Cartilage defect repair in a rat model via a nanocomposite hydrogel loaded with melatonin-loaded gelatin nanofibers and menstrual blood stem cells: an in vitro and in vivo study.

Cartilage damage caused by injuries or degenerative diseases remains a major challenge in the field of regenerative medicine. In this study, we developed a composite hydrogel system for the delivery of melatonin and menstrual blood stem cells (MenSCs) to treat a rat model of cartilage defect. The composite delivery system was produced by incorporation of melatonin into the gelatin fibers and dispersing these fibers into calcium alginate hydrogels. Various characterization methods including cell viability assay, microstructure studies, degradation rate measurement, drug release, anti-inflammatory assay, and radical scavenging assay were used to characterize the hydrogel system. MenSCs were encapsulated within the nanocomposite hydrogel and implanted into a rat model of full-thickness cartilage defect. A 1.3 mm diameter drilled in the femoral trochlea and used for the in vivo study. Results showed that the healing potential of nanocomposite hydrogels containing melatonin and MenSCs was significantly higher than polymer-only hydrogels. Our study introduces a novel composite hydrogel system, combining melatonin and MenSCs, demonstrating enhanced cartilage repair efficacy, offering a promising avenue for regenerative medicine.

Assessing the impact of hormonal contraceptive use on menstrual health among women of reproductive age - a systematic review.

BACKGROUND: Contraceptive methods are well-established in their ability to prevent pregnancy and increase individual agency in childbearing. Evidence suggests that contraceptives can also be used to treat adverse conditions associated with menstruation, including abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders.This review investigates the effects of contraceptive techniques such as contraceptive pills, and long-acting reversible contraceptives (e.g. intrauterine devices, implants) on menstrual morbidity. METHODS: Over ten databases with no geographical boundaries were searched from inception until October 2023. Study designs were one of the following types to be included: parallel or cluster randomised controlled trials, controlled clinical trials, controlled before and after studies, interrupted time series studies, cohort or longitudinal analyses, regression discontinuity designs, and case-control studies. Ten team members screened the papers in pairs with a Kappa score of more than 7, and Covidence was used. Conflicts were resolved by discussion, and the full papers were divided among the reviewers to extract the data from eligible studies. RESULTS: Hormonal contraceptives are considered a well-tolerated, non-invasive, and clinically effective treatment for abnormal and prolonged uterine bleeding, heavy menstrual bleeding, painful menstruation, endometriosis, uterine fibroids, and premenstrual dysphoric disorders. Our studies investigating quality of life or well-being in women with heavy menstrual bleeding, endometriosis, or uterine fibroids have found improvements in all dimensions assessed. CONCLUSIONS: Hormonal contraceptives significantly reduce pain, symptom severity, and abnormal bleeding patterns associated with women who suffer from heavy menstrual bleeding, endometriosis, and uterine fibroids.

Hormonal contraceptives significantly reduce pain, symptom severity, and abnormal bleeding patterns associated with women who suffer from heavy menstrual bleeding, endometriosis, and uterine fibroids. Findings can inform clinical practice and policy decisions to ensure that women have access to safe and effective contraceptive options that promote both reproductive and non-reproductive health.

Danazol's use for menstrual suppression in transgender individuals: A retrospective multi-site cohort study.

BACKGROUND: Danazol is a synthetic progestin with androgenic effects that is approved by the Food and Drug Administration for treatment of endometriosis, benign fibrocystic breast disease, and hereditary angioedema. In recent years, increasing numbers of transgender and nonbinary individuals seeking menstrual suppression have been offered danazol due to its potential to both induce amenorrhea and cause reversible androgenic side effects including pigmentation of vellus hairs and voice changes, which may be desirable in this population. There are currently no studies assessing use of danazol within the transgender population for menstrual suppression. OBJECTIVE: This study's primary aim was to evaluate the use of danazol as a menstrual suppression agent in transgender patients. DESIGN: This was a retrospective multisite cohort study of all individuals who had been on danazol at two tertiary care centers between 2000 and 2022. METHODS: All patients prescribed danazol were identified using a search of the electronic medical records. For demographic purposes, comparisons were made between those who did and did not use danazol for the purpose of menstrual suppression. A detailed chart review was then performed to analyze the experiences of menstrual suppression in transgender and nonbinary patients. RESULTS: Most transgender and nonbinary patients on danazol for menstrual suppression remained on it at their most recent follow-up visit, and many charts noted improvements in gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy menstrual bleeding. Most transgender patients achieved amenorrhea. CONCLUSION: Danazol may be a reasonable option for menstrual suppression in transgender and nonbinary patients. Our findings show its potential to not only induce amenorrhea but cause desired androgenic symptoms and improve gender dysphoria, pelvic pain, dysmenorrhea, endometriosis, and heavy bleeding. While the androgenic effects of danazol are less desirable in cisgender populations, it is an attractive option for menstrual suppression in transgender and nonbinary patients.

