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• 80 women were randomized to random start nomegestrol acetate/estradiol (n=40) or control (n=40) before undergoing hysteroscopic polypectomy. • Endometrial thickness both pre- and post- hysteroscopic polypectomy was significantly thinner for the intervention group (p < 0.001). • Endometrial preparation, visualization quality, and procedural satisfaction were higher in the intervention group (p < 0.001). • Random start nomegestrol acetate/estradiol provides rapid, satisfactory, low-cost endometrial preparation before polypectomy. To evaluate the use of oral nomegestrol acetate/estradiol in random start rapid preparation of endometrium before office hysteroscopic polypectomy. Multicenter, prospective, randomized controlled trial. University hospitals. 80 adult women undergoing office hysteroscopic polypectomy between January 2023 and March 2024 were randomized to intervention (n = 40) or control (n = 40). Exclusion criteria included the presence of endouterine pathology other than endometrial polyps solely. Subjects in the intervention group were treated with oral nomegestrol acetate/estradiol 1.5 mg/2.5 mg/day started taking the drug from an indefinite time in the menstrual cycle (random start) for 14 days. Subjects in the control group did not receive any pharmaceutical treatment and underwent polypectomy between days 8 and 11 of the menstrual cycle. On the day of the procedure, the difference in pre- and post-office hysteroscopic polypectomy endometrial ultrasound thickness was statistically significant between the two groups, with endometrial thickness in both measurements being thinner for the intervention group (p < 0.001). In the nomegestrol acetate/estradiol-treated group, compared with the control, there was also a statistically significant difference in the physician's assessment of the quality of endometrial preparation (p < 0.001), the quality of visualization of the uterine cavity (p < 0.001), and satisfaction with the performance of the procedure (p < 0.001). Finally, all surgical outcomes analyzed were better in the treatment group. Treatment with nomegestrol acetate/estradiol could provide rapid, satisfactory and low-cost preparation of the endometrium before office polypectomy, thus improving surgical performance and woman's compliance. ClinicalTrials.gov NCT06316219. [ABSTRACT FROM AUTHOR]

To evaluate whether the thromboembolic risk and contraceptive effectiveness of NOMAC-E2 observed in the PRO-E2 study can be extended to each participating country, as lifestyle, cardiovascular risk factors and prescribing habits may differ geographically. This analysis was performed on the PRO-E2 Italian subpopulation, where smoking habit and women over 35 years were more prevalent compared with the overall study population. Data from NOMAC-E2 or levonorgestrel-containing COCs (COCLNG) new users were descriptively analysed. Incidence rates of thrombosis (events/10,000 women-years [WY]) and the Pearl Index (pregnancies/100 WY) were calculated. Overall, 11,179 NOMAC-E2 and 8,504 COCLNG users were followed up to 2 years (34,869 WY). The NOMAC-E2 cohort included more women over 35 vs. COCLNG (37.7% vs. 31.8%; p = 0.001). A comparable low risk of combined deep venous thrombosis of lower extremities (DVT) and pulmonary embolism (PE) was observed in NOMAC-E2 (1.7/10,000 WY; 95% CI: 0.21–6.2) and COCLNG users (6.6/10,000 WY; 95% CI: 2.4–14.4). Similar results were obtained by considering all thromboembolic events (VTE). Unintended pregnancies did not differ between NOMAC-E2 (0.12/100 WY; 95% CI: 0.06–0.21) and COCLNG (0.15/100 WY; 95% CI: 0.08–0.26) cohorts. Despite the higher age and tobacco use, findings from the Italian subpopulation were broadly consistent with overall PRO-E2 results, confirming a similar low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 and COCLNG. This subgroup analysis of the PRO-E2 study provides comprehensive epidemiological data on the use of combined oral contraceptives in a large Italian cohort, with a higher prevalence of women over 35 years and smokers. The study confirms the low thromboembolic risk and high contraceptive effectiveness of NOMAC-E2 pill. [ABSTRACT FROM AUTHOR]

