Search

Highlights • Surveillance for women with medically inoperable, stage I endometrial cancer (EC) depends on the management strategy. • Uterine sampling may be omitted for asymptomatic women with medically inoperative Stage I EC treated with radiation. • Endometrial sampling effectively detects recurrence among medically inoperable EC patients treated with progestin therapy. • Patient adherence to follow-up should be considered when recommending treatment for clinical stage I EC., It is unclear if surveillance for postmenopausal women with medically inoperable stage 1 endometrial cancer (EC) should differ depending on their management strategy. Thus, we investigated the utility of surveillance endometrial sampling among 53 postmenopausal women with medically inoperable, clinical stage I, grade 1 endometrioid EC who received either progestin therapy or radiation between 2009 and 2018, at a single academic institution. Frequency and results of endometrial sampling, as well as recurrence and survival rates were studied. Of 53 patients, 18 (34.0%) received progestin therapy and 35 (66.0%) radiation. Medically managed patients were treated with megestrol acetate (27.7%), a levonorgestrel intrauterine device (27.7%), or both (44.4%). Radiated patients were mostly treated with high-dose rate brachytherapy only (77.1%). Surveillance endometrial sampling (median procedures = 4, range 1–10) was strictly adhered to among all patients who received progestin therapy, but infrequently (6/35, 17.1%) performed among radiated patients, yielding no positive results. Three recurrences occurred over the median follow-up of 38 months. Two (11%) women in the progestin therapy group recurred locally and were diagnosed by endometrial sampling. One (3%) patient in the radiation group recurred distally in the lung 25.3 months after completing brachytherapy. We conclude that appropriate surveillance for women with medically inoperable, clinical stage I, grade 1 EC depends on the management strategy. For those treated with progestins, surveillance with endometrial sampling every 3–6 months can reveal local recurrence. However, given the excellent local control after radiation, endometrial sampling may not be warranted for women treated with definitive radiation.

PURPOSE: Megestrol acetate is a synthetic progestogen used to treat some cancers and cancer-associated cachexia, but its potential interactions with other drugs are not well known. This study aims to determine the regulation of drug metabolizing enzymes by megestrol acetate. METHODS: Primary human hepatocytes were treated and analyzed by PCR array to identify genes involved in drug metabolism that are impacted by megestrol acetate. P450 3A4 (CYP3A4) reporter gene assay and HPLC analyses of nifedipine metabolites were used to determine CYP3A4 gene expression and activities. Competitive ligand binding assay was used to determine the affinity of megestrol acetate toward human pregnane x receptor (hPXR). Electrophoretic mobility shift assay and mammalian two hybrid assay were used to determine the mechanism of megestrol to activate hPXR. RESULTS: The levels and activities of CYP3A4 were significantly induced (> 4-folds) by megestrol acetate in human hepatocytes and HepG2 cells. Megestrol treatment induced CYP3A4 through the activation of hPXR, a ligand-activated transcription factor that plays a role in drug metabolism and transport. Other tested nuclear receptors showed no response. The mechanism studies showed that megestrol activated hPXR by binding to the ligand binding domain (LBD) of hPXR and increasing the recruitment of the cofactors such as steroid receptor cofactor (SRC-1). CONCLUSION: The results suggest that megestrol acetate is a specific inducer of CYP3A4 mediated by hPXR and therefore has the potential to cause drug interactions, especially in the co-administration with drugs that are substrates of CYP3A4.

Objective. To study the clinical efficacy of integrated traditional Chinese medicine (TCM) and Western medicine (WM) in treating endometrial cancer and the influence on ultrasound, magnetic resonance imaging (MRI), tumor markers, human epididymis protein 4 (HE4) and carbohydrate antigen 125 (CA125). Method. A total of 152 cases of patients with endometrial carcinoma were randomly divided into two groups: the TCM + WM group and the WM group. The WM group was treated with megestrol acetate tablets, and the TCM + WM group was treated with Radix Astragali injection on the basis of the control group. The levels of inflammatory factors, HE4 and CA125 in serum, were detected using enzyme-linked immunosorbent assay (ELISA) or radioimmunoassay. The characteristics of ultrasound images and MRI images were observed and recorded. Toxicity, side effects, and the 3-year cumulative survival rate after treatment were assessed. Results. After treatment, the levels of interleukin-4 (IL-4), tumor necrosis factor-alpha (TNF-α), and high-sensitivity C-reactive protein (hs-CRP) in both groups decreased, and the decrease in the TCM + WM group was more obvious than that in the WM group. There were statistically significant differences between the two groups in lesion shape, boundary, blood flow signal, lesion diameter, resistance index (RI), echo, intima thickness, and muscle layer infiltration from transvaginal ultrasound images after treatment. The diameter, echo, boundary, shape, composition, and enhancement degree of lesions between the two groups have a significant difference. Moreover, the levels of serum HE4 and CA125 in both groups decreased after treatment, and the decrease in the TCM + WM group was more obvious than that in the WM group. There were statistically significant differences between the two groups in the occurrence of myelosuppression, abnormal liver function, decreased platelet number, gastrointestinal reactions, leukopenia, and cardiotoxicity. After three years of follow-up, the cumulative survival rate of the TCM + WM group was 76.32%, and the cumulative survival rate of the WM group was 57.89%. Conclusion. Radix Astragali injection combined with megestrol acetate tablets has obvious therapeutic effects against endometrial cancer. Through vaginal ultrasonography and MRI, it can significantly improve the size, shape, and blood flow signals of patients’ lesions, reduce the level of serum inflammatory factors and tumor markers HE4 and CA125, reduce the incidence of toxic and side reactions, improve the patient’s immunity, improve the patient’s condition significantly, and prolong the survival time of patients.

