OBJECTIVE:To determine the feasibility of using a novel negative pressure device for effectiveness and safety in treating genitourinary syndrome of menopause (GSM). METHODS:An unblinded feasibility study was performed in 12 women with GSM using the VITA AV Clinical System: a system with a disposable intravaginal tip with circumferential orifices, connected to a vacuum pump. Negative pressure draws the vaginal epithelium into the orifices, inducing microtrauma and a regenerative physiological response. Women underwent familiarization sessions with increasing negative pressure to the vaginal epithelium for 3 minutes, followed by three monthly sessions at 3, 4, and 5 minutes, respectively. Efficacy was assessed on the change in the most bothersome symptom (MBS) and vaginal health maturation index scores at 1 and 12 months after treatment. Tolerability was determined by pain scores during treatment. Safety data were collected throughout. RESULTS:All women completed the study and tolerated maximum negative pressure while reporting negligible to no pain during treatment. Seven of the 12 reported improvement, and 3 reported complete resolution in MBS at 1 month. Nine remained improved at 12 months. Vaginal maturation index improved in 92% at 1 month and 66% at 12 months. All women rated their satisfaction with the device as good to very good. No adverse or device-related events occurred. CONCLUSION:Negative pressure treatment was tolerated by women affected by GSM with no safety issues, and with observed favorable changes in reported symptoms and objective assessments. Controlled studies are warranted with larger sample sizes and increased frequency of follow-up to assess the time course of improvements.

Objective: To report pregnancy outcomes following intratubal insemination without catheterization using the FemaSeed device in a population of low sperm count couples. Methods: A prospective, single-arm, historical control, pivotal trial (Clinicaltrials.gov NCT04968847) of females aged 19-40 years with male-factor or unexplained infertility and total motile sperm count of 1-20 million undergoing intratubal insemination (ITI) with the FemaSeed device, conducted at twelve academic and private medical centers in the USA. Pregnancy was confirmed at 3 weeks (-7 days) by serum β-hCG and follow-up continued at 7 weeks (±7 days) for safety, including pregnancy test by serum β-hCG and ultrasonography. Results: The pregnancy rate for ITI with FemaSeed per subject was 26.3% (95%CI: 13.4‒43.1%; n=10/38) and 17.5% per cycle (95%LCB: 7.6%, 95%CI: 5.7‒29.4%; n=10/57), which was significantly higher than the performance goal of 7% based on the historical control (one-sided P=0.041). The cumulative pregnancy rates through the first and second ITI cycles were 15.8% (95%CI: 7.4‒31.8%) and 30.7% (95%CI: 16.5‒52.5%), respectively. Safety reports were consistent with intrauterine insemination (IUI), of note ectopic pregnancy and uterine perforation occurred in 0.5% (95%CI: <0.05‒2.5%; n=1/222) and 0.0% of cycles, respectively. Conclusion: Targeted intratubal insemination of washed spermatozoa using the FemaSeed ITI device is a safe artificial insemination technique that demonstrated high effectiveness for couples with male-factor/unexplained infertility associated with low male sperm count. Delivery of washed spermatozoa directly into the utero-tubal ostium and fallopian tube without catheterization likely increases sperm-oocyte interaction, suggestive of improved efficiency over conventional intrauterine insemination particularly for male-factor infertility

From the Case Western Reserve School of Medicine, Cleveland, OH. Received November 14, 2022; revised and accepted November 14, 2022. Funding/support: None reported. Financial disclosure/conflicts of interest: J.H.L. receives funding from Bayer Healthcare and Aveta. Address correspondence to: James H. Liu, MD, Professor Emeritus, Case Western Reserve School of Medicine, Cleveland, OH 44106. E-mail: [email protected]

