Polysaccharide-fecal microbiota-based colon-targeted self-nanoemulsifying drug delivery system of curcumin for treating polycystic ovarian syndrome.

The gut microbiome is involved in the pathogenesis of many diseases including polycystic ovarian syndrome (PCOS). Modulating the gut microbiome can lead to eubiosis and treatment of various metabolic conditions. However, there is no proper study assessing the delivery of microbial technology for the treatment of such conditions. The present study involves the development of guar gum-pectin-based solid self-nanoemulsifying drug delivery system (S-SNEDDS) containing curcumin (CCM) and fecal microbiota extract (FME) for the treatment of PCOS. The optimized S-SNEDDS containing FME and CCM was prepared by dissolving CCM (25 mg) in an isotropic mixture consisting of Labrafil M 1944 CS, Transcutol P, and Tween-80 and solidified using lactose monohydrate, aerosil-200, guar gum, and pectin (colon-targeted CCM solid self-nanoemulsifying drug delivery system [CCM-CT-S-SNEDDS]). Pharmacokinetic and pharmacodynamic evaluation was carried out on letrozole-induced female Wistar rats. The results of pharmacokinetic studies indicated about 13.11 and 23.48-fold increase in AUC of CCM-loaded colon-targeted S-SNEDDS without FME (CCM-CT-S-SNEDDS (WFME)) and CCM-loaded colon-targeted S-SNEDDS with FME [(CCM-CT-S-SNEDDS (FME)) as compared to unprocessed CCM. The pharmacodynamic study indicated excellent recovery/reversal in the rats treated with CCM-CT-S-SNEDDS low and high dose containing FME (group 13 and group 14) in a dose-dependent manner. The developed formulation showcasing its improved bioavailability, targeted action, and therapeutic activity in ameliorating PCOS can be utilized as an adjuvant therapy for developing a dosage form, scale-up, and technology transfer.

Kuntai Capsule Combined With Letrozole on Gonadal Hormone Levels and Ovarian Function in Patients With PCOS: A Systematic Review and Meta-Analysis.

Background: The efficacy of Kuntai capsule combined with letrozole (LE) in improving ovarian function of polycystic ovary syndrome (PCOS) has been evaluated before, but there is still a lack of evidence-based support for the regulation of sex hormone levels. In recent years, new randomized clinical trials (RCTs) have been reported on the effect of combined therapy on regulating sex hormone levels. Objective: We aimed to systematically evaluate the efficacy of Kuntai capsule combined with LE in the treatment of PCOS. Methods: A search across the China Biomedical Literature Database (CBM), China National Knowledge Infrastructure (CNKI), China Science and Technology Journal Database (VIP), Wanfang database, PubMed, Web of Science, The Cochrane Library, and Embase was conducted on Kuntai capsule combined with LE in the treatment of PCOS. The time of the self-built database was up to April 30, 2021. RCTs of LE in the control group and LE combined with Kuntai capsule in the experimental group were selected. RevMan5.3 software was used for data analysis. Results: A total of 17 studies were gathered, which included 1,684 patients. The meta-analysis results showed that the total effective rate of the combined group was 93.36% and that of the LE group was 78.15%. The improvement in the ovulation rate, pregnancy rate, number of mature follicles, endometrial thickness, cervical mucus score, and serum follicle stimulating hormone (FSH), luteinizing hormone (LH), and prolactin (PRL) in the combined group was consistent with the results of a previous meta-analysis and was better than that in the LE group (p < 0.05). In addition, the combination group was better than the LE group in regulating the levels of estradiol (E2) and testosterone (T) (p < 0.05). There were no adverse drug reactions in the two groups during treatment. Conclusion: As a type of pure traditional Chinese medicine preparation, Kuntai capsule combined with LE had a better effect than LE alone in the treatment of PCOS, with advantages mainly reflected in enhancing ovarian function and regulating the levels of sex hormones in vivo, among others, but the value of combined therapy still needs to be verified by more high-quality RCTs.

ΔKi67 proliferation index as independent predictive and prognostic factor of outcome in luminal breast cancer: data from neoadjuvant letrozole-based treatment.