Introduction Primary surgery is effective in low-risk endometrial cancer (EC). However, in young women, this approach compromises fertility. Therefore, fertility-sparing management in the case of atypical endometrial hyperplasia, or grade 1 EC limited to the endometrium can be considered. Evidence acquisition We performed a literature review to identify studies involving women with EC or atypical hyperplasia who underwent fertility-sparing management. We conducted multiple bibliographic databases research from their inception to May 2020. Evidence synthesis Oral therapy with medroxyprogesterone acetate and megestrol acetate is recommended based on extensive experience, although without consensus on dosages and treatment length. The pooled complete response rate, recurrence rate, and pregnancy rate of EC were 76.3%, 30.7% and 52.1%, respectively. Endometrial hyperplasia was associated with better outcomes. LNG-IUSs appears an alternative treatment, particularly in patients who do not tolerate oral therapy. In a randomized controlled trial, megestrol acetate plus metformin guaranteed an earlier complete response rate than megestrol acetate alone for endometrial hyperplasia. Hysteroscopic resection followed by progestogens is associated with a higher complete response rate, live birth rate, and lower recurrence rate than oral progestogens alone. Pooled complete response, recurrence, and live birth rates were 98.1%, 4.8% and 52.6%. Conclusions Fertility preservation appears feasible in young patients with grade 1 EC limited to the endometrium or atypical endometrial hyperplasia. Progestins are the mainstay of such management. The addition of Metformin and hysteroscopic resection seems to provide some improvements. However, fertility preservation is not the standard approach for staging and treatment, potentially worsening oncologic outcomes.

Anorexia and cachexia are major clinical problems seen in a large proportion of patients with advanced cancer. Weight loss has also been identified as an indicator of poor prognosis in cancer patients. Around 20% of patients with advanced cancer present mortality from the effects of malnutrition rather than from cancer itself. Early nutrition intervention has seen to improve outcomes in cancer patients such as weight gain, treatment tolerance, and improved quality of life (QoL). Effective therapies for addressing these threatening conditions are lacking. Pharmacotherapeutic agents such as corticosteroids, megestrol acetate, and cyproheptadine have several adverse reactions and also lack satisfactory results. Rasayana therapy is known to prevent loss of body mass and at the same time help to improve appetite and increase patient's QoL. The Rasayana compound used by us to prevent cachexia mainly includes swarna sindoor, Hirak bhasma, and suvarna bhasma. To evaluate benefits of Rasayana therapy on these variables, we maintain complete documentation of different clinical variables in all cancer patients. Here, in this observational study, we analyzed the data collected from a group of stage IV breast cancer patients (n = 30) receiving Rasayana therapy. Patients were followed at an interval of every 15 days from baseline for 3 months. Furthermore, at each visit, there weight was recorded on calibrated digital weight balance. QoL in these patients was recorded at quarterly interval using functional assessment of cancer therapies questionnaire. It was seen that in the duration of 3 months patients appetite increased significantly (P = 0.03). Significant weight gain was seen in patients (P = 0.04). Significant improvement was also seen in QoL especially related to QoL subdomains of physical wellbeing (P = 0.01), emotional wellbeing (P < 0.04), and functional wellbeing (P < 0.001). Rasayana therapy was seen to be well tolerated by all patients.

Introduction/Background Endometrial cancer (EC) is the most commonly diagnosed gynecological malignancy in the developed countries. Obesity, diabetes mellitus and infertility are some of the contributory factors. Some patients with EC wish to preserve their fertility or others have several comorbidities that contraindicate surgery. These groups of patients could benefit from a conservative treatment strategy such as the use of metformin. This agent is an option in women with increased EC risk as well as in those with atypical endometrial hyperplasia. Methodology We evaluated the protective effects of metformin in EC patients, its preventive role in breast cancer and obese patients and its effectiveness, safety and efficacy in addition to progesterone monotherapy in treatment of fertility sparing candidates. We reviewed the literature and then conducted a meta-analysis of the relevant parameters. A total of 6 studies was included in the meta-analysis. Results Comparing the pre-surgical treatment with metformin versus placebo, meta-analysis of mean difference in Ki-67 after treatment among two groups, revealed no difference (MD -7.10, 95% CI -23.31 to 9.11, p=0.39). Meta-analysis of fertility sparing EC management with a combination of megestrol acetate (MA) and metformin (500 mg three times a day) in comparison with monotherapy with 160 mg daily MA revealed no difference in either complete response or partial response rates (166 patients OR 2.94, 95% CI 0.85 to 10.15, p=0.09 and 166 patients OR 0.76, 95% CI 0.34 to 1.66, p=0.49, respectively). Regarding breast cancer survivors under tamoxifen, metformin was related with significantly reduced median endometrial thickness after 52 weeks of evaluation when compared to women in placebo group (2.3 mm vs 3.0 mm, p=0.05). Conclusion Metformin neither was found to have a preventative role against the development of endometrial cancer nor a beneficial one in addition to the progesterone monotherapy for EC fertility sparing candidates. However, metformin was found to be protective in breast cancer survivors under tamoxifen. Disclosures Nothing to disclose.