Summary: Background: Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC. Methods: Observational cohort study using SNDS data (France). Women included had ≥ one dispensing of NOMAC between 2007 and 2017 (no dispensing in 2006). Exposure was defined as a cumulative dose >150 mg NOMAC within six months after first dispensing. A control group of women (cumulative dose ≤150 mg) was assembled. The outcome was surgery (resection or decompression) or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma. Findings: In total, 1,060,779 women were included in the cohort (535,115 in the exposed group and 525,664 in the control group). The incidence of meningioma in the two groups was 19.3 and 7.0 per 100,000 person-years, respectively (age-adjusted RRa = 2.9 [2.4–3.7]). The RRa for a cumulative dose of more than 6 g NOMAC was 12.0 [9.9–16.0]. In the event of treatment discontinuation for at least one year, the risk of meningioma was identical to that in the control group (RRa = 1.0 [0.8–1.3]). The location of meningiomas in the anterior and middle part of the skull base was more frequent with exposure to NOMAC. Interpretation: We observed a strong dose-dependent association between prolonged use of NOMAC and the risk of intracranial meningiomas. These results are comparable to those obtained for cyproterone acetate, although the magnitude of the risk is lower. It is now recommended to stop using NOMAC if a meningioma is diagnosed. Funding: The French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI-PHARE.

To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40. In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight. Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9–13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6–15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01–0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03–0.18). No differential effect on mood and weight was observed between cohorts. NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women. [ABSTRACT FROM AUTHOR]

Objective: To investigate unintended pregnancy and changes in mood, acne, and weight in NOMAC-E2 vs levonorgestrel-containing COC (COCLNG) users under 25 years. Methods: In this large, observational study, new users (first-ever users of an eligible COC or restarting with the same or a new eligible COC after a break of at least 2 months) of NOMAC-E2 and COCLNG were recruited in 12 countries in Europe, Australia, and Latin America and followed up via questionnaires for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 women-years). Crude (HRcrude) and adjusted hazard ratios (HRadj) were calculated. Mood and acne changes were defined as change of score from baseline. Weight change was defined as percent change of body weight. Results: Overall, 12,829 NOMAC-E2 users and 17,095 COCLNG users under 25 were followed-up. The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort; confirmed events: 30 NOMAC-E2 (PI 0.24; 95% CI, 0.16–0.35) vs 94 COCLNG (PI 0.51; 95% CI, 0.41–0.62). The HRcrude for unintended pregnancy comparing NOMAC-E2 to COCLNG was 0.47 (95% CI, 0.31–0.71) and the HRadj was 0.52 (95% CI, 0.34–0.78). No differential effect on acne, mood, and weight was observed between cohorts. Conclusions: NOMAC-E2 shows a significantly better contraceptive effectiveness in young women and has no differential effect on acne, mood, and weight compared to COCLNG. [ABSTRACT FROM AUTHOR]

Objective To investigate safety and effectiveness of NOMAC-E2 and levonorgestrel-containing COCs (COCLNG) in users over 40.Methods In this large, observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed-up via questionnaires. Incidence of venous thromboembolism (VTE) was expressed as incidence rate (IR; events/104 women-years [WY]). Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 WY). Mood and weight changes were defined as mean changes in mood score and percentage of body weight.Results Overall, 7,762 NOMAC-E2 and 6,059 COCLNG users over 40 were followed-up. NOMAC-E2 showed no increased VTE risk compared to COCLNG; confirmed events: 5 NOMAC-E2 (IR 5.9; 95% CI, 1.9–13.7) vs 4 COCLNG (IR 5.9; 95% CI, 1.6–15.1). Unintended pregnancy did not differ substantially between cohorts; confirmed events: 4 NOMAC-E2 (PI 0.05; 95% CI, 0.01–0.13) vs 5 COCLNG (PI 0.08; 95% CI, 0.03–0.18). No differential effect on mood and weight was observed between cohorts.Conclusions NOMAC-E2 can be considered a valid alternative to COCLNG in perimenopausal women.