To evaluate the impact of Amniograft placement after hysteroscopic resection of IUA on pregnancy outcomes Patients who underwent hysteroscopic resection of IUA with or without Amniograft (treatment vs. control) from 2014-2022 from a single academic-based fertility center were included. Amniografts were placed with a uterine balloon that was removed after 2 weeks; otherwise, balloon was placed based on the surgeon discretion. Patients received 4 weeks of estrogen supplementation with 1 week of progesterone overlap postoperatively. Patient characteristics obtained included age, BMI, gravidity, parity, amenorrhea status, IUA staging (based on the AFS/ASRM 1988 guideline and on the consensus of 2 authors), cause of IUA, history of previous hysteroscopy, and whether uterine balloon was placed. Primary outcomes include PR and LBR. Other outcomes included return of menses. Statistical analysis including T-test and Chi-squared test as appropriate, and multiple logistic regression models were utilized. P<0.05 was statistically significant. A total of 89 unique patients were included in this study: 58 in the control group and 31 in the treatment group. There was no difference in age, BMI, gravidity, parity, amenorrhea status, and cause of IUA. The treatment group had more patients with advanced stage II or III (C 62.1% vs T 93.6%, p=0.0002) and a history of failed hysteroscopy (C 22.4% vs T 51.6%, p=0.009). There was no difference in the fertility treatment patients received or the number of amenorrheic patients who had return of menses after surgery. In an adjusted model, controlling for possible confounders, the PR (C 39.7% vs. 35.5, p=ns) and LBR (C 27.5% vs. T 19.4%, p=ns) were not significantly different between control and treatment groups. No difference was also seen in PR and LBR when comparing patients in three groups: those who underwent hysteroscopy without a balloon (n=35), with a balloon only (n=23), and with a balloon plus Amniograft (n=31). A sensitivity analysis of advanced stage II and III IUA showed no difference in PR (C 36.1% vs.T 34.5%, p=ns) and LBR (C 25.0%, vs T 20.7%, p=ns); however, a history of failed hysteroscopy was a predictor of negative pregnancy outcome in these models (PR OR 0.10, 95% CI 0.02-0.4; LBR OR 0.21, 95% CI 0.04-0.89). Therefore, an additional sub-analysis was performed on patients with advanced stage II or III IUA with a history of failed hysteroscopy. Although not statistically significant, there is a trend towards improved outcomes with Amniograft treatment (PR: 8.3% vs 20.0%, p=ns; LBR: 8.3% vs. 13.3%, p=ns). Amniograft treatment has been previously reported as a promising option for patients with IUA. This current study suggests that Amniograft treatment may not improve PR or LBR overall. However, a subgroup of patients with advanced stage IUA with a history of failed hysteroscopy may benefit from this treatment. Additional studies are needed.

From the Department of Reproductive Biology, Case Western Reserve School of Medicine, Cleveland, OH. Received July 14, 2023; revised and accepted July 17, 2023. Funding/support: None reported. Financial disclosures/conflicts of interest: Bayer Pharmaceutical as Chair of Data Adjudication Committee, Femasys for reading ultrasounds in the study, and Consultant for Vesta startup for device development Address correspondence to James H. Liu, MD, Professor Emeritus, Department of Reproductive Biology, Case Western Reserve School of Medicine, Cleveland, OH 44106. E-mail: [email protected]

The repeated use of a sperm donor within a restricted geographic area may lead to the inadvertent consanguineous unions between the sibling offspring. The purpose of this single site retrospective analysis was to determine the frequency with which a sperm donor was used for two or more Intended Parent (IP) couples.

