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Objective: To compare the efficacy of the levonorgestrel intrauterine system (LNG-IUS) versus megestrol acetate (MA) in inducing complete regression among women with atypical endometrial hyperplasia (AEH) who declined hysterectomy. Methods: In this single-center, open-label randomized controlled trial, we included 148 women with AEH who declined hysterectomy. We randomized participants to receive either daily oral MA 160 mg (n=74) or apply LNG-IUS (n=74) and scheduled their follow-up by endometrial sampling at 3, 6, 9, 12, 18, and 24 months. The success rate and duration until complete regression were the primary outcomes. Results: The mean duration until complete regression was 5.52 months (95% confidence interval [CI]=4.85-6.18) for the LNG-IUS group versus 6.87 months (95% CI=6.09-7.64) for the megestrol group (log-rank test p-value=0.011). The cumulative regression rate after 12 months was 91.9% with the LNG-IUS versus 77% with MA (p=0.026). Weight gain in the MA group vs LNG-IUS group after one year (4.7±4 kg vs. 2.7±2.6 kg, 95% CI=0.89-3.12; p=0.001) and after two years of therapy (7.8±5.1 kg vs. 4.1±2.9 kg, 95% CI=2.29-5.06; p<0.001). Conclusion: Compared to MA, the LNG-IUS was more efficacious in treating AEH in women who declined hysterectomy, especially those with moderate/severe obesity, with fewer adverse effects and less weight gain. Extending therapy to 12 months for persistent cases would improve regression rates with reasonable safety. Alternate hysteroscopic and office sampling seemed convenient for follow-up. [ABSTRACT FROM AUTHOR]

Purpose: The objective of the trial was to compare the regression rate of atypical endometrial hyperplasia (AEH) in patients treated with megestrol acetate (MA) vs. levonorgestrel-intrauterine device (LNG-IUS). We also aimed to assess the fertility and pregnancy outcomes in these patients. Methods: The study was a phase II multi-centre randomised controlled trial on the use of MA compared to LNG-IUS in the treatment of AEH conducted from January 2020 to January 2024 in Singapore. Women who were diagnosed with AEH and between 21 and 40 years old were included. The patients were randomised to receive either MA (160 mg orally daily) or LNG-IUS. The primary outcomes assessed were the regression rates at 3 months, 6 months and 9 months of treatment. The secondary outcomes assessed were the side effects, patient acceptability and fertility outcomes. Results: Thirty-six patients completed the trial. The overall regression rate was 88.9% by 9 months. There was no statistically significant difference in the 9-month complete regression rate between MA vs. LNG-IUS. There was also no significant difference in side effects and weight change between both arms. Nineteen patients were actively pursuing fertility after complete regression. There were 8 pregnancies achieved, with resultant 4 live births and 4 miscarriages. Conclusion: Our study confirms a high regression rate of AH with medical treatment. LNG-IUS is a non-inferior treatment compared to megestrol acetate. Successful pregnancy outcomes can be achieved after regression of AEH. Long-term studies of sufficient sample-size are needed to assess for fertility and pregnancy outcomes, risk of recurrence and long-term risk of malignancy. Trial registration number: The study was registered with the Health Science Authority (HSA) (License No.: CTA1900087) on September 5, 2019: https://eservice.hsa.gov.sg/prism/ct%5fr/enquiry.do?action=loadSpecificDetail. The trial was registered retrospectively on ClinicalTrials.gov (ID: NCT05492487) on April 7, 2022: https://clinicaltrials.gov/study/NCT05492487. [ABSTRACT FROM AUTHOR]

Abstract There is inconsistent evidence relating to the effects of megestrol acetate (MA) supplementation on cancer patients suffering from anorexia–cachexia syndrome. This review aimed to examine the dose–response effect of MA supplementation in patients with cancer‐associated anorexia/cachexia. Relevant keywords were searched in PubMed, Scopus and ISI Web of Science from inception to June 2023 for randomized controlled trials (RCTs) examining the effect of MA on pathologies in patients with cancer‐associated cachexia. Our primary outcomes were changes in body weight and appetite. However, fatigue and quality of life were secondary outcomes. The mean difference (MD) and 95% confidence interval (95% CI) were estimated using the random‐effects method. Thirteen trials comprising 1229 participants (mean age 60 years) were identified. The results of our highest versus lowest analysis revealed that MA supplementation was not associated with any increase in body weight (MD: 0.64 kg, 95% CI [−0.11, 1.38], P = 0.093, I2 = 69.1%; GRADE = very low certainty). Twelve trials, including 14 effect sizes derived from 1369 patients (intervention = 689, control = 680), provided data on the effect of MA on body weight. Subgroup analyses showed a significant increase in body weight following short‐term intervention (≤8 weeks) and a combination of radiation/chemotherapy as concurrent treatment. A linear dose–response meta‐analysis indicated that each 200 mg/day increment in MA consumption had a significant increase in weight gain (MD: 0.44; 95% CI [0.13, 0.74], P = 0.005; I2 = 97.1%); however, the magnitude of the effect was small. MA administration significantly affected the quality of life based on pooled effect sizes (MD: 1.15, 95% CI [0.76, 1.54], P

