Onset of Acute Intermittent Porphyria After Etonogestrel Implant Insertion: A Case Report.

A 17-year-old previously healthy female developed posterior reversible encephalopathy syndrome 1 week after etonogestrel implantation. She had a previous etonogestrel implant removed 4 months prior after unrelenting abdominal pain and hyponatremia with a negative workup for other etiologies, including hypercoagulable disorders and malignancy. This second insertion and resulting hospitalization allowed for the diagnosis of acute intermittent porphyria (AIP) to be confirmed. Progesterone can induce enzymatic activity upstream of porphobilinogen deaminase, the enzyme implicated in AIP, resulting in build-up of toxic metabolites. AIP requires high clinical suspicion for diagnosis but should be considered when hormonal triggers lead to unexplained neurovisceral symptoms.

Effect of progestin-based contraceptives on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls.

Adolescent girls bear a disproportionate burden of both the HIV epidemic and unintended pregnancies; yet important questions remain unanswered regarding the effects of hormonal contraceptives on the vaginal immune microenvironment, which can impact HIV susceptibility in this group. Multiple studies report genital immune alterations associated with the progestin-based contraceptive Depot medroxyprogesterone acetate (DMPA) in adult women, but there is little available data in adolescents. The objective of this longitudinal cohort study was to evaluate the effects of short-term use of three progestin-based contraceptives, levonorgestrel intrauterine device (LNG-IUD), subdermal etonogestrel (ETNG), and injectable DMPA, on HIV-associated vaginal immune biomarkers and microbiome in adolescent girls. Fifty-nine sexually active, HIV-uninfected girls aged 15-19, were recruited from the Washington DC metro area and self-selected into Control (condoms only), combined oral contraceptive pills, LNG-IUD, ETNG and DMPA groups. Vaginal swabs were collected at baseline prior to contraceptive use and at 3-month follow-up visit. Vaginal secretions were tested for pro-inflammatory (IL-1α, IL-1ß, TNF-α, IL-6, IL-8, MIP-3α, IP-10, RANTES, MIP-1α, MIP-1ß) and anti-inflammatory/anti-HIV (Serpin-A1, Elafin, Beta-Defensin-2, SLPI) immune biomarkers using ELISA and for anti-HIV activity using TZM-bl assay. Vaginal microbiome was evaluated using 16S rRNA gene sequencing. Data were analyzed using SAS Version 9. Among the 34 participants who completed both visits, no significant changes in median biomarker concentrations, HIV inhibition and microbiome composition were observed between baseline and follow-up visits for any of the contraceptive groups. IL-8 (p<0.01), MIP-3α (0.02), Elafin (p = 0.03) and RANTES (p<0.01) differed significantly by race whereas IL-6 was significantly different by age (p = 0.03). We conclude that 3-month use of LNG-IUD, ETNG and DMPA have minimal effects on adolescent vaginal immune microenvironment, and therefore unlikely to impact HIV risk. Future studies with larger sample size and longer follow-up are recommended to continue to evaluate effects of contraceptives on the lower genital tract immunity and susceptibility to sexually transmitted infections.

Offering extended use of the contraceptive implant via an implementation science framework: a qualitative study of clinicians' perceived barriers and facilitators.

BACKGROUND: The etonogestrel contraceptive implant is currently approved by the United States Food and Drug Administration (FDA) for the prevention of pregnancy up to 3 years. However, studies that suggest efficacy up to 5 years. There is little information on the prevalence of extended use and the factors that influence clinicians in offering extended use. We investigated clinician perspectives on the barriers and facilitators to offering extended use of the contraceptive implant. METHODS: Using the Consolidated Framework for Implementation Research (CFIR), we conducted semi-structured qualitative interviews. Participants were recruited from a nationwide survey study of reproductive health clinicians on their knowledge and perspective of extended use of the contraceptive implant. To optimize the diversity of perspectives, we purposefully sampled participants from this study. We used content analysis and consensual qualitative research methods to inform our coding and data analysis. Themes arose deductively and inductively. RESULTS: We interviewed 20 clinicians including advance practice clinicians, family medicine physicians, obstetrician/gynecologist and complex family planning sub-specialists. Themes regarding barriers and facilitators to extended use of the contraceptive implant emerged. Barriers included the FDA approval for 3 years and clinician concern about liability in the context of off-label use of the contraceptive implant. Educational materials and a champion of extended use were facilitators. CONCLUSIONS: There is opportunity to expand access to extended use of the contraceptive implant by developing educational materials for clinicians and patients, identifying a champion of extended use, and providing information on extended use prior to replacement appointments at 3 years.