Simple Summary Endometrial cancer is the most common malignancy of the female genital tract, and in 14% of cases, is diagnosed in premenopausal women, While, the cancer appears in 5% in women of childbearing age. Preserving fertility in these women should be the goal of cancer practice. The aim of our study is to describe pregnancy outcomes of our center in women with G1 endometrial endometrioid cancer and atypical endometrial hyperplasia/endometrial intraepithelial neoplasm undergone conservative treatment. Moreover, for the first time, obstetric and oncological outcomes are described in a long follow up, including women with minimal myometrial infiltration. Abstract Endometrial cancer (EC) is the fourth largest female cancer in Europe and North America. In 5% of cases, the diagnosis is made in women who wish to become pregnant. In our retrospective study, we reported our experience about fertility sparing treatment of G1 endometrioid endometrial cancer (G1 EEC) or atypical endometrial hyperplasia/endometrial intraepithelial neoplasm (AEH/EIN) in young women desiring pregnancy treated in our Center. Conservative treatment was based on operative hysteroscopy and hormone therapy with megestrol acetate (160 mg/die for 9 months). For the first time we included women with G1 EEC with minimal myometrial infiltration. The minimum follow-up period was two years and consisted of serial outpatient hysteroscopies with endometrial biopsies. Among the 36 women with G1 EEC we observed one case of disease persistence and four recurrences and four recurrences among the 46 women diagnosed with AEH/EIN. To date, 35 live births were obtained in both groups. Our results advance the hypothesis that conservative treatment can represent a safe and feasible alternative to propose to young women with desire for pregnancy. Further randomized and multicentric studies are needed to arrive at unambiguous and standardized guidelines on the surgical and medical treatment of young women with EEC or AEH/EIN.

Purpose To explore the clinical outcomes of megestrol acetate alone or plus metformin in young women with grade 2 stage IA endometrial carcinoma who ask for preserved fertility. Methods Patients with stage IA grade 2 endometrial carcinoma who asked for fertility-sparing treatment in the Obstetrics and Gynecology Hospital of Fudan University between 2015 and 2017 were enrolled and retrospectively reviewed. Results Four patients were included and treated with oral megestrol acetate (160 mg per day), while metformin (500 mg, thrice daily) was added for patients with metabolic syndrome. Regular hysteroscopic examination was performed every 3 months during the conservative treatment. Overall, 75% (3/4) of the patients had a complete response, one relapsed and achieved a complete response after changing the therapy plan, and one patient had an indication of myometrial invasion during fertility-sparing treatment and chose to remove uterus. Conclusions Fertility-sparing treatment for stage IA grade 2 endometrial carcinoma patients is worth exploration. Megestrol acetate with or without metformin combined with hysteroscopic lesion ablation may be an effective therapy.

We aimed to investigate the effectiveness of continuing medical therapy in patients who did not achieve complete response (CR) despite 9 months of progestin treatment. We also sought to determine the prognostic factors associated with achieving CR among these patients.We retrospectively analyzed 51 patients with presumed stage IA, grade 1 or 2 endometrioid adenocarcinoma who had persistent disease on biopsy performed at 9-12 months after at least 9 months of progestin-based therapy. Data on clinicopathological factors and oncological and obstetrical outcomes following continuous hormonal treatment were extracted from the patients' medical records and analyzed. Univariate and multivariate analyses for predicting CR were performed.Thirty-seven (72.5%) of 51 patients achieved CR after prolonged fertility-sparing treatment. Median time to CR from starting initial progestin was 17.3 months (range, 12.1-91.7 months). On univariate analysis, history of polycystic ovarian syndrome, histologic grade 2, and not achieving partial response (PR) until 12 months were significantly associated with failure to CR (odds ratio [OR], 6.188, 95% confidence interval [CI], 1.405-27.244, p = 0.018; OR, 9.722, 95% CI, 1.614-58.581, p = 0.013; and OR, 21.750, 95% CI, 4.016-117.783, p 0.001, respectively). Multivariate analysis revealed that not achieving PR until 12 months was an independent prognostic factor predicting failure to CR after prolonged progestin therapy (OR, 21.803, 95% CI, 3.601-132.025, p = 0.001).Continued medical treatment is effective for persistent early endometrial carcinoma after at least 9 months of progestin therapy in young women who want to preserve their fertility.

