Progesterone is the standard therapy for endometrial hyperplasia, but the added benefit of metformin on histological remission and metabolic outcomes remains unclear. This study aims to compare the efficacy and safety of progestin monotherapy versus metformin plus progestin therapy in women with endometrial hyperplasia. The trial design is a single-center, open-label, parallel-group, randomized clinical trial conducted at Kosar Hospital, Qazvin, Iran, between May 2023 and July 2024. One hundred women aged 18-55 years with histologically confirmed endometrial hyperplasia were randomized 1:1 to receive progestin alone (n = 50) or metformin plus progestin (n = 50). Progestin monotherapy was administered as megestrol acetate 40 mg daily (atypical hyperplasia) or medroxyprogesterone acetate 10 mg/day cyclically (non-atypical). The combination group received the same progestin regimen plus metformin 500 mg twice daily for 3 months. All participants completed follow-up. At 3 months, histological remission was achieved in 82% (41/50) of the progestin group and 76% (38/50) of the combination group (adjusted RR 0.94; 95% CI 0.76-1.16; p = 0.56). At 6 months, remission rates were 92% and 88%, respectively (adjusted RR 0.98; 95% CI 0.86-1.11; p = 0.76). Addition of metformin was associated with a statistically significant but very modest reduction in BMI over 6 months (adjusted mean difference - 0.15 kg/m[2]; 95% CI - 0.25 to - 0.06; p = 0.001), without significant effects on fasting blood glucose (FBS). No Grade ≥ 3 or serious adverse events occurred; mild gastrointestinal adverse events were more frequent in the progestin plus metformin group. In this randomized clinical trial, the addition of metformin (1000 mg/day) to progestin therapy was not associated with a statistically significant difference in histological remission at 6 months compared with progestin monotherapy in women with endometrial hyperplasia. Future trials with patient stratification by metabolic and clinical characteristics may clarify subgroups that could benefit from adjunctive metformin. Iranian Registry of Clinical Trials (IRCT20230128057254N1), retrospectively registered on October 30, 2023.

Menopausal hormone therapy (MHT) remains the most effective treatment for vasomotor symptoms (VMS) and other manifestations of menopause; however, its use is limited in women with contraindications to oestrogen. Progestogen monotherapy, though historically underutilized, represents a viable alternative in this population. This narrative review summarizes the indications, efficacy, and limitations of progestogen monotherapy as MHT. A structured literature search identified systematic reviews, guidelines, randomized controlled trials, and cohort studies evaluating progestogen monotherapy for menopausal symptom management, bone health, and oncologic safety. Evidence supports its use in patients with contraindications specific to oestrogen, including those with certain gynecologic malignancies (e.g., low-grade endometrial stromal sarcoma, select ovarian cancers), prior venous thromboembolism, coronary artery disease, compensated liver disease, and endometriosis. Contraindications to progestogen monotherapy are limited to unexplained abnormal vaginal bleeding and personal history of breast cancer, with caution utilised in patients with meningioma. Clinical data demonstrate that progestogens provide significant VMS relief, with efficacy observed across oral, intramuscular, and transdermal preparations. Micronized progesterone shows additional benefits for sleep quality, while synthetic progestins such as medroxyprogesterone acetate, megestrol acetate, and norethindrone acetate variably confer bone protection. Effects on mood appear neutral overall. Breast cancer risk associated with progestogen monotherapy remains uncertain due to limited and underpowered studies. Despite promising evidence, research is constrained by heterogeneous methodologies, small sample sizes, and lack of contemporary trials directly comparing progestogen monotherapy with standard MHT or nonhormonal alternatives. In conclusion, progestogen monotherapy is an effective, well-tolerated, and under-recognized therapeutic option for women with contraindications to oestrogen-containing MHT. Its optimal use may be tailored to clinical context: micronized progesterone for sleep disturbance, norethindrone acetate for bone health, or progestins with known antineoplastic properties in hormone-sensitive tumours. Larger, high-quality studies are needed to better define long-term safety and efficacy.

The main objective of this study is to evaluate the impact of therapeutic regimens and visceral fat dynamics on complete remission rates in fertility-preserving management of atypical endometrial hyperplasia (AEH) and early endometrial cancer (EC) and to identify modifiable predictors of treatment efficacy. This interim analysis is based on data from an ongoing, prospective, open-label randomized controlled trial (Chinese Clinical Trial Registry ChiCTR2200067099). Conducted in accordance with the pre-specified study protocol, the analysis included the first 73 enrolled participants, who were randomized to either GnRH-a combined with daily letrozole or high-dose oral progestins (medroxyprogesterone acetate or megestrol acetate). All patients received standardized lifestyle interventions (diet and exercise). The exploratory aim was to assess the association between early changes in body composition - measured using the InBody 770 analyzer over 12 weeks - and treatment response. Multivariate logistic regression analyses were performed to assess the association between treatment outcomes and changes in weight and body fat distribution. In this interim analysis, 73 patients were enrolled, including 31 patients with AEH (42.5%) and 42 patients with EC (57.5%). After 12 weeks of treatment, 40 patients achieved CR, while 33 cases did not. After implementing positive education and lifestyle interventions, patients experienced reductions in weight and indicators of body fat distribution after 12 weeks of treatment. The gonadotropin-releasing hormone agonist plus aromatase inhibitors (GnRH-a + AIs) group showed a significantly higher complete response rate than the megestrol acetate/medroxyprogesterone acetate (MA/MPA) group (75.6 vs 28.1%; risk difference: 0.48, 95% CI: 0.27-0.68). After adjustment for covariates, each 1 cm increase in baseline hip circumference was associated with 7.187-fold higher odds of complete response rate (OR = 7.19, 95% CI: 1.03-50.41, P = 0.047). Conversely, progestin therapy (vs GnRH-a + AIs) was associated with 92.7% lower odds of CR rate (OR = 0.07, 95% CI: 0.02-0.35, P = 0.001). Furthermore, a reduction in visceral fat area (per 1 cm2 decrease) was associated with 35.9% higher odds of complete response (OR = 1.36, 95% CI: 1.02-1.81, P = 0.034). Conversely, progestin therapy (vs GnRH-a + AIs) was associated with 89.2% lower odds of CR rate (OR = 0.108, 95% CI: 0.015-0.773, P = 0.027). We found that treatment regimen selection critically influences therapeutic outcomes in fertility-sparing management. Our study shows that reducing visceral fat area substantially improves treatment efficacy, making it a key indicator for predicting treatment effects. This study is part of a registered clinical trial (Chinese Clinical Trial Registry ID: ChiCTR2200067099; registered December 27, 2022).

