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.

Long acting progestogens versus combined oral contraceptive pill for preventing recurrence of endometriosis related pain: the PRE-EMPT pragmatic, parallel group, open label, randomised controlled trial.

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.

Assessing ovarian stimulation with letrozole and levonorgestrel intrauterine system after combined fertility-sparing approach for atypical endometrial lesions: a retrospective case-control study.

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.

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.

Levonorgestrel-releasing intrauterine device therapy vs oral progestin treatment for reproductive-aged patients with endometrial intraepithelial neoplasia: a systematic review and meta-analysis.

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.

A 52-mg levonorgestrel-releasing intrauterine system vs bipolar radiofrequency nonresectoscopic endometrial ablation in women with heavy menstrual bleeding: long-term follow-up of a multicenter randomized controlled trial.

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.

Midostaurin drug interaction profile: a comprehensive assessment of CYP3A, CYP2B6, and CYP2C8 drug substrates, and oral contraceptives in healthy participants.

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.

Efficacy of fertility-sparing treatment with LNG-IUS is associated with different ProMisE subtypes of endometrial carcinoma or atypical endometrial hyperplasia.

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.

Adenomyosis: Diagnosis and Management.

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.

Clinical efficacy of levonorgestrel intrauterine system (Mirena) combined with hysteroscopy in the treatment of perimenopausal AUB patients.

Perimenopausal abnormal uterine bleeding (AUB) is most common in ovulation dysfunction, which seriously compromises patients' health. This study aims to evaluate the efficacy of levonorgestrel intrauterine system (Mirena) plus hysteroscopy respectively in perimenopausal AUB. Sixty perimenopausal AUB patients treated with hysteroscopic electric resection in our hospital between January 2020 and December 2020 were enrolled and randomized to control group given dydrogesterone and study group treated with Mirena, with 30 cases in each group. The treatment efficacy, sex hormone level, hemoglobin (Hb) level, endometrial thickness and menstruation conditions were compared. The total efficacy was higher in the study group than that in the control group (P<0.05). The study group had lower follicle-stimulating hormone (FSH), luteinizing hormone (LH), and estradiol (E2) levels and higher Hb levels compared with those of the control group (all P<0.05). Thinner endometrial thickness, lower pictorial blood loss assessment chart (PBAC) scores and shorter duration of menstruation were observed in the study group (all P<0.05). Both Mirena and dydrogesterone enhance the clinical efficacy of hysteroscopic treatment of perimenopausal AUB patients, with the advantages of Mirena being more promising.

Levonorgestrel-releasing intrauterine system versus oral medroxyprogesterone acetate in infertile women with endometrial hyperplasia without atypia.

RESEARCH QUESTION: How does use of a levonorgestrel-releasing intrauterine system (LNG-IUS) in infertile women with endometrial hyperplasia without atypia affect endometrial hyperplasia regression and pregnancy rates compared with oral medroxyprogesterone acetate (MPA)? DESIGN: This prospective cohort study included 215 infertile women with an indication for assisted reproductive technology (ART) and a diagnosis of endometrial hyperplasia without atypia. Endometrial hyperplasia was diagnosed by hysteroscopic endometrial biopsy. At the time of first- and second-line treatment, patients were offered therapy with either oral MPA 10 mg daily or LNG-IUS. Follow-up biopsies were scheduled after 90 days' treatment. After endometrial hyperplasia regression, patients were admitted to IVF/intracytoplasmic sperm injection (ICSI) cycles. RESULTS: Baseline characteristics and confounders including age at diagnosis, body mass index and duration of infertility did not differ between LNG-IUS users and control participants and were accounted for using propensity score weighting. Endometrial hyperplasia regression rate at first follow-up was higher in the LNG-IUS group than the oral progestins group (28/28, 100% and 110/187, 58.8%; P < 0.001), while that after second-line treatment was comparable between the two groups (89/91, 97.8% and 122/124, 98.4%; P = 0.22). Clinical pregnancy rate, miscarriage rate and cumulative live birth rate following ART in patients ever receiving LNG-IUS were similar to those of patients receiving only MPA (34% versus 39.5%, 22.6% versus 34.7% and 26.4% versus 25.8%). CONCLUSION: Endometrial hyperplasia regression is greater in women receiving LNG-IUS compared with oral MPA, while live birth rates following ART are comparable between the two groups. The use of LNG-IUS does not jeopardize the chances of pregnancy in women seeking fertility treatment.

