Phase 1 randomized trials to assess safety, pharmacokinetics, and vaginal bleeding associated with use of extended duration dapivirine and levonorgestrel vaginal rings.

BACKGROUND: Vaginal rings formulated to deliver two drugs simultaneously have potential as user-controlled, long-acting methods for dual prevention of HIV and pregnancy. METHODS: Two phase 1 randomized trials (MTN-030/IPM 041 and MTN-044/IPM 053/CCN019) respectively enrolled 24 and 25 healthy, HIV-negative participants to evaluate safety, pharmacokinetics, and vaginal bleeding associated with use of a vaginal ring containing 200mg dapivirine (DPV) and 320mg levonorgestrel (LNG) designed for 90-day use. MTN-030/IPM 041 compared the DPV/LNG ring to a DPV-only ring (200mg) over 14 days of use. MTN-044/IPM 053/CCN019 compared continuous or cyclic use of the DPV/LNG ring over 90 days of use. Safety was assessed by recording adverse events (AEs). DPV and LNG concentrations were quantified in plasma, cervicovaginal fluid, and cervical tissue. Vaginal bleeding was self-reported. RESULTS: There were no differences in the proportion of participants with grade ≥2 genitourinary AEs or grade ≥3 AEs with DPV/LNG ring vs. DPV ring use (p = .22), or with DPV/LNG ring continuous vs. cyclic use (p = .67). Higher plasma DPV concentrations were observed in users of DPV/LNG compared to DPV-only rings (Cmax p = 0.049; AUC p = 0.091). Plasma DPV and LNG concentrations were comparable with continuous and cyclic use (Cmax p = 0.74; AUC p = 0.25). With cyclic use, median nadir plasma DPV concentration was approximately 300 pg/mL two days after removal and median t1/2 for cervicovaginal fluid DPV concentration was 5.76 hours (n = 3). Overall bleeding experiences did not differ between continuous and cyclic users (p = 0.12). CONCLUSIONS: The extended duration DPV/ LNG rings were well tolerated and the observed DPV concentrations in plasma and cervicovaginal fluid when used continuously exceeded concentrations observed in previous DPV ring efficacy studies. LNG concentrations in plasma were comparable with other efficacious LNG-based contraceptives. Genital DPV concentrations had a short half-life and were thus not well sustained following ring removal.

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.

Effects of the selective AMPA modulator NBI-1065845 on the pharmacokinetics of midazolam or ethinyl estradiol-levonorgestrel in healthy adults.

This parallel-arm, phase I study investigated the potential cytochrome P450 (CYP)3A induction effect of NBI-1065845 (TAK-653), an investigational α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor potentiator in phase II development for major depressive disorder. The midazolam treatment arm received the sensitive CYP3A substrate midazolam on Day 1, followed by NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with midazolam, then NBI-1065845 alone on Day 15. The oral contraceptive treatment arm received ethinyl estradiol-levonorgestrel on Day 1, then NBI-1065845 alone on Days 5-13; on Day 14, NBI-1065845 was administered with ethinyl estradiol-levonorgestrel, then NBI-1065845 alone on Days 15-17. Blood samples were collected for pharmacokinetic analyses. The midazolam treatment arm comprised 14 men and 4 women, of whom 16 completed the study. Sixteen of the 17 healthy women completed the oral contraceptive treatment arm. After multiple daily doses of NBI-1065845, the geometric mean ratios (GMRs) (90% confidence interval) for maximum observed concentration were: midazolam, 0.94 (0.79-1.13); ethinyl estradiol, 1.00 (0.87-1.15); and levonorgestrel, 0.99 (0.87-1.13). For area under the plasma concentration-time curve (AUC) from time 0 to infinity, the GMRs were as follows: midazolam, 0.88 (0.78-0.98); and ethinyl estradiol, 1.01 (0.88-1.15). For levonorgestrel, the GMR for AUC from time 0 to the last quantifiable concentration was 0.87 (0.78-0.96). These findings indicate that NBI-1065845 is not a CYP3A inducer and support its administration with CYP3A substrates. NBI-1065845 was generally well tolerated, with no new safety signals observed after coadministration of midazolam, ethinyl estradiol, or levonorgestrel.

