Nestorone Research Articles

Polymorphism characterization of segesterone acetate: A comprehensive study using XRPD, FT-IR and Raman spectroscopy

Segesterone acetate (SA) is a promising and recently approved drug substance used as a contraceptive. SA has two major polymorphic forms, Form I and II. We have shown through indirect analysis that Form I is the more thermodynamically stable polymorphic form at room temperature, however, during the manufacturing process of SA drug products the solid-state stability must be shown to be under control. In the present work, a systematic study has been done using X-ray powder diffraction (XRPD), Fourier Transformed Infrared spectroscopy (FT-IR), and room temperature Raman spectroscopy on both micronized and non-micronized SA powder samples. XRPD showed a crystalline structure in both powder samples with a distinct coexistence of the polymorphic Forms I and II which was confirmed by FT-IR and Raman spectroscopy. The study showed that after thermal annealing a noticeable reduction of the amount of polymorphic Form II was found in both samples. Our results suggest the possibility of reducing the amount of SA Form II by thermal treatment inducing an irreversible solid-state transition to yield the thermodynamically more stable polymorphic Form I. To quantify the ratio of polymorphs I and II we have implemented a method that can be used as a routine analysis step in the manufacturing process of SA.

Long-Lasting, Patient-Controlled, Procedure-Free Contraception: A Review of Annovera with a Pharmacist Perspective.

Annovera (segesterone acetate and ethinyl estradiol vaginal system) is a US Food and Drug Administration FDA-approved long-lasting, reversible contraceptive that is fully administered by the user and does not require a procedure for insertion or removal. The vaginal system is in the shape of a ring and contains low doses of a novel progestin, egesterone acetate, and ethinyl estradiol. It is made of silicone and is fully pliable and flexible. The vaginal system is reusable for 13 cycles, using a 21 days in/7 days out regimen, providing women with the ability to control their fertility. Particularly now during the COVID-19 pandemic when access to contraception has been further reduced, patients may benefit from a method that is both long-lasting and patient-controlled.

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

ObjectiveTo 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 DesignWe 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. ResultsThe 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). ConclusionsThe 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. ImplicationsThe 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.

Dose-finding study of a 90-day contraceptive vaginal ring releasing estradiol and segesterone acetate

ObjectiveTo evaluate serum estradiol (E2) concentrations during use of 90-day contraceptive vaginal rings releasing E2 75, 100, or 200 mcg/day and segesterone acetate (SA) 200 mcg/day to identify a dose that avoids hypoestrogenism. Study designWe conducted a multicenter dose-finding study in healthy, reproductive-aged women with regular cycles with sequential enrollment to increasing E2 dose groups. We evaluated serum E2 concentrations twice weekly for the primary outcome of median E2 concentrations throughout initial 30-day use (target ≥40 pg/mL). In an optional 2-cycle extension substudy, we randomized participants to 2- or 4-day ring-free intervals per 30-day cycle to evaluate bleeding and spotting based on daily diary information. ResultsSixty-five participants enrolled in E2 75 (n = 22), 100 (n = 21), and 200 (n = 22) mcg/day groups; 35 participated in the substudy. Median serum E2 concentrations in 75 and 100 mcg/day groups were <40 pg/mL. In the 200 mcg/day group, median E2 concentrations peaked on days 4–5 of CVR use at 194 pg/mL (range 114–312 pg/mL) and remained >40 pg/mL throughout 30 days; E2 concentrations were 37 pg/mL (range 28–62 pg/mL) on days 88–90 (n = 11). Among the E2 200 mcg/day substudy participants, all had withdrawal bleeding following ring removal. The 2-day ring-free interval group reported zero median unscheduled bleeding and two (range 0–16) and three (range 0–19) unscheduled spotting days in extension cycles 1 and 2, respectively. The 4-day ring-free interval group reported zero median unscheduled bleeding or spotting days. ConclusionsEstradiol concentrations with rings releasing E2 200 mcg/day and SA 200 mcg/day avoid hypoestrogenism over 30-day use. ImplicationsA 90-day contraceptive vaginal ring releasing estradiol 200 mcg/day and segesterone acetate 200 mcg/day achieves estradiol concentrations that should avoid hypoestrogenism and effectively suppresses ovulation.