Using danazol to stop periods in transgender individualsDanazol has previously been used to help treat pain and bleeding related to endometriosis. However, danazol can have certain androgenic side effects (acne, deepening of the voice) that cisgender women (individuals who were assigned female at birth and identify with the female gender) often find undesirable, but that could be desirable in transgender patients seeking to affirm their gender by stopping periods. Our study looked at danazol use for period suppression, as well as for other reasons. We found that most transgender patients using danazol for period suppression found it to be successful and remained on it at follow-up appointments, and that many transgender patients saw improved gender dysphoria, pelvic pain, pain during periods, endometriosis, and heavy period bleeding. These findings suggest that danazol may be a good option for menstrual suppression in transgender individuals as any experienced androgenic effects may help with gender dysphoria, whether individuals are not yet ready to start testosterone or do not desire testosterone therapy at all.

Human Menstrual Blood-Derived Stem Cells Protect against Tacrolimus-Induced Islet Dysfunction via Cystathionine ß-Synthase Mediated IL-6/STAT3 Inactivation.

Diabetes imposes a huge burden worldwide. Islet transplantation is an alternative therapy for diabetes. However, tacrolimus, a kind of immunosuppressant after organ transplantation, is closely related to post-transplant diabetes mellitus. Mesenchymal stem cells (MSCs) have attracted interest for their potential to alleviate diabetes. In vivo experiments revealed that human menstrual blood-derived stem cells (MenSCs) treatment improved tacrolimus-induced blood glucose, body weight, and glucose tolerance disorders in mice. RNA sequencing was used to analyze the potential therapeutic targets of MenSCs. In this study, we illustrated that cystathionine ß-synthase (CBS) contributed to tacrolimus -induced islet dysfunction. Using ß-cell lines (MIN6, ß-TC-6), we demonstrated that MenSCs ameliorated tacrolimus-induced islet dysfunction in vitro. Moreover, MenSC reduced the tacrolimus-induced elevation of CBS levels and significantly enhanced the viability, anti-apoptotic ability, glucose-stimulated insulin secretion (GSIS), and glycolytic flux of ß-cells. We further revealed that MenSCs exerted their therapeutic effects by inhibiting CBS expression to activate the IL6/JAK2/STAT3 pathway. In conclusion, we showed that MenSCs may be a potential strategy to improve tacrolimus-induced islet dysfunction.

Association between COVID-19 vaccination and menstruation: a state of the science review.

INTRODUCTION: Menstrual health is a key patient-reported outcome beyond its importance as a general indicator of health and fertility. However, menstrual function was not measured in the clinical trials of COVID-19 vaccines. The purpose of this review was to synthesise the existing literature on the relationship between COVID-19 vaccination and menstrual health outcomes. METHODS: A PubMed search to 31 October 2023 identified a total of 53 publications: 11 prospective cohort studies, 11 retrospective cohort studies or registry-based cohort studies, and 31 cross-sectional or retrospective case-control studies. RESULTS: Identified studies were generally at moderate-to-high risk of bias due to retrospective design, interviewer bias, and failure to include a non-vaccinated control group. Nonetheless, the bulk of the literature demonstrates that COVID-19 vaccine is associated with temporary changes in menstrual characteristics (cycle length and flow) and menstrual pain. Follicular phase (at the time of vaccination) is associated with greater increases in cycle length. Evidence suggests temporary post-vaccine menstrual changes in adolescents, abnormal vaginal bleeding in postmenopausal individuals, and a potential protective effect of using hormonal contraception. CONCLUSIONS: In this review we found evidence supporting an association between the COVID-19 vaccine and menstrual health outcomes. Given the importance of menstrual function to overall health, we recommend that all future vaccine trials include menstruation as a study outcome. Future vaccine studies should include rigorous assessment of the menstrual cycle as an outcome variable to limit sources of bias, identify biological mechanisms, and elucidate the impact of stress.