Zibotentan Can Be Co-administered with Contraceptives Containing Ethinyl Estradiol and Levonorgestrel: A Pharmacokinetic Drug-Drug Interaction Study.

The endothelin A receptor antagonist zibotentan, combined with the sodium-glucose co-transporter-2 inhibitor dapagliflozin, is being investigated for the treatment of chronic kidney disease with high proteinuria. To allow women of childbearing potential access to this treatment, highly effective contraception is required and drug interactions compromising contraception reliability must be avoided. This study investigated the risk of pharmacokinetic (PK) interaction between zibotentan and the contraceptives ethinyl estradiol and levonorgestrel. A single-sequence, within-participant comparison study was conducted in 24 healthy women of non-childbearing potential, comparing the PK of ethinyl estradiol/levonorgestrel alone and with zibotentan. Single oral doses of 0.06 mg ethinyl estradiol/0.3 mg levonorgestrel were administered on Days 1 and 15; zibotentan 10 mg was dosed orally, once-daily through Days 6-19. PK profiles were determined and ethinyl estradiol/levonorgestrel PK was compared between Day 1 and 15 based on geometric least-squares mean ratios of PK parameters, including maximum observed concentration (Cmax) and area under the plasma concentration-time curve from zero to infinity (AUCinf). Co-administration with zibotentan did not affect ethinyl estradiol PK (geometric mean ratio [90% confidence interval] Cmax 1.05 [0.99-1.11], AUCinf 1.00 [0.96-1.05]), while a weak interaction (increased exposure) was observed for levonorgestrel (Cmax 1.12 [1.02-1.23], AUCinf 1.30 [1.21-1.39]), which was regarded as without clinical relevance. Plasma exposure of ethinyl estradiol/levonorgestrel was not reduced by multiple-dose zibotentan. In conclusion, contraception containing ethinyl estradiol/levonorgestrel is regarded possible under zibotentan-containing treatments. This expands choices for women of childbearing potential, supporting diversity in the ZENITH High Proteinuria trial.

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.

Use of progestogens and the risk of intracranial meningioma: national case-control study.

OBJECTIVE: To assess the risk of intracranial meningioma associated with the use of selected progestogens. DESIGN: National case-control study. SETTING: French National Health Data System (ie, Système National des Données de Santé). PARTICIPANTS: Of 108 366 women overall, 18 061 women living in France who had intracranial surgery for meningioma between 1 January 2009 and 31 December 2018 (restricted inclusion periods for intrauterine systems) were deemed to be in the case group. Each case was matched to five controls for year of birth and area of residence (90 305 controls). MAIN OUTCOME MEASURES: Selected progestogens were used: progesterone, hydroxyprogesterone, dydrogesterone, medrogestone, medroxyprogesterone acetate, promegestone, dienogest, and intrauterine levonorgestrel. For each progestogen, use was defined by at least one dispensation within the year before the index date (within three years for 13.5 mg levonorgestrel intrauterine systems and five years for 52 mg). Conditional logistic regression was used to calculate odds ratio for each progestogen meningioma association. RESULTS: Mean age was 57.6 years (standard deviation 12.8). Analyses showed excess risk of meningioma with use of medrogestone (42 exposed cases/18 061 cases (0.2%) v 79 exposed controls/90 305 controls (0.1%), odds ratio 3.49 (95% confidence interval 2.38 to 5.10)), medroxyprogesterone acetate (injectable, 9/18 061 (0.05%) v 11/90 305 (0.01%), 5.55 (2.27 to 13.56)), and promegestone (83/18 061 (0.5%) v 225/90 305 (0.2 %), 2.39 (1.85 to 3.09)). This excess risk was driven by prolonged use (≥one year). Results showed no excess risk of intracranial meningioma for progesterone, dydrogesterone, or levonorgestrel intrauterine systems. No conclusions could be drawn concerning dienogest or hydroxyprogesterone because of the small number of individuals who received these drugs. A highly increased risk of meningioma was observed for cyproterone acetate (891/18 061 (4.9%) v 256/90 305 (0.3%), odds ratio 19.21 (95% confidence interval 16.61 to 22.22)), nomegestrol acetate (925/18 061 (5.1%) v 1121/90 305 (1.2%), 4.93 (4.50 to 5.41)), and chlormadinone acetate (628/18 061 (3.5%) v 946/90 305 (1.0%), 3.87 (3.48 to 4.30)), which were used as positive controls for use. CONCLUSIONS: Prolonged use of medrogestone, medroxyprogesterone acetate, and promegestone was found to increase the risk of intracranial meningioma. The increased risk associated with the use of injectable medroxyprogesterone acetate, a widely used contraceptive, and the safety of levonorgestrel intrauterine systems are important new findings.