A technology evaluation of Annovera: a segesterone acetate and ethinyl estradiol vaginal ring used to prevent pregnancy for up to one year

ABSTRACT Introduction The segesterone acetate and ethinyl estradiol contraceptive vaginal ring (SA/EE CVR) was FDA-approved in August 2018 and is now available in the U.S. The CVR is placed vaginally for 21 days followed by a 7-day ring-free interval, when withdrawal bleeding typically occurs. One ring can be used for up to a year (13 cycles). Areas covered This review summarizes this novel method of contraception, including the delivery system and the hormonal components. We describe the potential market, how it is used, the pharmacokinetic properties of the device, and results of clinical trials including efficacy, bleeding profile, acceptability, and safety. Expert opinion The SA/EE CVR represents the first long-lasting user-controlled hormonal contraceptive device. The bleeding pattern is highly favorable and consistent over the entire year and is associated with very low discontinuation. Efficacy and safety are similar to other methods of combined hormonal contraceptives. Unscheduled ring removals increase the risk of failure. Further studies are needed to evaluate continuous use of the ring for greater than 21 days, and potential non-contraceptive benefits of the ring such as reduced menstrual bleeding.

SAT-013 Segesterone Acetate (SA) Serum Levels with a Statistical Model of Continued Use of the SA/Ethinyl Estradiol (EE) Contraceptive Vaginal System

The novel, ring-shaped, contraceptive vaginal system (CVS; Annovera™), contains 103 mg of SA and 17.4 mg of EE, and delivers a mean dose of SA 0.15/EE 0.013 mg/day. The CVS was designed to last thirteen cycles in a 21 day-in/7 day-out regimen. Objectives of these analyses were to determine the amount of SA/EE remaining in the CVS after 13 cycles of use and to estimate the SA level in serum after 1 year of continuous use.Residual SA/EE levels from CVS used by women (n=18) for 13 cycles of 21/7 regimen in a phase 3 clinical trial were further analyzed in vitro. Hypothetical SA level in serum after 1 year of continuous use was estimated using data from 39 women who participated in a 13-cycle pharmacokinetic study of the 21/7 CVS regimen. The serum data were used to construct a statistical model for the change in serum SA concentrations from cycle 1 to cycle 13. The data from each individual subject was modeled to estimate the serum SA level based on days of use. Each subject’s model was then used to estimate the serum SA level after 364 days of continuous CVS use. The average of all 364-day values from valid models was then calculated.After 13 cycles of a 21/7 regimen, the amount of SA/EE remaining in the CVS was 61.7 mg/14.0 mg (60%/80% of the original SA/EE load), which established the release of 0.15 mg SA and 0.013 mg EE per day for a total of 273 days. The model predicted that the mean serum SA level after 364 days of continuous use was 71 pmol/L with a lower limit of the 90% CI of 52 pmol/L.A high percentage of SA/EE remained in the CVS after 13 cycles of use. Serum SA levels predicted by the model following 1 year of continuous use were similar to those previously observed (mean 73 pmol/L) at 1 year in a SA silicone implant trial in which there were no reported pregnancies at 1 year (Sivin et al, Contraception. 2004;69:137-144). No pregnancy or PK data with continuous use of the CVS is available at this time. Further study on the continuous use of the CVS is warranted.