Outcomes of Vaginal Repair and Vaginal Repair Combined With GnRHa Administration in the Treatment of Cesarean Section Scar Defects: A Randomized Clinical Trial.

STUDY OBJECTIVE: To prospectively investigate whether the application of vaginal repair (VR) of cesarean section scar defect (CSD) combined with a gonadotropin-releasing hormone agonist (GnRHa) achieve better clinical outcomes than VR alone. DESIGN: A randomized clinical trial. SETTING: University Hospital. PATIENTS: A total of 124 women with CSD were undergoing expectant management from December 2016 to September 2021. 61 were randomized to VR+ GnRHa and 63 to VR alone. INTERVENTION: Vaginal repair combined with GnRHa and vaginal repair alone. MEASURES AND MAIN RESULTS: The primary outcome was the duration of menstruation and thickness of the remaining muscular layer (TRM) at 6 months after surgery. Secondary outcomes included the length, width, and depth of the CSD; operation time; estimated blood loss; hospitalization time; and operative complications. Women were treated with either VR (n = 63) or VR + GnRHa (n = 61). Menstruation and TRM in patients pre vs post comparisons either with VR or VR + GnRHa are significantly improved (p <.05). Significant differences in menstruation duration and TRM occurred in patients treated with VR + GnRHa compared with those treated with VR (p <.05). Moreover, the rate of CSD after surgery in the VR group was significantly higher than that in the VR + GnRHa group (p = .033), and CSD patients in the VR + GnRHa group achieved better therapeutic effects than those in the VR group (p = .017). Patients who received VR + GnRHa had a shorter menstruation duration and a greater increment of TRM postoperatively than patients treated with VR alone (p = .021; p = .002, respectively). CONCLUSION: VR + GnRHa therapy has a greater potential to improve scar healing and reduce the number of menstruation days than VR alone for symptomatic women with CSD.

Timing of onset of menses after GnRH agonist treatment for central precocious puberty.

OBJECTIVES: To understand possible predictors of the onset of menses after gonadotropin-releasing hormone agonist treatment cessation in girls with central precocious puberty (CPP). METHODS: This exploratory post hoc analysis of a phase 3 and 4 trial of girls with CPP treated with once-monthly intramuscular leuprolide acetate examined onset of menses after treatment completion using a time-to-event analysis. Pretreatment and end-of-treatment chronologic age (CA), bone age (BA)/CA ratio, and Tanner breast stage; pretreatment menses status; and end-of-treatment BA and body mass index (BMI) were studied as potential factors influencing the onset of menses. RESULTS: Median time to first menses after stopping treatment was 18.3 months among 35 girls (mean age at onset of treatment, 6.8 years) examined. Of 26 girls experiencing menses, 11 (42 %) menstruated at 16-21 months after stopping treatment. Most girls with pretreatment BA/CA≥1.4 started menstruating very close to 18 months after stopping treatment; those with less advanced BA/CA experienced menses at 9-18 months. End-of-treatment BA/CA≥1.2 was associated with a quicker onset of menses (14.5 vs. 18.5 months for BA/CA<1.2, p=0.006). End-of-treatment BA≥12 years predicted longer time to menses. No relationship with time to menses was observed for pretreatment menarche status, pretreatment or end-of-treatment Tanner breast stage (<3/≥3) or CA (<6/≥6 or ≤11/>11), or end-of-treatment BMI percentiles (<85.6/≥85.6 and <92.6/≥92.6). CONCLUSIONS: Pretreatment menarche status or CA do not appear to predict onset of menses, but pre- and end-of-treatment BA/CA may be helpful in anticipating time to first menses after stopping treatment.

