Potential determinants of early discontinuation of Etonogestrel implant: a cohort prospective study.

OBJECTIVE: To assess the frequency of early discontinuation of Implanon as a method of contraception. METHODS: The cohort prospective study was conducted at the Obstetrics and Gynaecology Department, Al-Yarmouk Teaching Hospital, Baghdad, Iraq from January 2017 to January 2021, after approval from the ethics review committee of the College of Medicine, Al-Mustansiriyha University, Bghadad, Iraq, and comprised women of childbearing age seeking long-acting contraception. The participants received Implanon, an etonorgestril implant, under local anaesthesia, and were followed up for 12 months for possible side effects. Data was analysed using SPSS 26. RESULTS: There were 115 women with mean age 29.8±6 years (range: 15-44 years) and mean body mass index 27±4.9 kg/m2. Early discontinuation of the plant was done by 32(27.8%) subjects, and the overall incidence of early Implanon removal per 1,000 women per month was 14.47 (95% confidence interval: 10.24-20.47). Lower body mass index, dizziness and insertion-site side effects were the potential determinants of early discontinuation (p<0.05). CONCLUSIONS: More than a quarter of the sample opted for early Implanon discontinuation. Low body mass index, dizziness and insertion-site side effects were potential determinants of early removal.

The impact of using the levonorgestrel-releasing intrauterine device on the incidence of acne in adolescents and young women.

PURPOSE: To evaluate the impact of levonorgestrel-releasing intrauterine device (LNG-IUD) use on the incidence of acne in adolescents and young women. METHODS: A narrative review was conducted in PubMed, Embase, Cochrane, and SciELO assessing the incidence of acne in adolescents and young women using LNG-IUD (13.5, or 19.5 mg, or 52 mg). Cohort, cross-sectional studies, clinical trials, and meta-analyses were included, without a date limit. Studies that didn't evaluate women in the age of interest were excluded. Only articles in English were selected. RESULTS: Nine articles were included in this narrative review. Only clinical trials, cohort studies, and cross-sectional studies were evaluated. Two cross-sectional studies evaluated the incidence of acne in women using any contraceptive methods, with the incidence of acne being 36% in women aged 17 to 47 using LNG-IUD in one study. In another study, acne incidence ranged from 2 to 8% in women using any contraceptive methods, with higher rates in younger women and LNG-IUD users. The incidence of acne varies and participants between 16 to 35 years were more likely to report new acne or worsening of pre-existing acne. In a prospective cohort study of women between 16 and 24 years, acne was a common adverse effect, with 44% in the first year. CONCLUSION: The data indicate variability in the incidence of acne among LNG-IUD users, with a higher prevalence observed in younger women. Further research should focus on the effects of LNG-IUD on acne in young populations, with rigorous study designs and consideration of previous contraceptive use.

The levonorgestrel-releasing intrauterine device (LNG-IUD) is an important tool in the prevention of unplanned pregnancies in adolescents and young women. Acne is a possible adverse effect that could lead to discontinuation of the method.

Migration of a contraceptive implant to the lung.

This case report details a rare case of contraceptive implant migration in a young woman. The migration was discovered three years post-insertion during a routine replacement visit. Despite the absence of pulmonary symptoms, a CT scan revealed the implant in the inferior lobe of the right lung. The patient was referred for further evaluation, but immediate surgical removal was deferred. This case report highlights the importance of healthcare providers recognising migration as a rare complication during implantation and suggests self-examination as a potential preventive strategy.

Early endovascular retrieval of a migrated Implanon NXT from a branch of the right pulmonary artery.

A woman in her 20s was referred to a tertiary hospital emergency department for management of a migrating Implanon NXT. The Implanon was inserted 1 week prior by the patient's general practitioner who was unable to palpate the Implanon after insertion and hence, ordered an ultrasound scan which showed an actively migrating Implanon in the left basilic vein. She had mild chest pain, and her physical examination, ECG and blood tests were unremarkable. A CT chest showed a 31 mm foreign body within the right lower lobar artery. The foreign body was removed by interventional radiology by accessing the right internal jugular vein under ultrasound guidance and inserting a 6 FR pig catheter into the pulmonary trunk. The position was confirmed with angiogram and the foreign body was removed using a goose neck snare. The patient was discharged the same day with no complications, and fell pregnant a few months afterwards.