Effect of progestin on thyroid function in female Wistar rats.

Introduction: To characterize the influence of female-specific hormones on women's thyroid function, the study investigated the influence of extra progestin from oral contraceptives on inducing thyroid dysfunction. Methods: Sixty female Wistar rats were divided into six groups based on levonorgestrel or desogestrel administration as the main active agents: control, low (0.0039 mg*20-fold), medium (0.0039 mg*100-fold), high (0.0318 mg*100-fold) levonorgestrel (pure product); and low (0.0083 mg*20-fold) and high (0.0083 mg*100-fold) desogestrel (pure product). Progestin was administered by gavage every 4 days for 1 month. Statistical analysis was performed using one-way analysis of variance and the Kruskal-Wallis test. Results: Following levonorgestrel gavage, serum free T4 and thyroidstimulating hormone levels were significantly lower in the experimental group than that in the control group (p=0.013 and 0.043). After desogestrel gavage, the serum free T4 and free T3 levels were lower in the experimental group than that in the control group (p=0.019 and 0.030). Thyroid hormone antibody concentrations were lower in rats administered levonorgestrel and desogestrel than that in control rats. Moreover, exposure to progestin upregulated the expression of the thyroid-stimulating hormone receptor and sodium iodide symporter in thyroid. Discussion: Progestin stimulation enhanced the proliferation of follicular epithelial cells in rat thyroid tissues. Progestin exposure could cause thyroid dysfunction by upregulating the transcription of thyroid-stimulating hormone receptor and sodium iodide symporter in thyroid, thus inducing pathomorphological changes in rats' thyroid.

Use of etonogestrel subcutaneous implant in Sardinia, Italy: women's compliance and satisfaction.

PURPOSE OF THE ARTICLE: The main aim of the study was to analyze the population of women who used etonogestrel implant, the reason that led them to this type of contraception, and the degree of compliance with it. Materials and methods: We carried out a retrospective study on women who had etonogestrel subcutaneous implant placed (n°47) over a 6-year period (2015-2021). We submitted the women a series of questions by telephone questionnaire (range 10-72 months after placements, mean 40 months) that investigated the comorbidities and side effects related to etonogestrel implant. MATERIALS AND METHODS: We carried out a retrospective study on women who had etonogestrel subcutaneous implant placed (n°47) over a 6-year period (2015-2021). We submitted the women a series of questions by telephone questionnaire (range 10-72 months after placements, mean 40 months) that investigated the comorbidities and side effects related to etonogestrel implant. RESULTS: The average age of placement of etonogestrel implant was 33.8 ± 3.45 years. As regards level of education, 16/47 (34%) of the women had a university degree, 21/47 (44%) had a high school diploma and 10/47 (21%) had a secondary school diploma. The 12/47 (25%) of the women were, at the time of the counselling, unemployed and only 8% did not use in the past contraceptive methods other than etonogestrel implant. The 92% of women choose etonogestrel implant because it offered safe, comfortable and long-lasting contraception. Among the main side effects evaluated, we reported spotting in 24 out of 47 (51%), headache in 4 out of 47 (8.5%). The 85% of the women recommended etonogestrel implant to their friends as a contraceptive method, with an approval rating for the implant, expressed a rating from 1 to 10 with the mean that was 7.79, the median 8. CONCLUSIONS: Our results are of interest because they derive from a region of Italy in which the Long acting reversible contraception (LARC) is strongly underused. Etonogestrel implant was a safe and effective, long-acting, reversible hormonal contraception (LARC) and majority of women recommended the etonogestrel implant to their friends as a contraceptive method.