Objective: Megestrol acetate (MA) is used to manage anorexia and cachexia in patients with advanced cancer. This study investigated the prescription patterns of MA in patients with metastatic gastric cancer, as well as evaluated its impact on survival outcomes and the incidence of venous thromboembolism (VTE). Methods: A Health Insurance Review and Assessment (HIRA) service database was used to investigate differences in baseline characteristics, survival, and the incidence of VTE according to MA prescription patterns (i.e., prescription vs. no prescription) in patients diagnosed with metastatic gastric cancer from July 2014 to December 2015. Results: A total of 1938 patients were included in this study. In total, 65% of the patients were prescribed MA. Older age, treatment in tertiary hospitals, and palliative chemotherapy were statistically significant predictive factors for MA prescription. Continuous prescription of MA was observed in 37% of patients. There was no statistically significant difference in survival between the MA and non-MA prescription groups on multivariate analysis. Among the 1427 patients included in the analysis for VTE incidence, 4.3% and 2.9% were diagnosed with VTE during the follow-up period in the MA and non-MA prescription groups, respectively. However, there was no statistically significant difference in VTE diagnosis between the groups on multivariate analysis. Conclusion: MA is commonly prescribed for metastatic gastric cancer, especially in elderly patients and those undergoing palliative chemotherapy, without significantly affecting survival or VTE risk. [ABSTRACT FROM AUTHOR]

Regulation of the reproductive capacity of cats using megestrol acetate (a gestagenic preparation) contributes to the development of pathological processes in the uterus, ovaries, and imbalance of gonadal hormones. Therefore, it is essential to investigate and scientifically substantiate the pathogenetic processes in the body of cats under medical contraception. The purpose of this study was to substantiate the pathomorphological changes and dynamics of certain blood parameters in the body of cats under the use of megestrol acetate. The study employed clinical (examination, palpation), laboratory (haematological, biochemical, hormonal), morphological (examination of the genital organs of cats amputated during ovariohysterectomy) methods. A decrease in ovarian size in hypotrophic cats by 11.3×9.05% was found compared to the ovaries of healthy cats. The dependence of megestrol acetate administration on the occurrence of cystic formations in the ovaries was found, with an increase in ovaries in the experimental group by 1.7×2.47 times in follicular cysts and by 1.9×3.1 and 2.5×3.9 times in luteal cysts and polycystic cysts, respectively. It was found that the uterus in cats with megestrol acetate was increased by 3.16×1.93 times in the right horn and 2.84×2.1 times in the left horn compared to the uterus of healthy cats. The dynamics of progesterone (increase by 37.85%), follicle-stimulating hormone (decrease by 43.75%) and oestradiol (increase by 72.15%) were determined in comparison with intact animals. The increase in serum glucose levels in cats after megestrol administration by 34.31%, total protein by 25.0% and creatinine by 11.10%, aspartate aminotransferase by 43.84% (1.78 times) and alanine aminotransferase by 49.84% (1.99 times), and serum urea by 58.71% was substantiated. At the same time, haemoglobin levels decreased by 16.5%. The findings of this study can be used in the development of new methods and regimens of medical contraception with minimisation of risks of complications of the reproductive system, regulation of reproductive capacity, and prevention of infertility in cats

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action. [ABSTRACT FROM AUTHOR]