Association Between Intrauterine System Hormone Dosage and Depression Risk.

OBJECTIVE: The authors compared the associated risk of incident depression between first-time users of low-, medium-, and high-dose levonorgestrel-releasing intrauterine systems (LNG-IUSs). METHODS: This national cohort study was based on Danish register data on first-time users of LNG-IUSs, 15-44 years of age, between 2000 and 2022. Cox regression and a G-formula estimator were used to report 1-year average absolute risks, risk differences, and risk ratios of incident depression, defined as initiation of an antidepressant or receipt of a depression diagnosis, standardized for calendar year, age, education level, parental history of mental disorders, endometriosis, menorrhagia, polycystic ovary syndrome, dysmenorrhea, leiomyoma, and postpartum initiation. RESULTS: In total, 149,200 women started using an LNG-IUS, among whom 22,029 started a low-dose one (mean age, 22.9 years [SD=4.5]), 47,712 a medium-dose one (mean age, 25.2 years [SD=6.2]), and 79,459 a high-dose one (mean age, 30.2 years [SD=5.6]). The associated subsequent 1-year adjusted absolute risks of incident depression were 1.21% (95% CI=1.06-1.36), 1.46% (95% CI=1.33-1.59), and 1.84% (95% CI=1.72-1.96), respectively. For the users of high-dose LNG-IUSs, the risk ratios were 1.52 (95% CI=1.30-1.74) and 1.26 (95% CI=1.10-1.41) compared with users of the low- and medium-dose LNG-IUSs, respectively. For users of medium-dose LNG-IUSs, the risk ratio was 1.21 (95% CI=1.03-1.39) compared with users of low-dose LNG-IUSs. CONCLUSIONS: First-time use of an LNG-IUS was positively associated with incident depression in an LNG-dose-dependent manner across low-, medium-, and high-dose LNG-IUSs. Although the observational design of the study does not permit causal inference, the dose-response relationship contributes to the body of evidence suggesting a relationship between levonorgestrel exposure and risk of depression.

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.

The association between BMI and continuity of etonogestrel (ENG)-releasing implant.

OBJECTIVE: The etonogestrel-releasing implant is a long-acting reversible contraception that is recommended by the Food and Drug Administration for 3 years and has been proven to be highly effective and convenient. Adverse effects including irregular bleeding patterns, weight gain, and acne are reported to be the main reasons for treatment discontinuation. The aim of this study is to learn the association between body mass index (BMI, calculated as weight in kilograms divided by the square of height in meters) and the incidence of side effects and adherence to treatment. METHODS: This is a retrospective cohort study, conducted at a single university-affiliated medical clinic, including all women who underwent etonogestrel-releasing implant (Nexplanon®; New Jersey, USA, Organon USA Inc., Merck and Co) insertion between January 2019 and December 2021. Cases where abnormalities were reported during the insertion procedure or missing data were excluded from the study. Information on patients' demographic, medical history, obstetric and gynecological history, and follow-up was collected from electronic medical files. The primary outcome was defined as the rate of implant removal in the different obesity classes. Data are presented as median and interquartile range. The study was approved by institutional review board. RESULTS: The study population included 1318 women, of whom 466 (35%) requested early removal of the implant. Women's demographic and clinical characteristics were comparable between women who requested early removal and those with full-length treatment. The median time for early removal was 12 (6-20) months from insertion. Irregular bleeding was the most frequent reason for early removal in both groups and was more than twice as prevalent in the early removal group (239 [51.29%] vs 193 [22%], P = 0.001). The early removal group had fewer obese women (BMI ≥30) compared with women who had full-length treatment (163 [31.8%] vs 350 [68.2%], P = 0.03), with comparable rates of class 3 obesity women (BMI ≥40) (P = 0.68). Multi-regression logistic analysis including age, BMI, parity and side effects found that the presence of side effects is the only independent predictor significantly associated with early implant removal (B = 1.74, P = 0.04). CONCLUSIONS: Continuation of etonogestrel-releasing implant contraception treatment was associated with the presence of side effects that were more often reported in non-obese women. BMI was not found to be a significant factor influencing adherence to treatment.

Risk of Stroke in Women Using Levonorgestrel-Releasing Intrauterine Device for Contraception.

