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1.
PLoS One ; 19(5): e0299802, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38722832

RESUMEN

BACKGROUND: Contraceptive use has complex effects on sexual behaviour and mood, including those related to reduced concerns about unintended pregnancy, direct hormonal effects and effects on endogenous sex hormones. We set out to obtain robust evidence on the relative effects of three contraceptive methods on sex behaviours, which is important for guiding contraceptive choice and future contraceptive developments. METHODS: This is a secondary analysis of data from the Evidence for Contraceptive Options and HIV Outcomes (ECHO) randomized trial in which 7,829 HIV-uninfected women from 12 sites in Eswatini, Kenya, South Africa and Zambia seeking contraception were randomly assigned to intramuscular depot-medroxyprogesterone acetate (DMPA-IM), the copper intrauterine device (Cu-IUD) or the levonorgestrel (LNG) implant. Data collected for 12 to 18 months using 3-monthly behavioural questionnaires that relied on recall from the preceding 3 months, were used to estimate relative risk of post-baseline sex behaviours, as well as sexual desire and menstrual bleeding between randomized groups using modified Poisson regression. RESULTS: We observed small but generally consistent effects wherein DMPA-IM users reported lower prevalence of specified high risk sexual behaviours than implant users than Cu-IUD users (the '>' and '<' symbols indicate statistically significant differences): multiple sex partners 3.6% < 4.8% < 6.2% respectively; new sex partner 3.0% < 4.0% <5.3%; coital acts 16.45, 16.65, 17.12 (DMPA-IM < Cu-IUD); unprotected sex 65% < 68%, 70%; unprotected sex past 7 days 33% <36%, 37%; sex during vaginal bleeding 7.1%, 7.1% < 8.9%; no sex acts 4.1%, 3.8%, 3.4% (DMPA-IM > Cu-IUD); partner has sex with others 10% < 11%, 11%. The one exception was having any sex partner 96.5%, 96.9% < 97.4% (DMPA-IM < Cu-IUD). Decrease in sexual desire was reported by 1.6% > 1.1% >0.5%; amenorrhoea by 49% > 41% >12% and regular menstrual pattern by 26% <35% < 87% respectively. CONCLUSIONS: These findings suggest that women assigned to DMPA-IM may have a modest decrease in libido and sexual activity relative to the implant, and the implant relative to the Cu-IUD. We found more menstrual disturbance with DMPA-IM than with the implant (and as expected, both more than the Cu-IUD). These findings are important for informing the contraceptive choices of women and policymakers and highlight the need for robust comparison of the effects of other contraceptive methods as well.


Asunto(s)
Dispositivos Intrauterinos de Cobre , Levonorgestrel , Acetato de Medroxiprogesterona , Conducta Sexual , Humanos , Femenino , Levonorgestrel/administración & dosificación , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/efectos adversos , Dispositivos Intrauterinos de Cobre/efectos adversos , Conducta Sexual/efectos de los fármacos , Adulto , Adulto Joven , Anticonceptivos Femeninos/administración & dosificación , Adolescente , Inyecciones Intramusculares , Anticoncepción/métodos , Implantes de Medicamentos
2.
BMJ ; 385: e079006, 2024 05 15.
Artículo en Inglés | MEDLINE | ID: mdl-38749550

RESUMEN

OBJECTIVES: To evaluate the clinical effectiveness of long acting progestogens compared with the combined oral contraceptive pill in preventing recurrence of endometriosis related pain. DESIGN: The PRE-EMPT (preventing recurrence of endometriosis) pragmatic, parallel group, open label, randomised controlled trial. SETTING: 34 UK hospitals. PARTICIPANTS: 405 women of reproductive age undergoing conservative surgery for endometriosis. INTERVENTIONS: Participants were randomised in a 1:1 ratio using a secure internet facility to a long acting progestogen (depot medroxyprogesterone acetate or levonorgestrel releasing intrauterine system) or the combined oral contraceptive pill. MAIN OUTCOME MEASURES: The primary outcome was pain measured three years after randomisation using the pain domain of the Endometriosis Health Profile 30 (EHP-30) questionnaire. Secondary outcomes (evaluated at six months, one, two, and three years) included the four core and six modular domains of the EHP-30, and treatment failure (further therapeutic surgery or second line medical treatment). RESULTS: 405 women were randomised to receive a long acting progestogen (n=205) or combined oral contraceptive pill (n=200). At three years, there was no difference in pain scores between the groups (adjusted mean difference -0.8, 95% confidence interval -5.7 to 4.2, P=0.76), which had improved by around 40% in both groups compared with preoperative values (an average of 24 and 23 points for long acting progestogen and combined oral contraceptive pill groups, respectively). Most of the other domains of the EHP-30 also showed improvement at all time points compared with preoperative scores, without evidence of any differences between groups. Women randomised to a long acting progestogen underwent fewer surgical procedures or second line treatments compared with those randomised to the combined oral contraceptive pill group (73 v 97; hazard ratio 0.67, 95% confidence interval 0.44 to 1.00). CONCLUSIONS: Postoperative prescription of a long acting progestogen or the combined oral contraceptive pill results in similar levels of improvement in endometriosis related pain at three years, with both groups showing around a 40% improvement compared with preoperative levels. While women can be reassured that both options are effective, the reduced risk of repeat surgery for endometriosis and hysterectomy might make long acting reversible progestogens preferable for some. TRIAL REGISTRATION: ISRCTN registry ISRCTN97865475.