Objective: To investigate unintended pregnancy and changes in mood, acne, and weight in NOMAC-E2 vs levonorgestrel-containing COC (COCLNG) users under 25 years.Methods: In this large, observational study, new users (first-ever users of an eligible COC or restarting with the same or a new eligible COC after a break of at least 2 months) of NOMAC-E2 and COCLNG were recruited in 12 countries in Europe, Australia, and Latin America and followed up via questionnaires for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (PI; contraceptive failures/100 women-years). Crude (HRcrude) and adjusted hazard ratios (HRadj) were calculated. Mood and acne changes were defined as change of score from baseline. Weight change was defined as percent change of body weight.Results: Overall, 12,829 NOMAC-E2 users and 17,095 COCLNG users under 25 were followed-up. The risk of unintended pregnancy was statistically significantly lower in the NOMAC-E2 cohort; confirmed events: 30 NOMAC-E2 (PI 0.24; 95% CI, 0.16–0.35) vs 94 COCLNG (PI 0.51; 95% CI, 0.41–0.62). The HRcrude for unintended pregnancy comparing NOMAC-E2 to COCLNG was 0.47 (95% CI, 0.31–0.71) and the HRadj was 0.52 (95% CI, 0.34–0.78). No differential effect on acne, mood, and weight was observed between cohorts.Conclusions: NOMAC-E2 shows a significantly better contraceptive effectiveness in young women and has no differential effect on acne, mood, and weight compared to COCLNG.

Abstract Background To evaluate the effects of a combined oral contraceptive containing 1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) or 2 mg/daily dienogest (DNG) oral progestin on endometriosis-associated chronic pelvic pain (CPP) and on the quality of life (QoL) and sexual function, by a randomized study design. Methods The E2/NOMAC group and DNG group included 99 and 98 women, respectively. The levels of CPP were measured by the visual analogic scale (VAS). The QoL scores were investigated by the Short Form-36 questionnaire (SF-36). Finally, sexual function was studied using the Female Sexual Function Index (FSFI), while sexual distress was studied by the Female Sexual Distress Scale (FSDS). The study had 3, 6 and 12-month follow-ups. Results The intra-group analysis showed an improvement of the VAS score from baseline to the 12-month follow-up in the women of both groups (p

Progestin resistance is a major obstacle to conservative therapy in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). However, the related inducing factor is yet unclear. In this study, thyroid hormone and its receptor α (TRα) and β (TRβ) of patients were assayed. THRB-silenced RL95-2 and KLE EC cells were cultured to investigate the response of progestins. Transcriptomics and Western blotting were performed to investigate the changes in signaling pathways. We found that THRB, rather than THRA, knockdown promoted the viability and motilities of RL95-2 cells but not KLE cells. The suppressive effect of progestins on cell growth and motility significantly decreased in THRB-silenced RL95-2 cells. Multiple proliferation-related signaling pathways were enriched, and the activities of mammalian targets of rapamycin (mTOR)/4e-binding protein 1 (4EBP1)/eukaryotic translation initiation factor 4G (eIF4G) rather than phosphorylated protein kinase B (Akt) were remarkably boosted. Progestin treatment enhanced the effects, and the augmentation was partially abated on supplementation with T3. In THRB-knockdown KLE cells, the progestins-activated partial signaling pathway expression (either mTOR or eIF4G), and supplementation with T3 did not induce noticeable alterations. The serum levels of triiodothyronine (T3) were significantly lower in patients with EC compared with healthy women. A strong expression of TRβ was observed in most patients with EC and EAH sensitive to progestin treatment. In contrast, TRα positive expression was detected in less than half of the patients sensitive to progestin therapy. In conclusion, THRB knockdown enhanced the viability and motility of type I EC cells and attenuated the suppressive effects of progestins by activating the mTOR-4EBP1/eIF4G pathway. Lower expression of THRB is likely correlated with progesterone resistance. [ABSTRACT FROM AUTHOR]

Purpose: To report the results of systematic meningioma screening program implemented by French authorities in patients exposed to progestin therapies (cyproterone (CPA), nomegestrol (NA), and chlormadinone (CMA) acetate). Methods: We conducted a prospective monocentric study on patients who, between September 2018 and April 2021, underwent standardized MRI (injection of gadolinium, then a T2 axial FLAIR and a 3D-T1 gradient-echo sequence) for meningioma screening. Results: Of the 210 included patients, 15 (7.1%) had at least one meningioma; seven (7/15, 47%) had multiple meningiomas. Meningiomas were more frequent in older patients and after exposure to CPA (13/103, 13%) compared to NA (1/22, 4%) or CMA (1/85, 1%; P = 0.005). After CPA exposure, meningiomas were associated with longer treatment duration (median = 20 vs 7 years, P = 0.001) and higher cumulative dose (median = 91 g vs. 62 g, P = 0.014). Similarly, their multiplicity was associated with higher dose of CPA (median = 244 g vs 61 g, P = 0.027). Most meningiomas were ≤ 1 cm3 (44/58, 76%) and were convexity meningiomas (36/58, 62%). At diagnosis, patients were non-symptomatic, and all were managed conservatively. Among 14 patients with meningioma who stopped progestin exposure, meningioma burden decreased in 11 (79%) cases with no case of progression during MR follow-up. Conclusion: Systematic MR screening in progestin-exposed patients uncovers small and multiple meningiomas, which can be managed conservatively, decreasing in size after progestin discontinuation. The high rate of meningiomas after CPA exposure reinforces the need for systematic screening. For NA and CMA, further studies are needed to identify patients most likely to benefit from screening. [ABSTRACT FROM AUTHOR]