Análisis y consideraciones técnicas acerca de dispositivos intrauterinos de levonorgestrel para la evaluación de productos similares y genéricos / Analysis and technical considerations about levonorgestrel intrauterine devices for the evaluation of generic and similar products

Los dispositivos intrauterinos hormonales de levonorgestrel son métodos anticonceptivos seguros y eficaces. Al igual que los medicamentos convencionales, una vez expirada la patente, las autoridades regulatorias de salud pueden aprobar el registro de productos similares. El objetivo de ello es disminuir los costos, considerando el elevado precio del producto original. Este tipo de productos están regulados y se aplican requisitos generales similares a los medicamentos tradicionales para demostración de seguridad y eficacia. Las propiedades mecánicas únicas del producto de referencia plantean un gran desafío a los productos similares. El presente artículo analiza de manera comparativa las características de los diversos sistemas intrauterinos hormonales de levonorgestrel, disponibles en el mercado. La autoridad sanitaria y los diversos centros clínicos deben considerar que en este tipo de productos no hay, hasta la fecha en el mundo, genéricos intercambiables y que por lo tanto, se debe decidir la intercambiabilidad de éstos sobre la base de estudios de bioequivalencia in vivo, luego de la demostración de equivalencia farmacéutica in vitro, tal y como sugiere la FDA, o en su defecto deberían ser registrados como productos nuevos, con estudios clínicos apropiados que demuestren seguridad y eficacia.

Levonorgestrel hormonal intrauterine systems are safe and effective contraceptive methods. Like conventional drugs, once the patent expires, health regulatory authorities can approve the registration of similar products. The objective of this is to reduce costs, considering the high price of the original product. These types of products are regulated as drugs and similar general requirements apply to traditional drugs for demonstration of safety and efficacy. The unique mechanical properties of the reference product pose a great challenge to similar products. This article comparatively analyzes the characteristics of the various levonorgestrel hormonal intrauterine systems available on the market. Therefore, the health authority and clinical centers must consider that up to date, there are no interchangeable generics in this type of products worldwide. Thus, their interchangeability must be decided on the basis of in vivo bioequivalence studies after the demonstration of in vitro pharmaceutical equivalence, as suggested by the FDA. Without that, they should be registered as new products, with appropriate clinical studies that demonstrate safety and efficacy.

The suture fixation of levonorgestrel-releasing intrauterine device using the hysteroscopic cold-knife surgery system: an original method in treatment of adenomyosis.

