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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.

Abstract 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

Key Clinical Message: Cerebral Venous Sinus Thrombosis (CVST) is a subtype of venous thromboembolism, which occurs in the dural venous sinuses. Blockage of the venous drainage of the brain leads to the development of hemorrhages. Strokes can hence develop in any individual, irrespective of age or sex. CVST is a very serious condition requiring immediate thrombolysis to prevent residual neurological deficits. We report the case of a lady aged 25 years, who presented to the emergency department with a severe diffuse headache for 4 days, associated with vomiting. This was followed by multiple episodes of seizures and altered sensorium the previous day. She had been taking desogestrel for the past 2 months. On examination, the patient was unconscious and febrile (102.8 F). On admission, Glasgow Coma Scale score of E2V2M3 and bilateral extensor plantar response were noted. Signs of meningeal irritation were absent. Her pupils were mid‐dilated, sluggishly reactive to light, and papilledema was present bilaterally. Based on imaging studies, she was diagnosed with a case of CVST. Her homocysteine levels were elevated. She recovered on appropriate treatment and was discharged on Ryle's feeding tube after 26 days of hospital stay with a Glasgow Coma Scale score of E4V5M6 and a flexor plantar response. The case emphasizes the need to rule out CVST in young adult females on oral contraceptive pills (OCP) presenting with severe neurological dysfunction. Vigilant screening, clinical suspicion and timely management can help cut down the associated mortality and morbidity in such cases. [ABSTRACT FROM AUTHOR]

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 [ABSTRACT FROM AUTHOR]

Key Clinical Message Cerebral Venous Sinus Thrombosis (CVST) is a subtype of venous thromboembolism, which occurs in the dural venous sinuses. Blockage of the venous drainage of the brain leads to the development of hemorrhages. Strokes can hence develop in any individual, irrespective of age or sex. CVST is a very serious condition requiring immediate thrombolysis to prevent residual neurological deficits. We report the case of a lady aged 25 years, who presented to the emergency department with a severe diffuse headache for 4 days, associated with vomiting. This was followed by multiple episodes of seizures and altered sensorium the previous day. She had been taking desogestrel for the past 2 months. On examination, the patient was unconscious and febrile (102.8 F). On admission, Glasgow Coma Scale score of E2V2M3 and bilateral extensor plantar response were noted. Signs of meningeal irritation were absent. Her pupils were mid‐dilated, sluggishly reactive to light, and papilledema was present bilaterally. Based on imaging studies, she was diagnosed with a case of CVST. Her homocysteine levels were elevated. She recovered on appropriate treatment and was discharged on Ryle's feeding tube after 26 days of hospital stay with a Glasgow Coma Scale score of E4V5M6 and a flexor plantar response. The case emphasizes the need to rule out CVST in young adult females on oral contraceptive pills (OCP) presenting with severe neurological dysfunction. Vigilant screening, clinical suspicion and timely management can help cut down the associated mortality and morbidity in such cases.

ObjectivesLong-acting reversible contraceptives are effective contraceptives for women with HIV, but there are limited data on etonogestrel implant and antiretroviral therapy pharmacokinetic drug-drug interactions. We evaluated etonogestrel/antiretroviral therapy drug-drug interactions, and the effects of etonogestrel on ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, and efavirenz pharmacokinetics.Study designWe enrolled postpartum women using etonogestrel implants and receiving ritonavir-boosted-atazanavir, ritonavir-boosted-lopinavir, or efavirenz-based regimens between 2012 and 2015. Etonogestrel implants were inserted 2 to 12 weeks postpartum. We performed pharmacokinetic sampling pre-etonogestrel insertion and 6 to 7 weeks postinsertion. We measured antiretroviral concentrations pre and postetonogestrel insertion, and compared etonogestrel concentrations between antiretroviral regimens. We considered a minimum serum etonogestrel concentration of 90 pg/mL adequate for ovulation suppression.ResultsWe collected pharmacokinetic data for 74 postpartum women, 22 on ritonavir-boosted-atazanavir, 26 on ritonavir-boosted-lopinavir, and 26 on efavirenz. The median serum concentrations of etonogestrel when co-administered were highest with etonogestrel/ritonavir-boosted-atazanavir (604 pg/mL) and etonogestrel/ritonavir-boosted-lopinavir (428 pg/mL), and lowest with etonogestrel/efavirenz (125 pg/mL); p < 0.001. Minimum concentration (Cmin) of ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were lower after etonogestrel implant insertion, but overall exposure, predose concentrations, clearance, and half-lives were unchanged. We found no significant change in efavirenz exposure after etonogestrel insertion.ConclusionsUnlike efavirenz, ritonavir-boosted-atazanavir and ritonavir-boosted-lopinavir were not associated with significant decreases in etonogestrel concentrations. Efavirenz was associated with a significant decrease in etonogestrel concentrations.ImplicationsThe findings demonstrate no interactions between etonogestrel and ritonavir-boosted-lopinavir or ritonavir-boosted-atazanavir, but confirm the decreased efficacy of etonogestrel with efavirenz-based antiretrovirals. This information should be used to counsel women with HIV who desire long-acting reversible contraceptives.