Etonogestrel implant is a safe and effective, long-acting, reversible hormonal contraception (LARC). The majority of women in our study choose the etonogestrel implant for its characteristics; among the main side effects evaluated we reported spotting and headache. The majority of women recommended the etonogestrel implant to their friends as a contraceptive method.

Migration of etonogestrel subcutaneous contraceptive implants: systematic review and recommendations for practice.

INTRODUCTION: Migration is a rare but serious complication of the etonogestrel contraceptive implant, and little is known about its extent. PURPOSE: To document and characterise cases of etonogestrel contraceptive implant migration in the scientific literature. METHODS: A systematic review of Medline, Embase and Global Health databases was carried out between January 2000 and January 2023 to identify articles presenting implant migrations. Narrative reviews, conference abstracts and articles not written in English or French were excluded. RESULTS: Forty-five articles, mostly published since 2016, were identified (eight case series and 37 case reports), for a total of 148 independent cases of migration: in pulmonary blood vessels (n = 74), in non-pulmonary blood vessels (n = 16) and extravascular (n = 58). Many patients are asymptomatic and migration is often an incidental finding. A non-palpable implant and symptoms related to implant location (intra- or extra-vascular) may be indicative of migration. Inadequate insertion and normal or underweight appear to increase the risk of migration. Scientific societies and authors offer practical strategies to deal with implant migration. CONCLUSION: Professionals who insert and remove contraceptive implants must be adequately trained. They need to be on the lookout for implant migration, and promptly refer patients to appropriate care if migration is suspected.

This systematic review documents and characterises 148 cases of vascular and extravascular etonogestrel contraceptive implant migration. Healthcare professionals must be aware of this rare but serious complication and be adequately trained to insert and remove contraceptive implants.

Nexplanonectomy-the surgical removal of an embolized implanted contraceptive device: a case report and review of the literature.

BACKGROUND: Nexplanon implants are a common hormonal contraceptive modality. Though rare, these devices can embolize into the injured wall of the basilic vein, through the right heart, and finally wedge itself into a pulmonary artery. With adherence to the arterial wall over time, it becomes less amenable to endovascular retrieval. Patients may present with symptoms mimicking a pulmonary embolism, or without any symptoms at all. In asymptomatic cases, endovascular retrieval and/or surgery is required when patients wish to begin having children prior to biological inactivity. The current literature showed as little as nine case reports detailing lung tissue removal in the aim of reversing a patient's implanted contraceptive device. CASE PRESENTATION: A 22-year-old asymptomatic active-duty Caucasian female presented for elective outpatient Nexplanon removal. The suspicion of possible implant migration arose when it was discovered to be non-palpable in her left arm. After plain film x-rays failed to localize the implant, a chest x-ray and follow-up Computed Tomography (CT) scan revealed that the Nexplanon had migrated to a distal branch of the left pulmonary artery. Due to the patient's strong desires to begin having children, the decision was made for removal. Initial endovascular retrieval failed due to Nexplanon encapsulation within the arterial wall. Ultimately, the patient underwent a left video-assisted thoracoscopic surgery (VATS) for exploration and left lower lobe basilar S7-9 segmentectomy, which successfully removed the Nexplanon. CONCLUSIONS: Implanted contraceptive devices can rarely result in migration to the pulmonary vasculature. These radiopaque devices are detectable on imaging studies if patients and clinicians are unable to palpate them. An endovascular approach should be considered first to spare lung tissue and avoid chest-wall incisions, but can be complicated by encapsulation and adherence to adjacent tissue. A VATS procedure with single-lung ventilation via a double-lumen endotracheal tube allows surgeons to safely operate on an immobilized lung while anesthesiologists facilitate single-lung ventilation. This patient's case details the uncommon phenomenon of Nexplanon migration, and the exceedingly rare treatment resolution of lung resection to remove an embolized device.