OBJECTIVE: To introduce an effective approach using the hysteroscopic cold-knife surgery system (HCSS) for suture fixation of the levonorgestrel-releasing intrauterine device (LNG-IUD) in patients with adenomyosis. DESIGN: Video description of the surgical procedures to demonstrate the detailed technique. The study was reviewed and approved by the institutional review board of Hangzhou Women's Hospital. SETTING: Maternity hospital. PATIENT(S): A 39-year-old woman diagnosed with adenomyosis had endured 7 years of severe dysmenorrhea and 4 years of heavy menstrual bleeding. She had a past medical history that was significant for expulsion of an LNG-IUD. Transvaginal ultrasonography revealed that her uterus was enlarged by adenomyosis. She insisted on preserving fertility potential. INTERVENTION(S): We proceeded with the HCSS and the uterine cavity was found enlarged significantly. In consideration of the patient's strong desire for maintaining fertility options, the fixation of the LNG-IUD on the intrauterine posterior wall with an Ethibond suture was performed successfully through an endoscopic needle driver and a knot-pushing device. Proficient endoscopic suturing is the key to the technique. Informed consent was obtained from the patient. MAIN OUTCOME MEASURE(S): Feasibility and value of using the HCSS to fix an LNG-IUD for treatment of adenomyosis. RESULT(S): The LNG-IUD was fixed successfully by the HCSS with an Ethibond suture on the posterior wall of the uterus within 30 minutes, and the intraoperative blood loss was 2 mL. The patient was discharged 24 hours postoperatively without any adverse perioperative complications. At the one-year follow-up, the patient reported obvious relief of her dysmenorrhea and menorrhagia and no more experience with expulsion. Ultrasound demonstrated normal position of the IUD at 1, 3, 6, and 12 months postoperatively. CONCLUSION(S): Hysteroscopy presents a clear visual field to locate and fix the IUD. In patients with adenomyosis suffering from dysmenorrhea or excessive menstrual blood loss, suture fixation of the LNG-IUD using the HCSS can be a minimally invasive and effective alternative for treating adenomyosis, especially in patients who have previously expelled an LNG-IUD, preventing the risk of expulsion.

Optimal duration of fertility-sparing hormonal treatment for early-stage endometrioid endometrial cancer.

OBJECTIVES: To analyze the oncologic outcomes of long-term fertility-sparing treatment (FST) in patients with early-stage endometrial cancer (EC) and to determine the optimal duration of FST that would not hamper survival outcomes. METHODS: Patients undergoing FST for presumed stage IA, grade 1 EC between 2005 and 2018 were retrospectively analyzed. Oncologic outcomes were compared between the group with ≤6 months of FST and the group with >6 months of FST. Segmented regression analysis was used to estimate the dynamic changes in cumulative complete response (CR) rates according to FST duration. RESULTS: A total of 122 patients received oral progestin, with concurrent levonorgestrel-releasing intrauterine device use in 108 (88.5%) and 105 (86.1%) achieved CR with a median time to achieve CR of 10 (3-42) months. Of the patients not achieving CR at 6 months of FST, 95.1% (78/82) continued further FST. The overall CR rate (88.9% [32/36] vs. 84.9% [73/86], P = 0.436] was not significantly different between the groups with ≤6 and > 6 months of FST. The changes in cumulative CR rates were significantly different between the two segments divided by 15 months from the initial FST (P = 0.0015, segmented regression analysis). The overall progressive disease (PD) rate was 3.3% (4/122), and PD was first detected during 9-12 months of FST. CONCLUSION: Patients not achieving CR and not showing PD at 6 months of FST could continue further FST. If disease progression is excluded, 15 months of FST can be considered as the cutoff for the optimal FST duration.

Continuation rates of the 52-mg levonorgestrel-releasing intrauterine system according to the primary reason for its use / Taxas de continuação com o sistema intrauterino de liberação de levonorgestrel de 52mg de acordo com o motivo principal de seu uso

Abstract Objective To evaluate whether continuation rates with the 52-mg levonorgestrelreleasing intrauterine system (LNG-IUS) up to 5 years after placement differed between women using the method exclusively for contraception and those using the device for medical reasons alone. Methods A retrospective cohort study was conducted in a family planning clinic with 5,034 LNG-IUS users: 4,287 using the method exclusively for contraception and 747 for medical reasons alone. The continuation rate at 1 to 5 years of use was calculated by life table analysis. Results Initially, the continuation rate was significantly higher in the contraception group: 85.8 versus 83.4 and 77.4 versus 76.0 per 100 women-years in the 1st and 2nd years of use, respectively. There were more discontinuations due to bleeding/spotting in the medical reasons group in the first two years. The discontinuation rate according to reason for use was not significantly different from the third to the fifth year of use. No women discontinued due to amenorrhea in either group. Conclusion The continuation rate was significantly higher in the contraception group in the first two years of use. Amenorrhea was not a reason for discontinuation in either group, suggesting that counselling in this respect was adequate. Nevertheless, counselling could perhaps have been better with regards to the expected long period of bleeding and spotting in the first two years after placement.