BACKGROUND: The commonly used combined hormonal contraceptives with progestins and ethinylestradiol are associated with an increased risk of ischemic stroke (IS). Progestin-only preparations, including levonorgestrel-releasing intrauterine devices (LG-IUDs), are not associated with an increased risk, and in smaller studies, the risk is even reduced. The risk of intracerebral hemorrhage (ICH) has never been investigated. We studied the risk of IS and ICH in women using LG-IUDs compared with women not using hormonal contraceptives. METHODS: In this Danish historical cohort study (2004-2021), we followed nonpregnant women (18-49 years) registering incident IS and ICH in relation to use of LG-IUDs/nonuse of hormonal contraceptives utilizing Danish high-quality registries with nationwide coverage. Poisson regression models adjusting for age, ethnicity, education, calendar year, and medication use for risk factors were applied. RESULTS: A total of 1 681 611 nonpregnant women contributed 11 971 745 person-years (py) of observation. Mean age at inclusion was 30.0 years; mean length of follow-up was 7.1 years; 2916 women (24.4 per 100 000 py) had IS; 367 (3.1 per 100 000 py) had ICH. Of these, 364 784 were users of LG-IUD contributing 1 720 311 py to the investigation; mean age at start of usage was 34.6 years. Nonusers of hormonal contraceptives contributed 10 251 434 py; mean age at inclusion was 30.0 years. The incidence rate of IS/ICH among LG-IUD users was 19.2/3.0 and among nonusers, it was 25.2/3.1 per 100 000 py. After adjustment, incidence rate ratio for IS was 0.78 (CI, 0.70-0.88), and for ICH it was 0.94 (CI, 0.69-1.28). CONCLUSIONS: The use of LG-IUD was associated with a 22% lower incidence rate of IS without raising the incidence rate of ICH. The finding raises the question of whether levonorgestrel, in addition to its contraceptive properties, could have the potential to prevent IS.

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.

Association of levonorgestrel-releasing intrauterine device with gynecologic and breast cancers: a national cohort study in Sweden.

BACKGROUND: The levonorgestrel-releasing intrauterine device (LNG-IUD) is widely used for the treatment of menorrhagia, dysmenorrhea, and for contraception. However, the association between the use of LNG-IUD and the risk of site-specific gynecologic and breast cancers remains inconclusive. OBJECTIVE: We aim to address this knowledge gap by investigating whether the use of LNG-IUD is associated with a significant risk of site-specific gynecologic and breast cancers. This will be achieved by accessing the nationwide Swedish Registers, with consideration given to the influence and potential interaction of family history of cancer. STUDY DESIGN: A total of 514,719 women aged 18 to 50 years who have used LNG-IUD between July 2005 and December 2018 were identified from the Swedish Prescribed Drug Register and randomly matched with 1,544,157 comparisons who did not use LNG-IUD at a ratio of 1:3. The propensity score was calculated and matched among women who used LNG-IUD and the matched comparisons. The follow-up period started from the date of the first prescription of LNG-IUD for users as well as for their matched comparisons and ended at the date of diagnosis of gynecologic and breast cancers, date of death from any cause, and the end of the study period, whichever came first. The Cox proportional hazard model with a competing risk analysis was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs). Additive interaction was calculated as the relative excess risk for interaction, while multiplicative interaction was calculated by including a product term in the regression model. RESULTS: The use of LNG-IUD was associated with a 13% higher risk of breast cancer (adjusted HR, 1.13; 95% CI, 1.10-1.17), a 33% lower risk of endometrial cancer (adjusted HR, 0.67; 95% CI, 0.56-0.80), a 14% lower risk of ovarian cancer (adjusted HR, 0.86; 95% CI, 0.75-0.99), and a 9% reduced risk of cervical cancer (adjusted HR, 0.91; 95% CI, 0.84-0.99) compared to women who did not use LNG-IUD. A significant additive interaction between LNG-IUD use and family history of cancer was observed in breast cancer, indicating a relative 19% excess risk for interaction (P<.002), and 1.63 additional cases per 10,000 person-years. CONCLUSION: The risk of gynecologic and breast cancers exhibits a site-specific effect among LNG-IUD users. It is important to note that the observed effect is small for breast cancer and the results are limited by the observational study design. Clinical recommendations regarding the use of LNG-IUD should carefully weigh its potential benefits and risks. Close monitoring is advisable for the potential development of breast cancer, particularly among women with a family history of breast cancer.