Background and purpose: A dose‐dependent association between the use of cyproterone acetate (CPA) and intracranial meningioma has been identified but data for other potent progestogens are scarce. The association was assessed between intracranial meningioma surgery and exposure to three potent progestogens: CPA (≥25 mg/day), nomegestrol acetate (NOMAC) (3.75–5 mg/day) and chlormadinone acetate (CMA) (2–10 mg/day). Methods: In this nationwide population‐based case–control study, cases underwent surgery for intracranial meningioma in France from 2009 to 2018. They were matched to five control subjects for sex, year of birth and area of residence. Progestogen exposure was defined as progestogen use within the year before surgery for cases or the same date for their controls. Results: In total, 25,216 cases were included (75% women, median age 58 years). Progestogen exposure was noted for 9.9% of cases (2497/25,216) and 1.9% (2382/126,080) of controls, with an odds ratio (OR) of 6.7 (95% confidence interval [CI] 6.3–7.1). The OR was 1.2 (1.0–1.4) for short‐term use (<1 year) and 9.5 (8.8–10.2) for prolonged use. A strong association was identified for prolonged use of CPA (OR = 22.7, 95% CI 19.5–26.4), NOMAC (OR = 6.5, 95% CI 5.8–7.2) and CMA (OR = 4.7, 95% CI 4.5–5.3). Progestogen exposure increased the risk of meningioma for all histological grades and anatomical sites, particularly for the anterior and middle skull base: OR = 35.7 (95% CI 26.5–48.2) and 23.9 (95% CI 17.8–32.2) for CPA. The estimated number of attributable cases was 2124 (95% CI 2028–2220) (212/year). Conclusion: A strong association between prolonged exposure to potent progestogens and surgery for meningioma was observed. The risk increased from CMA to NOMAC to CPA. Individuals should be informed of this risk. This study highlights a strong association between prolonged use of nomegestrol and chlormadinone acetate (two potent progestogens) and intracranial meningioma, although weaker than that of cyproterone acetate. The estimated number of cases was higher than 2000 in France over 10 years. [ABSTRACT FROM AUTHOR]

Bleeding irregularities are one of the major reasons for discontinuation of oral contraceptives (OCs), and therefore clinicians need to set expectations during consultations. In this review we provide an overview of bleeding data of recently marketed cyclic combined OCs (COCs) and one progestin-only pill (POP). We evaluated data from phase 3 trials (≥12 months) used to gain regulatory approval. Overall, each type of OC has its own specific bleeding pattern. These patterns however were assessed by using different bleeding definitions, which hampers comparisons between products. In COCs, the estrogen balances the effects of the progestin on the endometrium, resulting in a regular bleeding pattern. However, this balance seems lost if a too low dose of ethinylestradiol (EE) (e.g., 10 µg in EE/norethindrone acetate 1 mg) is used in an attempt to lower the risk of venous thromboembolism. Replacement of EE by 17β-estradiol (E2) or E2 valerate could lead to suboptimal bleeding profile due to destabilization of the endometrium. Replacement of EE with estetrol (E4) 15 mg in the combination with drospirenone (DRSP) 3 mg is associated with a predictable and regular scheduled bleeding profile, while the POP containing DRSP 4 mg in a 24/4 regimen is associated with a higher rate of unscheduled and absence of scheduled bleeding than combined products. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effects of a combined oral contraceptive containing 1.5 mg 17b-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) or 2 mg/daily dienogest (DNG) oral progestin on endometriosis-associated chronic pelvic pain (CPP) and on the quality of life (QoL) and sexual function, by a randomized study design.Methods: The E2/NOMAC group and DNG group included 99 and 98 women, respectively. The levels of CPP were measured by the visual analogic scale (VAS). The QoL scores were investigated by the Short Form-36 questionnaire (SF-36). Finally, sexual function was studied using the Female Sexual Function Index (FSFI), while sexual distress was studied by the Female Sexual Distress Scale (FSDS). The study had 3, 6 and 12-month follow-ups.Results: The intra-group analysis showed an improvement of the VAS score from baseline to the 12-month follow-up in the women of both groups (p < 0.001). The inter-group comparison showed a similar improvement of CPP (p = 0.06). Women on DNG had better SF-36 somatic (p < 0.01) and FSFI scores (p < 0.006) than women on E2/NOMAC at the 6- and 12-month follow-ups.Conclusions: The results support the efficacy of both hormonal treatments, even if DNG was more effective than E2/NOMAC in a limited intergroup comparison. [ABSTRACT FROM AUTHOR]