A direct comparison of the transcriptional activities of progestins used in contraception and menopausal hormone therapy via the mineralocorticoid receptor

A variety of structurally and functionally distinct progestins is used in contraception and menopausal hormone therapy (MHT). Some progestins elicit off-target effects by binding to steroid receptors other than the progesterone receptor, which may impact their therapeutic and side-effect profiles. We directly compared the binding affinities, efficacies and potencies of selected progestins via the mineralocorticoid receptor (MR). We did not detect a significant difference in the affinities of medroxyprogesterone acetate (MPA), norethisterone acetate (NET-A), levonorgestrel (LNG), gestodene (GES), etonogestrel (ETG), nestorone (NES) and nomegestrel acetate (NoMAC) for the MR, while these were significantly lower compared to drospirenone (DRSP). While GES and NoMAC display affinities indistinguishable from progesterone (P4), the binding affinity of DRSP is significantly greater and all other progestins significantly lower than that of P4. Dose-response analyses showed that P4, GES and ETG display indistinguishable MR antagonist potencies for transactivation to the well-known MR antagonist spironolactone, while LNG, NoMAC and DRSP are significantly more potent than spironolactone and MPA, NET-A and NES are significantly less potent. Similar to our previous findings for NET-A, we show that LNG, GES, ETG and NES dissociate between transactivation and transrepression via the MR. Together our results provide strong evidence for progestin- and promoter-specific transcriptional effects via the MR, which are poorly predicted by relative binding affinities. A comparison of the binding affinities and potencies with reported free serum concentrations of progestins relative to the endogenous mineralocorticoid aldosterone, suggest that all progestins except MPA, NET-A and NES will likely compete with aldosterone for binding to the MR in vivo at doses used in hormonal therapy to elicit physiologically significant off-target effects.

The Effects of Annovera™ and Tampon Co-Usage on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol

The Effects of Annovera™ and Tampon Co-Usage on the Pharmacokinetics of Segesterone Acetate and Ethinyl Estradiol

In silico study of the active components (17α-ethinyl estradiol and segesterone acetate) of annovera as a novel vaginal contraceptive system by docking of their binding to estrogen and progesterone receptors

The main purpose of the present research article is the docking analysis of active substances of annovera (segesterone acetate and ethinyl estradiol) with progesterone and estrogen receptors (PR and ER), respectively. The first step of this study is optimizing the title compounds using B3LYP/6-311++G(d,p) basis set of theory at room temperature in the isolated form of Gaussian 03 software. The frontier molecular orbital (FMO) theory is used to understand the reactivity and stability of the said compounds. The global reactivity indices indicate that both molecules have similar electrophilicity. After the quantum mechanical (QM) study, the docking analyses of the compounds embedded in the active sites of the receptors (PR and ER) are done using Molegro Virtual Docker (MVD) software. The docking studies show that the steric interactions play the main role in ligands complex formation with the receptors.

Comprehensive overview of the recently FDA-approved contraceptive vaginal ring releasing segesterone acetate and ethinylestradiol: A new year-long, patient controlled, reversible birth control method

ABSTRACTIntroduction: This is an overview of the recently FDA-approved silicone elastomer combined hormonal contraceptive vaginal ring (CVR), which is used cyclically for up to 1 year, eliminating resupply challenges. This ring requires no refrigeration, simplifying the supply chain. Developed by the Population Council, this CVR will soon be marketed in the United States as Annovera™ by TherapeuticsMD.Areas Covered: The composition of the elastomer ring and the chemical, pharmacokinetic and pharmacodynamic properties of both hormonal components are discussed. Results of the clinical trials of its efficacy, tolerability, safety, and acceptability follow. Finally, subanalyses from the clinical trials are presented to guide clinicians in counseling potential users.Expert Opinion: This CVR introduces a new progestin – segesterone acetate (SA) – that has no androgenic or estrogenic action in vitro or in vivo, but has the highest anti-ovulatory potential of all available progestins. SA is paired with EE in an intravaginal elastomer ring, that is used cyclically (21 days in place/7 days removed) to provide 12 months (13 cycles) of contraception. This once-a-month, self-applied CVR offers a convenient, rapidly reversible, year-long contraception with efficacy and side effect profiles similar to other combined hormonal methods, for women with BMI < 29 kg/m2.