Asunto(s)
Anticonceptivos Orales Combinados , Endometriosis , Levonorgestrel , Acetato de Medroxiprogesterona , Humanos , Femenino , Endometriosis/cirugía , Endometriosis/tratamiento farmacológico , Endometriosis/complicaciones , Anticonceptivos Orales Combinados/uso terapéutico , Anticonceptivos Orales Combinados/administración & dosificación , Adulto , Levonorgestrel/administración & dosificación , Levonorgestrel/uso terapéutico , Acetato de Medroxiprogesterona/administración & dosificación , Acetato de Medroxiprogesterona/uso terapéutico , Dolor Pélvico/tratamiento farmacológico , Dolor Pélvico/prevención & control , Dolor Pélvico/etiología , Progestinas/administración & dosificación , Progestinas/uso terapéutico , Dimensión del Dolor , Prevención Secundaria/métodos , Resultado del Tratamiento , Adulto Joven , Dispositivos Intrauterinos Medicados
3.
Clin Transl Sci ; 17(5): e13791, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38700236

RESUMEN

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.


Asunto(s)
Anticonceptivos Orales Combinados , Etinilestradiol , Levonorgestrel , Midazolam , Humanos , Midazolam/farmacocinética , Midazolam/administración & dosificación , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Etinilestradiol/efectos adversos , Femenino , Adulto , Masculino , Adulto Joven , Anticonceptivos Orales Combinados/administración & dosificación , Anticonceptivos Orales Combinados/farmacocinética , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Interacciones Farmacológicas , Combinación de Medicamentos , Voluntarios Sanos , Adolescente , Citocromo P-450 CYP3A/metabolismo , Persona de Mediana Edad , Área Bajo la Curva , Inductores del Citocromo P-450 CYP3A/administración & dosificación , Inductores del Citocromo P-450 CYP3A/farmacología
4.
Eur J Drug Metab Pharmacokinet ; 49(3): 367-381, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38554232

RESUMEN

BACKGROUND AND OBJECTIVE: Abrocitinib is an oral small-molecule Janus kinase (JAK)-1 inhibitor approved for the treatment of moderate-to-severe atopic dermatitis. In vitro studies indicated that abrocitinib is a weak time-dependent inhibitor of cytochrome P450 (CYP) 2C19/3A and a weak inducer of CYP1A2/2B6/2C19/3A. To assess the potential effect of abrocitinib on concomitant medications, drug-drug interaction (DDI) studies were conducted for abrocitinib with sensitive probe substrates of these CYP enzymes. The impact of abrocitinib on hormonal oral contraceptives (ethinyl estradiol and levonorgestrel), as substrates of CYP3A and important concomitant medications for female patients, was also evaluated. METHODS: Three Phase 1 DDI studies were performed to assess the impact of abrocitinib 200 mg once daily (QD) on the probe substrates of: (1) 1A2 (caffeine), 2B6 (efavirenz) and 2C19 (omeprazole) in a cocktail study; (2) 3A (midazolam); and (3) 3A (oral contraceptives). RESULTS: After multiple doses of abrocitinib 200 mg QD, there is a lack of effect on the pharmacokinetics of midazolam, efavirenz and contraceptives. Abrocitinib increased the area under the concentration time curve from 0 to infinity (AUCinf) and the maximum concentration (Cmax) of omeprazole by approximately 189 and 134%, respectively. Abrocitinib increased the AUCinf of caffeine by 40% with lack of effect on Cmax. CONCLUSIONS: Based on the study results, abrocitinib is a moderate inhibitor of CYP2C19. Caution should be exercised when using abrocitinib concomitantly with narrow therapeutic index medicines that are primarily metabolized by CYP2C19 enzyme. Abrocitinib is a mild inhibitor of CYP1A2; however, the impact is not clinically relevant, and no general dose adjustment is recommended for CYP1A2 substrates. Abrocitinib does not inhibit CYP3A or induce CYP1A2/2B6/2C19/3A and does not affect the pharmacokinetics of contraceptives. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov registration IDs: NCT03647670, NCT05067439, NCT03662516.