Gene expression associated with unfavorable vaginal bleeding in women using the etonogestrel subdermal contraceptive implant: a prospective study.

To evaluate gene expression associated with unfavorable vaginal bleeding in users of the Etonogestrel (ENG) contraceptive implant. Prospective study involving 100 women who intended to use the ENG implant. Exclusion criteria included abnormal uterine bleeding, inability to attend a 1-year follow-up, and implant removal for reasons unrelated to vaginal bleeding or loss of follow-up. We obtained endometrial biopsies before implant placement and assessed the expression of 20 selected genes. Users maintained a uterine bleeding diary for 12 months post-implant placement. For statistical analysis, we categorized women into those with or without favorable vaginal bleeding at 3 and 12 months. Women with lower CXCL1 expression had a 6.8-fold increased risk of unfavorable vaginal bleeding at 3 months (OR 6.8, 95% CI 2.21-20.79, p < 0.001), while those with higher BCL6 and BMP6 expression had 6- and 5.1-fold increased risks, respectively. By the 12-month follow-up, women with lower CXCL1 expression had a 5.37-fold increased risk of unfavorable vaginal bleeding (OR 5.37, 95% CI 1.63-17.73, p = 0.006). Women with CXCL1 expression < 0.0675, BCL6 > 0.65, and BMP6 > 3.4 had a higher likelihood of experiencing unfavorable vaginal bleeding at 3 months, and CXCL1 < 0.158 at 12 months. Users of ENG contraceptive implants with elevated BCL6 and BMP6 expression exhibited a higher risk of breakthrough bleeding at the 3-month follow-up. Conversely, reduced CXCL1 expression was associated with an elevated risk of bleeding at both the 3 and 12-month follow-ups.

Pilot study of a novel, alternative subdermal scapular insertion site for the etonogestrel contraceptive implant.

OBJECTIVES: To assess the pharmacokinetics and pharmacodynamics of the etonogestrel (ENG) contraceptive implant when inserted at an alternative scapular site. STUDY DESIGN: We conducted a pilot study of healthy, reproductive-age females who underwent subdermal insertion of an ENG implant over the inferior edge of the nondominant scapula (scapular insertion). We measured serum ENG levels over 1 year at nine time points. Participants completed questionnaires on insertion site and bleeding side effects. We collected photographs and video recordings of insertion and removal techniques. RESULTS: We enrolled five participants (as prespecified), their median age was 26.0 years (range: 19.6-30.3), and median body mass index was 25.0 kg/m2 (range: 22.0-28.0). All serum ENG concentrations remained >90 pg/mL and were within the range of published data for arm insertion of ENG implant at all time points. The mean serum ENG level was 511.7 pg/mL (±168.2) at 1 week and 136.6 pg/mL (±21.8) at 12 months. During the first week after insertion, four of five participants noted insertion site pain with a median pain score of 2 (range 1-3), but all noted resolution by week two. Participants reported variable bleeding patterns consistent with standard ENG implant placement. At the end of the study, all participants reported satisfaction with the implant and would recommend scapular insertion to a friend. CONCLUSIONS: Scapular insertion of the ENG contraceptive implant has similar pharmacokinetics to arm insertion over 1 year of use. This novel, alternative site was well tolerated and demonstrated similar bleeding side effects to standard arm insertion. IMPLICATIONS: Subdermal scapular insertion of the etonogestrel contraceptive implant demonstrated similar pharmacokinetics to arm insertion over 1 year of use. Our pilot data support scapular insertion as an alternative site for ENG contraceptive implants, which could be beneficial for certain patient populations.

Etonogestrel-releasing subdermal contraceptive implant: Budget impact analysis based on the Brazilian private healthcare system.