AimsRandomised controlled trials (RCTs) demonstrated benefits of pharmacological interventions for cachexia in improving weight and appetite. However, comparative efficacy and safety are not available. We conducted a systematic review and network meta-analysis (NMA) to evaluate the relative efficacy and safety of pharmacological interventions for cachexia.MethodsPubMed, EmBase, Cochrane, and ClinicalTrials.gov were searched for RCTs until October 2019. Key outcomes were total body weight (TBW) improvement, appetite (APP) score and serious adverse events. Two reviewers independently extracted data and assessed risk of bias. NMA was performed to estimate weight gain and APP score increase at 8 weeks, presented as mean difference (MD) or standardised MD with 95% CI.Results80 RCTs (10 579 patients) with 12 treatments were included. Majority is patients with cancer (7220). Compared with placebo, corticosteroids, high-dose megestrol acetate combination (Megace_H_Com) (≥400 mg/day), medroxyprogesterone, high-dose megestrol acetate (Megace_H) (≥400 mg/day), ghrelin mimetic and androgen analogues (Androgen) were significantly associated with MD of TBW of 6.45 (95% CI 2.45 to 10.45), 4.29 (95% CI 2.23 to 6.35), 3.18 (95% CI 0.94 to 5.41), 2.66 (95% CI 1.47 to 3.85), 1.73 (95% CI 0.27 to 3.20) and 1.50 (95% CI 0.56 to 2.44) kg. For appetite improvement, Megace_H_Com, Megace_H and Androgen significantly improved standardised APP score, compared with placebo. There is no significant difference in serious adverse events from all interventions compared with placebo.ConclusionsOur findings suggest that several pharmacological interventions have potential to offer benefits in treatment of cachexia especially Megace_H and short-term use corticosteroids. Nonetheless, high-quality comparative studies to compare safety and efficacy are warranted for better management of cachexia.

Patient: Female, 45-year-old Final Diagnosis: Endometrial cancer Symptoms: Abdominal discomfort • abdominal distension Medication: — Clinical Procedure: Hormone therapy • surgery removal Specialty: Oncology Objective: Rare co-existance of disease or pathology Background: Carcinoma arising from an endometriosis-associated abdominal wall scar is a rare entity, with only a few case reports published in the literature. The management is very controversial due to on its own rarity, and there are no specific guidelines. Treatment with a multidisciplinary team is important to achieve the best outcome. Case Report: We report the case of a 45-year-old woman diagnosed with a growing painless lesion in the right lower quadrant. We decided to perform Tru-Cut biopsy of the abdominal wall lesion, but unfortunately the pathological report was inconclusive at that time. Due to the presence of a highly suspicious lesion, the gynecologic oncologist together with the plastic surgeon and connective tissue surgeon decided to perform a wide resection of the abdominal wall along with hysterectomy and salpingo-oophorectomy. The final pathology report demonstrated endometriosis associated with an endometrioid adenocarcinoma grade II in the abdominal wall tumor. She was restaged with new imaging exams before the definition of the best adjuvant treatment, which showed suspicious bilateral inguinal and right axillary (1.9 cm) lymph nodes, with no other sites of metastatic disease. She was treated with megestrol acetate 160 mg/daily for 8 months, with a partial response. Conclusions: Carcinoma arising from an endometriosis-associated abdominal wall scar is a rare entity, and there are no no specific treatment guidelines. Such patients must be assessed by a multidisciplinary team for decision making. Options for adjuvant and palliative treatment for endometrial cancer are generally used for the treatment of this entity. The main purpose of this article is to report this rare presentation and perform a review of the literature about diagnosis, clinical presentation, treatment, and prognosis.

Ethnopharmacological relevance Astragalus membranaceus (Fisch.) and Bunge and Paeonia japonica (Makino)Miyabe & H.Takeda have been traditionally used to improve the poor quality of life such as weakness, lack of appetite, fatigue, and malaise which is considered with cachexia condition. Aim of the study We investigated anti-cachectic effects of a herbal formula composed of Astragalus membranaceus and Paeonia japonica (APX) and the molecular mechanisms of APX in C26 cancer-induced cachexia mice and TNF-a-treated C2C12 myotubes. Additionally synergistic anti-cachectic effects of APX were compared to those of individual herbal extracts and megestrol acetate. Methods and materials The forty-two BALB/c mice were randomly divided into 6 groups: normal (nontreatment), control (C26 injection), AM (C26 injection with Astragalus membranaceus), PJ (C26 injection with Paeonia japonica), APX (C26 injection with combination of Astragalus membranaceus and Paeonia japonica and MA (C26 injection with megestrol acetate). All mice were orally administered DW (normal and control groups) or 100 mg/kg AM, PJ, APX or MA for 10 days. In the animal model, several tissues were weighed, and muscle tissue and blood were used to measure pro-inflammatory cytokines. C2C12 myotubes were exposed to 100 ng/mL TNF- α with or without 10 μg/mL of AM, PJ, APX or MA for 48 h. The cells were used to immunofluorescence staining and western blot analyses. Results C26 injection induced notable body and muscle weight loss while APX administration significantly attenuated these alterations and the decrease of muscle weights and strength. APX also significantly attenuated the abnormal elevations in the concentration of three muscle atrophy-inducible cytokines; serum and muscle TNF-α,muscle TWEAK and IL-6 in C26 tumor-bearing mice. In the TNF-α-treated C2C12 myotube model, TNF-α treatment notably decreased MyH but activated atrophic proteins (MuRF and Fbx32) along with p38 and NFκB while these molecular alterations were significantly ameliorated by APX treatment. These pharmacological actions of APX were supported by the results of immunofluorescence staining to MyH expression and the translocation of NFκB into the nucleus in C2C12 myotubes. Conclusions Our data indicate the potential of an herbal formula, APX as an anti-cachexia agent; the effect of APX was superior to that of megestrol acetate overall especially for muscle atrophy. The underlying mechanisms of this herbal formula may involve the modulation of muscle atrophy-promoting molecules including p38, NFκB, TNF-α and TWEAK.