Abnormal Uterine Bleeding Associated With Hormonal Contraception.

Abnormal uterine bleeding is a common and bothersome symptom in people using hormonal contraception, and it can lead to discontinuation of reliable methods of contraception and unintended pregnancies. Clinicians should counsel individuals about the potential for abnormal bleeding at initiation of the contraceptive method. After considering and excluding other potential causes of abnormal uterine bleeding, clinicians can offer treatment options specific to each hormonal contraceptive method. This article includes algorithms to help clinicians treat abnormal uterine bleeding in people using levonorgestrel intrauterine devices, depo-medroxyprogesterone acetate, progestin implant, progestin-only pills, and combined hormonal contraception. For patients with levonorgestrel intrauterine devices, physicians should first ensure that the device is correctly placed within the uterus, then consider nonsteroidal anti-inflammatory drugs as a first-line treatment for abnormal uterine bleeding; estradiol can be used if nonsteroidal anti-inflammatory drugs are ineffective. For depo-medroxyprogesterone acetate or progestin implant users, combined oral contraceptives or nonsteroidal anti-inflammatory drugs may be considered. For patients using norethindrone progestin-only pills, changing to drospirenone progesterone-only pills may help reduce the bleeding. In people using combined hormonal contraception, it may be helpful to increase estrogen content from 20 mcg to 35 mcg per day, decrease the hormone-free interval (from seven to four or five days) in people using cyclic contraception, or start a trial of low-dose doxycycline. For continuous combined contraception users, adding a hormone-free interval of four or five days can help regulate bleeding patterns.

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.

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).

Progestins as a Contributing Factor to Hepatocellular Adenoma: A Case Series and Literature Review.

STUDY OBJECTIVE: To explore the role of progestins as potential contributing factors for the development of hepatocellular adenoma (HA) METHODS: We describe 3 cases of adolescents and young adults who developed HA while on norethindrone (NET), as well as their management. In addition, we provide a comprehensive literature review on the association between progestins and HA. RESULTS: Since 1983, 16 cases of HA in patients on progestins have been reported. Ten patients were on NET and 5 on a prodrug of NET (4 on norethindrone acetate [NETA] and 1 on lynestrenol). One individual had a norgestrel implant. Eight subsequently ceased all hormones: 4 experienced a size reduction, and 3 had complete resolution of their HA. Among our patients, 1 ceased NET and instead had a levonorgestrel intrauterine device inserted, and another swapped from NET to oral medroxyprogesterone acetate. Both experienced complete resolution of their HA. The third ceased NET and underwent a hysterectomy, with size reduction of her HA. CONCLUSION: These cases and the literature review suggest an association between progestin exposure, in particular NET and its prodrugs, and the development of HA. The pathophysiology is unknown but may include peripheral conversion of NET and NETA to ethinyl estradiol or a specific action of 19-nortestosterone derivatives on hepatocytes, especially those with higher systemic doses compared with the levonorgestrel intrauterine device. There are no case reports relating to other forms of progestins, such as 17-hydroxyprogesterone, which may be important when considering alternative therapeutic options in females requiring effective menstrual management who have comorbidities.

Evaluating resectoscopy and the levonorgestrel intrauterine system for intermenstrual bleeding associated with cesarean scar defects: A retrospective study of treatment outcomes.