High rates of unplanned pregnancies persist despite pharmacological developments and advancements in contraceptive methods. Here, we demonstrate that the etonogestrel-releasing subdermal contraceptive implant (IMP-ETN) may be an appropriate and cost-effective alternative to levonorgestrel-releasing intrauterine systems (LNG-IUSs) for women in Brazil. For our pharmacoeconomic analysis, we reviewed the literature on IMP-ETN regarding its acceptance, eligibility criteria, choice, relations with age, adverse events and, finally, the unmet need in the fee-for-service private healthcare sector. We considered qualitative observations in combination with quantitative analysis and performed a deterministic sensitivity analysis to investigate whether this technology can be self-sustainable over a period of five years. The target population for this analysis comprised 158,696 women. Compared with the continued use of LNG-IUSs, adopting the IMP-ETN can result in a cost avoidance of $ 7.640.804,02 in the first year and $ 82,455,254.43 in five years. Disseminating information among physicians will promote this change and strengthen the potential cost avoided by private health system payers. These savings can be used to improve other healthcare programs and strategies. Moreover, the principles of care can be promoted by improving and adapting healthcare systems and expanding treatment and follow-up strategies. This would also provide support to women's reproductive rights and improve their quality of life. Our results suggest that the IMP-ETN has a favorable cost-effectiveness profile. Given all its advantages and negative incremental cost impact over a period of five years, the IMP-ETN may be a more favorable alternative to LNG-IUSs. Therefore, it should be offered to beneficiaries with a private healthcare plan. This analysis overcomes previous barriers to the use of cost-benefit models, and our results may help balance decision-making by policymakers, technical consultants, and researchers.

Outcomes of etonogestrel subdermal contraceptive implants: A single center cross-sectional study.

OBJECTIVES: To examine the prevalence of menstrual irregularities, side effects, and discontinuation rates of etonogestrel subdermal implants (ESI) in women attending King Abdulaziz Medical City, Jeddah, Saudi Arabia. METHODS: This cross-sectional was carried out based on electronic medical records and a phone-based questionnaire administered to women who underwent ESI insertion in a single tertiary care hospital in Jeddah, Saudi Arabia, between 2019 and 2022. The primary objective was the prevalence of menstrual abnormalities. The secondary study objective included the discontinuation rate, reasons for discontinuation, and ESI side effects. RESULTS: In total, 345 women with ESI were included in this study. The prevalence of any type of menstrual abnormalities was 88%. Other side effects included skin and mood changes, arm pain, and numbness. The discontinuation rate was 11% in the first year and 22% before the completion of 36 months. CONCLUSION: Although menstrual abnormalities are a common side effect of ESI, only 22% of users discontinued this method of contraception.

Development and verification of mechanistic vaginal absorption and metabolism model to predict systemic exposure after vaginal ring and gel application.

AIMS: The current work describes the development of mechanistic vaginal absorption and metabolism model within Simcyp Simulator to predict systemic concentrations following vaginal application of ring and gel formulations. METHODS: Vaginal and cervix physiology parameters were incorporated in the model development. The study highlights the model assumptions including simulation results comparing systemic concentrations of 5 different compounds, namely, dapivirine, tenofovir, lidocaine, ethinylestradiol and etonogestrel, administered as vaginal ring or gel. Due to lack of data, the vaginal absorption parameters were calculated based on assumptions or optimized. The model uses release rate/in vitro release profiles with formulation characteristics to predict drug mass transfer across vaginal tissue into the systemic circulation. RESULTS: For lidocaine and tenofovir vaginal gel, the predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits. The average fold error (AFE) and absolute AFE indicating bias and precision of predictions range from 0.62 to 1.61. For dapivirine, the pharmacokinetic parameters are under and overpredicted in some studies due to lack of formulation composition details and relevance of release rate used in ring model. The predicted to observed AUC0-t and Cmax ratios were well within 2-fold error limits for etonogestrel and ethinylestradiol vaginal ring (AFEs and absolute AFEs from 0.84 to 1.83). CONCLUSION: The current study provides first of its kind physiologically based pharmacokinetic framework integrating physiology, population and formulation data to carry out in silico mechanistic vaginal absorption studies, with the potential for virtual bioequivalence assessment in the future.