Eficacia y seguridad del uso extendido de anticonceptivos orales combinados / Efficacy and safety of extended use of combined oral contraceptives

Los anticonceptivos orales combinados constituyen hoy en día uno de los métodos anticonceptivos más populares a nivel mundial. Su composición consiste en una combinación de análogos de hormonas sexuales femeninas que se administran en bajas dosis diarias, manteniendo constante su concentración sanguínea y evitando de esta forma los cambios en el eje endócrino que estimulan la ovulación. Con el objetivo de recrear los procesos fisiológicos, la mayoría de las formulaciones comprenden un intervalo de 4 a 7 días libres de hormonas en el cual se genera el sangrado por deprivación.A partir de una viñeta clínica en la que una paciente sana desea posponer su hemorragia por deprivación, y tras realizar una búsqueda bibliográfica que prioriza las investigaciones más recientes y de mejor calidad, la autora revisa la evidencia sobre el uso de hormonas sin intervalo libre, especialmente su efectos sobre la eficacia y la incidencia de efectos adversos. (AU)

Nowadays, combined oral contraceptives are one of the most popular contraceptive methods worldwide. Its composition consists of a combination of similar female sex hormones administered in low daily doses, keeping their blood concentration constant and thus avoiding changes in the endocrine axis that stimulate ovulation. In order to recreate physiological processes, most formulations include an interval of 4 to 7 hormone-free days in which withdrawal bleeding occurs.Starting from a clinical vignette in which a healthy patient desires to postpone her withdrawal bleeding, and after conducting a bibliographic search that prioritizes the most recent and best-quality research, the author reviews the evidence about the use of hormones without free interval, especially their effects on efficacy and the incidence of adverse effects. (AU)

Bleeding profile and safety of a levonorgestrel 13.5 mg intrauterine device versus Nova T copper 380 mm2 intrauterine device: Results of a 3-year, single-center, randomized phase 4 study.

OBJECTIVE: To assess the bleeding profiles of the levonorgestrel 13.5 mg intrauterine device (LNG13.5-IUD) and Nova T copper 380 mm2 IUD (Cu380-IUD). STUDY DESIGN: Single-center, evaluator-masked, randomized study conducted in women aged 18-45 years starting these methods. Primary outcomes were number of bleeding days, self-reported bleeding intensity, Pictorial Blood Assessment Chart (PBAC) score, and blood biochemical values at baseline, months 3, 6, 12, 24, and 36 per 90-day reference periods except for PBAC (months). Secondary objectives were presence/duration/intensity of dysmenorrhea and tolerability. RESULTS: We included 106 women aged 32.5 ± 6.7 years: 55 with LNG13.5-IUD and 51 with Cu380-IUD. Data for LNG13.5-IUD versus Cu380-IUD at baseline and month 36 (both respectively) were as follows: (1) median (25th; 75th percentile) number of bleeding days: 12 (9.0; 15.0) versus 12 (9.0; 15.0), p = 0.82, and 4 (0; 13.7) versus 15 (14.2; 20.0), p < 0.001; (2) mean bleeding intensity: 1.7 for both, p = 0.66, and 0.7 and 2.2, p < 0.001. Forty percent versus 0% presented with amenorrhea at month 36; (3) mean PBAC score (95% Confidence interval (CI): 50.7 (16.6; 84.7) versus 130.4 (95.7; 165.0) at month 1, and 7.9 (-26.7; 42.6) versus 126 (90.7; 161.2), p < 0.001; (4) median (25th; 75th percentile) ferritin levels (Ug/L) 33 (19; 53) versus 30 (19; 45), p = 0.70, and 59 (42; 84) versus 21 (8; 39). We did not observe changes or differences between groups in hemoglobin and hematocrit. The duration and intensity of dysmenorrhea were significantly lower with LNG13.5-IUD versus Cu380-IUD. Adverse events were those expected. CONCLUSIONS: LNG13.5-IUD is associated with a significant reduction in blood loss and dysmenorrhea compared with Cu380-IUD. IMPLICATIONS: Women eligible for a levonorgestrel 13.5 mg intrauterine device (IUD) or a copper 380 mm2 IUD should be informed of the differences in bleeding profiles-one of the main causes for IUD discontinuation-so they can compare this information against their bleeding expectations.

