Due to its favourable bleeding pattern and cycle control, the 15 mg E4/DRSP combination is the preferred combination for further phase III clinical development.

The reduction in coagulation markers suggests an anticoagulant effect from DRSP. The indications of a low thrombosis risk for E4 preparations should be validated in larger studies. IMPLICATION STATEMENT.

Objective: The aim of this study was to select the minimum effective dose of estetrol (E4) for the treatment of vasomotor symptoms in postmenopausal women. Methods: This was a multicenter, randomized, double-blind, placebo-controlled study. Postmenopausal women ( n = 257, of whom 32 were hysterectomized) aged 40 to 65 years, with ≥7 moderate to severe hot flushes (HFs) per day, or 50 or more moderate to severe HFs weekly, received 2.5, 5, 10, or 15 mg E4, or placebo once-daily for a period of 12 weeks. Efficacy was assessed by recording the frequency and severity of HFs. Overall safety was assessed by recording adverse events, measuring endometrial thickness, and monitoring bleeding patterns. Treatment groups were compared using analysis of covariance. Results: The frequency of moderate to severe HFs decreased with all E4 doses. The difference in the percentage change of weekly HF frequency was significant for 15 mg E4 versus placebo at both W4 (−66% vs −49%, P = 0.032) and W12 (−82% vs −65%, P = 0.022). The decrease in severity of HFs was significantly more pronounced for 15 mg E4 than for placebo at both W4 (−0.59 vs −0.33, P = 0.049) and W12 (−1.04 vs −0.66, P = 0.049); the other doses failed to achieve statistical significance. In nonhysterectomized women, endometrial thickness increased during treatment and normalized following progestin treatment at study completion. No endometrial hyperplasia was observed. Conclusions: Estetrol 15 mg is considered to be the minimum effective daily oral dose for treatment of vasomotor symptoms. Its current seemingly favorable safety profile is further to be confirmed in phase 3 clinical development. Video Summary: .

Objectives: To evaluate the effect on endocrine and metabolic parameters of a new combined oral contraceptive (COC) containing estetrol (E4) and drospirenone (DRSP). Study design: Randomized, open-label, controlled, 3-arm, parallel study. Healthy subjects received either E4 15 mg/DRSP 3 mg (E4/DRSP) ( n = 38), or ethinylestradiol (EE) 30 μg/levonorgestrel (LNG) 150 μg ( n = 29), or EE 20 μg/DRSP 3 mg ( n = 31) for 6 treatment cycles. Median percentage change from baseline to cycle 3 and to cycle 6 were evaluated for endocrine parameters, liver proteins, lipid profile, and carbohydrate metabolism. Results: At cycle 6, E4/DRSP treatment had less effect on gonadotropins (follicle stimulating hormone [FSH] + 30.5%, luteinizing hormone [LH] −7.5%) compared to EE/LNG (FSH −84.0%, LH −92.0%) and EE/DRSP (FSH −64.0%, LH −90.0%). With E4/DRSP increases in total cortisol ( + 26.0%) and cortisol binding globulin ([CBG] ( + 40.0%) were less compared to EE/LNG (cortisol + 109.0%, CBG + 152.0%) and EE/DRSP (cortisol + 107.0%, CBG + 140.0%). Liver proteins, except CRP, increased, but the effect was less pronounced with E4/DRSP for angiotensinogen ( + 75.0%) compared to EE/LNG ( + 170.0%) and EE/DRSP ( + 206.5%) and for sex hormone binding globulin ([SHBG] + 55.0%), compared to EE/LNG ( + 74.0%) and EE/DRSP ( + 251.0%).E4/DRSP had minimal impact on lipid parameters; the largest effect was observed for triglycerides ( + 24.0%), which was less compared to EE/LNG ( + 28.0%) and EE/DRSP ( + 65.5%). E4/DRSP had no effect on carbohydrate metabolism. Conclusions: E4/DRSP treatment has limited effects on endocrine and metabolic parameters. The effects on gonadotropins, cortisol, CBG, angiotensinogen, SHBG and triglycerides were less pronounced compared to EE-containing products. Implications statement: Combining E4 15 mg with DRSP 3 mg resulted in a COC with a different metabolic profile in comparison to EE-containing products. The clinical relevance of these findings needs to be further assessed, using clinical endpoints to establish the safety profile of this new COC.

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ObjectiveTo evaluate a new levonorgestrel-releasing intrauterine system (LNG-IUS) called Levosert® for the treatment of heavy menstrual bleeding (HMB) in comparison to the reference product Mirena®.MethodsA multicentre, randomised, controlled trial, in non-menopausal women diagnosed with functional HMB (defined as menstrual blood loss [MBL] ≥ 80 mL) randomised to either Levosert® or Mirena® and followed for up to one year. MBL was evaluated using a validated modified version of the Wyatt pictogram.ResultsA total of 280 women were randomised (141 to Levosert® and 139 to Mirena®). During the one-year treatment period, both Levosert® and Mirena® dramatically decreased MBL and increased haemoglobin and ferritin levels. There were no statistically significant differences between Levosert® and Mirena® regarding any of the parameters evaluated during the study. Similar bleeding patterns were observed in both groups. Levosert® was inserted with the same ease as Mirena®. Both treatments were associated with identical expulsion rates and no perforations occurred in either treatment group.ConclusionLevosert®, a new LNG-IUS designed to release the same daily amount of LNG as Mirena®, is highly effective in the treatment of HMB. No differences were observed between Levosert® and Mirena® regarding all evaluated outcomes, including safety profile.