Asunto(s)
Interacciones Farmacológicas , Pirimidinas , Sulfonamidas , Humanos , Femenino , Adulto , Adulto Joven , Pirimidinas/farmacocinética , Pirimidinas/administración & dosificación , Citocromo P-450 CYP1A2/metabolismo , Masculino , Etinilestradiol/farmacocinética , Voluntarios Sanos , Anticonceptivos Hormonales Orales/farmacocinética , Citocromo P-450 CYP2C19/metabolismo , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Anticonceptivos Orales Combinados/farmacocinética , Anticonceptivos Orales Combinados/administración & dosificación , Persona de Mediana Edad , Área Bajo la Curva , Combinación de Medicamentos
5.
Reprod Biomed Online ; 48(5): 103750, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38430660

RESUMEN

RESEARCH QUESTION: Is ovarian stimulation with levonorgestrel intrauterine system (LNG-IUS) in situ and co-treatment with letrozole safe and effective in patients undergoing fertility-sparing combined treatment for atypical endometrial hyperplasia (AEH) or early endometrial cancer limited to the endometrium? DESIGN: Retrospective case-control study recruiting women who had undergone fertility-sparing 'combined' treatment and ovarian stimulation with letrozole and LNG-IUS in situ. The 'three steps' hysteroscopic technique was used. Once complete response was achieved, the ovaries were stimulated, and mature oocytes cryopreserved. The LNG-IUS was removed, and embryos transferred. A comparative analysis was conducted between the two control groups of the initial outcomes of ART (number of oocytes and MII oocytes retrieved): healthy infertile women undergoing ovarian stimulation for IVF/ICSI (control group A); and patients diagnosed with breast cancer who underwent ovarian stimulation with letrozole (control group B). RESULTS: Of the 75 patients analysed, 15 underwent oocyte cryopreservation after achieving a complete response to fertility-sparing treatment (study group); 30 patients in control group A and B, respectively. No statistically significant differences were observed in retrieved oocytes and mature oocytes between the study and control groups. In the nine patients who underwent embryo transfer, clinical pregnancy (55.6%), cumulative live birth (44.4%) and miscarriage (20%) rates were reported. In three patients with AEH, recurrence occurred (12%) at 3, 6 and 16 months after removing the LNG-IUS to attempt embryo transfer, respectively. CONCLUSION: Fertility-sparing hysteroscopic combined treatment and subsequent ovarian stimulation with letrozole and LNG-IUS in situ could be suggested to women with AEH or early endometrial cancer who ask for future fertility preservation.


Asunto(s)
Neoplasias Endometriales , Preservación de la Fertilidad , Letrozol , Levonorgestrel , Inducción de la Ovulación , Humanos , Femenino , Levonorgestrel/administración & dosificación , Levonorgestrel/uso terapéutico , Letrozol/uso terapéutico , Letrozol/administración & dosificación , Estudios Retrospectivos , Adulto , Inducción de la Ovulación/métodos , Estudios de Casos y Controles , Preservación de la Fertilidad/métodos , Embarazo , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/complicaciones , Criopreservación , Hiperplasia Endometrial/tratamiento farmacológico , Dispositivos Intrauterinos Medicados , Índice de Embarazo
6.
Contraception ; 134: 110420, 2024 06.
Artículo en Inglés | MEDLINE | ID: mdl-38462205

RESUMEN

OBJECTIVES: To understand patterns in demand for emergency contraception (EC), we characterize the sales of over-the-counter (OTC) levonorgestrel (LNG) EC in the United States from traditional retail outlets. STUDY DESIGN: We describe sales of OTC LNG EC using retail sales data aggregated from traditional retail channels, including grocery stores, drug stores, mass merchandisers, club stores, dollar stores, and military outlets. RESULTS: Sales of OTC LNG EC doubled between 2016 and 2022 (approximately 7.2-14.8 million). CONCLUSIONS: Increasing sales of EC are consistent with increased use and use frequency of EC by those at risk of pregnancy in the United States. IMPLICATIONS: OTC LNG EC sales since 2016 exceed what national survey usage estimates would suggest, indicating that national surveys underreport EC use, those using EC purchase it somewhat frequently, and/or individuals stockpile EC for later use. The role of EC in individual contraceptive strategies, particularly as access to reproductive healthcare is restricted, warrants further study.