AIM: To compare and evaluate the efficacy of the levonorgestrel-releasing intrauterine system (LNG-IUD) and resectoscopy remodeling procedure for intermenstrual bleeding associated with previous cesarean delivery scar defect (PCDS). METHODS: A retrospective comparative study was conducted on patients with PCDS receiving LNG-IUD (levonorgestrel 20 µg/24 h, N = 33) or resectoscopy remodeling (N = 27). Treatment outcomes were compared over 1, 6, and 12 months. Outcomes in patients with a retroverted or large uterus size, defect size, and local vascularization also were evaluated. RESULTS: At 12 months post-treatment, there were no significant differences between groups in efficacy rate; however, the reduction of intermenstrual bleeding days was higher in the LNG-IUD group than in the resectoscopy group (13.6 vs. 8.5 days, p = 0.015). Within the first year, both groups experienced a reduction in bleeding days, but the decrease was greater in the LNG-IUD group. Individuals exhibiting increased local vascularization at the defect site experienced more favorable outcomes in the LNG-IUD group than the resectoscopy group (p = 0.016), and who responded poorly tended to have a significantly larger uterus in the LNG-IUD group (p = 0.019). No significant differences were observed in treatment outcomes for patients with a retroverted uterus or large defect in either group. CONCLUSIONS: Our findings support that the LNG-IUD is as effective as resectoscopy in reducing intermenstrual bleeding days associated with PCDS and can be safely applied to patients without recent fertility aspirations. Patients with increased local vascularization observed during hysteroscopy may benefit more from LNG-IUD intervention than resectoscopy.

Five-year Contraceptive Use of 52-mg Levonorgestrel Releasing Intrauterine System in Young Women, Menstrual Patterns, and New Contraceptive Choice.

OBJECTIVE: To evaluate the continuation rates of the 52-mg levonorgestrel-releasing intrauterine system (LNG-IUS) during the first 5 years of use, reasons for its discontinuation, bleeding patterns, and new contraceptive choice after the 5th year, in adolescents and young women. METHODS: The present study was a 5-year prospective cohort conducted in a Family Planning Service of a tertiary hospital in Brazil. We selected 100 healthy women between 15 and 24 years old who used 52-mg LNG-IUS for contraception. The clinical follow-up of these women took place from June 2017 to December 2022. The study evaluated the continuation rates of the method, reasons for its discontinuation, bleeding patterns, and new contraceptive choice after the 5th year. Continuous data were reported as mean ± standard deviation (SD) and range (minimum-maximum). Categorical variables were described as percentages. RESULTS: The continuation rates of LNG-IUS were 89.1% (82/92), 82.9% (72/87), 75.3% (64/85), 70.5% (60/85), and 64.2% (54/84) in the 1st, 2nd, 3rd, 4th, and 5th years of use, respectively. The main reason for discontinuation was acne (11/30). Amenorrhea rates were 50, 54.1, 39, 35.7, and 51.8% at 12, 24, 36, 48, and 60 months, respectively. All patients who completed the study and needed contraception after the 5th year opted for long-acting contraceptive methods (LARC). CONCLUSION: The LNG-IUS showed high continuation rates in adolescents and young women in the first 5 years of use. Most patients who completed the study chose a LARC method after the 5th year.

OBJETIVO: Avaliar as taxas de continuação do sistema intrauterino liberador de levonorgestrel (SIU-LNG) 52 mg durante os primeiros 5 anos de uso, razões de sua descontinuação, padrões de sangramento e nova escolha contraceptiva após o 5° ano, em adolescentes e mulheres jovens. MéTODOS: O estudo foi uma coorte prospectiva de 5 anos realizada em um Serviço de Planejamento Familiar de um hospital terciário no Brasil. Selecionamos 100 mulheres saudáveis entre 15 e 24 anos que usaram o SIU-LNG 52 mg para contracepção. O acompanhamento clínico dessas mulheres ocorreu de junho de 2017 a dezembro de 2022. O estudo avaliou as taxas de continuação do método, razões de sua descontinuação, padrões de sangramento e nova escolha contraceptiva após o 5° ano. Os dados contínuos foram relatados como média ± DP e intervalo (mínimo-máximo). As variáveis categóricas foram descritas como porcentagens. RESULTADOS: As taxas de continuação do SIU-LNG foram 89,1% (82/92), 82,9% (72/87), 75,3% (64/85), 70,5% (60/85) e 64,2% (54/84) no 1°, 2°, 3°, 4° e 5° anos de uso, respectivamente. O principal motivo de descontinuação foi a acne (11/30). As taxas de amenorreia foram de 50, 54,1, 39, 35,7 e 51,8% aos 12, 24, 36, 48 e 60 meses, respectivamente. Todas as pacientes que completaram o estudo e necessitaram de contracepção após o 5° ano optaram por métodos contraceptivos de longa duração (LARC). CONCLUSãO: O SIU-LNG apresentou altas taxas de continuação em adolescentes e mulheres jovens nos primeiros 5 anos de uso. A maioria das pacientes que completou o estudo escolheu um método LARC após o 5° ano.