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.

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.

Safety testing of Ovaprene: An investigational nonhormonal monthly vaginal contraceptive.

OBJECTIVES: Evaluate the safety of Ovaprene, an investigational nonhormonal vaginal contraceptive designed for monthly use. STUDY DESIGN: Open-label, multicenter study enrolling heterosexually-active women with previous permanent contraception who underwent assessments during five menstrual cycles: baseline postcoital test cycle, diaphragm postcoital test cycle, Ovaprene safety cycle, and two Ovaprene postcoital test cycles. Safety outcomes included treatment-emergent adverse events, systemic laboratory findings, pelvic examinations, colposcopies, Nugent scores, determination of community state types of vaginal microbiota, and anti-Escherichia coli activity and inflammatory markers in cervicovaginal fluids. RESULTS: We enrolled 38 participants. Of these, 33 used Ovaprene and completed 77 Ovaprene cycles. The most common product-related urogenital treatment-emergent adverse events were bacterial vaginosis and vaginal odor. The frequency of transitioning from Lactobacillus-dominated community state type to community state type IV (not Lactobacillus-dominated) was similar before Ovaprene use and afterwards. Mean Nugent scores were <4 at each visit without a discernible upward trend. Inflammatory markers showed wide variation but no upward trend, and E. coli inhibitory activity of cervical secretions did not change. We found no Staphylococcus aureus, the causative agent in toxic shock syndrome, on used Ovaprenes or in vaginal samples. No clinically important changes in systemic laboratory findings, pelvic examinations, or colposcopies occurred during Ovaprene use. CONCLUSIONS: Ovaprene use did not result in cervicovaginal irritation or adverse effects on resident vaginal microbiota and did not impact transitions from a Lactobacillus-dominated community state type to community state type IV. IMPLICATIONS: The finding that the use of Ovaprene, an investigational monthly user-controlled nonhormonal vaginal contraceptive, does not appear to result in adverse changes in vaginal health during short-term use supports further evaluation of the contraceptive potential of the device.

The impact of embedment of the side arms of 52 mg levonorgestrel-intrauterine device on bleeding and pain: A prospective cohort study.

PURPOSE: The purpose of this study was to analyse the impact of embedment of side arms of the levonorgestrel 52 mg intrauterine device (LNG-IUD) in the myometrium (assessed by three-dimensional transvaginal ultrasound (3D-TVUS)) on uterine bleeding and pain. MATERIALS AND METHODS: We performed a prospective cohort study in a large Dutch teaching hospital between February 2015 and December 2016. Participants over 18 years of age who selected a LNG-IUD for contraception or because of heavy menstrual bleeding were eligible for inclusion. Six weeks after insertion, a 3D-TVUS was performed to diagnose embedment of the side arms. At that moment participants filled in questionnaires about their bleeding pattern and pelvic pain. Menstruation patterns 'no bleeding', 'regular menstruation', 'sometimes a day of spotting (maximum once a week)' were classified as favourable bleeding pattern. Menstruation patterns 'heavy menstrual bleeding', 'several days a week bleeding days', 'several days a week spotting days', 'continuously spotting', and 'completely irregular cycle' were classified as unfavourable bleeding pattern. Univariate and multivariate logistic regression analysis was used to calculate odds ratios (OR) and 95 %-confidence intervals (CI). The multivariate analysis included endometrial thickness, reason for insertion and parity. The analysis of pelvic pain additionally included previous insertion. RESULTS: A total of 220 participants were evaluated for the study of whom 176 returned the questionnaires. Embedment of the side arms was observed in 43 of the 176 responding participants (24.4 %). Favourable bleeding pattern was reported by 25/43 (58.1 %) participants with embedment and 53/133 (39.8 %) participants without embedment (ORadj 1.8, 95 % CI 0.9-3.9). Pelvic pain was reported by 4/43 (9.3 %) participants with embedment and 24/133 (18.1 %) participants without embedment (ORadj 0.3; CI 0.1-1.2). CONCLUSIONS: The present study suggests that embedment of the side arms of the LNG-IUD in the myometrium assessed by 3D-TVUS is not associated with a unfavourable bleeding pattern nor pelvic pain six weeks after insertion. From this point of view, we do not recommend to perform standard 3D-TVUS for the purpose of excluding or demonstrating embedment.