Bleeding profile associated with 1-year use of the segesterone acetate/ethinyl estradiol contraceptive vaginal system: pooled analysis from Phase 3 trials

ObjectivesTo describe bleeding patterns among users of the segesterone acetate (SA) and ethinyl estradiol (EE) contraceptive vaginal system (CVS), and identify factors associated with unscheduled bleeding/spotting (B/S). Study designWe pooled results from two multicenter, single-arm, open-label, pivotal, phase 3 studies of the SA/EE CVS conducted in 17 US and 7 international sites. Participants (age 18–40 years; BMI ≤29 kg/m2) followed a 21/7-day in/out schedule of CVS use for up to 13 cycles and recorded vaginal bleeding daily in paper diaries. Scheduled and unscheduled B/S were summarized by cycle. We used multiple logistic regression to identify factors associated with unscheduled bleeding/spotting, based on the first 4 cycles only. ResultsAnalysis included data from 2070 participants (16,408 cycles). Ninety-eight percent documented scheduled B/S [mean (SD): 4.9 (1.1) days/cycle)]. Absence of scheduled B/S was 5–8% of women/cycle. Unscheduled B/S ranged from 13.2% to 21.7% of women per cycle. Few women (1.8%) discontinued prematurely due to unacceptable bleeding. Black women were more likely to report unscheduled B/S than White women [Adjusted odds ratio (AOR) = 1.49, 95% confidence interval (CI) = 1.14–1.94]. Women with fewer years of schooling [<high school (AOR=0.62, 95% CI=0.43–0.90); high school graduate (AOR: 0.76, 95% CI=0.60–0.97)] were less likely to report any episode of unscheduled B/S compared to college graduates. ConclusionsParticipants using the SA/EE CVS up to 13 cycles reported good cycle control. Discontinuation due to unacceptable bleeding was very low. Further research into demographic/other differences with reported unscheduled bleeding is warranted. ImplicationsSince good cycle control is a key factor influencing contraceptive selection, adherence and continuation of combined hormonal contraceptives, the favorable bleeding profiles experienced by women during the SA/EE CVS clinical trials provide reassuring information for prospective users.

Efficacy of the 1-year (13-cycle) segesterone acetate and ethinylestradiol contraceptive vaginal system: results of two multicentre, open-label, single-arm, phase 3 trials

SummaryBackgroundA ring-shaped, contraceptive vaginal system designed to last 1 year (13 cycles) delivers an average of 0·15 mg segesterone acetate and 0·013 mg ethinylestradiol per day. We evaluated the efficacy of this contraceptive vaginal system and return to menses or pregnancy after use.MethodsIn two identically designed, multicentre, open-label, single-arm, phase 3 trials (one at 15 US academic and community sites and one at 12 US and international academic and community sites), participants followed a 21-days-in, 7-days-out segesterone acetate and ethinylestradiol contraceptive vaginal system schedule for up to 13 cycles. Participants were healthy, sexually active, non-pregnant, non-sterilised women aged 18–40 years. Women were cautioned that any removals during the 21 days of cyclic use should not exceed 2 h, and used daily paper diaries to record vaginal system use. Consistent with regulatory requirements for contraceptives, we calculated the Pearl Index for women aged 35 years and younger, excluding adjunctive contraception cycles, as the primary efficacy outcome measure. We also did intention-to-treat Kaplan-Meier life table analyses and followed up women who did not use hormonal contraceptives or desired pregnancy after study completion for 6 months for return to menses or pregnancy. The trials are registered with ClinicalTrials.gov, numbers NCT00455156 and NCT00263341.FindingsBetween Dec 19, 2006, and Oct 9, 2009, at the 15 US sites, and between Nov 1, 2006, and July 2, 2009, at the 12 US and international sites we enrolled 2278 women. Our overall efficacy analysis included 2265 participants (1130 in the US study and 1135 in the international study) and 1303 (57·5%) participants completed up to 13 cycles. The Pearl Index for the primary efficacy group was 2·98 (95% CI 2·13–4·06) per 100 woman-years, and was well within the range indicative of efficacy for a contraceptive under a woman's control. The Kaplan-Meier analysis revealed the contraceptive vaginal system was 97·5% effective, which provided further evidence of efficacy. Pregnancy occurrence was similar across cycles. All 290 follow-up participants reported return to menses or became pregnant (24 [63%] of 38 women who desired pregnancy) within 6 months.InterpretationThe segesterone acetate and ethinylestradiol contraceptive vaginal system is an effective contraceptive for 13 consecutive cycles of use. This new product adds to the contraceptive method mix and the 1-year duration of use means that women do not need to return to the clinic or pharmacy for refills every few months.FundingEunice Kennedy Shriver National Institute of Child Health and Human Development of the National Institutes of Health, the US Agency for International Development, and the WHO Reproductive Health Research Department.