The effectiveness of desogestrel for endometrial protection in women with abnormal uterine bleeding-ovulatory dysfunction: a non-inferiority randomized controlled trial.

Women with chronic abnormal uterine bleeding-ovulatory dysfunction (AUB-O) are at increased risk of endometrial neoplasia. We conducted a non-inferiority randomized controlled trial to determine the effectiveness of two cyclic-progestin regimens orally administered 10 d/month for 6 months on endometrial protection and menstruation normalization in women with AUB-O. There were 104 premenopausal women with AUB-O randomized to desogestrel (DSG 150 µg/d, n = 50) or medroxyprogesterone acetate (MPA 10 mg/d, n = 54) group. Both groups were comparable in age (44.8 ± 5.7 vs. 42.5 ± 7.1 years), body mass index (24.8 ± 4.7 vs. 24.9 ± 4.7 kg/m2), and AUB characteristics (100% irregular periods). The primary outcome was endometrial response rate (the proportion of patients having complete pseudodecidualization in endometrial biopsies during treatment cycle-1). The secondary outcome was clinical response rate (the proportion of progestin withdrawal bleeding episodes with acceptable bleeding characteristics during treatment cycle-2 to cycle-6). DSG was not inferior to MPA regarding the endometrial protection (endometrial response rate of 78.0% vs. 70.4%, 95% CI of difference - 9.1-24.4%, non-inferiority limit of - 10%), but it was less effective regarding the menstruation normalization (acceptable bleeding rate of 90.0% vs 96.6%, P = 0.016).Clinical trial registration: ClinicalTrials.gov (NCT02103764, date of approval 18 Feb 2014).

Post-treatment anti-Mullerian hormone (AMH) levels predict long-term ovarian dysfunction in women with hematological malignancies.

Fertility is a concern in young female survivors of hematological malignancies. We evaluated post-treatment ovarian function in patients by measuring anti-Müllerian hormone (AMH) and conventional hormone levels to correlate with menstruation and fertility.The prospective cohort study included 29 reproductive-aged women diagnosed with Hodgkin lymphoma (n = 11), non-Hodgkin lymphoma (n = 9) or acute myeloid leukemia (n = 9). Hormone assays were measured after treatment was completed and compared to age-matched healthy controls. Menstrual changes and postmenopausal symptoms were assessed annually.Serum AMH levels were significantly lower compared to controls at 12 months after treatment [1.0 (0.18-1.8) vs. 2.2 (1.8-4.8) ng/mL; P < .001). At 12 months, FSH and LH levels were significantly higher compared to controls. The interruption of menstrual cycles was observed in 80% (22/27) of patients. Normal menstruation returned at a median of 1.5 months after cessation of treatment in 71% of patients, while 29% of patients had persistent amenorrhea. Low AMH levels at 12 months after therapy (<1 ng/mL) correlated more strongly with abnormal menstrual cycles than normal AMH levels (46% vs. 0%, P = .04). Four patients with low AMH consulted an infertility clinic.In summary, low serum AMH at 12 months after chemotherapy was associated with persistent menstrual abnormalities.

An endocrine perspective on menstrual suppression for adolescents: achieving good suppression while optimizing bone health.

Suppression of menstruation and/or ovarian function in adolescent girls may be desired for a variety of reasons. Numerous medical options exist. The choice of the appropriate modality for an individual patient depends on several factors based on differences in the efficacy of achieving menstrual suppression as well as in their side effect profiles. Adolescence is also a period of bone mass accrual in girls, and several of these modalities may negatively influence peak bone mass. This review focuses on the efficacy of achieving menstrual suppression and the effect on bone health of the various options through an overview of the current literature and also highlights areas in need of further research.

Five-year changes in ovarian function restoration in premenopausal patients with breast cancer taking tamoxifen after chemotherapy: An ASTRRA study report.