ObjectivesTo assess referral center outcomes with removal of difficult or nonpalpable contraceptive implants using high-frequency point-of-care ultrasonography.Study designWe present a case series examining patients referred to our specialty center from January 2019 through September 2020 for difficult or nonpalpable implant removal.ResultsOf the 54 referrals, 6 had palpable implants and 48 required ultrasonography. We localized 46 (96%) implants in-office, including 13 located subfascially; 2 Implanon implants could not be localized. We successfully completed 50 (96%) of 52 attempted in-office removals, including 12 (92%) subfascial implants.ConclusionHigh-frequency point-of-care ultrasonography can effectively localize nonpalpable contraceptive implants leading to successful in-office removal.ImplicationsSpecialists can use high-frequency point-of-care ultrasonography to localize nonpalpable implants without formal radiology scans and skilled technologists, optimizing patient time and convenience. However, the probe is expensive, and providers may need to consider this cost in the context of reimbursement for these highly specialized procedures.

Among young persons, ease of use, high efficacy, and high acceptability makes the etonogestrel contraceptive implant an important choice for this age group. Adolescent-friendly, patient-centered counseling considers the patient's cognitive development, the influence of friends and family, as well as their own preferences and values. Age-appropriate language, graphics, and models are useful to explain contraceptive options and relevant side effects. Effectiveness, reversibility, safety, noncontraceptive benefits, and side effects are important attributes and should be discussed when teens are choosing a contraceptive method. In this review we describe suggested best practices for counseling adolescents about the etonogestrel implant so they can make informed, prudent decisions about using this contraceptive method.

ObjectivesTo evaluate pharmacokinetics and pharmacogenetics of contraceptive implant progestin concentrations in HIV-positive women initiating efavirenz (EFV)-containing or nevirapine (NVP)-containing antiretroviral therapy (ART).DesignWe analyzed stored samples from women self-reporting implant use in the Partners PrEP Study.MethodsPlasma samples collected every 6 months were analyzed for levonorgestrel and etonogestrel concentrations. Progestin concentrations from samples collected after ART initiation were compared with pre-ART concentrations for intraindividual comparisons. We used adjusted linear mixed models to compare hormone concentrations between individuals on EFV and NVP to a no ART group. We then evaluated whether possessing certain alleles with known or possible influences on EFV, NVP, or progestin metabolism were associated with changes in progestin concentrations or modified the association between ART use and progestin concentrations.ResultsOur analysis included 11 women who initiated EFV, 13 who initiated NVP, and 36 who remained ART-naive. In the EFV group, the adjusted geometric mean ratio (aGMR) of levonorgestrel was 0.39 [90% confidence intervals (0.31, 0.49); P