A key tool for monitoring breast cancer patients under neoadjuvant treatment is the identification of reliable predictive markers. Ki67 has been identified as a prognostic and predictive marker in ER-positive breast cancer. Ninety ER-positive, HER2 negative locally advanced breast cancer patients received letrozole (2.5 mg daily) and cyclophosphamide (50 mg daily) with/without Sorafenib (400 mg/bid daily) for 6 months before undergoing surgery. Ki67 expression and tumor size measured with caliber were determined at baseline, after 30 days of treatment and at the end of treatment. Patients were assigned to a clinical response category according to Response Evaluation Criteria in Solid Tumors, both at 30 days and before surgery and further classified as high-responder and low-responder according to the median variation of Ki67 values between biopsy and 30 days and between biopsy and surgery time. The predictive role of Ki67 and its changes with regard to clinical response and survival was analyzed. No differences in terms of survival outcomes emerged between the arms of treatment, while we observed a higher percentage of women with progression or stable disease in arm with the combination containing Sorafenib (20.5% vs 7.1%, p = 0.06). Clinical complete responders experienced a greater overall variation in Ki67 when compared with partial responders and patients with progressive/stable disease (66.7% vs 30.7%, p = 0.009). High responders showed a better outcome than low responders in terms of both disease-free survival (p = 0.009) and overall survival (p = 0.002). ΔKi67 score evaluated between basal and residual tumor at definitive surgery showed to be highly predictive of clinical complete response, and a potential parameter to be used for predicting disease-free survival and overall survival in luminal breast cancer treated with neoadjuvant endocrine-based therapy.

Effects of the Fertility Drugs Clomiphene Citrate and Letrozole on Kiss-1 Expression in Hypothalamic Kiss-1-Expressing Cell Models.

Clomiphene citrate (CC) and letrozole stimulate the hypothalamic-pituitary-ovarian axis and are used widely as oral fertility drugs to induce folliculogenesis. We examined whether these drugs increase Kiss-1 expression in hypothalamic cell models. We utilized two hypothalamic cell models, mHypoA-50 and mHypoA-55, which originated from Kiss-1 neurons in the anteroventral periventricular (AVPV) nucleus and arcuate (ARC) nucleus of the mouse hypothalamus, respectively. The cells were stimulated with CC or letrozole, after which Kiss-1 mRNA expression was determined. CC stimulated Kiss-1 gene expression in mHypoA-50 and mHypoA-55 cells. The basal expression of Kiss-1 was significantly increased in the presence of estradiol (E2) in mHypoA-50 cells, and the CC-induced increase in Kiss-1 expression was not observed in the presence of E2 in these cells. In contrast, E2 did not modify the basal expression of Kiss-1 in mHypoA-55 cells, and CC-induced Kiss-1 expression was still observed in the presence of E2. The significant increase in Kiss-1 gene expression in mHypoA-50 and mHypoA-55 cells was blunted in the presence of estrogen receptor antagonists. Aromatase was expressed in mHypoA-50 and mHypoA-55 cells. Letrozole, an aromatase inhibitor, increased Kiss-1 expression in mHypoA-55 ARC cells but not in mHypoA-50 AVPV cells. Although the basal expression of Kiss-1 was increased by E2, letrozole did not modulate Kiss-1 expression in mHypoA-50 cells. Letrozole-induced Kiss-1 gene expression in mHypoA-55 cells was not modulated in the presence of E2. The fertility drugs CC and letrozole modulated Kiss-1 expression in hypothalamic cell models.