Conservative treatment of symptomatic uterine fibroids continues to be a major gynecologic challenge. Although surgical approaches such as myomectomy are effective, it becomes less effective in younger patients as new myomas emerge overtime. Medical treatment with gonadotropin releasing hormone (GnRH) analogs such as depo-leuprolide is effective in suppressing fibroid growth but remains a short-term option and is associated with profound hypoestrogenic symptoms. A recent combination of oral GnRH antagonist (elagolix) with steroid add-back (1Schlaff W.D. Ackerman R.T. Al-Hendy A. Archer D.F. Barnhart K.T. Bradley L.D. et al.Elagolix for heavy menstrual bleeding in women with uterine fibroids.N Engl J Med. 2020; 382: 328-340Crossref PubMed Scopus (47) Google Scholar) has shown promise in minimizing hypoestrogenic side effects, but it is still too soon to judge its commercial success. Since 2012, ulipristal acetate, a selective progesterone receptor modulator, has shown to be effective in rapidly reducing abnormal uterine bleeding, decreasing uterine fibroid size, and improving the quality of life in women with symptomatic uterine fibroids and was approved for this indication by the European Union at a 5-mg dose given in 3-month cycles (2Garnock-Jones K.P. Duggan S.T. Ulipristal acetate: a review in symptomatic uterine fibroids.Drugs. 2017; 77: 1665-1675Crossref PubMed Scopus (8) Google Scholar). The clinical efficacy of ulipristal acetate was demonstrated in randomized trials in a predominantly Caucasian population in the European-based Pearl I–IV trials and in a predominantly Black US population in the Venus I–II trials (3Liu J.H. Soper D. Lukes A. Gee P. Kimble T. Kroll R. et al.Ulipristal acetate for treatment of uterine leiomyomas: a randomized controlled trial.Obstet Gynecol. 2018; 132: 1241-1251Crossref PubMed Scopus (20) Google Scholar). In addition, these trials demonstrated dose–response differences between the 5- and 10-mg treatment groups. This issue of racial differences in response to ulipristal acetate is further explored by Osuga et al. (4Osuga Y. Nakano Y. Yamauchi Y. Takanashi M. Ulipristal acetate compared with leuprorelin acetate for Japanese women with symptomatic uterine fibroids: a phase III randomized controlled trial.Fertil Steril. 2021; 116: 189-197Abstract Full Text Full Text PDF Scopus (3) Google Scholar) in an Asian population in this issue of Fertility and Sterility. In Asians, preliminary dose-finding trials indicated a dose-dependent effect for achieving amenorrhea and suggested that the 10-mg dose was optimal in this population. Osuga et al. (4Osuga Y. Nakano Y. Yamauchi Y. Takanashi M. Ulipristal acetate compared with leuprorelin acetate for Japanese women with symptomatic uterine fibroids: a phase III randomized controlled trial.Fertil Steril. 2021; 116: 189-197Abstract Full Text Full Text PDF Scopus (3) Google Scholar) compared this ulipristal acetate dose vs. depo-leuprolide in a randomized double-blinded, non-inferiority trial. Their results were similar to the Pearl and Venus trials and confirmed a rapid onset of amenorrhea in most of ulipristal acetate-treated women with a median time to amenorrhea of 6 days vs. 9 days for depo-leuprolide therapy. Normalization of uterine bleeding for ulipristal acetate was observed in 94.8% of the population, and ulipristal acetate was not inferior to depo-leuprolide. The study was of modest size with 97 subjects per group and, thus, was not powered to demonstrate side effects such as severe liver injury. The clinical promise of ulipristal acetate has been overshadowed by after-marketing isolated reports of severe liver failure requiring liver transplantation in five patients. The estimated incidence of this complication is approximately 10 out of 100,000, and it is hypothesized to be a rare idiosyncratic type of drug-induced liver injury. Review of these cases demonstrates a probable link to ulipristal acetate administration with a variable latency period with the first sign of liver toxicity ranging from the first few days of intake to 6 months. For this reason, the European Medical Agency suspended marketing of ulipristal acetate for fibroids in March 2020. Additionally, ulipristal acetate has not been authorized in the US by the Food and Drug Administrationfor this indication. In contrast, 30 mg of ulipristal acetate continues to be marketed in both the European Union and the US for postcoital contraception without restrictions. Critics have questioned the risk–benefit assessment of ulipristal acetate drug-induced liver injury vs. the risk of surgical treatment of fibroids such as hysterectomy. The risk of death from laparoscopic hysterectomy for fibroids in the US is 12 out of of 100,000, and that for abdominal hysterectomy is 32 out of 100,000 (5Siedhoff M.T. Wheeler S.B. Rutstein S.E. Geller E.J. Doll K.M. Wu J.M. et al.Laparoscopic hysterectomy with morcellation vs abdominal hysterectomy for presumed fibroid tumors in premenopausal women: a decision analysis.Am J Obstet Gynecol. 2015; 212: 591.e1-591.e8Abstract Full Text Full Text PDF Scopus (86) Google Scholar), compared with the risk of ulipristal acetate drug-induced liver injury of 10 out of 100,000. Although this is not an apples-to-apples comparison, it does raise the following issue: are our medical decisions truly risk-based? Ulipristal acetate compared with leuprorelin acetate for Japanese women with symptomatic uterine fibroids: a phase III randomized controlled trialFertility and SterilityVol. 116Issue 1PreviewTo evaluate the efficacy and safety of ulipristal acetate (UPA) for uterine fibroids (UFs), a phase III study was conducted with leuprorelin (LEU) as a comparator. This is the first confirmatory trial of UPA for UFs among Asians. Full-Text PDF Open Access

Progestogens are steroid compounds that have the ability to induce secretory transformation in the endometrium and are utilized in menopausal hormone therapy to prevent endometrial hyperplasia and endometrial cancer. Progestogens can be derived from 21-carbon or 19-carbon steroid cytoskeletons and thus have different properties and metabolic effects beyond the progestational effects on the endometrium. This limited review will focus on the available progestogens utilized in combination hormone therapy including progesterone, medroxyprogesterone acetate, norethindrone, norethindrone acetate, levonorgestrel, and drospirenone. The impact of progestogens on a variety of target tissues including the endometrium, breast, cardiovascular system, brain, and bone, will be reviewed. Last, the current clinical regimens that can be utilized by clinicians will be discussed.