BACKGROUND: Adding ovarian function suppression (OFS) after chemotherapy improves survival in young women with moderate- and high-risk breast cancer. Assessment of ovarian function restoration after chemotherapy becomes critical for subsequent endocrine treatment and addressing fertility issues. PATIENTS AND METHODS: In the adding OFS after chemotherapy trial, patients who resumed ovarian function up to 2 years after chemotherapy were randomised to receive either 5 years of tamoxifen or adding 2 years of OFS with tamoxifen. Ovarian function was evaluated from enrolment to randomisation, and patients who did not randomise because of amenorrhoea for 2 years received tamoxifen and were followed up for 5 years. Prospectively collected consecutive hormone levels (proportion of patients with premenopausal follicle-stimulating hormone [FSH] levels <30 mIU/mL and oestradiol [E2] levels ≥40 pg/mL) and history of menstruation were available for 1067 patients with breast cancer. RESULTS: Over 5 years of tamoxifen treatment, 69% of patients resumed menstruation and 98% and 74% of patients satisfied predefined ovarian function restoration as per serum FSH and E2 levels, respectively. Menstruation was restored in 91% of patients younger than 35 years at baseline, but in only 33% of 45-year-old patients over 5 years. Among these patients, 41% experienced menstruation restoration within 2 years after chemotherapy and 28% slowly restored menstruation after 2-5 years. Younger age (<35 years) at baseline, anthracycline without taxanes and ≤90 days of chemotherapy were predictors of menstruation restoration. CONCLUSIONS: During 5 years of tamoxifen treatment after chemotherapy, two-thirds of the patients experienced menstruation restoration, especially patients younger than 35 years. Young age, Adriamycin without taxanes and short duration of chemotherapy appeared to have a positive effect on ovarian reserves in the long term. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT00912548.

Does menstruation-related headache occur exclusively in women with migraine?

To determine the relation between headache and menstruation in women with migraine and the use of estrogen by these women. This was a prospective, cross-sectional, observational study with group comparison, using non-random sample and convenience. We interviewed 79 women diagnosed with migraine or tension-type headache (TTH), according to the ICHD-3, regarding the relation between headache and menstruation. Of the 79 women with headache, 60 (76%) had migraine and 19 (24%) had episodic TTH. The most frequent subtype of migraine was without aura (54/60, 90%). The age ranged from 18 to 42 years, with an average of 22.6 ± 4.1 years. Migraine affected women aged 22.4 ± 3.6 years, whereas in TTH, the age was 23.0 ± 5.4 years. Menstruation-related headache occurred in 41.9% of women with migraine and in only 6.3% of those with TTH. These differences were significant (χ2 = 5.2; p = 0.022). Of the five women diagnosed with migraine with aura, two used estrogen. Menstruation-related headache predominates in women with migraine and often women with migraine with aura use estrogen.

Options for Prevention and Management of Menstrual Bleeding in Adolescent Patients Undergoing Cancer Treatment: ACOG Committee Opinion, Number 817.

ABSTRACT: Obstetrician-gynecologists frequently are consulted either before the initiation of cancer treatment to request menstrual suppression or during an episode of severe heavy bleeding to stop bleeding emergently. Adolescents presenting emergently with severe uterine bleeding usually require only medical management; surgical management rarely is required. Surgical management should be considered for patients who are not clinically stable, or for those whose conditions are not suitable for medical management or have failed to respond appropriately to medical management. When used continuously, combined hormonal contraceptives are effective for producing amenorrhea, although complete amenorrhea cannot be guaranteed. The risk of venous thromboembolism in patients with cancer is compounded by multiple factors, including presence of metastatic or fast-growing, biologically aggressive cancers; hematologic cancers; treatment-related factors such as surgery or central venous catheters; and the number and type of comorbid conditions. Although as a group, patients undergoing cancer treatment are at elevated risk of venous thromboembolism compared with the general population, this risk may be extremely elevated for certain patients and existing guidance on risk stratification should be consulted. The decision to use estrogen in patients with cancer should be tailored to the individual patient after collaborative consideration of the risk-benefit ratio with the patient and the health care team; the patient should be closely monitored for known adverse effects such as liver toxicity and venous thromboembolism.

Predicting menstrual bleeding patterns with levonorgestrel-releasing intrauterine systems.