WHO grade II progestin-related meningiomas have been reported in recent series but we found no previous study describing their long-term outcome. Our study aimed to evaluate patients operated on for high-grade intracranial meningioma and who underwent long-term exposure to high dose of cyproterone acetate, nomegestrol acetate, and chlormadinone acetate. Our study retrospectively included 9 patients with high-grade progestin-related intracranial meningioma between December 2006 and September 2021. In each patient, clinico-radiological follow-up was performed every 6 months after diagnosis and treatment withdrawal recommendation. The mean progestative exposure was 11.4 years. Edema existence or absence of cleft sign on MRI were the key factors for surgical indication. All patients underwent surgery. Adjuvant radiotherapy was indicated in 1 patient, and Gamma Knife radiosurgery was proposed in 2 other patients for a second location of meningioma. Six patients harbored a grade II chordoid meningioma subtype with 100% PR expression and 3 patients a grade II atypical meningioma subtype with lower PR expression. The mean follow-up was 8.1 years and none of the 9 patients presented with a recurrence. Patients with grade II progestin-related meningiomas have less tumor recurrence after surgery than patients with sporadic grade II meningiomas, especially after progestin withdrawal. The presence/appearance of peri-meningioma edema and the absence of cleft sign before volumetric change should suggest the existence of an underlying WHO grade II meningiomas. In these cases, surgical resection may immediately be considered and adjuvant radiotherapy should be reserved for proven recurrence cases. [ABSTRACT FROM AUTHOR]

To assess and compare the risk of venous thromboembolism (VTE) and arterial thromboembolism (ATE) in NOMAC-E2 users with levonorgestrel-containing combined oral contraceptive (COCLNG) users. This large, prospective, observational active surveillance study used a non-inferiority design. New users of NOMAC-E2 and COCLNG were recruited in 12 countries in Australia, Europe, and Latin America. Women were followed up directly and self-reported outcomes of interest were validated via treating physicians. The main outcome of interest was VTE, specifically deep venous thrombosis of the lower extremities (DVT) and pulmonary embolism (PE). Secondary outcomes included all VTE and ATE. Data on confounders were captured and independent blinded adjudication assessed the classification of events. Incidence rates, crude (HRcrude), and adjusted (HRadj) hazard ratios were calculated. A total of 101,498 women (49,598 NOMAC-E2 users and 51,900 COCLNG users) were enrolled and followed for up to 2 years (144,901 WY of observation). NOMAC-E2 users had a higher mean age (31.0 ± 8.63 years) than COCLNG users (29.3 ± 8.53 years) but other baseline characteristics were similar between the cohorts. The main analysis comparing the risk of DVT of the lower extremities and PE in NOMAC-E2 users versus COCLNG users yielded an HRadj of 0.59 (95% CI, 0.25–1.35) (adjusted for age, BMI, family history of VTE, and current duration of use). The risk of all VTE and ATE was not higher in NOMAC-E2 users compared with COCLNG users. NOMAC-E2 use was not associated with a higher risk of VTE or ATE compared with COCLNG. [ABSTRACT FROM AUTHOR]