This multi-site, double blind, parallel arm, fixed dose, randomised placebo controlled phase III study compared megestrol acetate 480 mg/day with dexamethasone 4 mg/day for their net effects on appetite in people with cancer anorexia. Patients with advanced cancer and anorexia for ≥ 2 weeks with a score ≤ 4 (0–10 numeric rating scale (NRS) 0 = no appetite, 10 = best possible appetite) were recruited. Participants received megestrol 480 mg or dexamethasone 4 mg or placebo daily for up to 4 weeks. Primary outcomes were at day 7. Responders were defined as having a ≥ 25% improvement in NRS over baseline. There were 190 people randomised (megestrol acetate n = 61; dexamethasone n = 67, placebo n = 62). At week 1 (primary endpoint), 79·3% in the megestrol group, 65·5% in the dexamethasone group and 58·5% in the placebo group (p = 0.067) were responders. No differences in performance status or quality of life were reported. Treatment emergent adverse events were frequent (90·4% of participants), and included altered mood and insomnia. Hyperglycemia and deep vein thromboses were more frequent when on dexamethasone than the other two arms. There was no difference in groups between the three arms, with no benefit seen over placebo with anorexia improving in all arms.Trail registration: The trial was registered on 19/08/2008 with the Australian New Zealand Clinical Trials Registry (ACTRN12608000405314).

Introduction: Megestrol acetate (MA) is a synthetic progestin often used for appetite stimulation and weight gain in patients with cachexia related to AIDS, cancer or terminal illness. MA is frequently implicated in development of both glucocorticoid excess and adrenal insufficiency (AI) in a somewhat unpredictable manner. Less commonly reported adverse effects of MA include dysfunction of the hypothalamic pituitary axis. Few cases in literature exist regarding the use of MA in young, healthy patients and the potential clinical severity of pituitary dysfunction in this population. Case : A 24-year-old male was previously healthy but frustrated by an inability to gain muscle mass. Evaluation one-year prior was unrevealing and included a total testosterone of 1100ng/dL (264-916ng/dL). In the interim, he was prescribed MA 625/5mg for 2 months with rapid development of abdominal adiposity, depressed mood, low libido and erectile dysfunction. Repeat evaluation revealed a precipitous drop in total testosterone to 66 ng/dL at which point he self-discontinued MA. He then began to experience palpitations, sweats, poor concentration, and undesirable weight loss along with worsening symptoms of sexual and erectile dysfunction. Three months after MA discontinuation, he appeared well with physical examination and vital signs within normal limits. Surprisingly, repeat studies revealed total testosterone Discussion: MA, by virtue of affinity for glucocorticoid receptors, has the potential to cause hyperglycemia and Cushing’s syndrome. Secondary AI often results from withdrawal of MA however central AI can also occur with active administration by unclear mechanisms. Hypogonadism and hyperprolactinemia are additional under-reported adverse effects of MA with symptoms often masked by AI or elements of chronic illness. In study of men age 60-85 year on MA, a mean percentage change of ACTH -89.5%, LH -49%, TSH -14.7% and Prolactin +150% were seen from baseline after 12 weeks of therapy as was decreased cortisol. Limited data exists in young patients such as ours given limited indications for the agent’s use. Importantly, MA should be prescribed with understanding that weight gain is predominantly adipose rather than muscle mass and that its safety is limited by potential HP axis dysfunction, namely adrenal and gonadal deficiencies.