ObjectivesTo evaluate if a simple method for characterizing vaginal bleeding patterns in etonogestrel contraceptive implant users can predict subsequent patterns and bleeding-related discontinuation over the first 2 years of use.Study designWe reanalyzed phase 3 study bleeding data for non-breastfeeding participants from the United States, Europe, Russia and Chile during the first 2 years of implant use to characterize and correlate bleeding patterns. We used 90-day reference periods with period 1.1 starting at Day 29 and ending at Day 118. We dichotomized bleeding patterns as "favorable" (amenorrhea, infrequent bleeding and normal frequency bleeding without prolonged bleeding) or "unfavorable' (prolonged and/or frequent bleeding) and tracked user groups based on these bleeding patterns in reference period 1.1 through Year 1 and from Year 1 through Year 2, respectively.ResultsWe evaluated data from 537 and 428 women with up to 1 and 2 years use, respectively. Of the 325 (60.5%) women with favorable bleeding in reference period 1.1, 275 (84.6%) reported favorable bleeding also in reference period 2, 197 (60.6%) reported favorable bleeding throughout Year 1, and favorable bleeding in 75-85% of reference periods in Year 2. Among 212 (39.5%) women with unfavorable bleeding in reference period 1.1, 118 (55.7%) continued with unfavorable bleeding in reference period 2, while about 40%-50% reported favorable patterns in RP 2, 3 and/or 4. Initial favorable bleeding resulted in lower discontinuation rates than initial unfavorable bleeding in years 1 (3.7% vs 12.7%, p≪.0001) and 2 (2.5% vs 16.5%, p≪.0001).ConclusionImplant users with favorable bleeding in the first reference period are likely to continue with favorable bleeding over the next 2 years. Initial bleeding patterns predict overall continuation rates in years 1 and 2. Implications Statement When evaluating vaginal bleeding in any 90-day reference period over 2 years of etonogestrel implant use, approximately 80% of women with favorable and 40% with unfavorable bleeding patterns will have favorable bleeding in the next reference periods. These findings can facilitate counseling regarding bleeding for women using the etonogestrel implant.

Introduction. The frequency of side effects when taking combined oral contraceptives (COCs) is still high, which is the reason for refusal to take COCs by women worldwide with a frequency of 30 to 81 %. Management of side effects will help increase the user's adherence to the chosen method of contraception.Aim: to identify approaches to prevent users from refusing to take COCs due to side effects and increase adherence to their use.Materials and Мethods. The search for foreign literary sources in English was carried out in the international bases PubMed/MEDLINE, Google Scholar, Cochrane Library, in Russian in еLibrary database, by keywords: «hormonal contraception», «combined oral contraceptives», «side effects», «adherence». Search depth was 30 years (1992–2022). 437 and 74 articles were identified, respectively, of which the review included 44 manuscripts that satisfied the criteria for inclusion on the topic studied: full-text manuscripts with the results of original studies, systematic reviews and meta-analyses.Results. In the literature, there is a lower incidence of side effects of COCs containing 30–35 µg of ethinylestradiol (tri- and monophasic) compared with 20 micrograms of ethinylestradiol. It was found that the risk of intermenstrual bleeding is 30 % lower when using COCs containing thirdgeneration progestogens compared with second-generation progestogens (relative risk (RR) = 0.71; 95 % confidence interval (CI) = 0.55–0.91) using monophasic combinations as an example. The use of a three-phase COC containing desogestrel (DSG) was characterized by a low incidence of irregular bleeding (3.3 % in the first cycle and a decrease to 2.3 % by the 12th cycle), no effect on physiological parameters, a decrease in blood androgens content and a positive effect on seborrhea and acne, excellent tolerance (2.6% failures due to adverse events). Three-phase COCs are characterized by a lower frequency of intermenstrual bleeding (by 2 times) and amenorrhea (by 3 times) compared with other COCs. A positive effect on reducing the frequency of irregular spotting and breakthrough bleeding was shown when switching from a COC of another composition to a three-phase one containing DSG, and continuing to use it.Conclusion. A three-phase COC containing DSG continues to be a topical hormonal contraceptive for women both for the first time and when switching from another COC due to side effects, including those associated with menstrual irregularities.

