestation located in a noncommunicating rudimentary horn, methotrexate may provide another treatment option or act as a useful adjunct to surgical intervention. We present a case of a successful pregnancy termination of a gestation located in a noncommunicating rudimentary horn with subsequent elective laparoscopic resection.