Simple Summary: Preclinical studies have shown an anti-neoplastic effect of progestins against adrenal cortical carcinoma. Progestins have a positive effect on patient cenesthesia and may make standard chemotherapy more tolerable. In this study, the addition of megestrol acetate to the etoposide, doxorubicin, cisplatin, and mitotane regimen (EDP-M) in patients with ACC and a low PS allowed the administration of EDP-M at adequate doses, and the efficacy was not inferior to that of EDP-M administered to patients with a good PS. Since a low PS is a predictive factor of poor efficacy of antineoplastic treatments in cancer patients, these results suggest a potentiating effect of megestrol acetate to EDP-M and provide the rationale for the ongoing randomized study at the Medical Oncology of Brescia. (1) Background: The standard first-line therapy for advanced adrenocortical carcinoma (ACC) is represented by EDP-M (etoposide, doxorubicin, cisplatin + mitotane). Progestins have shown cytotoxic activity both in vitro and in vivo on ACC; better EDP-M tolerability and efficacy have been hypnotized due to the association with progestins. (2) Methods: The feasibility and tolerability of EDP-M combined with oral megestrol acetate (EDP-MM) were tested in 24 patients (pts) affected by metastatic ACC with a low performance status (PS); the case group was compared with a 48 pts control group according to the propensity score. The secondary objectives were clinical benefit rate (CBR), progression-free survival (PFS), and overall survival (OS). (3) Results: Thirteen pts (54.2%) in the EDP-MM population experienced progestin-related toxicities; in particular, five pts experienced vaginal bleeding (20.8%); four pts experienced weight gain (16.7%); and thromboembolic events, worsening of hypertension, skin rashes, and hyperglycemia were registered in one patient each (4.2%). This led to the discontinuation of megestrol acetate in four pts (16.7%). EDP-M-related toxicities were similar in both groups. No differences in PFS and OS curves were observed; the CBR was 75.0% and 60.4%, respectively. (4) Conclusions: The association of EDP-M + megestrol acetate in ACC pts with a low PS is feasible and well tolerated; its efficacy appeared to be non-inferior to EDP-M administered to pts with a good PS. [ABSTRACT FROM AUTHOR]

To compare the effects of levonorgestrel-intrauterine system (LNG-IUS) with or without oral megestrol acetate (MA) versus MA alone on fertility-preserving treatment in patients with atypical endometrial hyperplasia (AEH). This was a single-center phase II study with an open-label, randomized, controlled trial conducted between July 2017 and June 2020 at the Obstetrics and Gynecology Hospital of Fudan University, Shanghai, China. A total of 180 patients (18–45 years) with primary AEH were randomly assigned (1:1:1) to the MA (N = 60), LNG-IUS (N = 60), or MA + LNG-IUS (N = 60) groups, in which the patients received MA (160 mg orally daily), LNG-IUS, or MA + LNG-IUS (MA 160 mg orally daily plus LNG-IUS), respectively. The primary endpoint was complete response (CR) rate at 16 weeks of treatment. The secondary endpoints were CR rate at 32 weeks of treatment, adverse events, and recurrence and pregnancy rates. All analyses were conducted in a modified intention to treat (ITT) population who underwent randomization and in whom treatment was initiated. The Kaplan-Meier estimate of 16-week CR rates (with 95% confidence interval) were 19.2% (9.0–29.4%) in the MA group, 35.0% (22.8–47.2%) in the LNG-IUS group, and 29.4% (17.2–41.6%) in the MA + LNG-IUS groups. Side effects such as weight gain, increased nocturnal urine, night sweat, insomnia and edema face seemed to occur less frequently in LNG-IUS group compared with MA group. No difference was found among groups regarding second endpoints. LNG-IUS or LNG-IUS plus MA did not show significant therapeutic benefit compared with MA alone. Further studies including sufficient sample-size are needed to validate these findings due to the underpowered design of this trial. This study was supported by the National Key Research and Development Program of China (Grant No 2019YFC1005200 and 2019YFC1005204), Shanghai Medical Centre of Key Programs for Female Reproductive Diseases (Grant No. 2017ZZ010616), Shanghai sailing program (Grant No. 19YF1404200), and Shen Kang clinical project (SHDC22021219). Trial registration ClinicalTrials.gov NCT03241888. https://www.clinicaltrials.gov/ct2/show/NCT03241888?term=NCT03241888&draw=2&rank=1 • In AEH patients, LNG-IUS or LNG-IUS plus MA might not show significant therapeutic benefit compared with MA alone. • Use of LNG-IUS alone might be associated with less adverse events than MA alone. • LNG-IUS combined with MA might have more side effects compared with MA alone. [ABSTRACT FROM AUTHOR]