Asunto(s)
Comercio , Anticoncepción Postcoital , Levonorgestrel , Medicamentos sin Prescripción , Levonorgestrel/provisión & distribución , Levonorgestrel/administración & dosificación , Estados Unidos , Humanos , Medicamentos sin Prescripción/provisión & distribución , Medicamentos sin Prescripción/economía , Femenino , Anticoncepción Postcoital/estadística & datos numéricos , Comercio/estadística & datos numéricos , Anticonceptivos Poscoito/provisión & distribución , Anticonceptivos Poscoito/economía , Embarazo
7.
Int J Gynaecol Obstet ; 165(3): 1199-1209, 2024 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-38299835

RESUMEN

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.


Asunto(s)
Dispositivos Intrauterinos Medicados , Levonorgestrel , Hemorragia Uterina , Humanos , Femenino , Estudios Prospectivos , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Adulto , Hemorragia Uterina/genética , Dispositivos Intrauterinos Medicados/efectos adversos , Endometrio , Anticonceptivos Femeninos/administración & dosificación , Anticonceptivos Femeninos/efectos adversos , Expresión Génica , Adulto Joven , Persona de Mediana Edad
8.
Horm Behav ; 161: 105506, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38387104

RESUMEN

Estradiol and progesterone potentiate and attenuate reward processes, respectively. Despite these well-characterized effects, there is minimal research on the effects of synthetic estrogens (e.g., ethinyl estradiol, or EE) and progestins (e.g., levonorgestrel, or LEVO) contained in clinically-utilized hormonal contraceptives. The present study characterized the separate effects of repeated exposure to EE or LEVO on responding maintained by a reinforcing visual stimulus. Forty ovary-intact female Sprague-Dawley rats received either sesame oil vehicle (n = 16), 0.18 µg/day EE (n = 16), or 0.6 µg/day LEVO (n = 8) subcutaneous injections 30-min before daily one-hour sessions. Rats' responding was maintained by a 30-sec visual stimulus on a Variable Ratio-3 schedule of reinforcement. The day after rats' last session, we determined rats estrous cycle phase via vaginal cytology before sacrifice and subsequently weighing each rat's uterus to further verify the contraceptive hormone manipulation. The visual stimulus functioned as a reinforcer, but neither EE nor LEVO enhanced visual stimulus maintained responding. Estrous cytology was consistent with normal cycling in vehicle rats and halting of normal cycling in EE and LEVO rats. EE increased uterine weights consistent with typical uterotrophic effects observed with estrogens, further confirming the physiological impacts of our EE and LEVO doses. In conclusion, a physiologically effective dose of neither EE nor LEVO did not alter the reinforcing efficacy of a visual stimulus reinforcer. Future research should characterize the effects of hormonal contraceptives on responding maintained by other reinforcer types to determine the generality of the present findings.


Asunto(s)
Etinilestradiol , Levonorgestrel , Ratas Sprague-Dawley , Animales , Femenino , Etinilestradiol/farmacología , Etinilestradiol/administración & dosificación , Levonorgestrel/farmacología , Levonorgestrel/administración & dosificación , Ratas , Refuerzo en Psicología , Estimulación Luminosa/métodos , Ovario/efectos de los fármacos , Ciclo Estral/efectos de los fármacos
9.
J Natl Cancer Inst ; 116(5): 653-664, 2024 May 08.
Artículo en Inglés | MEDLINE | ID: mdl-38305500