Objective To assess the efficacy of metformin in megestrol acetate (MA)-based fertility-sparing treatment for patients with atypical endometrial hyperplasia (AEH) and endometrioid endometrial cancer (EEC). Design A randomised, single-centre, open-label, controlled trial conducted between October 2013 and December 2017. Setting Shanghai OBGYN Hospital of Fudan University, China. Population A total of 150 patients (18-45 years old) with primary AEH or well-differentiated EEC were randomised into an MA group (n = 74) and an MA plus metformin group (n = 76). Methods Patients with AEH or EEC were firstly stratified, then randomised to receive MA (160 mg orally, daily) or MA (160 mg orally, daily) plus metformin (500 mg orally, three times a day). Main outcomes and measures The primary efficacy parameter was the cumulate complete response (CR) rate within 16 weeks of treatment (16w-CR rate); the secondary efficacy parameters were 30w-CR rate and adverse events. Results The 16w-CR rate was higher in the metformin plus MA group than in the MA-only group (34.3 versus 20.7%, odds ratio [OR] 2.0, 95% confidence interval [CI] 0.89-4.51, P = 0.09) but the difference was more significant in 102 AEH patients (39.6 versus 20.4%, OR 2.56, 95% CI 1.06-6.21, P = 0.04). This effect of metformin was also significant in non-obese (51.4 versus 24.3%, OR 3.28, 95% CI 1.22-8.84, P = 0.02) and insulin-sensitive (54.8 versus 28.6%, OR 3.04, 95% CI 1.03-8.97, P = 0.04) subgroups of AEH women. No significant result was found in secondary endpoints. Conclusion As a fertility-sparing treatment, metformin plus MA was associated with a higher early CR rate compared with MA alone in AEH patients. Tweetable abstract For AEH patients, metformin plus MA might be a better fertility-sparing treatment to achieve a higher early CR rate compared with MA alone.

Objective In 5-30% of cases, endometrial cancer occurs in women age 45 or younger. A valid option for women desiring fertility is primary hormonal treatment, such as oral megestrol acetate (MA) alone or combined with hysteroscopic resection1, or levonorgestrel-releasing intrauterine system (LNG-IUS); however, 20-30% and 41% patients undergoing progestin-based treatments alone failed to achieve complete response (CR) and recur2. The current knowledge is drawn from observational cohort studies on small series of patients for which long follow-up is rare3. Moreover, the worldwide data on hysteroscopic treatment are still limited4. Here, we evaluated the prognostic outcome of a large, single-institution series of young women diagnosed with endometrial atypical hyperplasia (EAH)/endometrioid intraepithelial neoplasia (EIN) and early stage endometrial cancer (EEC) who were selected for fertility preservation and treated with oral MA combined with hysteroscopic resection in the subgroup of patients carrying a single lesion. Study Design Patients with EAH/EIN (n= 49) or well differentiated EEC (n= 36), FIGO stage IA (no myometrial invasion at MRI) were prospectively included from June 2007 to December 2019. The inclusion criteria for conservative treatment followed NCCN guidelines 20185. All patients received MA 160 mg daily for a minimum of 6 months and were evaluated by hysteroscopy-guided biopsy and ultrasounds every three months until achieving CR. Next, follow-up was performed every 3 months until pregnancy was obtained. Only suspected single lesion (cancerous polyp or neoformation) were hysteroscopically removed before progestin treatment with the NEMos (Neoplasia Endometrium Myometrium organized sections) technique1,6. Multifocal lesions were treated with MA alone. Results The median follow-up time was 36 months (range 6-150). A total of 82 patients (96.5%) achieved CR. The mean treatment duration for achieving CR was 4.51 months (range 3-18 months). Hysteroscopic removal of EAH/EIN or EEC prior to therapy was the only factor significantly associated with shorter treatment duration to achieve CR (p=0.001). Patients who underwent hysteroscopic resection plus MA (n=15) or MA therapy alone (n=67) achieved CR in 3.4 months (range 3-18) and 4.75 months (range 3-18), respectively. The cumulative relapse rate was 62% (51/82) and the median time to relapse was 21 months (28 months for EAH/EIN and 21 months for EEC). Patients with lesion removed by hysteroscopy plus MA relapsed later (average 38, median 33, range 6-150 months) compared to patients who were treated with MA alone (average 27, median 18, range 6-108 months) (p=0.043) (Fig. 1). Among the 82 patients who achieved CR, 52 patients planned for parenthood; and 26 patients (50%) achieved at least one pregnancy. Only 4 patients received in vitro fertilization. Spontaneous miscarriage rate was 17% (9 out of 52 cases) and live birth rate was 32.7% (17 out of 52 cases), respectively. Conclusion In this study, we report our institutional experience with a large series of EAH/EIN (n=49) and EEC (n=36) patients eligible for fertility-sparing treatment with MA alone or combined with NEMo’s hysteroscopic resection1,5. We found that hysteroscopic resection of EAH/EIN or EEC in combination with oral progestin therapy was significantly associated with shorter treatment duration to achieve CR and longer time to relapse, compared to patients treated with progestin therapy alone. This large, single-institution study provides convincing data on the efficacy of MA plus hysteroscopic resection in conservative treatment of both EAH/EIN and EC patients, which will have to be confirmed in a prospective multi-institutional trial.

The incidence and mortality rates from endometrial cancer are rising worldwide. Although there are many chemotherapeutic and targeted therapy agents for ovarian and primary peritoneal cancers, very few therapies are available to treat advanced, recurrent, or metastatic endometrial cancer. Traditionally, therapy for endometrial cancer was based on histopathology alone. However, recent genomic studies have identified distinct molecular subtypes of endometrial cancer. These subtypes provide significant prognostic and therapeutic information. In the coming years, there is going to be an increasing reliance on the molecular and genomic features of endometrial cancers to guide treatment. Megestrol acetate has been used for several years for palliative treatment of advanced endometrial cancer. Recently, pembrolizumab has also been approved for microsatellite instability high endometrial cancers.