To assess and compare the risk of unintended pregnancy in NOMAC-E2 users with levonorgestrel-containing COC (COCLNG) users in clinical practice. In this observational study, new users1 of NOMAC-E2 and COCLNG were recruited in Europe, Australia, and Latin America and followed for up to 2 years. Unintended pregnancy was expressed by the Pearl Index (contraceptive failures per 100 women-years [WY]), crude hazard ratios (HRcrude) and adjusted hazard ratios (HRadj). Overall, 44,559 and 46,754 users were recruited to the NOMAC-E2 and COCLNG user cohorts, respectively. There were 64 unintended pregnancies in NOMAC-E2 users (0.15 per 100 WY; 95% CI, 0.11–0.19) and 200 in COCLNG users (0.41 per 100 WY; 95% CI, 0.35–0.47). The unintended pregnancy risk was statistically significantly lower in the NOMAC-E2 cohort (p<.0001) compared to the COCLNG user cohort. The HRadj of NOMAC-E2 vs COCLNG was 0.45 (95% CI, 0.34–0.60; adjusted for age, body mass index, gravidity, COC user status, education level). NOMAC-E2 demonstrated superior contraceptive effectiveness compared to COCLNG, likely due to the comparatively short hormone-free interval and possibly reinforced by the long half-life of NOMAC. [ABSTRACT FROM AUTHOR]

Background: Nomegestrol acetate (NOMAC) is a synthetic potent progestogen. This study aimed to assess the risk of intracranial meningioma associated with the prolonged use of NOMAC., Methods: Observational cohort study using SNDS data (France). Women included had ≥ one dispensing of NOMAC between 2007 and 2017 (no dispensing in 2006). Exposure was defined as a cumulative dose >150 mg NOMAC within six months after first dispensing. A control group of women (cumulative dose ≤150 mg) was assembled. The outcome was surgery (resection or decompression) or radiotherapy for one or more intracranial meningioma(s). Poisson models assessed the relative risk (RR) of meningioma., Findings: In total, 1,060,779 women were included in the cohort (535,115 in the exposed group and 525,664 in the control group). The incidence of meningioma in the two groups was 19.3 and 7.0 per 100,000 person-years, respectively (age-adjusted RRa = 2.9 [2.4-3.7]). The RRa for a cumulative dose of more than 6 g NOMAC was 12.0 [9.9-16.0]. In the event of treatment discontinuation for at least one year, the risk of meningioma was identical to that in the control group (RRa = 1.0 [0.8-1.3]). The location of meningiomas in the anterior and middle part of the skull base was more frequent with exposure to NOMAC., Interpretation: We observed a strong dose-dependent association between prolonged use of NOMAC and the risk of intracranial meningiomas. These results are comparable to those obtained for cyproterone acetate, although the magnitude of the risk is lower. It is now recommended to stop using NOMAC if a meningioma is diagnosed., Funding: The French National Health Insurance Fund (Cnam) and the French National Agency for Medicines and Health Products Safety (ANSM) via the Health Product Epidemiology Scientific Interest Group EPI-PHARE., Competing Interests: We declare no financial relationships with any organizations that might have an interest in the submitted work in the previous three years and no other relationships or activities that could appear to have influenced the submitted work., (© 2024 The Author(s).)

Progestin resistance is a major obstacle to conservative therapy in patients with endometrial cancer (EC) and endometrial atypical hyperplasia (EAH). However, the related inducing factor is yet unclear. In this study, thyroid hormone and its receptor α (TRα) and β (TRβ) of patients were assayed. THRB-silenced RL95-2 and KLE EC cells were cultured to investigate the response of progestins. Transcriptomics and Western blotting were performed to investigate the changes in signaling pathways. We found that THRB, rather than THRA, knockdown promoted the viability and motilities of RL95-2 cells but not KLE cells. The suppressive effect of progestins on cell growth and motility significantly decreased in THRB-silenced RL95-2 cells. Multiple proliferation-related signaling pathways were enriched, and the activities of mammalian targets of rapamycin (mTOR)/4e-binding protein 1 (4EBP1)/eukaryotic translation initiation factor 4G (eIF4G) rather than phosphorylated protein kinase B (Akt) were remarkably boosted. Progestin treatment enhanced the effects, and the augmentation was partially abated on supplementation with T3. In THRB-knockdown KLE cells, the progestins-activated partial signaling pathway expression (either mTOR or eIF4G), and supplementation with T3 did not induce noticeable alterations. The serum levels of triiodothyronine (T3) were significantly lower in patients with EC compared with healthy women. A strong expression of TRβ was observed in most patients with EC and EAH sensitive to progestin treatment. In contrast, TRα positive expression was detected in less than half of the patients sensitive to progestin therapy. In conclusion, THRB knockdown enhanced the viability and motility of type I EC cells and attenuated the suppressive effects of progestins by activating the mTOR-4EBP1/eIF4G pathway. Lower expression of THRB is likely correlated with progesterone resistance.