Current Medical Therapy for Adenomyosis: From Bench to Bedside.

Adenomyosis, characterized by the growth of endometrial tissue within the uterine wall, poses significant challenges in treatment. The literature primarily focuses on managing abnormal uterine bleeding (AUB) and dysmenorrhea, the main symptoms of adenomyosis. Nonsteroidal anti-inflammatory drugs (NSAIDs) and tranexamic acid provide limited support for mild symptoms or symptom re-exacerbation during hormone therapy. The levonorgestrel-releasing intrauterine system (LNG-IUS) is commonly employed in adenomyosis management, showing promise in symptom improvement and reducing uterine size, despite the lack of standardized guidelines. Dienogest (DNG) also exhibits potential benefits, but limited evidence hinders treatment recommendations. Danazol, while effective, is limited by androgenic side effects. Combined oral contraceptives (COCs) may be less effective than progestins but can be considered for contraception in young patients. Gonadotropin-releasing hormone (GnRH) agonists effectively manage symptoms but induce menopausal symptoms with prolonged use. GnRH antagonists are a recent option requiring further investigation. Aromatase inhibitors (AIs) show promise in alleviating AUB and pelvic pain, but their safety necessitates exploration and limited use within trials for refractory patients. This review highlights the complexity of diagnosing adenomyosis, its coexistence with endometriosis and uterine leiomyomas, and its impact on fertility and quality of life, complicating treatment decisions. It emphasizes the need for research on guidelines for medical management, fertility outcomes, long-term effects of therapies, and exploration of new investigational targets. Future research should optimize therapeutic strategies, expand our understanding of adenomyosis and its management, and establish evidence-based guidelines to improve patient outcomes and quality of life.

Changes in hair cortisol concentration in intrauterine device initiators: A prospective cohort study.

OBJECTIVES: Prior studies found increased hair cortisol concentration (a surrogate marker for hypothalamic-pituitary-adrenal axis activation) in users of the levonorgestrel intrauterine device (LNG 52 mg IUD). We evaluated change in hair cortisol and psychometric tests in women initiating a copper (CuT380 IUD) or LNG 52 mg IUD. STUDY DESIGN: We prospectively enrolled healthy women initiating an LNG 52 mg IUD or CuT380 IUD. Participants provided hair and blood samples and completed psychometric inventories (Patient Health Questionnaire-9, Positive and Negative Affect Schedule, and Psychological General Well-Being Index) after IUD insertion and at 6 and 12 months. We used liquid chromatography with tandem mass spectrometry to measure hair cortisol concentrations. We compared hair cortisol concentrations and psychometric test changes from baseline to 6 and 12 months using independent two-sample t tests. RESULTS: We enrolled 39 of our targeted 86 participants (LNG 52 mg IUD 26, CuT380 IUD 13). Thirty-eight subjects (LNG 52 mg IUD 25, CuT380 IUD 13) completed 6 months of follow-up. We found no difference between cohorts in the mean change in hair cortisol concentrations at 6 months (LNG 52 mg IUD n = 21 [-0.01 pg/mg (95% CI -1.26, 1.23); CuT380 IUD n = 13 [-1.31 pg/mg (-3.36, 0.73)]). While psychometric inventory results remained within normal ranges, LNG 52 mg IUD users reported a trend toward more favorable changes over time. CONCLUSIONS: We did not find clinically important differences in hair cortisol concentrations following initiation of a CuT380 IUD or LNG 52 mg IUD; psychometric inventories demonstrated no adverse effect of hormonal IUDs on mood. IMPLICATIONS: Our findings of similar hair cortisol concentrations following the initiation of either the LNG 52 mg IUD or CuT380 IUD suggest that hormonal IUDs do not increase cortisol concentrations or alter stress reactivity, and favorable effects on psychometric inventories provide further reassurance that the LNG 52 mg IUD has no adverse impact on mood. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT03499379.