Synthetic progestins are widely used pharmaceutical agents that have become common contaminants in the aquatic environment. The potential adverse effects of long-term exposure on aquatic wildlife, however, are not fully understood. The aim of this study was to investigate the endocrine disruption in Chinese rare minnow (Gobiocypris rarus) in response to megestrol acetate (MTA) exposure. Newly-hatched Chinese rare minnow larvae were exposed to MTA at a nominal concentration of either 1 ng/L (detected concentrations ranged from 0.18 to 0.93 ng/L) or 10 ng/L (detected concentrations ranged from 4.27 to 9.64 ng/L) for 6 months and the effects on growth, sex steroid hormones, gonadal histology, and steroidogenic genes expression were determined. After 6 months of exposure to a nominal concentration of 10 ng/L MTA, the body weight and condition factors were significantly increased in fish of both sexes. Exposure to a nominal concentration of 10 ng/L MTA significantly reduced plasma concentrations of estradiol and 11-ketotestosterone in female fish while also reducing testosterone and 11-ketotestosterone in male fish. Gonad histology revealed significantly reduced proportions of vitellogenic oocytes in female fish exposed to a nominal concentration of 10 ng/L MTA and induction of atretic follicles in female fish exposed to both nominal concentrations of MTA. The expression of cyp19a1a and cyp17a1 in the gonads was up-regulated in the ovaries while down-regulated in the testes. Our results indicate that MTA can induce endocrine disruption in Chinese rare minnow at the low concentrations found in contaminated environments. This indicates a potentially high ecological risk from MTA to fish populations in MTA-contaminated aquatic environments in China and may also in other regions.

The increasing older adult population guarantees that healthcare providers are more likely to encounter patients requiring treatment for unintended weight loss. Due to physiologic changes that occur in the older adult, it is important to know how to assess for, and diagnose unintended weight loss, as well as understand the treatment options. In addition to the use of enteral and parenteral nutrition, appetite stimulants have been used in older adults. Understanding the dosage, side effects, and proper usage of appetite stimulants, such megestrol acetate, mirtazapine, and dronabinol, is crucial in order to provide safe and effective patient care.

Highlights • Endometrial cancer has been diagnosed synchronous with missed abortion. • Endometrial cancer treatment decisions depend on future reproductive desires. • Fertility sparing hormonal therapy is effective for noninvasive endometrial cancer., Background Endometrial cancer is the most common gynecologic cancer in the United States; however, reports of endometrial cancer diagnosed in the setting of intrauterine gestation are rare. Case We describe the case of a clinical stage IA grade 1 endometrioid endometrial adenocarcinoma diagnosed at the time of D&C performed for missed abortion in a gravida 1 para 0 female with no identifiable risk factors. Fertility-sparing treatment, with combined oral megestrol acetate and levonorgestrel intrauterine system, was used to manage this incidentally-diagnosed carcinoma with endometrial sampling every 3 months.

In 1993, megestrol acetate (MA) was approved by the US Food and Drug Administration for the treatment of anorexia, cachexia, or unexplained weight loss in patients with acquired immunodeficiency syndrome. The mechanism by which MA increases appetite is unknown, and its effectiveness for anorexia and cachexia in neoplastic, elderly, and acquired immunodeficiency syndrome patients is under investigation. This is an updated version of a Cochrane systematic review first published in 2005 and later updated in 2013 entitled ‘Megestrol acetate for the treatment of anorexia–cachexia syndrome’. MA vs. placebo: in studies where MA was compared with placebo, the overall results showed that MA patients gained weight (mean difference, MD 2.25 kg, 95% CI [1.19, 3.3]) but did not gain quality of life (QOL) (standarized mean difference, SMD 0.5, 95% CI [−0.13, 1.13]), with more adverse events (relative risk, RR 1.46, 95% CI [1.05, 2.04]), but no difference in deaths (RR 1.26, 95% CI [0.70, 2.27]). MA vs. no treatment: MA patients gained weight (MD 1.45 kg, 95% CI [0.15, 2.75]) but did not gain QOL (standardized mean difference 3.89 95% CI [−14, 6.28]). There was no increase in adverse events (RR 0.90, 95% CI [0.39, 2.08]) or deaths (RR 1.01, 95% CI [0.42, 2.45]). MA vs. active drugs: MA patients gained weight (MD 2.5 kg, 95% CI [0.37, 4.64]) but did not gain QOL (MD 0.20 95% CI [−0.02, 0.43]) and did not report an increase in adverse events (RR 1.05 95% CI [0.95, 1.16]) or in deaths (RR 1.53, 95% CI [1.02, 2.29]) Different doses of MA: in studies where lower doses of MA were compared with higher doses of MA, we did not find differences either in weight gain (MD −0.94 kg, 95% CI [−3.33, 1.45]), QOL (MD 0.31 95% CI [−0.19, 0.81]), or adverse events (RR 1.34, 95% CI [0.65, 2.76]). Thus, we cannot reach a conclusion for an optimal dose of MA.