Reprint of: Beyond contraception and hormone replacement therapy: Advancing Nestorone to a neuroprotective drug in the clinic

Neurological diseases such as ischemic stroke can be debilitating and have limited treatments available. The progestin Nestorone® (segesterone acetate) has been evaluated for use in birth control and hormone replacement therapy due to its potency and high affinity for the progesterone receptor. Interestingly, Nestorone also exerts neuroprotection in animals afflicted with various central nervous system diseases, including stroke, which implicates its potential for treating these maladies in clinical settings. In fact, a recent Brain Research paper by Tanaka and colleagues demonstrates Nestorone’s ability to reduce infarct sizes and preclude functional impairments in rats subjected to ischemic stroke. This commentary highlights Nestorone’s properties as a progestin, its neuroprotective capabilities in animal studies, and how the Tanaka team’s findings and previous clinical trials contribute to Nestorone’s translation into a therapeutic agent for stroke and other neurological diseases.

015 Evidence of Low Androgenicity and Little Impact on Sexual Function or Activity with Annovera™, a Novel Contraceptive Vaginal System Releasing Segesterone Acetate and Ethinyl Estradiol

015 Evidence of Low Androgenicity and Little Impact on Sexual Function or Activity with Annovera™, a Novel Contraceptive Vaginal System Releasing Segesterone Acetate and Ethinyl Estradiol

Efficacy and Safety of a 1-Year Segesterone Acetate and Ethinyl Estradiol Contraceptive Vaginal System

To report the efficacy and safety of a ring-shaped, 1-year (13 cycles) contraceptive vaginal system (CVS) releasing systemically a daily mean of segesterone acetate 150 mcg and ethinyl estradiol 13 mcg. Efficacy and safety are reported from two multicenter, 1-year, open-label, Phase 3 trials (one U.S., one international); a 1-year pharmacokinetic study; and three safety substudies from a Phase 3 study. Twenty-seven clinical study sites inside and outside of the United States. Women ages 18–40 years who were sexually active and had regular menstrual cycles. Participants were instructed to use the CVS on a 21/7-day, in–out continuous schedule and to not remove the CVS for more than 2 hours during the ring-in period. The primary efficacy outcome was the Pearl Index (PI) for women 35 years old or younger. The intention-to-treat Kaplan–Meier life-table analysis was a secondary outcome. Safety was assessed by adverse events (AEs) and substudy data evaluating endometrial, vaginal microbiology, and liver protein changes. A total of 2,265 participants’ data were analyzed for efficacy and 2,308 for safety. The primary PI of 2.98, 95% CI [2.13, 4.06], indicated excellent efficacy. Women who followed use instructions had greater efficacy, PI = 2.10, 95% CI [1.37, 3.06], than those who removed the CVS for more than 2 hours, PI = 5.89, 95% CI [3.46, 9.27], p = .0024. The CVS was 97.3% effective in life-table analyses. Most women were satisfied/very satisfied with the CVS (91%), found it easy to use (91%), and would recommend it to a friend (84%). Treatment-related AEs most frequently reported included headache (n = 601, 26%), nausea (n = 420, 18%), vaginal discharge–vulvovaginal mycotic infection (n = 242, 10%), and abdominal pain (n = 225, 10%). Discontinuations for these complaints were low (<1.5%). Four (0.2%) women experienced venous thromboembolism, 3 of whom had thrombosis risk factors. Substudies revealed no unexpected safety signals. The segesterone acetate and ethinyl estradiol CVS, recently approved by the U.S. Food & Drug Administration, is an effective, 1-year, procedure-free, user-controlled contraceptive that women found acceptable. Efficacy was lower for those who removed the CVS for more than 2 hours during the ring-in period, an important topic for nurses to emphasize when counseling their patients. The CVS also has a safety profile in line with other ethinyl estradiol–based hormonal contraceptives.