RESUMEN

BACKGROUND: We conducted a systematic review and meta-analysis to examine outcomes of patients with endometrial intraepithelial neoplasia treated with oral progestins or a levonorgestrel-releasing intrauterine device (IUD). METHODS: We conducted a systematic review across 5 databases to examine outcomes of progestational treatment (oral progestins or levonorgestrel-releasing IUD) for patients with endometrial intraepithelial neoplasia. The primary outcome was the best complete response rate within 12 months of primary progestational treatment. Sensitivity analyses were performed by removing studies with extreme effect sizes. Secondary outcomes included the pooled pregnancy rate. RESULTS: We identified 21 eligible studies, including 824 premenopausal patients with endometrial intraepithelial neoplasia, for our meta-analysis. Among these, 459 patients received oral progestin, and 365 patients received levonorgestrel-releasing IUD as a primary progestational treatment. The pooled best complete response proportion within 12 months was 82% (95% confidence interval [CI] = 69% to 91%) following oral progestin treatment and 95% (95% CI = 81% to 99%) following levonorgestrel-releasing IUD treatment. After removing outlier studies, the pooled proportion was 86% (95% CI = 75% to 92%) for the oral progestin group and 96% (95% CI = 91% to 99%) for the levonorgestrel-releasing IUD group, with reduced heterogeneity. The pooled pregnancy rate was 50% (95% CI = 35% to 65%) after oral progestin and 35% (95% CI = 23% to 49%) after levonorgestrel-releasing IUD treatment. CONCLUSIONS: This meta-analysis provides data on the effectiveness of oral progestins and levonorgestrel-releasing IUD treatment within 12 months of treatment among premenopausal patients with endometrial intraepithelial neoplasia. Although based on small numbers, the rate of pregnancy after treatment is modest. These data may be beneficial for selecting progestational therapies that allow fertility preservation for patients with endometrial intraepithelial neoplasia.


Asunto(s)
Neoplasias Endometriales , Dispositivos Intrauterinos Medicados , Levonorgestrel , Índice de Embarazo , Progestinas , Humanos , Femenino , Levonorgestrel/administración & dosificación , Progestinas/administración & dosificación , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/patología , Embarazo , Administración Oral , Carcinoma in Situ/tratamiento farmacológico , Carcinoma in Situ/patología , Adulto , Resultado del Tratamiento
10.
Cancer Chemother Pharmacol ; 93(5): 439-453, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38270613

RESUMEN

PURPOSE: Midostaurin, approved for treating FLT-3-mutated acute myeloid leukemia and advanced systemic mastocytosis, is metabolized by cytochrome P450 (CYP) 3A4 to two major metabolites, and may inhibit and/or induce CYP3A, CYP2B6, and CYP2C8. Two studies investigated the impact of midostaurin on CYP substrate drugs and oral contraceptives in healthy participants. METHODS: Using sentinel dosing for participants' safety, the effects of midostaurin at steady state following 25-day (Study 1) or 24-day (Study 2) dosing with 50 mg twice daily were evaluated on CYP substrates, midazolam (CYP3A4), bupropion (CYP2B6), and pioglitazone (CYP2C8) in Study 1; and monophasic oral contraceptives (containing ethinylestradiol [EES] and levonorgestrel [LVG]) in Study 2. RESULTS: In Study 1, midostaurin resulted in a 10% increase in midazolam peak plasma concentrations (Cmax), and 3-4% decrease in total exposures (AUC). Bupropion showed a 55% decrease in Cmax and 48-49% decrease in AUCs. Pioglitazone showed a 10% decrease in Cmax and 6% decrease in AUC. In Study 2, midostaurin resulted in a 26% increase in Cmax and 7-10% increase in AUC of EES; and a 19% increase in Cmax and 29-42% increase in AUC of LVG. Midostaurin 50 mg twice daily for 28 days ensured that steady-state concentrations of midostaurin and the active metabolites were achieved by the time of CYP substrate drugs or oral contraceptive dosing. No safety concerns were reported. CONCLUSION: Midostaurin neither inhibits nor induces CYP3A4 and CYP2C8, and weakly induces CYP2B6. Midostaurin at steady state has no clinically relevant PK interaction on hormonal contraceptives. All treatments were well tolerated.


Asunto(s)
Bupropión , Citocromo P-450 CYP2B6 , Citocromo P-450 CYP2C8 , Citocromo P-450 CYP3A , Interacciones Farmacológicas , Midazolam , Estaurosporina , Humanos , Área Bajo la Curva , Bupropión/farmacocinética , Bupropión/administración & dosificación , Anticonceptivos Orales/administración & dosificación , Anticonceptivos Orales/farmacología , Anticonceptivos Orales/farmacocinética , Citocromo P-450 CYP2B6/metabolismo , Citocromo P-450 CYP2B6/genética , Citocromo P-450 CYP2C8/metabolismo , Citocromo P-450 CYP3A/metabolismo , Combinación de Medicamentos , Etinilestradiol/farmacocinética , Etinilestradiol/administración & dosificación , Etinilestradiol/farmacología , Voluntarios Sanos , Levonorgestrel/farmacocinética , Levonorgestrel/administración & dosificación , Levonorgestrel/farmacología , Midazolam/farmacocinética , Midazolam/administración & dosificación , Pioglitazona/farmacología , Pioglitazona/administración & dosificación , Pioglitazona/farmacocinética , Estaurosporina/análogos & derivados , Estaurosporina/farmacología , Estaurosporina/farmacocinética , Estaurosporina/administración & dosificación , Masculino , Femenino , Adolescente , Adulto Joven , Adulto , Persona de Mediana Edad
11.
Am J Obstet Gynecol ; 230(5): 542.e1-542.e10, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38280433