Introduction: McCune–Albright Syndrome (MAS) is a rare congenital sporadic disorder characterized by fibrous bone dysplasia, café-au-lait pigmented spots on the skin, and non-gonadotropin dependent precocious puberty (PP), which is caused by a postzygotic somatic activating mutation in the GNAS gene encoding the alpha subunit of Gs protein. In our case study, we recorded a girl with the onset of MAS and treated her with Chinese medicinal herbs combined with megestrol acetate. We aim to provide a method for the treatment of children with this rare form of precocious puberty. Case Presention: A 4-year-old girl presented with vaginal bleeding and enlarged breasts. The activating mutation of GNAS was not detected in the patient’s peripheral blood samples, as some had reported. Because of peripheral PP and fibrous dysplasia of the diagnosed bone, the patient was considered as MAS. We chose the Chinese medicinal herbs combined with megestrol acetate for treatment, and the patient was effectively treated. Conclusion: The combination therapy of Chinese medicinal herbs plus megestrol acetate in managing PP in an MAS is one of the useful treatments.

Objective To assess whether dietary supplements that are herbal and/or animal-derived products, marketed for enhancing metabolism or promoting energy, "adrenal fatigue," or "adrenal support," contain thyroid or steroid hormones. Methods Twelve dietary adrenal support supplements were purchased. Pregnenolone, androstenedione, 17-hydroxyprogesterone, cortisol, cortisone, dehydroepiandrosterone sulfate, synthetic glucocorticoids (betamethasone, dexamethasone, fludrocortisone, megestrol acetate, methylprednisolone, prednisolone, prednisone, budesonide, and triamcinolone acetonide) levels were measured twice in samples in a blinded fashion. This study was conducted between February 1, 2016, and November 1, 2016. Results Among steroids, pregnenolone was the most common hormone in the samples. Budesonide, 17-hydroxyprogesterone, androstenedione, cortisol, and cortisone were the others in order of prevalence. All the supplements revealed a detectable amount of triiodothyronine (T3) (63-394.9 ng/tablet), 42% contained pregnenolone (66.12-205.2 ng/tablet), 25% contained budesonide (119.5-610 ng/tablet), 17% contained androstenedione (1.27-7.25 ng/tablet), 8% contained 17-OH progesterone (30.09 ng/tablet), 8% contained cortisone (79.66 ng/tablet), and 8% contained cortisol (138.5 ng/tablet). Per label recommended doses daily exposure was up to 1322 ng for T3, 1231.2 ng for pregnenolone, 1276.4 ng for budesonide, 29 ng for androstenedione, 60.18 ng for 17-OH progesterone, 277 ng for cortisol, and 159.32 ng for cortisone. Conclusion All the supplements studied contained a small amount of thyroid hormone and most contained at least 1 steroid hormone. This is the first study that measured thyroid and steroid hormones in over-the-counter dietary "adrenal support" supplements in the United States. These results may highlight potential risks of hidden ingredients in unregulated supplements.

Background: The effects of the glucocorticoid and progesterone receptor agonist megestrol on declarative memory, and the ability of phenytoin to block these effects, were assessed. Methods: Healthy volunteers received each medication combination (placebo and megestrol, phenytoin and megestrol, and placebo and placebo) using a randomized, crossover design. The Rey Auditory Verbal Learning Test assessed declarative memory. Results: Megestrol was associated with a significant reduction in declarative memory (p = 0.0008), which was attenuated by phenytoin, and was associated with significant cortisol suppression compared to placebo (p < 0.001). Conclusion: Changes in memory and cortisol suppression were found in healthy volunteers given megestrol.

Aim The aim of the present study was to evaluate the role of metformin in endometrial cancer (EC), focusing on its potential preventive effect in breast cancer and obese patients and its safety and efficacy when added to progesterone monotherapy in EC patients who wish to preserve their fertility. Methods We reviewed the literature and then conducted a meta-analysis of the relevant parameters. Results A total of 6 studies was included in the meta-analysis. Regarding the pre-surgical treatment with metformin versus placebo, meta-analysis of mean difference in Ki-67 after treatment among two groups, revealed no difference (MD -7.10, 95% CI -23.31 to 9.11, p = 0.39). Meta-analysis of fertility sparing EC management with a combination of megestrol acetate (MA) and metformin (500 mg three times a day) in comparison with monotherapy with 160 mg daily MA revealed no difference in either complete response or partial response rates (166 patients OR 2.94, 95% CI 0.85 to 10.15, p = 0.09 and 166 patients OR 0.76, 95% CI 0.34 to 1.66, p = 0.49, respectively). As far as breast cancer survivors under tamoxifen are concerned, metformin was associated with significantly reduced median endometrial thickness after 52 weeks of evaluation compared to women in placebo group (2.3 mm vs 3.0 mm, p = 0.05). Conclusions Metformin neither was found to be an anti-proliferative agent against the development of endometrial cancer nor beneficial in addition to the progesterone monotherapy for EC fertility sparing candidates. However, a protective effect of metformin was demonstrated in breast cancer survivors under tamoxifen. Clinical outcomes of the ongoing trials are warranted to evaluate the therapeutic use of metformin in EC.