PURPOSE: To develop a bleeding-pattern prediction model to inform counselling on amount and regularity of bleeding after levonorgestrel-releasing intrauterine system (LNG-IUS) placement. MATERIALS AND METHODS: Fixed-cluster and regression-tree models were developed using bleeding data pooled from two clinical trials of LNG-IUSs. Models were trained and cross-validated on LNG-IUS 12 data, then applied to LNG-IUS 20 and LNG-IUS 8 data. Three clusters were generated for the fixed-cluster model: predominantly amenorrhoea; predominantly spotting; and predominantly bleeding. A random-forest model predicted the future-bleeding cluster, then the probability of cycle regularity was calculated. In the regression-tree model, women were assigned by the model to less- or more-bleeding groups. RESULTS: With LNG-IUS 12 (n = 1351) in the fixed-cluster model, 70.4% of women were correctly classified. The correct classification rates for LNG-IUS 20 (n = 216) and LNG-IUS 8 (n = 1300) were 72.2% and 69.0%. The probability distribution for cycle regularity showed regular and irregular bleeding were best separated with LNG-IUS 12 data, and less well with LNG-IUS 20 and LNG-IUS 8 data. In the regression-tree model there was high variability in the more- and less-bleeding group distributions with LNG-IUS 12 data. CONCLUSIONS: A fixed-cluster model predicted bleeding patterns better than a regression-tree model in women using LNG-IUS, yielding understandable, informative output.

Progestogens or progestogen-releasing intrauterine systems for uterine fibroids (other than preoperative medical therapy).

BACKGROUND: Uterine fibroids can cause heavy menstrual bleeding. Medical treatments are considered to preserve fertility. It is unclear whether progestogens or progestogen-releasing intrauterine systems can reduce fibroid-related symptoms. This is the first update of a Cochrane Review published in 2013. OBJECTIVES: To determine the effectiveness of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. SEARCH METHODS: We searched the Cochrane Gynaecology and Fertility Group Specialised Register, CENTRAL, MEDLINE, Embase, and PsycINFO databases to July 2020. We also searched trials registers for ongoing and registered trials, and checked references of relevant trials. SELECTION CRITERIA: All identified published or unpublished randomised controlled trials (RCTs) assessing the effect of progestogens or progestogen-releasing intrauterine systems in treating premenopausal women with uterine fibroids. DATA COLLECTION AND ANALYSIS: Two authors independently extracted data, assessed risk of bias, and assessed the quality of the evidence using the GRADE approach. MAIN RESULTS: This updated review included four studies with 221 women with uterine fibroids. The evidence was very low quality, downgraded for serious risk of bias, due to poor reporting of study methods, and serious imprecision. Levonorgestrel-releasing intrauterine device (LNG-IUS) versus hysterectomy There was no information on the outcomes of interest, including adverse events. LNG-IUS versus low dose combined oral contraceptive (COC) At 12 months, we are uncertain whether LNG-IUS reduced the percentage of abnormal uterine bleeding, measured with the alkaline hematin test (mean difference (MD) 77.50%, 95% confidence interval (CI) 70.44 to 84.56; 1 RCT, 44 women; very low-quality evidence), or the pictorial blood assessment chart (PBAC; MD 34.50%, 95% CI 11.59 to 57.41; 1 RCT, 44 women; very low-quality evidence); increased haemoglobin levels (MD 1.50 g/dL, 95% CI 0.85 to 2.15; 1 RCT, 44 women; very low-quality evidence), or reduced fibroid size more than COC (MD 1.90%, 95% CI -12.24 to 16.04; 1 RCT, 44 women; very low-quality evidence). The study did not measure adverse events. LNG-IUS versus oral progestogen (norethisterone acetate (NETA)) Compared to NETA, we are uncertain whether LNG-IUS reduced abnormal uterine bleeding more from baseline to six months (visual bleeding score; MD 23.75 points, 95% CI 1.26 to 46.24; 1 RCT, 45 women; very low-quality evidence); increased the percentage of change in haemoglobin from baseline to three months (MD 4.53%, 95% CI 1.46 to 7.60; 1 RCT, 48 women; very low-quality evidence), or from baseline to six months (MD 10.14%, 95% CI 5.57 to 14.71; 1 RCT, 45 women; very low-quality evidence). The study did not measure fibroid size. Spotting (adverse event) was more likely to be reported by women with the LNG-IUS (64.3%) than by those taking NETA (30%; 1 RCT, 45 women; very low-quality evidence). Oral progestogen (dienogest, desogestrel) versus goserelin acetate Compared to goserelin acetate, we are uncertain whether abnormal uterine bleeding was reduced at 12 weeks with dienogest (PBAC; MD 216.00 points, 95% CI 149.35 to 282.65; 1 RCT, 14 women; very low-quality evidence) or desogestrel (PBAC; MD 78.00 points, 95% CI 28.94 to 127.06; 1 RCT, 16 women; very low-quality evidence). Vasomotor symptoms (adverse events, e.g. hot flashes) are only associated with goserelin acetate (55%), not with dienogest (1 RCT, 14 women; very low-quality evidence) or with desogestrel (1 RCT, 16 women; very low-quality evidence). The study did not report fibroid size. AUTHORS' CONCLUSIONS: Because of very low-quality evidence, we are uncertain whether the LNG-IUS reduces abnormal uterine bleeding or increases haemoglobin levels in premenopausal women with uterine fibroids, compared to COC or norethisterone acetate. There was insufficient evidence to determine whether the LNG-IUS reduces the size of uterine fibroids compared to COC. We are uncertain whether oral progestogens reduce abnormal uterine bleeding as effectively as goserelin acetate, but women reported fewer adverse events, such as hot flashes.