Use of letrozole after aromatase inhibitor-based therapy in postmenopausal breast cancer (NRG Oncology/NSABP B-42): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: The optimal duration of extended therapy with aromatase inhibitors in patients with postmenopausal breast cancer is unknown. In the NSABP B-42 study, we aimed to determine whether extended letrozole treatment improves disease-free survival after 5 years of aromatase inhibitor-based therapy in women with postmenopausal breast cancer. METHODS: This randomised, double-blind, placebo-controlled, phase 3 trial was done in 158 centres in the USA, Canada, and Ireland. Postmenopausal women with stage I-IIIA hormone receptor-positive breast cancer, who were disease-free after about 5 years of treatment with an aromatase inhibitor or tamoxifen followed by an aromatase inhibitor, were randomly assigned (1:1) to receive 5 years of letrozole (2·5 mg orally per day) or placebo. Randomisation was stratified by pathological node status, previous tamoxifen use, and lowest bone mineral density T score in the lumbosacral spine, total hip, or femoral neck. The primary endpoint was disease-free survival, defined as time from randomisation to breast cancer recurrence, second primary malignancy, or death, and was analysed by intention to treat. To adjust for previous interim analyses, the two-sided statistical significance level for disease-free survival was set at 0·0418. This study is registered with ClinicalTrials.gov, number NCT00382070, is active, and is no longer enrolling patients. FINDINGS: Between Sept 28, 2006, and Jan 6, 2010, 3966 patients were randomly assigned to receive letrozole (n=1983) or placebo (n=1983). Follow-up information was available for 3903 patients for the analyses of disease-free survival. Median follow-up was 6·9 years (IQR 6·1-7·5). Letrozole treatment did not significantly improve disease-free survival (339 disease-free survival events were reported in the placebo group and 292 disease-free survival events were reported in the letrozole group; hazard ratio 0·85, 95% CI 0·73-0·999; p=0·048). 7-year disease-free survival estimate was 81·3% (95% CI 79·3-83·1) in the placebo group and 84·7% (82·9-86·4) in the letrozole group. The most common grade 3 adverse events were arthralgia (47 [2%] of 1933 patients in the placebo group vs 50 [3%] of 1941 patients in the letrozole group) and back pain (44 [2%] vs 38 [2%]). The most common grade 4 adverse event in the placebo group was thromboembolic event (eight [<1%]) and the most common grade 4 adverse events in the letrozole group were urinary tract infection, hypokalaemia, and left ventricular systolic dysfunction (four [<1%] each). INTERPRETATION: After 5 years of aromatase inhibitor-based therapy, 5 years of letrozole therapy did not significantly prolong disease-free survival compared with placebo. Careful assessment of potential risks and benefits is required before recommending extended letrozole therapy to patients with early-stage breast cancer. FUNDING: National Cancer Institute, Korea Health Technology R&D Project, Novartis.

A randomized controlled trial comparing lifestyle intervention to letrozole for ovulation in women with polycystic ovary syndrome: a study protocol.

BACKGROUND: Polycystic ovary syndrome (PCOS) affects between 8 and 18% of women and is the leading cause of female anovulatory infertility. Unfortunately, common treatments for women trying to conceive can be ineffective as well as disruptive or harmful to patients' quality of life. Despite evidence that women with PCOS have expressed the need for alternative fertility treatments, lifestyle interventions incorporating a nutritional plan with supplementation, increased physical activity, and techniques for stress management have not been combined as a program and studied in this population. Literature suggests that each of these individual components can positively influence reproductive hormones and metabolic health. METHODS/DESIGN: This is a randomized controlled trial which will include 240 women diagnosed with PCOS, according to the Rotterdam criteria, who are trying to conceive. Participants will be randomized to either a comprehensive lifestyle intervention program or prescribed an oral fertility medication, letrozole. These two groups will be further randomized to consume either myo-inositol or a placebo. Participants will be between the ages of 18 and 37 years. Exclusion criteria include women who have already begun fertility treatment, who are currently using myo-inositol or have taken it within the past 3 months, or who are being treated for, or have a history of, an eating disorder. The primary outcome will be the ovulation rate, the secondary outcome will be conception. Other outcomes include miscarriage rates, validated rating measures of overall quality of life (including social, relational, mind/body and emotional sub-categories) and mental health scores (depression, anxiety, and stress). DISCUSSION: This trial will determine the effectiveness of a structured lifestyle-based comprehensive intervention program for women with PCOS experiencing infertility. In addition, it will determine whether supplementing with myo-inositol provides any further benefit. The objective of this study is to assess a possible non-pharmacological solution to ovulatory dysfunction in these patients and perhaps improve other associated features of PCOS. TRIAL REGISTRATION: ClinicalTrials.gov, ID: NCT02630485 . Registered on 15 December 2015.