Hormone-associated meningiomas tend to stop growing or decrease in size after cessation of certain progestins, mainly cyproterone acetate. We report three observations on the natural history of hormone-associated intraosseous meningiomas, showing in a first patient that those tumors may grow rapidly under nomegestrol. We then demonstrate the sustained growth of intraosseous hormone-associated meningiomas after cessation of promesgestone and nomegestrol, independently of the intracranial portion, which concurrently decreased in size in the second case or was resected at the time of nomegestrol withdrawal in the third case, thus giving new insights into the tumorigenesis mechanisms of hormone-associated intraosseous meningiomas. [ABSTRACT FROM AUTHOR]

Purpose: The improving knowledge of interactions between meningiomas and progestin refines the management of this specific condition. We assessed the changes over time of the management of progestin-associated meningiomas. Methods: We retrospectively studied consecutive adult patients who had at least one meningioma in the context of progestin intake (October 1995–October 2018) in a tertiary adult Neurosurgical Center. Results: 71 adult women with 125 progestin-associated meningiomas were included. The number of progestin-associated meningioma patients increased over time (0.5/year before 2008, 22.0/year after 2017). Progestin treatment was an approved indication in 27.0%. A mean of 1.7 ± 1.2 meningiomas were discovered per patient (median 1, range 1–6). Surgery was performed on 36 (28.8%) meningiomas and the histopathologic grading was WHO grade 1 in 61.1% and grade 2 in 38.9%. The conservative management of meningiomas increased over time (33.3% before 2008, 64.3% after 2017) and progestin treatment withdrawal increased over time (16.7% before 2008, 95.2% after 2017). Treatment withdrawal varied depending on the progestin derivative used (88.9% with cyproterone acetate, 84.6% with chlormadinone acetate, 28.6% with nomegestrol acetate, 66.7% with progestin derivative combination). The main reason for therapeutic management of meningiomas was the presence of clinical signs. Among the 54 meningiomas managed conservatively for which the progestin had been discontinued, MRI follow-up demonstrated a regression in 29.6%, a stability in 68.5%, and an ongoing growth in 1.9% of cases. Conclusions: Conservative management, including progestin treatment discontinuation, has grown over time with promising results in terms of efficacy and safety. [ABSTRACT FROM AUTHOR]

Background: To evaluate the effects of a 24/4 regimen combined oral contraceptive (COC) containing 1.5 mg 17β-estradiol (E2) and 2.5 mg nomegestrol acetate (NOMAC) compared to on-demand nonsteroidal anti-inflammatory drugs (NSAIDs) on women affected by endometriosis-associated chronic pelvic pain (the primary end point) and their quality of life (QoL) and sexual function (the secondary end points). Materials and Methods: Ninety-nine women on E2/NOMAC constituted the study group; and 63 women on NSAIDs constituted the control group. The visual analogic scale was used to measure the levels of pelvic pain, dysmenorrhea, and dyspareunia. To assess their QoL, sexual function, and sexual distress, the Short Form-36 (SF-36), the Female Sexual Function Index (FSFI), and the Female Sexual Distress Scale (FSDS) were used, respectively. The study included two follow-ups at 3 and 6 months. Results: Improvement in chronic pelvic pain was observed in the study group at both the 3- and 6-month follow-ups (p < 0.001). SF-36, FSFI, and FSDS had a similar trend at the 3- and 6-month follow-ups (p < 0.001). Women on NSAIDs did not report any reduction in pain symptoms or improvement in QoL (p ≤ 0.4). However, they had a limited improvement of their FSFI and FSDS (p < 0.001). The improvement of the pain symptoms, QoL, FSFI, and FSDS, was more evident in women on E2/NOMAC than in those on NSAIDs, when the study group and control group values were compared at the 3- and 6-month follow-ups (p < 0.001). Conclusions: Women on E2/NOMAC COC showed a better reduction of endometriosis-associated chronic pelvic pain and an improvement of their QoL and sexual activity than those of the women on NSAIDs. [ABSTRACT FROM AUTHOR]