Effects of depot medroxyprogesterone acetate, the copper IUD and the levonorgestrel implant on testosterone, sex hormone binding globulin and free testosterone levels: ancillary study of the ECHO randomized clinical trial.

BACKGROUND: Robust information on relative effects of hormonal contraceptives on endogenous androgens is important for understanding beneficial and adverse effects, method choice and development of new methods. METHODS: In this ancillary study at the East London, South Africa site of the ECHO multicentre randomized trial, we compared effects of three contraceptive methods on serum androgen levels among contraceptive users aged 18 to 35 years. Participants were allocated by centrally-managed randomization to open label depot medroxyprogesterone acetate (DMPA-IM), copper intrauterine device (IUD) or levonorgestrel implant. The primary outcome was free testosterone at 6 months. RESULTS: We analysed stored baseline and 6-month serum samples in 398/615 participants (DMPA-IM 131/205, IUD 135/205 and implant 132/205). Median testosterone levels at baseline were DMPA-IM 0.82, IUD 0.9 and implant 0.87 nmol/L; at 6 months, DMPA 0.68 (lower than IUD, mean percentage difference 28.35, (p <  0.001), IUD 0.86 (unchanged) and implant 0.66, lower than IUD, mean percentage difference - 22.98, p <  0.001). Median SHBG levels at baseline were DMPA 52.4, IUD 50.5 and implant 55.75 nmol/L; at 6 months, DMPA 40.65, lower than IUD (mean percentage difference 21.19, p = 0.005), IUD 49.1 (unchanged), and implant 23.35 nmol/L, lower than IUD (mean percentage difference - 50.04, p <  0.001 and than DMPA (mean percentage difference - 39.45, p <  0.001). Free testosterone levels at baseline were DMPA 10, IUD 12 and implant 11 pmol/L; at 6 months, DMPA 11, less than IUD (mean percentage difference 13.53, p = 0.047), IUD 12 and implant 14, higher than IUD (mean percentage difference 14.15, p = 0.038) and than DMPA, (mean percentage difference 29.60, p < 0.001). CONCLUSIONS: This is the first randomized trial to show lower SHBG and higher free testosterone with the levonorgestrel implant than with DMPA, and contrasts with reports of increased SHBG with combined oral ethinyl estradiol/levonorgestrel use, and reduced androgens (and impaired sexual function) reported with the etonorgestrel implant. The higher free testosterone with the LNG implant might improve sexual function, mood and bone health as well as increasing side-effects such as acne and hirsutism, and is consistent with the greater sexual activity (with respect to multiple sex partners, new sex partner and unprotected sex) with the implant compared with DMPA documented in the ECHO study. ECHO TRIAL REGISTRATION: ClinicalTrials.gov , number NCT02550067 15/09/2015. Contraception, or family planning, is central to the role of women in societies. It is most important to have accurate information on the relative side-effects of various contraceptive options in order to empower women to make informed choices regarding their preferred method. Hormonal contraceptives contain various forms of the female sex hormones, estrogens and/or progestogens. These hormones have direct effects on the users, as well as modifying the levels of the users' own circulating sex hormones, both the 'female' and the 'male' sex hormones (androgens). In this study, consenting participants requesting contraception, were allocated randomly to receive either depot medroxyprogesterone acetate (DMPA-IM) a 3-monthly progestogen injection, the copper intrauterine device (IUD), a non-hormonal contraceptive inserted within the womb, or the levonorgestrel implant, a device placed under the skin which releases a progestogen for 5 years. We measured the participants' androgen levels after 6 months, and found for the first time that the active form of testosterone (free testosterone) was 29% higher with the implant than with DMPA-IM. The level with the IUD was intermediate, and significantly different from the other two methods. This finding is relevant to the effects experienced by users of these methods, because free testosterone has effects on sexual function, bone health and mood, as well as on conditions such as acne and hair distribution patterns.

The use of LNG-IUS-19.5 mg in daily gynecological routine practice in Germany: data from the Kyleena™ Satisfaction Study (KYSS).