Compare the Efficacy of Dienogest and the Levonorgestrel Intrauterine System in Women with Adenomyosis.

PURPOSE: The goal of this study was to examine the efficacy and safety of the levonorgestrel intrauterine system (LNG-IUS) versus dienogest (DNG) in female subjects with symptomatic uterine adenomyosis. METHODS: This study enrolled 117 women with symptomatic adenomyosis who visited our hospital from May 1, 2019, to June 30, 2022. Participants were randomized to either the LNG-IUS group (n = 48) or the DNG group (n = 79) in an as-controlled clinical trial for 36 months. Visual analog scale (VAS) scores, uterine volume, endometrial thickness, serum carcinoma antigen 125 level, estradiol, follicle-stimulating hormone, luteinizing hormone, and side effects were assessed to compare the efficacy of LNG-IUS and DNG. FINDINGS: The VAS pain score was significantly decreased in both groups after 3 months of treatment. Three months later, patients receiving DNG reported significantly lower VAS scores compared with those treated with LNG- IUS (P < 0.05). Compared with LNG-IUS, DNG effectively controlled uterine volume growth after 12 months of treatment but neither significantly reduced uterine volume. During the treatment period, endometrial thickness in both groups was maintained at 0.4 to 0.7 cm. IMPLICATIONS: Both DNG and LNG-IUS significantly improved adenomyosis-associated pain after 3 months of treatment. Compared with LNG-IUS, DNG was shown to continuously relieve the symptoms of pain and effectively control the growth of uterine volume.

A systematic review and meta-analysis of the prevalence and association between levonorgestrel and ectopic pregnancy.

BACKGROUND: The use of levonorgestrel emergency oral contraceptives (EOCs) is one of the factors that may be associated with ectopic pregnancy. We aimed to investigate the incidence of ectopic pregnancy in EOC users and the association between EOCs and ectopic pregnancy. RESEARCH DESIGN AND METHODS: We searched for articles that provided the incidence of and the association between levonorgestrel EOCs and ectopic pregnancy in women of reproductive ages in CINAHL Complete, Medline, OpenDissertations, Scopus, Science Direct, and Thai Journal Online. The risk of bias was assessed by Risk Of Bias In Non-randomized Studies or Risk of Bias 2. A meta-analysis was conducted using the random-effects model. RESULTS: We retrieved 1839 nonredundant articles from the systematic search. The meta-analysis showed that the prevalence of ectopic pregnancy was not statistically different from zero (pooled prevalence estimate = 0.029%; 95%CI: -0.006, 0.065; N = 9; I2 = 0) and rare. In addition, levonorgestrel EOCs increased the risk of ectopic pregnancy (OR = 6.17; 95%CI: 3.78, 10.08; N = 5; I2 = 43%). CONCLUSIONS: Women with extrauterine or ectopic pregnancy had higher odds of using levonorgestrel emergency oral contraceptives than those with intrauterine pregnancy. However, the prevalence of ectopic pregnancy is rare.

Drug-induced liver injury secondary to increased levonorgestrel exposure in a patient taking ritonavir.

We report the first published case of a drug induced liver injury (DILI) presumed secondary to a drug-drug interaction between ritonavir and levonorgestrel progestogen-only emergency contraception (POEC). Our patient is a 25-year-old female living with human immunodeficiency virus (HIV), taking antiretroviral therapy (ART) containing tenofovir alafenamide/emtricitabine and darunavir/ritonavir. She was found to have elevated transaminases at a routine clinic appointment consistent with hepatocellular DILI. Further investigation found the most likely cause of this was a drug-drug interaction (DDI) between the ritonavir component of her ART and recent use of levonorgestrel POEC 3 days earlier. Evidence suggests that ritonavir increases levonorgestrel exposure, yet our patient received double the usual dose as per dispensing guidance at the time. We review the pharmacokinetics of ritonavir-levonorgestrel DDIs and highlight the need for consistent guidelines on this topic.