Objective: To evaluate endometrial progesterone receptor (PGR) expression in menopausal women who used vaginal 4-mu g and 10-mu g estradiol (E2) inserts or placebo. Methods: REJOICE was a randomized, placebo-controlled trial investigating vaginal E2 inserts in women with moderate to severe dyspareunia due to menopause. In this post hoc analysis, 25 eligible women with endometrial biopsies were randomly selected from each treatment group (4-mu g and 10-mu g E2 vaginal inserts and placebo). Endometrial biopsy sections were immunostained using an anti-PR (A and B) monoclonal antibody. Cell staining was quantified using an artificial intelligence feature-recognition algorithm. Mean PGR expression levels were analyzed between baseline and week 12. Results: PGR expression results were available for 22 women in the 4-mu g E2 group, and 25 women each for the 10-mu g E2 and placebo groups. Similar PGR expression levels were observed at baseline (0.301-0.470 pmol/mg) and after 12 weeks of treatment (0.312-0.432 pmol/mg) for all treatment groups, with no significant differences between baseline and week 12. Conclusions: No meaningful differences in endometrial PGR expression were observed with the vaginal E2 (4- and 10-mu g) inserts at week 12 from baseline, supporting the hypothesis that local exposure to E2 from a low-dose, vaginal insert placed near the vaginal introitus will not be sufficient to upregulate endometrial PGR expression. Coupled with the lack of histologic changes and systemic absorption, our data suggest that these softgel vaginal E2 inserts would not be expected to stimulate endometrial hyperplasia leading to a potential endometrial safety issue in postmenopausal women with moderate to severe dyspareunia, a symptom of vulvar and vaginal atrophy. Further study on the endometrial safety of softgel vaginal E2 inserts is under way.

Objective: To predict serum segesterone (SA) and ethinyl estradiol (EE) levels after 364 days of hypothetical continuous use (without removal) of a cyclic contraceptive vaginal system (CVS) containing 0.15 mg SA and 0.013 mg EE. Study design: We used pharmacokinetic (PK) data (n = 37) from a multicenter, open-label, nonrandomized study of healthy women (18-38 years) that used the CVS for 13 cycles in a 21 days-in/7 days-out regimen to develop a linear regression model to predict daily serum SA and EE levels for 364 days of continuous CVS use. We then determined residual SA/EE levels in vitro from 18 randomly chosen CVS used by women who completed 13 cycles. Serum SA and EE levels were also predicted for 364 days of continuous CVS use in another in vitro study. Results: After a hypothetical 364 days of continuous CVS use, we predicted daily mean serum levels to be 184 pmol/L (95% confidence interval [CI], 102-332 pmol/L) for SA and 43 pmol/L (95% CI, 19-95 pmol/L) for EE. We did predict that serum EE levels would not accumulate over time. Residual SA and EE in the CVS were 60% and 80% of the original load after 13 cycles, respectively. Conclusion: The predicted serum SA level after 364 days of hypothetical continuous CVS use was comparable to reported levels at which no pregnancy occurred ( > 100 pmol/L), showing the potential of the CVS for one year of continuous use. Clinical trials on continuous CVS use are planned. Implications: Based on statistical modeling, the long-term, user-controlled contraceptive vaginal system containing segesterone acetate and ethinyl estradiol may have the potential to provide effective pregnancy prevention if used continuously (without removal) for one year. Further investigation is warranted. (c) 2021 The Authors. Published by Elsevier Inc. This is an open access article under the CC BY-NC-ND license ( http://creativecommons.org/licenses/by-nc-nd/4.0/ )