Efficacy of the 1-Year Segesterone Acetate/Ethinyl Estradiol Contraceptive Vaginal System [21OP

INTRODUCTION: A novel, ring-shaped, contraceptive vaginal system (CVS) containing segesterone acetate (SA), also known as Nestorone®, and ethinyl estradiol (EE) is designed to last 1 year (13 cycles), delivering an average of SA 0.15/EE 0.013 mg/day. Efficacy was evaluated in 2 multicenter, 1-year, open-label studies (one at 15 US sites; one at 5 US/7 international sites). METHODS: Women (18-40 yrs) used the CVS for 21 days/cycle followed by having it out for 7 days. Women were not to remove the CVS for >2 hours during the 21 days of use. The primary efficacy outcome was the Pearl Index (PI) for women ≤35 years of age, excluding cycles with adjunctive contraception. Secondary outcomes included the PI for subgroups and intention-to-treat Kaplan-Meier life-table analyses. RESULTS: Of 2265 participants analyzed, 1303 (57.5%) completed. The primary PI was 2.98 (95% CI [2.13-4.06]). The PI was 2.10 (95% CI [1.37-3.06]) in women who followed use instructions versus 5.89 (95% CI [3.46-9.27]) for women who documented removals >2 hours (P=0.0024). Significantly higher PIs were also observed in subgroups by age (18-19 yrs vs ≥36yrs), parity (≥1 vs 0), race (Black vs white), ethnicity (Hispanic vs non-Hispanic), and site (non-Europe vs Europe), but not by BMI. Life-table analyses revealed the CVS is 97.3% effective in preventing pregnancy. Pregnancies did not increase across cycles. CONCLUSION: The SA/EE CVS is an effective 1-year, procedure-free contraceptive controlled by women that can help address an unmet worldwide contraceptive need. Counseling to ensure correct use is essential for optimizing efficacy.

Segesterone Acetate/Ethinyl Estradiol 1-Year Contraceptive Vaginal System Safety Evaluation [12M

INTRODUCTION: A novel, 1-year contraceptive vaginal system (CVS) releasing a daily average of segesterone acetate (SA) 150 mcg and ethinyl estradiol (EE) 13 mcg has been developed. We evaluated clinical safety outcomes from nine studies conducted for product development. METHODS: We pooled data from four studies conducted with the final manufactured CVS, including a one-year, pharmacokinetic study; two 1-year duration, phase-3 trials; and a study extending treatment into a second year. The five other studies evaluated pilot SA/EE formulations. Safety was evaluated by adverse event (AE) reporting and three sub-studies of endometrial biopsies, vaginal microbiology, and liver proteins. RESULTS: The combined studies included 3052 women; 2308 (75.6%) women received the final manufactured CVS of whom, 999 (43.3%) completed 13 cycles. Treatment-related AEs most frequently reported included headache (n=601, 26%), nausea (n=420, 18%), vaginal discharge/vulvovaginal mycotic infection (n=242, 10%), and abdominal pain (n=225, 10%) However, <1.5% of women discontinued for each of these. Four (0.2%) women experienced venous thromboembolism (VTE), three of whom had other thrombosis risk factors (Factor V Leiden mutation [n=1]; BMI >29 kg/m2 [n=2]). Some participants (n=1107; 52.8%) reported at least 1 complete (24.5%) or partial (44.0%) expulsion during their use of the CVS; expulsions were most frequently reported in the initial cycle. Safety sub-studies revealed no unexpected safety signals. CONCLUSION: The 1-year SA/EE CVS has an acceptable safety profile, in line with other combination hormonal contraceptives. Similar prescribing precautions for combined hormonal contraceptives will apply and studies are warranted in obese women who are at higher VTE risk.