ObjectiveLimited guidance is available for the treatment of anorexia/cachexia in cancer patients. Appetite stimulation and weight gain are documented side effects of mirtazapine, so there is growing interest in its potential use this patient population. The objective of this review is to evaluate the safety and efficacy of mirtazapine for appetite stimulation and weight gain in cancer-associated cachexia/anorexia (CACS).Data sourcesA literature search was performed in December 2025 using PubMed, Embase and CENTRAL to screen for randomized controlled trials meeting the designated inclusion and exclusion criteria.Data summaryFive randomized controlled trials were reviewed. Two studies compared mirtazapine to placebo, two compared mirtazapine to megestrol acetate, and one compared mirtazapine to olanzapine. Overall risk of bias was low for two studies, with some concerns identified in three studies. While mirtazapine demonstrated significant improvement in appetite from baseline in most studies, it was only when compared to olanzapine that mirtazapine significantly improved appetite compared to a control. Conversely, one study demonstrated superiority of megestrol, and the remaining three studies did not identify a difference in appetite outcomes between mirtazapine and the control group. Secondary outcomes analyzed included weight and energy intake, though no significant differences were noted between mirtazapine and the control group in any study. Rates of adverse effects were similar between mirtazapine and all comparator arms.ConclusionsThe included studies did not demonstrate consistent improvement in appetite outcomes with use of mirtazapine, although use was associated with low risk of harm. More trials involving larger patient populations and longer study durations may be warranted to establish its role in CACS.

Background: Oral progestogens, including megestrol acetate (MA) and medroxyprogesterone acetate (MPA), have largely been superseded by aromatase inhibitors, tamoxifen, and selective oestrogen receptor degraders (SERDs) in oestrogen receptor-positive (ER-positive) metastatic breast cancer. However, they remain an option as late-line therapy after failure of standard treatments. Contemporary data are limited, particularly in patients previously treated with CDK4/6 inhibitors. Methods: We conducted a multi-site retrospective analysis of patients with ER-positive metastatic breast cancer treated with MA or MPA between 2014 and 2024 at four hospital sites across London, United Kingdom. Patients were identified using pharmacy dispensing records. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method and Cox regression. Subgroup analyses included prior CDK4/6 inhibitor exposure, histology and liver metastases. Results: A total of 116 patients were included. Median PFS was 2.4 months (95% CI 2.2-2.9), and median OS was 3.3 months (95% CI 2.7-4.9). Prior CDK4/6 inhibitor exposure was associated with shorter PFS (1.9 vs. 2.8 months; HR 1.59; 95% CI 1.08-2.35, p = 0.019) and a trend toward shorter OS (3.1 vs. 3.6 months; HR 1.18, 95% CI 0.80-1.75, p = 0.41). Similarly, liver metastases were associated with shorter PFS (2.3 vs. 2.8 months; HR 1.78, 95% CI 1.12-2.85, p = 0.015), with a trend toward worse OS (3.1 vs. 4.9 months; HR 1.45, 95% CI 0.93-2.25, p = 0.103). A subset of patients derived prolonged benefit, with a 6-month PFS rate of 16%. Toxicity was manageable; thromboembolic events and oedema occurred in 9% and 11% of patients respectively. Appetite improvement was reported in 10%. Conclusions: MA and MPA demonstrated modest but clinically relevant late-line activity in heavily pretreated, endocrine-refractory ER-positive metastatic breast cancer. While prior exposure to CDK4/6 inhibitors was associated with shorter PFS, patients without liver metastases appeared to derive the greatest benefit. These findings support a role for oral progestogens in selected patients who have exhausted standard therapeutic options.

Managing G2 endometrioid endometrial adenocarcinoma without progesterone receptor (PR) expression presents significant challenges, particularly when considering fertility preservation. Grade 2 tumors fall into an area of uncertainty within fertility-sparing strategies, making treatment decisions complex and requiring careful individualization. This case report describes a 41-year-old patient who, despite PR and PE negativity, responded to conservative management with hysteroscopic resection, a levonorgestrel-releasing intrauterine device, metformin, and later megestrol, achieving complete histological remission in 15 months. The difficulty in managing G2 tumors lies in their variable behavior, necessitating a multidisciplinary approach, strict monitoring, and adaptability based on treatment response. This case underscores that, although fertility preservation in PR-negative G2 tumors remains challenging, it is feasible in highly selected cases. The evolving literature suggests that alternative strategies, such as immune modulation and aromatase inhibitors, may further expand options. Individualized management remains crucial, balancing oncological safety with reproductive goals through continuous reassessment and engagement with emerging therapeutic evidence.