Higher baseline heart rate variability in CCHS patients with progestin-associated recovery of hypercapnic ventilatory response.

After a fortuitous observation of two cases of chemosensitivity recovery in women with congenital central hypoventilation syndrome (CCHS) who took desogestrel, we aimed to evaluate the ventilatory response to hypercapnia of five CCHS patients with or without treatment consisting of desogestrel (DESO) or levonorgestrel (LEVO). Only two patients became responsive to hypercapnia under treatment, according to their basal vagal heart rate variability. These results suggest that heart rate variability may be promising tool to discriminate patients susceptible to become responsive to hypercapnia under DESO-LEVO treatment.Clinical Trials Identifier NCT01243697.

Effectiveness and continuation rates of the etonogestrel-subdermal contraceptive implant versus short-acting contraceptive methods offered at no cost in Campinas, Brazil.

OBJECTIVES: To compare the efficacy, reasons for discontinuation and continuation rates of the etonogestrel (ENG)-subdermal contraceptive implant when offered at no cost, and the basis of free choice versus short-acting reversible contraceptive (SARC) methods including combined oral contraceptives (COCs), once-a-month injectables, vaginal ring, and patch. METHODS: We conducted a prospective study at the University of Campinas, Brazil, involving women aged 18 to 40 years. They were counseled on various contraceptive methods before entering the study and followed up every 3 months for up to 24 months. Satisfaction was assessed using a Likert scale. Survival rates were estimated using the Kaplan-Meier test, and curve comparisons were performed using the log-rank test. RESULTS: We enrolled 609 women including 358/609 women (58.8%) who chose the ENG-implant and 251/609 (41.2%) who chose SARC methods. Contraceptive failure and all other reasons for discontinuation were significantly higher in SARC users compared to the ENG-implant users (P < 0.001 and P = 0.002, respectively). The continuation rate was higher among ENG-implant users (89.9% and 75.4%) compared to SARC methods users (27.2% and 15.9%) up to 1 and 2 years after study initiation, respectively. Satisfaction was high in both groups (>82%). CONCLUSIONS: The ENG-implant showed higher contraceptive effectiveness and higher continuation rates than SARC methods up to 2 years after study initiation. Furthermore, users from both groups were highly satisfied with their contraceptive. The main reason for discontinuing use of the ENG-implant was bothersome uterine bleeding, while for SARC methods it was for personal reasons.

Amenorrhea in adolescents using the etonogestrel contraceptive implant.

OBJECTIVE: Clinical factors related to development of amenorrhea in adolescents with the etonogestrel contraceptive implant are not well-understood. The purpose of this study is to describe what baseline clinical characteristics are associated with amenorrhea in adolescents with a contraceptive implant 12 months after placement. STUDY DESIGN: This retrospective cohort study included 252 post-menarchal individuals aged 12-22 years with a contraceptive implant placed between 2016-2020. Data abstracted at insertion, three months post-insertion, and 12 months post-insertion included demographics, baseline bleeding pattern, prior contraception use, post-insertion bleeding pattern, and method discontinuation. We assessed possible predictive characteristics of our outcomes using bivariate and multivariable logistic regression analyses. RESULTS: Twenty nine percent of patients were amenorrheic 12 months after placement. Patients who were amenorrheic at 12 months were more likely to be obese (41.1% vs 24.6%, p = 0.01), to have been amenorrheic prior to implant insertion (16.9% vs 5.4%, p < 0.01, to have used hormonal contraception immediately prior to insertion (42.5% vs 26.3%, p = 0.01), to have had the most recent contraceptive method being another implant (12.3% vs 3.6%, p = 0.02), and to have developed amenorrhea within three months after placement (22.2% vs 12.6%, p < 0.01). After multivariable regression analysis, only obesity (adjusted odds ratio [aOR] 2.2 95% CI 1.1-4.2) and amenorrhea at three months (aOR 3.6, CI 1.1-11.5) were associated with amenorrhea at 12 months. CONCLUSION: Obesity and early amenorrhea were associated with 12-month amenorrhea in adolescents using the etonogestrel subdermal implant. Understanding this can help with contraceptive method selection and counseling for patients and providers. IMPLICATIONS: Obesity and early amenorrhea with the etonogestrel contraceptive implant are associated with longer-term amenorrhea in adolescents using this method. These findings can aid providers with method selection and pre-insertion decision-making for adolescents considering contraceptive implant use, as well as continued counseling after placement.