OR33-5 Low Systemic Levels of Segesterone Acetate are Required to Inhibit Ovulation in Women

A one-year segesterone acetate (SA)/ethinyl estradiol (EE) contraceptive vaginal system (CVS; Annovera™) used to prevent pregnancy in women of reproductive age, was recently approved by the FDA (August 2018). Efficacy (Pearl Index of 2.98) and safety of the CVS were demonstrated in two phase 3, open-label, multicenter studies conducted in the US and internationally. The ring is self-inserted, left in place for 21 days and removed for 7 days in each cycle, and provides contraceptive efficacy for up to 13 cycles of use. It is designed to release 150 mcg SA and 13 mcg EE per day. This report reviews the evidence of systemic serum SA levels required for ovulation inhibition. SA is a potent synthetic progestin when given parenterally (eg, subcutaneous implant, transdermal gel, or vaginal ring), but, due to rapid inactivation by first-pass hepatic metabolism, is not biologically active when administered orally. SA specifically binds to progesterone receptors; it does not bind to sex hormone-binding globulin (SHBG) and has no estrogenic or androgenic activity. The effects of SA on ovulation inhibition were first examined in dose-finding studies of subdermal implants, which showed that the mechanism of ovulation inhibition was concentration dependent.1,2 Another study of subdermal implants releasing 45-50 mcg SA/day, showed ovulation did not occur with SA plasma levels >105 pmol/L; women who ovulated had SA levels ranging from 68 to <105 pmol/L.3 The effects of SA on ovulation inhibition were also evaluated in vaginal rings delivering 3 different doses (50, 75, 100 mcg/day) of SA for 6 months.4 These doses effectively inhibited ovulation, with SA serum levels remaining fairly constant through the study at ~125, 200 and 250 pmol/L, respectively, decreasing slightly over time.4 A study using a SA/estradiol transdermal gel demonstrated full suppression of ovulation and follicle growth at SA levels of 250 pmol/L.5 For better cycle control, EE was added to the vaginal ring for SA/EE (mcg/mcg per day) dosages of 50/10, 50/20, 150/15 (actual delivery 150/13), 150/20 and 200/15; ovulation inhibition was also evaluated in two trials with these doses.6,7 Overall, serum SA levels achieved with these rings were in the range of 200-300 pmol/L, well above levels required to inhibit ovulation.6,7 In both trials, body weight/BMI was inversely correlated with SA levels.6,7 The SA/EE CVS prevents ovulation when SA serum levels remain above 105 pmol. SA/EE CVS is novel, procedure-free and long-acting reversible contraceptive that can be used for up to one year. 1. Lahteenmaki PL, et al. Fertil Steril. 1985;44:20-24. 2. Haukkamaa M, et al. Contraception. 1992;45:49-55. 3. Diaz S, et al. Contraception. 1995;51:33-38. 4. Brache V, et al. Contraception. 2001;63:257-261. 5. Brache V, et al. Contraception. 2015;92:289-297. 6. Fraser IS, et al. Contraception. 2005;72:40-45. 7. Sivin I, et al. Contraception. 2005;71:122-129.

SAT-219 A Novel 1-Year Contraceptive Vaginal System Delivering Segesterone Acetate and Ethinyl Estradiol: Effects on Lipids and other Hepatic Proteins