Relugolix for the treatment of uterine fibroids.

INTRODUCTION: Uterine fibroids (UF) are benign tumors common in premenopausal women, with strong impact on the health-care systems. For many years, surgery represented the only therapy for symptomatic fibroids. However, clinicians are observing a switch from surgery to noninvasive methods; in particular, medical treatment has been shown to be efficacious in obtaining a bleeding reduction and in ameliorating patient conditions. AREAS COVERED: The authors review the current options available for the treatment of women with UF, with a special focus on the newest one, relugolix. It is an orally active non-peptide Gonadotropin-releasing hormone (GnRH)-receptor antagonist recently licensed for women with symptomatic fibroids. Relugolix is a well-tolerated safe drug; it is effective in inducing a dose-dependent decrease in menstrual blood loss, with faster reduction of heavy menstrual bleeding (HMB) and a greater shrinkage in fibroid volume compared to the current standard of GnRH agonist treatment. EXPERT OPINION: Relugolix is a promising drug for the non-surgical treatment of women with UF. To date, the only published data come from a well-selected Japanese female population study while results from worldwide ongoing studies are ongoing in order to confirm the efficacy of this GnRH agonist receptor.

The impact of menstruation persistence or recovery after chemotherapy on survival in young patients with hormone receptor negative breast cancer.

INTRODUCTION: Hormone replacement therapy can diminish hormone depletion-related complaints in postmenopausal women, but is contraindicated for postmenopausal breast cancer (BC) patients. Recovery of menstruation after chemotherapy-induced amenorrhea in young hormone receptor-negative BC patients however, is accepted. To determine the safety of this strategy, we investigated the effect of recovery of menstruation on disease-free survival (DFS) and overall survival (OS) in young hormone receptor-negative BC patients treated with (neo)adjuvant chemotherapy. METHODS: We selected 636 patients from a single-center cohort with early stage hormone receptor-negative BC and under the age of 50 years when treated with chemotherapy. Sufficient data on course of menstruation in medical records was retrospectively found for 397 patients, of whom 299 patients (75%) had a recovery of menstruation after chemotherapy. We used Cox proportional hazards models to estimate hazard ratios (HR) for the effect of recovery of menstruation on DFS and OS. RESULTS: Patients with recovery of menstruation after chemotherapy less frequently had lymph node involvement at diagnosis (45% vs 66%, p = 0.001). After a median follow-up of 6.7 years, the adjusted hazard ratios were 1.45 (95% CI: 0.83-2.54) for DFS and 1.19 (95% CI: 0.71-1.98) for OS. CONCLUSION: No significantly increased recurrence risk was found for hormone receptor-negative BC patients with recovery of menstruation after chemotherapy. However, the outcome of the multivariable model is not reassuring and a potentially increased recurrence risk cannot be excluded. The results need to be validated in a larger prospective study for a more definitive answer.