Resumo Objetivo Avaliar a taxa de continuação até 5 anos de uso do sistema intrauterino liberador de 52-mg levonorgestrel por dia (SIU LNG) -IUS) é diferente entre mulheres que o usam exclusivamente como anticoncepcional que entre as que usam exclusivamente por razões médicas. Métodos Estudo retrospectivo realizado em uma clínica de Planejamento Familiar 5.034 usuárias de SIU LNG, 4.287 que optaram pelo método apenas como anticoncepcional e 747 que o usavamsomente por razoesmédicas. A taxa de continuação de um até cinco ano foi calculada por meio de análise de tabela de vida Resultados No início a taxa de continuação foi significativamente maior no grupo da anticoncepção: 85,8 versus 83,4 e 77,4 versus 76,0 por 100 anos-mulher no 1° e 2° ano de uso, respectivamente. Houve mais descontinuações por sangrado-manchado no grupo de razões médicas nos dos primeiros anos. A taxa de continuação não foi significativamente diferente desde o terceiro até o quinto ano de uso. Nenhuma mulher de ambos os grupos descontinuou por amenorreia. Conclusão A taxa de continuação foi significativamente maior no grupo de anticoncepção durante os dos primeiros anos de uso. Amenorreia não foi motivo de descontinuação em ambos os grupos, sugerindo que a orientação a esse respeito foi adequada. Entretanto, a orientação referente ao longo período de sangramentos irregulares nos dois primeiros anos após a inserção, precisaria ser melhorado.

Complete pathological response following levonorgestrel intrauterine device in clinically stage 1 endometrial adenocarcinoma: Results of a randomized clinical trial.

PURPOSE: Intrauterine levonorgestrel (LNG-IUD) is used to treat patients with endometrial adenocarcinoma (EAC) and endometrial hyperplasia with atypia (EHA) but limited evidence is available on its effectiveness. The study determined the extent to which LNG-IUD with or without metformin (M) or weight loss (WL) achieves a pathological complete response (pCR) in patients with EAC or EHA. PATIENTS AND METHODS: This phase II randomized controlled clinical trial enrolled patients with histologically confirmed, clinically stage 1 FIGO grade 1 EAC or EHA; a body mass index > 30 kg/m2; a depth of myometrial invasion of less than 50% on MRI; a serum CA125 ≤ 30 U/mL. All patients received LNG-IUD and were randomized to observation (OBS), M (500 mg orally twice daily), or WL (pooled analysis). The primary outcome measure was the proportion of patients developing a pCR (defined as absence of any evidence of EAC or EHA) after 6 months. RESULTS: From December 2012 to October 2019, 165 patients were enrolled and 154 completed the 6-months follow up. Women had a mean age of 53 years, and a mean BMI of 48 kg/m2. Ninety-six patients were diagnosed with EAC (58%) and 69 patients with EHA (42%). Thirty-five participants were randomized to OBS, 36 to WL and 47 to M (10 patients were withdrawn). After 6 months the rate of pCR was 61% (95% CI 42% to 77%) for OBS, 67% (95% CI 48% to 82%) for WL and 57% (95% CI 41% to 72%) for M. Across the three treatment groups, the pCR was 82% and 43% for EHA and EAC, respectively. CONCLUSION: Complete response rates at 6 months were encouraging for patients with EAC and EHA across the three groups. TRIAL REGISTRATION: U.S. National Library of Medicine, NCT01686126.