INTRODUCTION: We describe a systematic approach to mitigating obstetric hemorrhage risk at University Hospitals (UH), a northeast Ohio-based system of eighteen hospitals, including seven hospitals providing obstetric services and delivering approximately 8000 women/year. METHODS: From 2009-2015, obstetric hemorrhage (OBH) led to two maternal deaths and other harms in the form of excessive transfusions, ICU admissions, and hysterectomies as definitive treatment. OBH accounted for 11% of litigation costs ($7.4 M) during this period. To reduce harm associated with OBH, we implemented the following interventions: 1. Clinical Practice Guideline for management of anemia in pregnancy; 2. EMR field to capture hemorrhage risk factors and prompt type and cross on admission; 3. Mandating transfer of high risk patients for delivery at a tertiary care center; 4. Clinical Practice Guideline for management of OBH (including active management of third stage of labor); 5. Shifting from estimating to quantifying blood loss by weight; and 6. Standardization of OBH carts on all L&D units. RESULTS: From 2015-2017, there was: 40% increase in the number of patients admitted to L&D with hemoglobin >10 mg/dl; 68% decrease in the number of obstetric patients requiring transfusions of ≥four units of packed red blood cells; 77% decrease in the number of peri-partum hysterectomies; and 91% decrease in the number of patients admitted to ICU for OBH. There were no maternal deaths from OBH and no new suits or claims related to OBH between 2014 and 2018. CONCLUSION: This multifaceted intervention was associated with decreased patient harm and reduced litigation costs associated with obstetric hemorrhage.

To evaluate reproductive outcomes in FET cycles following hormonally programmed cycles vs alternate regimens of gonadotropin stimulated cycles or natural or letrozole-induced cycles. Within natural and letrozole cycles, pregnancy rates with and without hCG trigger to induce ovulation were compared. Retrospective cohort study. All programmed, natural cycle, letrozole, and gonadotropin stimulated FETs from a single academic center from 2017 – 2020 were evaluated. Programmed cycles consisted of oral micronized estradiol 2 mg TID starting day 1 of menses followed by intramuscular progesterone. Gonadotropin stimulated cycles consisted of ovulation induction with FSH and/or hMG starting on Day 1-5 of menses followed by hCG injection (“trigger”), with vaginal or intramuscular progesterone in the luteal phase. Natural cycles involved no medication in the follicular phase, whereas letrozole cycles consisted of letrozole 5 mg cycle day 3-7. For both natural and letrozole cycles, transfer was timed either to the patient’s own ovulation as measured by serum LH and progesterone or by ovulation induced by hCG trigger. Vaginal progesterone was used for luteal support. For the primary analysis, natural and letrozole cycles were included together in the natural group. One way- ANOVA was performed to compare baseline variables between cohorts. Chi-square was used to compare pregnancy outcome variables. Fisher’s Exact test was used to compare two groups when appropriate due to sample size. A p value <0.05 was considered significant. A total of 784 FETs were included: 728 programmed FETs, 24 natural cycle FETs, and 32 gonadotropin stimulated FETs. No statistical difference was found between all 3 cohorts based on age, BMI, endometrial thickness, or number of embryos transferred. Clinical pregnancy rates (CPR) or implantation rates (IPR) did not differ between programmed, natural/letrozole cycles, or gonadotropin stimulated FETs (54.3% vs 41.7% vs 59.4%, p=0.4) (46.3% vs 42.3% vs 48.8%, p= 0.9) respectively. Live birth/ongoing pregnancy rates were also not different (43.3% vs 41.7% vs 56.3%, p=0.3). Additionally, miscarriage rates did not differ between groups (10.3% vs 0% vs 3.1% p = 0.1). A subset analysis of natural cycle FETs showed no difference in letrozole induction versus spontaneous ovulation CPR (40% vs 42.9%, p=0.99), however natural/letrozole cycles with hCG trigger were associated with an increase in CPR (75% vs 25%, p=0.032). Our center utilizes stimulated FET cycles as an alternative for patients who do not achieve appropriate endometrial growth with traditional programmed FET. Our findings suggest stimulated FET cycles can be a successful alternative for patients whose lining is not appropriate in a programmed FET cycle. We use letrozole or natural cycle FETs in patients for whom a programmed or stimulated FET is not appropriate, with similar success rates. However, our study suggests use of an hCG trigger may improve outcomes in natural or letrozole cycles.