Dysmenorrhea and mastodynia are the most common gynecologic pain causes in women of all ages and races during their reproductive life. The following study aimed to show the influence of two POP´s in the development of dysmenorrhea and mastodynia after nine months of use. A total of 858 women with 6691 drospirenone (DRSP) cycles and 332 women with 2487 desogestrel (DSG) cycles were analyzed. Women included in this study were all child-bearing potentials, at risk of pregnancy, agreeing to use only the study medication for contraception for the duration of the study medication treatment, aged 18 to 45. At screening, 168 (19.6%) of the 858 patients using DRSP and 64 (19,3%) of the DSG patients reported that they had suffered from dysmenorrhea within six cycles prior to the first visit before starting with the medication. 20,2% of the DRSP and 10,9% of the DSG group had a sever dysmenorrhea. After 9 cycles this was reduced to 0,6% and 3,1% respectively. In total, 96 women (11.2%) in the DRSP and 49 (14,8%) experienced mastodynia within six cycles before the screening. Of these 91.6% in the DRSP group and 91,8% in the DSG group had no or mild mastodynoa at follow-up. The progestins 4 mg and desogestrel 0,075 mg showed a marked effect in the non-contraceptive aspects of dysmenorrhea and mastodynia so that new possibilities are opened for these two benign gynecological diseases. Future studies must reaffirm these first data. [ABSTRACT FROM AUTHOR]

BackgroundData evaluating the impact of contraceptives on the vaginal microbiome are limited and inconsistent.ObjectiveWe hypothesized that women initiating copper intrauterine device use would have increased bacterial vaginosis and bacterial vaginosis-associated microbes with use compared to women initiating and using hormonal contraceptive methods.Study designVaginal swabs (N = 1047 from 266 participants seeking contraception) for Nugent score determination of bacterial vaginosis and quantitative polymerase chain reaction analyses for assessment of specific microbiota were collected from asymptomatic, healthy women aged 18-35 years in Harare, Zimbabwe, who were confirmed to be free of nonstudy hormones by mass spectrometry at each visit. Contraception was initiated with an injectable (depot medroxyprogesterone acetate [n = 41], norethisterone enanthate [n = 44], or medroxyprogesterone acetate and ethinyl estradiol [n = 40]), implant (levonorgestrel [n = 45] or etonogestrel [n = 48]), or copper intrauterine device (n = 48) and repeat vaginal swabs were collected after 30, 90, and 180 days of continuous use. Self-reported condom use was similar across all arms at baseline. Quantitative polymerase chain reaction was used to detect Lactobacillus crispatus, L jensenii, L gasseri/johnsonii group, L vaginalis, L iners, Gardnerella vaginalis, Atopobium vaginae, and Megasphaera-like bacterium phylotype I from swabs. Modified Poisson regression and mixed effects linear models were used to compare marginal prevalence and mean difference in quantity (expressed as gene copies/swab) prior to and during contraceptive use.ResultsBacterial vaginosis prevalence increased in women initiating copper intrauterine devices from 27% at baseline, 35% at 30 days, 40% at 90 days, and 49% at 180 days (P = .005 compared to marginal prevalence at enrollment). Women initiating hormonal methods had no change in bacterial vaginosis prevalence over 180 days. The mean increase in Nugent score was 1.2 (95% confidence interval, 0.5-2.0; P = .001) in women using copper intrauterine devices. Although the frequency and density of beneficial lactobacilli did not change among intrauterine device users over 6 months, there was an increase in the log concentration of G vaginalis (4.7, 5.2, 5.8, 5.9; P = .046) and A vaginae (3.0, 3.8, 4.6, 5.1; P = .002) between baseline and 30, 90, and 180 days after initiation. Among other contraceptive groups, women using depot medroxyprogesterone acetate had decreased L iners (mean decrease log concentration = 0.8; 95% confidence interval, 0.3-1.5; P = .004) and there were no significant changes in beneficial Lactobacillus species over 180 days regardless of contraceptive method used.ConclusionCopper intrauterine device use may increase colonization by bacterial vaginosis-associated microbiota, resulting in increased prevalence of bacterial vaginosis. Use of most hormonal contraception does not alter vaginal microbiota.