Efectos adversos y motivos de retiro de implante subdérmico Jadelle® en usuarias de Policlínica de salud Sexual y Reproductiva del Hospital de Clínicas en período junio 2015- diciembre 2017 / Adverse effects and reasons of remove of subdermico implant Jadelle® in users of Sexual and Reproductive Health Clinics of Hospital de Clinicas in period june 2015-december 2017

INTRODUCCIÓN: La anticoncepción hormonal, a través de implantes subdérmicos, es uno de los métodos anticonceptivos reversibles de larga duración más eficaces en la actualidad que está disponible en nuestro país en forma gratuita en el sistema público. OBJETIVO: Reconocer los efectos adversos y los motivos de retiro del Implante Jadelle® en usuarias del Hospital de Clínicas, así como evaluar la información recibida por las usuarias al momento de la colocación. MATERIAL Y MÉTODOS: Un total de 160 pacientes participaron en el estudio a través de una encuesta previo consentimiento informado. Se utilizó la estadística descriptiva en números absolutos y porcentuales. Resultados: Previo al uso, recibieron información sobre los probables efectos adversos del método el 83% de ellas, y acerca de la efectividad del método el 89 %. En cuanto a efectos adversos los presentaron el 80,6% de las usuarias, siendo la irregularidad de la menstruación la causa más frecuente constituyendo un 61%. CONCLUSIONES: Es alta la frecuencia de pacientes que presentan efectos adversos y que solicitan retiro del implante antes del tiempo a causa de ello, 35% de las usuarias, siendo el principal motivo la irregularidad menstrual en un 43% de los casos. Es recomendable realizar un correcto asesoramiento previo a la colocación e incentivar a las pacientes a concurrir a los controles médicos, luego de la colocación, para brindar asesoramiento y tratamiento si se presentara algún efecto adverso, con el fin de obtener una mejor continuidad de uso del método.

INTRODUCTION: Hormonal contraception, through subdermal implants, is one of the most effective long active reversal contraceptive methods currently available in our country for free in the public system. OBJETIVE: Recognize the adverse effects and the reasons for its withdrawal in users of the Hospital de Clínicas as well as to evaluate the information received by the users at the time of placement. METHODOLOGY: A total of 160 patients participated in the work with prior informed consent through a survey. Descriptive statistics were used in absolute and percentage numbers. They received information on the probable adverse effects of the 83% pre-use method, about the effectiveness of the 89% method. RESULTS: Regarding adverse effects, they were present in 80.6% of the users; the being irregularity of menstruation is the most frequent, constituting 61%. Concluding that the frequency of patients presenting with adverse effects and requesting removal of the implant before the time is high because of it, 35% of the users who requested removal menstrual irregularities were the main reason for 43% of patients. CONCLUSIONS: It is advisable to make a correct advice prior to placement and encourage patients to attend medical controls, after placement, to provide advice and treatment if any adverse effect occurs, in order to give better use in terms of method time.

The paradigm of norgestimate: a third-generation testosterone-derivative progestin with a peripheral anti-androgenic activity and the lowest risk of venous thromboembolism.

INTRODUCTION: Norgestimate (NGM) is a testosterone derivative with peculiar receptor activities. AREAS COVERED: This is a narrative review of the available data on the pharmacotherapy of NGM in combined hormonal contraceptives (CHCs) in terms of contraceptive efficacy, venous thromboembolism (VTE) risk, safety, tolerability and bleeding patterns. A comprehensive literature review was conducted in August 2020 using PubMed with the keyword 'norgestimate'. EXPERT OPINION: NGM shows a mild estrogenic activity associated with anti-mineralocorticoid and anti-androgenic properties, largely responsible for the cardiovascular safety profile. The anti-androgenic property depends on the androgen receptor (AR) nuclear translocation (AR trafficking and its subnuclear distribution), the inhibition of 5α-reductase activity (it possesses higher activity compared to other available progestins), and the increase on sexual hormone binding globulin (SHBG) levels if combined with an estrogenic counterpart. NGM is one of the molecules that best modulates the power of ethinyl-estradiol on the thromboembolic risk, being associated with the lowest VTE risk between different CHCs. NGM has the advantage of retaining peripheral anti-androgenic activity, demonstrated by the impact on lipid and glucose metabolism, and it should be preferred if compared with other similar progestins of the same class of risk which are much more androgenic, such as levonorgestrel.