Selective estrogen receptor modulators (SERMs) are an increasingly important therapeutic modality that are used by clinicians on a daily basis. Unfortunately, clinicians have a limited understanding regarding the underlying mechanism(s) of how SERMs function and their increasingly useful role in the treatment of estrogen-responsive target tissues such as the breast, bone, vagina, uterine endometrium, and brain. This review will provide a basic understanding of our current knowledge of SERM pharmacodynamics and will highlight the clinical applications of Food and Drug Administration-approved SERMs in the treatment of vasomotor symptoms, osteoporosis, genitourinary syndrome of menopause, infertility, and breast cancer and its prevention. SERMs under development and natural phytoestrogens will also be reviewed.

Increasing numbers of women experience early menopause due in part to surgical treatment for benign gynecologic disorders and the rise in risk-reducing bilateral salpingo-oophorectomy in women with BRCA mutations. Unfortunately, the adverse health consequences of early loss of ovarian function accelerate the menopausal state and affect multiple systems, including cardiovascular, neurologic, bone, and connective tissue, and affect quality of life owing to vasomotor symptoms, mood, sleep, and sexual function. Yet many clinicians and women remain reluctant to use hormone therapy because of the Women's Health Initiative's adverse findings, even though they are not applicable to women with early menopause. This review examines the effects of early menopause and highlights the critical role of hormone therapy in this population.

To compare the ovulation rate in women with primary amenorrhea, hypogonadotropic hypogonadism (HH) randomized to three GnRH doses (10, 15, 20 μg per pulse) delivered subcutaneous every 90 minutes with the LutrePulse OmniPod Pump versus a placebo control. Multicenter, double-blind, randomized, placebo-controlled trial. Reproductive-aged women with primary amenorrhea, hypogonadotropic hypogonadism and a negative progestin challenge test were randomized to receive one of three GnRH doses or placebo. Baseline serum FSH and LH were <5 IU/L. Follicular and endometrial development were monitored by transvaginal ultrasound until a dominant follicle of ≥18 mm mean diameter and normal endometrium (thickness and pattern) were confirmed. If a dominant follicle was not observed after 21 days or if menses occurred, treatment was discontinued. Urine luteinizing hormone tests were used to time sexual intercourse. The primary endpoint was ovulation rate, defined as either a serum progesterone ≥6 ng/mL, positive β-hCG, or presence of a gestational sac. An adaptive design included interim analyses that allowed for trial continuation, early success, or stop for futility by utilizing pooled 15 and 20 μg efficacy versus placebo as the primary analysis. Across 24 trial sites, 39 subjects were randomized (N: 10, placebo; 10, 10 μg; 9, 15 μg; 10, 20 μg per pulse) and is one of the largest trials in this rare patient population. Demographics were similar across treatment arms with mean age 30.2 years and BMI 25.9 kg/m2. Mean treatment duration days were 21.1, 23.8, 34.4, and 32.0 for the placebo, 10, 15, and 20 μg doses, respectively. The pooled ovulation rate with LutrePulse 15 μg and 20 μg was 50.0% compared to 0% with placebo with p-value for the comparison of 0.0120, i.e. below a pre-defined success threshold of 0.0130 allowing for early trial termination for efficacy success at the first interim analysis with 37 subjects (N: 10, placebo; 9, 10 μg; 9, 15 μg; 9, 20 μg). One subject who did not complete 14-day pituitary priming in the 10 μg group was excluded from the efficacy analysis. A significant difference in the number of follicles with mean diameter ≥14 mm was seen on treatment day 18 for 15 μg versus placebo (p = 0.0143), and 20 μg versus placebo (p = 0.0060). Biochemical pregnancy was achieved in 8 subjects (3 in the 15 μg group and 5 in the 20 μg group), of these, 7 subjects (2 in the 15 μg group [22.2%] and all 5 in the 20 μg group [50.0%]) achieved a live birth in the final efficacy dataset (N=38). The most frequently reported adverse events were breast tenderness (2 events reported by 2 subjects in the 15 μg group and 2 events reported by 2 subjects in the 20 μg group) and hot flush reported by 3 subjects (2 events reported by 1 subject in the 15 μg group and 2 events reported by 2 subjects in the 20 μg group). LutrePulse administered as subcutaneous pulsatile injections with the OmniPod pump in doses of 10 μg, 15 μg, and 20 μg was well-tolerated, the pooled 15 and 20 μg doses were superior to placebo for the primary endpoint, ovulation rate, and the highest live birth rate was observed in subjects treated with the 20 μg dose.

Abstract 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.