OBJECTIVE:We evaluated a novel concept of initiating the etonogestrel implant as a "back-up" method in women who desire using combined oral contraceptives (COC) but want to decrease their risk of unintended pregnancy with a more effective method. STUDY DESIGN:In this prospective cohort study, we planned to include 20 women as a proof-of-concept. We enrolled both new COC starters and continuing COC users and placed an etonogestrel implant. Participants completed daily bleeding diaries and attended follow-up visits at 1, 3, and 6 months. We assessed implant continuation through six months of study participation and side effects with dual hormonal contraceptive use. RESULTS:Between September and December 2016, we enrolled 10 new starters and 10 current COC users. All participants completed 1-month follow-up, and 18 (90%) subjects completed the 3- and 6-month follow-up assessments. Two current COC users had the implant removed for mood changes before 6 months. At the 6-month follow-up visit, 10 women were using both pills and implant, seven relied on the implant only, and one was using a COC only. Three new starters chose implant removal at end of study participation; one for weight gain and acne, another for mood changes, and one for decreased libido. No subjects discontinued the implant for bleeding complaints. CONCLUSION:In this proof-of-concept study, women using COCs were willing to initiate the implant as a "back-up" method to improve pregnancy prevention. Most women continued the implant through 6 months and after completing study participation. IMPLICATIONS:Initiating the etonogestrel implant as a "back-up" method may be an option for women who desire more effective pregnancy prevention while using combined oral contraceptive pills for its bleeding profile or non-contraceptive benefits.

To evaluate the different effects of a progestin-only contraceptive with desogestrel (DSG) vs combined oral contraceptives (COCs) for a first line long-term treatment of endometriosis-related pain among patients seeking hormonal contraception. An observational retrospective cohort study was conducted in collaboration with a local outpatient clinic for endometriosis among a group of nulliparous young women (n = 216) with endometriosis-related pain and seeking contraception. The cohort was subdivided into a group (n = 73) treated as first line by DSG and another group (n = 75) treated by a COC. During the study, clinical symptoms, side effects and possible changes in OC type use were recorded. No significant difference was found between the two groups in terms of clinical characteristics and pain scores before treatment. After 6 months both treatments were effective in reducing endometriosis-related pain, and those treated with DSG showed lower levels of dysmenorrhea, dyspareunia and nonmenstrual pelvic pain than COCs group (p <.01). After 12 months, in DSG Group some patients (15%) switched from DSG to a COC for breakthrough bleeding, whereas in COC Group 48% of patients switched to another type of COC for reduced efficacy on pain and/or for side effects. After 3 years of OC treatment, in DSG Group 79% of patients maintained the same therapy, whereas in COC Group only 14% continued the same COC type, 37% switched to another COC and 47% to DSG. A progestin-only contraceptive with DSG is a valid option for long term management of endometriosis-related pain in patients seeking hormonal contraception. [ABSTRACT FROM AUTHOR]

ObjectiveThe objective was to monitor the effectiveness of the etonogestrel implant clinical training program through a voluntary active monitoring program (AMP).Study designUS health care providers underwent mandatory training by the manufacturer on etonogestrel implant insertion, localization and removal. After training, health care providers could enroll in a voluntary AMP to provide outcome data to meet a postmarketing commitment of the manufacturer with the US Food and Drug Administration (FDA). Those who volunteered completed and faxed forms to the manufacturer after implant insertion and removal detailing the procedure and device-related outcomes, including insertion-, localization- or removal-associated events. Experts reviewed outcome data quarterly, which the Sponsor then reported to the FDA.ResultsAmong 42,337 health care providers completing the training program, 4294 (10.1%) volunteered to participate in the AMP. The 26,198 forms submitted over 6.4 years included more insertion (n=20,497) forms than removal forms (n=5701). The volunteers reported 646 events on 566 (2.2%) forms related to insertion (n=197), localization (n=34), removal (n=357) and "other" (n=58). Clinically important events included noninsertion (n=4), serum etonogestrel positive but implant not found (n=1), and possible nerve (n=66) or vascular (n=5) injury. The reports did not include any insertion-, localization- or removal-associated hospitalizations. Eight (0.14%) removal reports described referral for surgical implant removal.ConclusionEvents related to insertion, localization or removal of the etonogestrel implant are uncommon among US providers who received mandatory training in the use of the implant.ImplicationsThis report presents results from the first mandatory US contraceptive training program. Health care providers volunteered to report information about etonogestrel implant insertion, localization and removal. Although the data do not demonstrate whether a mandatory program improves outcomes, they elucidate the utility and real-life experience that clinical training programs can provide.