RESUMEN

BACKGROUND: The symptom of heavy menstrual bleeding has a substantial impact on professional, physical, and social functioning. In 2021, results from a randomized controlled trial comparing a 52-mg levonorgestrel-releasing intrauterine system and radiofrequency nonresectoscopic endometrial ablation as treatments for women with heavy menstrual bleeding were published. Both treatment strategies were equally effective in treating heavy menstrual bleeding during 2-year follow-up. However, long-term results are also relevant for both patients and healthcare providers. OBJECTIVE: This study aimed to assess long-term differences in reintervention risk and menstrual blood loss in women with the symptom of heavy menstrual bleeding treated according to a strategy starting with a 52-mg levonorgestrel-releasing intrauterine system or radiofrequency nonresectoscopic endometrial ablation. STUDY DESIGN: This study was a long-term follow-up study of a multicenter randomized controlled trial (MIRA trial), in which women were allocated to either a 52-mg levonorgestrel-releasing intrauterine device (n=132) or radiofrequency nonresectoscopic endometrial ablation (n=138). Women from the original trial were contacted to fill out 6 questionnaires. The primary outcome was the reintervention rate after allocated treatment. Secondary outcomes included surgical reintervention rate, menstrual bleeding measured by the Pictorial Blood Loss Assessment Chart, (disease-specific) quality of life, sexual function, and patient satisfaction. RESULTS: From the 270 women who were randomized in the original trial, 196 (52-mg levonorgestrel-releasing intrauterine system group: n=94; radiofrequency nonresectoscopic endometrial ablation group: n=102) participated in this long-term follow-up study. Mean follow-up duration was 7.4 years (range, 6-9 years). The cumulative reintervention rate (including both medical and surgical reinterventions) was 40.0% (34/85) in the 52-mg levonorgestrel-releasing intrauterine system group and 28.7% (27/94) in the radiofrequency nonresectoscopic endometrial ablation group (relative risk, 1.39; 95% confidence interval, 0.92-2.10). The cumulative rate of surgical reinterventions only was significantly higher among patients with a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system compared with radiofrequency nonresectoscopic endometrial ablation (35.3% [30/85] vs 19.1% [18/94]; relative risk, 1.84; 95% confidence interval, 1.11-3.10). However, the hysterectomy rate was similar (11.8% [10/94] in the 52-mg levonorgestrel-releasing intrauterine system group and 18.1% [17/102] in the radiofrequency nonresectoscopic endometrial ablation group; relative risk, 0.65; 95% confidence interval, 0.32-1.34). Most reinterventions occurred during the first 24 months of follow-up. A total of 171 Pictorial Blood Loss Assessment Chart scores showed a median bleeding score of 0.0. No clinically relevant differences were found regarding quality of life, sexual function, and patient satisfaction. CONCLUSION: The overall risk of reintervention after long-term follow-up was not different between women treated according to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system and those treated using a strategy starting with radiofrequency nonresectoscopic endometrial ablation. However, women allocated to a treatment strategy starting with a 52-mg levonorgestrel-releasing intrauterine system had a higher risk of surgical reintervention, which was driven by an increase in subsequent endometrial ablation. Both treatment strategies were effective in lowering menstrual blood loss over the long term. The results of this long-term follow-up study can support physicians in optimizing the counseling of women with heavy menstrual bleeding, thus promoting informed decision-making regarding choice of treatment.


Asunto(s)
Técnicas de Ablación Endometrial , Dispositivos Intrauterinos Medicados , Levonorgestrel , Menorragia , Humanos , Femenino , Levonorgestrel/administración & dosificación , Levonorgestrel/uso terapéutico , Menorragia/cirugía , Técnicas de Ablación Endometrial/métodos , Adulto , Estudios de Seguimiento , Persona de Mediana Edad , Satisfacción del Paciente , Calidad de Vida , Reoperación/estadística & datos numéricos , Resultado del Tratamiento
12.
J Gynecol Oncol ; 35(3): e27, 2024 May.
Artículo en Inglés | MEDLINE | ID: mdl-38216133