Etonogestrel promotes respiratory recovery in an in vivo rat model of central chemoreflex impairment.

AIM: The central CO2 chemoreflex is a vital component of respiratory control networks, providing excitatory drive during resting conditions and challenges to blood gas homeostasis. The retrotrapezoid nucleus is a crucial hub for CO2 chemosensitivity; its ablation or inhibition attenuates CO2 chemoreflexes and diminishes restful breathing. Similar phenotypes characterize certain hypoventilation syndromes, suggesting underlying retrotrapezoid nucleus impairment in these disorders. Progesterone stimulates restful breathing and CO2 chemoreflexes. However, its mechanisms and sites of actions remain unknown and the experimental use of synthetic progestins in patients and animal models have been met with mixed respiratory outcomes. METHODS: We investigated whether acute or chronic administration of the progestinic drug, etonogestrel, could rescue respiratory chemoreflexes following selective lesion of the retrotrapezoid nucleus with saporin toxin. Adult female Sprague Dawley rats were grouped based on lesion size determined by the number of surviving chemosensitive neurons, and ventilatory responses were measured by whole body plethysmography. RESULTS: Ventilatory responses to hypercapnia (but not hypoxia) were compromised in a lesion-dependent manner. Chronic etonogestrel treatment improved CO2 chemosensitivity selectively in rats with moderate lesion, suggesting that a residual number of chemosensitive neurons are required for etonogestrel-induced CO2 chemoreflex recovery. CONCLUSION: This study provides new evidence for the use of progestins as respiratory stimulants under conditions of central hypoventilation and provides a new testable model for assessing the mechanism of action of progestins in the respiratory network.

Pharmacodynamic evaluation of the etonogestrel contraceptive implant initiated midcycle with and without ulipristal acetate: An exploratory study.

OBJECTIVE: To estimate the incidence of ovulation suppression within five days of etonogestrel 68 mg implant insertion in the presence of a dominant follicle with and without same-day ulipristal acetate. STUDY DESIGN: This single site non-masked, exploratory randomized trial recruited people age 18-35 years with regular menstrual cycles, no pregnancy risk, and confirmed ovulatory function. We initiated transvaginal ultrasound examinations on menstrual day 7-9 and randomized participants 1:1 to etonogestrel implant alone or with concomitant ulipristal acetate 30 mg oral when a dominant follicle reached ≥14 mm in diameter. We completed daily sonography and serum hormone levels for up to seven days or transitioned to labs alone if sonographic follicular rupture occurred. We defined ovulation as follicular rupture followed by progesterone >3 ng/mL. We calculated point estimates, risk ratios and 95% confidence intervals for ovulation for each group. Ovulation suppression of ≥44% in either group (the follicular rupture suppression rate with oral levonorgestrel emergency contraception), would prompt future method testing. RESULTS: From October 2020 to October 2022, we enrolled 40 people and 39 completed primary outcome assessments: 20 with etonogestrel implant alone (mean follicular size at randomization: 15.2 mm ± 0.9 mm) and 19 with etonogestrel implant + ulipristal acetate (mean follicular size at randomization: 15.4 mm ± 1.2 mm, p = 0.6). Ovulation suppression occurred in 13 (65%) of etonogestrel implant-alone participants (Risk ratio 0.6 (95% CI: 0.3, 1.1), p = 0.08) and seven (37%) of implant + ulipristal acetate participants. CONCLUSIONS: Ovulation suppression of the etonogestrel implant alone exceeds threshold testing for future research while the implant + ulipristal acetate does not. IMPLICATIONS: Data are lacking on midcycle ovulation suppression for the etonogestrel implant with and without oral ulipristal acetate. In this exploratory study, ovulation suppression occurred in 65% of implant participants and 37% of implant + ulipristal acetate participants. Ovulation suppression of the implant alone exceeds threshold testing for future emergency contraception research.