Objective: To illustrate the clinical course of a rare case of recurrent adult granulosa cell tumor (AGCT) and discuss the features and management for recurrences. Case report: A 56-year-old female was first diagnosed with AGCT in 2008 and had uneventful, regular follow-ups until 2013. Recurrence was suspected and proven by computed tomography-guided biopsy. After undergoing complete cytoreductive surgery (CRS) followed by adjuvant megestrol acetate then leuprolide acetate, another recurrence sprouted at the presacral area in 2017. On both occasions, CRS with no visible residual tumor were attained. The patient has remained in complete remission to date with progestin therapy. Conclusion: There are currently no standardized tumor markers, imaging exams, or therapies for managing AGCT recurrences. Whole exome sequencing analysis of our patient suggested possible association with triosephosphate isomerase 1 mutation. Regular follow-ups with at least two types of imaging exams and indefinite hormone therapy are crucial for this patient's remission.

A comparative analysis of the cytostatic effects of progestins (gestobutanoyl, megestrol acetate, amol, dienogest, and medroxyprogesterone acetate), glucocorticoids (hydrocortisone, dexamethasone), and diclofenac on tumor cells was carried out in order to confirm their in silico predicted probabilities experimentally. The results showed the different sensitivity of HeLa, MCF-7, Hep-2, K-562, and Wi-38 cell lines to progestins, glucocorticoids, and diclofenac. The minimum IC50 was found for progestin gestobutanoyl (GB) as 18 µM for HeLa cells, and varied from 31 to 38 µM for MCF-7, Hep-2, and K-562. Glucocorticoids and diclofenac were much less cytotoxic in the HeLa, MCF-7, and Hep-2 cell lines than progestins, with IC50 values in the range of 150–3000 μM. Myelogenous leukemia K-562 cells were the least sensitive to the action of progestins and glucocorticoids but the most sensitive to diclofenac, which showed a pronounced cytotoxic effect with an IC50 of 31 μM. As we have shown earlier, progestins can uniquely modulate MPTP opening via the binding of adenine nucleotide translocase. On this basis, we evaluated the expression of adenylate nucleotide translocase ANT1 (SLC25 A4) as a possible participant in cytotoxic action in these cell lines after 48 h incubation with drugs. The results showed that progestins differently regulated ANT1 expression in different cell lines. Gestobutanoyl had the opposite effect on ANT1 expression in the HeLa, K562, and Wi-38 cells compared with the other progestins. It increased the ANT1 expression more than twofold in the HeLa and K562 cells but had no influence on the Wi-38 cells. Glucocorticoids and diclofenac increased ANT1 expression in the Wi-38 cells and decreased it in the K562, MCF-7, and Hep-2 cells. The modulation of ANT1 expression discovered in our study can be a new explanation of the cytotoxic and cytoprotective effects of hormones, which can vary depending on the cell type. ANT isoforms in normal and cancerous cells could be a new target for steroid hormone and anti-inflammatory drug action.

Background: Fifteen percent of patients with endometrial cancer (EC) have advanced stage disease or develop a recurrence. Progestins have been applied as systemic treatment for decades, but there is limited evidence on response prediction with biomarkers and toxicity. Objectives: To review the response and toxicity of progestin therapy and stratify response to progesterone receptor (PR) expression and tumour grade. Search strategy: We used the search terms ‘Endometrial cancer’, ‘Progestins’, ‘Disease progression’, ‘Recurrence’ and related terms in Pubmed, Embase and Cochrane databases. Selection criteria: Studies on patients with advanced stage or recurrent EC treated with progestin monotherapy were included. Studies on adjuvant therapy, with fewer than ten cases and with sarcoma histology were excluded. Data collection and analysis: Evaluation for bias was performed with the Revised Cochrane RoB2 tool for randomised studies and the ROBINS-I tool for non-randomised studies. A random effects meta-analysis was performed with the overall response rate (ORR), clinical benefit rate and toxicity as primary outcome measures. Main results: Twenty-six studies (1639 patients) were included. The ORR of progestin therapy was 30% (95% CI 25–36), the clinical benefit rate was 52% (95% CI 42–61). In PR-positive EC, the ORR was 55%, compared with 12% in PR-negative disease (risk difference 43%, 95% CI 15–71). Severe toxicity occurred in 6.5%. Conclusions: Progestin therapy is a viable treatment option in patients with advanced stage and recurrent EC with low toxicity and high ORR in PR-positive disease. The role of PR expression in relation to progression-free survival and overall survival is unclear. [ABSTRACT FROM AUTHOR]