RESUMEN

OBJECTIVE: To determine whether proactive molecular risk classifier for endometrial cancer (ProMisE) could be used to assess the prognosis of patients with atypical endometrial hyperplasia (AEH) or early-stage endometrial cancer (EC) treated with levonorgestrel-releasing intrauterine system (LNG-IUS). METHODS: A retrospective cohort study was conducted among 93 AEH or early-stage EC patients who received LNG-IUS to preserve fertility . By immunohistochemistry and gene sequencing, 4 subtypes of ProMisE were identified (p53 wild type [p53 wt], mismatch repair-deficient [MMRd], p53-abnormal, and POLE-mutated). The primary outcome was the time to complete response (CR) after LNG-IUS therapy. Secondary outcomes included the recurrence rate after CR and success rate of conception. RESULTS: Among the 93 patients, 15 (16.1%) were classified as MMRd, 6 (6.5%) as POLE-mutated, 5 (5.4%) as p53-abnormal, and 67 (72.0%) as p53 wt. Comparison of serum cancer antigen 125, family history of tumor, and positive rates of programmed cell death 1 ligand 1 protein and Ki67 protein in 4 groups showed statistically significant differences (p<0.05). Patients with the p53-abnormal subtype had the lowest overall CR rate (40%) and the highest recurrence rate (2/2). Patients with POLE-mutated subtype had the best prognosis, and all 6 patients achieved CR. When patients achieved complete remission, assisted reproductive technology was more likely to help them conceive than natural conception (p<0.05). CONCLUSION: Patients with early-stage EC or AEH who are more likely to benefit from fertility-sparing treatment can be identified using ProMisE classifier. Patients with POLE-mutated are suitable for fertility-sparing treatment with LNG-IUS.


Asunto(s)
Hiperplasia Endometrial , Neoplasias Endometriales , Preservación de la Fertilidad , Dispositivos Intrauterinos Medicados , Levonorgestrel , Humanos , Femenino , Neoplasias Endometriales/tratamiento farmacológico , Neoplasias Endometriales/genética , Neoplasias Endometriales/patología , Levonorgestrel/administración & dosificación , Estudios Retrospectivos , Preservación de la Fertilidad/métodos , Adulto , Hiperplasia Endometrial/tratamiento farmacológico , Hiperplasia Endometrial/genética , Hiperplasia Endometrial/patología , Proteína p53 Supresora de Tumor/genética , Persona de Mediana Edad , Mutación , Proteínas de Unión a Poli-ADP-Ribosa/genética , Resultado del Tratamiento
13.
Fam Med ; 56(4): 259-263, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-38241742

RESUMEN

BACKGROUND AND OBJECTIVES: Only 20% of family physicians report providing long-acting reversible contraception (LARC). Clinician-related barriers include confidence and comfort with LARC counseling and insertion/removal, and limited availability and uptake. Training during residency may address barriers and increase access/availability of LARC to support reproductive autonomy. We sought to determine the impact of block scheduling LARC clinics on resident comfort and confidence with LARC counseling and insertion/removal. METHODS: LARC block schedules were established in a Midwest family medicine residency's primary clinic (FMC) and in a federally qualified health center rotation clinic. Baseline and end-of-study surveys, compared by Mann-Whitney U and Wilcoxon signed-rank tests, were used to assess comfort and confidence with counseling and inserting LARC. The number of LARC devices placed at the FMC were collected for the intervention year and the year prior. RESULTS: Twenty of 30 residents completed the baseline survey; 13 completed the end-of-study survey. At the group and individual levels, comfort increased for counseling on Levonorgestrel (LNG) intrauterine devices (IUDs) and for inserting implants and LNG IUDs. Individual comfort increased for copper IUDs. Resident willingness to recommend LARC increased, and more devices were placed during the intervention year than the year prior in the FMC (all: P<.05). CONCLUSIONS: Block scheduling of LARC clinics was associated with increased residents' comfort and confidence with counseling and placement of implants (LNG IUDs) and with an increase in LARCs placed at one clinic. Changes to scheduling may be an effective educational strategy that may increase access/availability to LARC.


Asunto(s)
Medicina Familiar y Comunitaria , Internado y Residencia , Anticoncepción Reversible de Larga Duración , Humanos , Medicina Familiar y Comunitaria/educación , Femenino , Consejo , Encuestas y Cuestionarios , Citas y Horarios , Adulto , Levonorgestrel/administración & dosificación
18.
JAMA ; 329(3): 257-259, 2023 01 17.
Artículo en Inglés | MEDLINE | ID: mdl-36548007

RESUMEN

This matched-cohort study uses data from the French National Health Insurance database to assess whether a 19.5-mg levonorgestrel intrauterine system, vs a 52-mg system, is associated with increased use of antidepressant, hypnotic, and anxiolytic medications.