Annovera™ is an FDA-approved contraceptive vaginal system (CVS) releasing 150 mcg segesterone acetate (SA), a new chemical entity, and 13 mcg ethinyl estradiol (EE) per day.1 We postulate that as a non-androgenic progestin, SA is unlikely to adversely affect lipids versus androgenic progestins. Here we review the effects of this CVS on lipids, glucose, coagulation factors and sex hormone-binding globulin (SHBG). Two pivotal, open-label, phase 3 trials and one PK trial evaluated women (18-40 years) who received the CVS for 13 cycles of 28 days over 12 months; one phase 3 study examined hepatic proteins in a substudy. The CVS was self-inserted, left in place for 21 days and removed for 7 days in each 28-day cycle. Lipids and glucose were measured at baseline and study end in the 3 trials. As previously reported, factor VIII, protein S (PS), fibrinogen, and SHBG were measured in the hepatic factors substudy.2 A total of 2308 women used the SA/EE CVS. Participants had a mean age of 26.7 years and mean BMI of 24.1 kg/m2. Most women were white (71%) and 14% were black. Women in the substudy (n=129) had similar mean ages and BMIs; 69% were white and 28% were black. In an integrated analysis of the phase 3 and PK studies, levels of total cholesterol increased by a mean +0.236 mmol/L from baseline to study end, as did HDL cholesterol (+0.162 mmol/L) and triglycerides (+0.193 mmol/L). At study end, LDL cholesterol decreased from baseline by a mean of -0.003 mmol/L. Glucose levels increased from baseline to study end by a mean +0.074 mmol/L. A prior study using the CVS showed lipid changes similar in direction and magnitude to other combined oral contraceptives (COC).3 Hepatic protein substudy results showed significant mean changes from baseline to study end for fibrinogen (+0.2±0.66 mg/mL [SD]; P=0.0052), factor VIII activity (+21%±55; P=0.0005), and PS activity (-8%±19; P=0.0043). Mean SHBG levels also significantly increased from baseline to study end by +81.7±94.3 nmol/L (P<0.0001).2 Another study comparing the CVS to an oral COC showed that the CVS had a hemostatic profile corresponding closely with that of the oral COC.4 Integrated safety data from two clinical studies, a hepatic substudy from one of the trials, and prior reports showed no clinically significant impact of the SA/EE CVS on lipids or glucose. The impact of the CVS on coagulation factors mirrored that of oral COCs. The significant increase in SHBG levels with the CVS was consistent with changes seen with other COCs containing EE and a non-androgenic progestin. The SA/EE CVS with a low dose of EE and the novel progestin, SA, has an acceptable metabolic profile with up to one year of use. 1. AnnoveraTM Prescribing Information. 2. Archer DF, et al. Contraception 2016;93(1):58-64. 3. Sitruk-Ware RL, et al. Contraception 2007;75(6):430-437. 4. Rad M, et al. Am J Obstet Gynecol 2006;195(1):72-77.

Bone turnover markers in women participating in a dose-finding trial of a contraceptive vaginal ring releasing Nestorone and estradiol

ObjectiveTo evaluate changes in the bone turnover markers CTx and P1NP during 6 months' use of novel continuous contraceptive vaginal rings delivering Nestorone (NES) 200 mcg/day and three doses of estradiol (E2) (10, 20, and 40 mcg/day). Study designThis randomized trial enrolled 189 women who used two consecutive vaginal rings over 180 days. Frequent blood sampling permitted analysis of NES, E2, CTx and P1NP concentrations. The bone-turnover marker analyses included only women with complete sampling and excluded women with characteristics that might interfere with accurate measurement of bone markers such as afternoon sampling, poor ring compliance or recent pregnancy. We evaluated the change from baseline to 6 months in CTx and P1NP, stratified by ring dose and by average circulating E2 concentrations. ResultsOne hundred fifty-one women completed the study, and 82 women had complete data available for the bone marker analyses; the three dosage groups were balanced with regard to baseline characteristics. E2 concentrations remained low throughout treatment, regardless of which dose ring the participant used. Individual CTx changes from baseline averaged 27±56% (p<.01). Similarly, individual P1NP changes averaged 11±33% (p=.04). These increases were within the premenopausal reference ranges, and unrelated to treatment dose or to circulating E2 concentrations. ConclusionsThe low E2 dose of these rings was associated with low E2 concentrations and modest increases in serum bone turnover makers. Because we have only 6-month bone turnover markers and no direct evidence of bone loss or bone density change, these results must be interpreted with caution. ImplicationsNestorone, a 19-norprogesterone derivative, leads to complete ovarian suppression, which should yield excellent contraceptive effectiveness. To prevent potential adverse effects on bone, the NES contraceptive ring should be combined with higher doses of E2 than were assessed in this study.