PURPOSE: The Kyleena™ Satisfaction Study (KYSS) provided the first data on 19.5 mg levonorgestrel-releasing intrauterine system (LNG-IUS-19.5 mg) use in routine clinical practice. Here we report results from the German participants in KYSS. METHODS: This prospective, observational, single-arm cohort study recruited women who independently chose to use LNG-IUS-19.5 mg during routine counseling in Germany. Overall satisfaction and bleeding profile satisfaction, continuation rates, and safety profile were evaluated at 12 months or premature end of observation (EoO). RESULTS: In the German study population, LNG-IUS-19.5 mg placement was attempted in 508 women and successful in 506 women. Mean age was 32.3 years, and 60.0% (n = 305/508) were parous. Placement was considered easy and associated with no more than mild pain, even in younger and nulliparous participants. Of those with satisfaction data available, 87.6% (n = 388/443) were satisfied with LNG-IUS-19.5 mg at 12 months/EoO. Satisfaction was similar for parous (86.9%, n = 238/274) and nulliparous (88.8%, n = 150/169) women, and was independent of age, prior contraceptive method, or reason for choosing LNG-IUS-19.5 mg. Most participants (73.6%, n = 299/406) were also satisfied with their bleeding profile at 12 months/EoO, independent of parity, age, prior contraceptive method, presence of amenorrhea or dysmenorrhea severity. The 12-month continuation rate was 84.1% (n = 427/508). Most discontinuations were due to loss to follow-up (8.5%, n = 43/508) or treatment-emergent adverse events (TEAEs) (4.7%, n = 24/508). TEAEs were reported in 12.6% (n = 64) of participants, with 9.3% (n = 47) considered to have an LNG-IUS-19.5 mg-related TEAE. CONCLUSION: Our real-world findings on LNG-IUS-19.5 mg use in German KYSS participants reflected its suitability for a broad population, including young and nulliparous women. CLINICAL TRIAL REGISTRATION: NCT03182140 (date of registration: June 2017).

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.

Gene expression associated with vaginal bleeding in women using the 52-mg levonorgestrel hormonal intrauterine device: A prospective study.

OBJECTIVE: To evaluate gene expression associated with vaginal bleeding in the 52-mg hormonal intrauterine device (IUD) users. MATERIALS AND METHODS: We conducted a prospective study involving 100 women seeking to use the 52-mg hormonal IUD for contraception. We excluded women with a history or current condition of abnormal uterine bleeding and who were unable to attend a 1-year follow up. Women who expelled the device, removed it for reasons unrelated to vaginal bleeding, or were lost to follow up were discontinued. We collected endometrial biopsies immediately before IUD placement and assessed 20 selected genes using reverse transcription quantitative polymerase chain reaction. Users maintained a uterine bleeding diary for 12 months following IUD insertion. For statistical analysis, participants were categorized into groups with or without vaginal bleeding at 3 and 12 months. RESULTS: Women with elevated CXCL9 expression had an 8.15-fold higher likelihood of experiencing vaginal bleeding at 3 months (odds ratio [OR] 8.15, 95% confidence interval [CI] 2.24-29.61, P = 0.001). At 12 months of follow up, women with increased TIMP1 expression had a 2.74-fold higher chance of experiencing vaginal bleeding (OR 2.74, 95% CI 1.08-6.95, P = 0.033). CXCL9 ≥ 1.5 and IL17A ≥ 0.68 were associated with a higher probability of vaginal bleeding at 3 months, while TIMP1 levels ≥0.943 were linked to an increased risk of bleeding at 12 months. CONCLUSION: Users of the 52-mg hormonal IUD with elevated relative CXCL9 expression face an increased risk of vaginal bleeding at 3-month follow up, whereas those with heightened TIMP1 expression are more likely to experience vaginal bleeding at 12 months.

Vaginal atrophy and genital pain in women on depot medroxyprogesterone acetate contraceptive injection.

Depot medroxyprogesterone acetate causes a hypo-estrogenic state in over half of users although clinical vaginal atrophy causing superficial dyspareunia is thought rarely to occur. This is a case series of ten women using depot medroxyprogesterone acetate who presented with superficial dyspareunia and clinical vaginal atrophy. The women were treated with vaginal estriol cream and their contraception was discontinued or changed. All patients had either a complete resolution of symptoms or a substantial improvement at follow-up, and the clinical and laboratory findings of vaginal atrophy had resolved. This case series demonstrates that vaginal atrophy may occur more frequently than previously thought.

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.