Genital epithelial barrier function is conserved by intravaginal rings releasing etonogestrel and ethinyl estradiol.

The injectable progestin depot-medroxyprogesterone acetate (DMPA) is a popular contraceptive choice in sub-Saharan Africa although mouse models indicate it weakens genital epithelial integrity and barrier function and increases susceptibility to genital infection. The intravaginal ring NuvaRing® is another contraceptive option that like DMPA suppresses hypothalamic pituitary ovarian (HPO) axis function with local release of progestin (etonogestrel) and estrogen (ethinyl estradiol). As we previously reported that treating mice with DMPA and estrogen averts the loss of genital epithelial integrity and barrier function induced by DMPA alone, in the current investigation we compared genital levels of the cell-cell adhesion molecule desmoglein-1 (DSG1) and genital epithelial permeability in rhesus macaques (RM) treated with DMPA or a NuvaRing®re-sized for RM (N-IVR). While these studies demonstrated comparable inhibition of the HPO axis with DMPA or N-IVR, DMPA induced significantly lower genital DSG1 levels and greater tissue permeability to intravaginally administered low molecular mass molecules. By identifying greater compromise of genital epithelial integrity and barrier function in RM administered DMPA vs. N-IVR, our results add to the growing body of evidence that indicate DMPA weakens a fundamental mechanism of anti-pathogen host defense in the female genital tract.

Efficacy of oral levonorgestrel emergency contraception with same day etonogestrel contraceptive implant: A prospective observational study.

OBJECTIVE: To determine a 1-month pregnancy rate point estimate and 95% confidence interval for guideline-supported, same-day initiation of an etonogestrel implant plus oral levonorgestrel emergency contraception. STUDY DESIGN: In this single-arm, prospective observational study, all emergency contraception clients who presented to four Planned Parenthood Association of Utah clinics from February 2021 to March 2023 received information about oral levonorgestrel with same-day etonogestrel implant insertion. Participants were ≤35 years and reported unprotected intercourse within 5 days with negative pregnancy testing. The primary outcome measure was a 1-month home pregnancy test. We calculated the efficacy using a test of proportions with Yates continuity correction. RESULTS: A total of 160 emergency contraception clients (7.6% of 2106 approached) enrolled and 153 had 1-month pregnancy outcomes. A positive pregnancy test occurred in 2 participants resulting in an overall pregnancy rate of 1.32% (95% confidence interval 0.23%-5.19%). Ultrasound gestational dating assigned conception of the first pregnancy to 8 days before enrollment. For the second pregnancy, ultrasound dating designated conception at 5 days prior to enrollment. Limiting the efficacy rate to the single pregnancy that occurred within 5 days of unprotected intercourse, we report a pregnancy rate of 0.66% (95% confidence interval 0.03%-4.19%). CONCLUSIONS: In this observational study of emergency contraception clients selecting oral levonorgestrel with same-day etonogestrel implant, we identified a pregnancy rate within the established range of oral emergency contraception methods alone. IMPLICATIONS: Clients presenting for emergency contraception may also desire ongoing highly-effective contraception, yet current clinical guidelines serve as a barrier to same-day method initiation for the etonogestrel implant and other hormonal methods. Improving access to contraceptive method initiation will reduce the ongoing risk of unwanted pregnancy for this population. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov NCT04678817; registered 12/16/20.