Asunto(s)
Dispositivos Intrauterinos Medicados , Levonorgestrel , Psicotrópicos , Francia , Levonorgestrel/administración & dosificación , Levonorgestrel/efectos adversos , Psicotrópicos/uso terapéutico , Dispositivos Intrauterinos Medicados/efectos adversos , Humanos , Femenino
19.
Am Fam Physician ; 105(1): 33-38, 2022 01 01.
Artículo en Inglés | MEDLINE | ID: mdl-35029928

RESUMEN

Adenomyosis is a clinical condition where endometrial glands are found in the myometrium of the uterus. One in three patients with adenomyosis is asymptomatic, but the rest may present with heavy menstrual bleeding, pelvic pain, or infertility. Heavy menstrual bleeding is the most common symptom. Adenomyosis is distinct from endometriosis (the presence of endometrial glands outside of the uterus), but the two conditions often occur simultaneously. Risk factors for developing adenomyosis include increasing age, parity, and history of uterine procedures. Most patients are diagnosed from 40 to 50 years of age, but younger patients with infertility are increasingly being diagnosed with adenomyosis as imaging modalities improve. Diagnosis of adenomyosis begins with clinical suspicion and is confirmed with transvaginal ultrasonography and pelvic magnetic resonance imaging. Treatment of adenomyosis typically starts with hormonal menstrual suppression. Levonorgestrel-releasing intrauterine systems have shown some effectiveness. Patients with adenomyosis may ultimately have a hysterectomy if symptoms are not controlled with medical therapy.


Asunto(s)
Adenomiosis/diagnóstico , Adenomiosis/tratamiento farmacológico , Adenomiosis/epidemiología , Adulto , Agentes Anticonceptivos Hormonales/administración & dosificación , Endometriosis/epidemiología , Femenino , Humanos , Histerectomía/métodos , Infertilidad/epidemiología , Dispositivos Intrauterinos Medicados , Levonorgestrel/administración & dosificación , Imagen por Resonancia Magnética/métodos , Menorragia/epidemiología , Persona de Mediana Edad , Dolor Pélvico/epidemiología , Embarazo , Factores de Riesgo , Ultrasonografía/métodos
20.
Gynecol Endocrinol ; 38(1): 68-72, 2022 Jan.
Artículo en Inglés | MEDLINE | ID: mdl-34672861

RESUMEN

OBJECTIVE: This study aims to assess sexual function (SF) and quality of life (QoL) among women using copper intrauterine devices (Cu-IUD), levonorgestrel-releasing intrauterine system (LNG-IUS) or etonogestrel(ENG)-releasing subdermal implant. METHODS: This is a cross-sectional study involving 213 women who are sexually active, using Cu-IUD, LNG-IUS or ENG implant for at least one year. SF assessment was carried out through the Female Sexual Function Index (FSFI) and QoL was made through The Short Form Health Research. RESULTS: Frequency of sexual dysfunction score in Cu-IUD users was 33.8%; 47.2% in LNG-IUS users and 47.8% in ENG-implant users, without difference between groups. Desire domain had higher score in Cu-IUD users (Cu-IUD:4.20 ± 1.15 × LNG-IUS:3.76 ± 1.17 × ENG-implant:3.63 ± 1.15; p = .009). Between Cu-IUD and LNG-IUS users there was no difference in FSFI score. Total FSFI score was higher in Cu-IUD group when compared only to ENG-implant (Cu-IUD:27.48 ± 6.14 × Implant:25.07 ± 6.89; p = .029). Regarding the QoL score, difference was found only in general health domain (Cu-IUD:65.22 ± 14.91 × LNG-IUS:62.61 ± 19.04 × Implant:58.33 ± 16.46; p = .034), with lower score for implant group. CONCLUSION: There was no difference in the SF total score between the users of Cu-IUD, LNG-IUS and ENG implant. However, the score of the FSFI desire domain and general health status were higher among users of the Cu-IUD.


Asunto(s)
Desogestrel/efectos adversos , Dispositivos Intrauterinos de Cobre/efectos adversos , Dispositivos Intrauterinos Medicados/efectos adversos , Levonorgestrel/efectos adversos , Calidad de Vida , Disfunciones Sexuales Fisiológicas/epidemiología , Adulto , Anticonceptivos Femeninos/administración & dosificación , Estudios Transversales , Desogestrel/administración & dosificación , Femenino , Humanos , Levonorgestrel/administración & dosificación
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