Objective: The great heterogeneity of meningiomas is challenging and we need to distinguish relevant subgroups. Spheno-orbital osteomeningiomas (SOOM) constitute a clinically specific entity, with slow-growing benign osteo-meningiomatous tumors, which recur after surgery in one fourth of cases. Neurosurgical daily practice, supported by the literature, shows that the vast majority of patients with SOOM are women, and we explored whether their epidemiological and hormonal profiles suggest a progesterone influence. Methods: We retrospectively documented all radiologically and histologically confirmed cases of SOOM operated in 2005–2019 in our institution. We completed the clinical and hormone history by systematic telephone interviews. Results: In the literature, SOOM occur significantly more often in women than other meningiomas (749/847, 86.4% versus 73.8%, p = 0.002). Among 175 cases, we included 124 patients, 93.5% were women, younger than men (51 ± 5 versus 63 ± 8, p = 0.02). Women' meningiomas showed more progesterone receptors (96.4% versus 50%, p < 0.001). Exogenous hormonal intake, reliable in 82 cases, concerned 83.3% (64/78) of women, with frequent progesterone intake: 13 oestroprogestogenic treatment only, with old-generation progesterone analogs, 41 progesterone analogs (cyproterone acetate, nomegestrol acetate, chlormadinone, promegestone, etonogestrel, levonogestrel), 7 substitutive hormonal therapy for menopause, 3 others. Duration of treatment was 2–40 years, median 10 years. Conclusions: SOOM develop preferentially in women in their fifties, who often received progesterone analogs, and show progesterone receptors. Progesterone analogs are incriminated in skull base meningiomas, and this is the first report on the prevalence of exogenous hormone therapy specifically in SOOM. Whether SOOM reduce after treatment discontinuation, in particular the osteoma part, needs to be explored. Anti-progesterone treatments may represent an avenue for future research in soom. [ABSTRACT FROM AUTHOR]

Background: The relationship between increased meningioma incidence and growth and long-term hormonal therapy with cyproterone acetate (CPA) in women has been recently established in literature. Following the raise in awareness from hormonal treatment, we describe a potential relationship between the progesterone agonist nomegestrol acetate (NOMAC) and meningioma growth.Methods: After implementation of a screening protocol to detect potential interactions between hormonal exposure and occurrence of meningioma, we identified patients taking NOMAC and newly diagnosed with a meningioma. NOMAC was stopped and those patients were followed tightly both clinically and radiologically. Retrospective volumetric analysis of the tumors was performed on the imaging.Results: Three patients were identified for the study. After cessation of the NOMAC, tumor shrinkage was documented for all meningiomas within the first month. Up to 70% of tumor volume reduction was observed during the first year of follow-up in one of them. None of the patients developed new symptoms.Conclusion: We report the first cases of meningiomas responsiveness to discontinuation of hormonal therapy with NOMAC. Similarly to cases associated with long-term CPA intake, tumor reduction, and improvement of clinical symptoms can be observed after cessation of NOMAC. [ABSTRACT FROM AUTHOR]

Cyproterone acetate (CPA) is an antiandrogenic drug which has recently been recognized to promote the occurrence and growth of intracranial meningiomas. Nomegestrol acetate (NOMAC) is a widely used progestin-like drug that could be suggested as an alternative for patients taking CPA. We report a case of CPA-related meningioma for which relay from CPA to NOMAC led to further tumor growth and cessation of NOMAC-induced tumor shrinkage. We suggest NOMAC can have a similar effect than CPA on meningiomas. The use of NOMAC as replacement for CPA in the presence of a meningioma should be discouraged until further evidence becomes available on the role of NOMAC in such instances. [ABSTRACT FROM AUTHOR]

Introduction: Following a historical overview, the ovulation-inhibiting effect of various orally administered estrogen-progestin combinations (combined oral contraceptives [COCs]) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Inhibition of ovulation with progestins alone; estrogens alone; various progestins in combination with ethinyl estradiol; various progestins in combination with natural estrogens (estradiol, estradiol valerate, and estetrol). Expert commentary: The original idea to achieve ovulation blockage through the administration of steroid hormones involved the use a progestogen (both progesterone and its synthetic homologous). The ability of a progestin to inhibit ovulation depends on the type of compound and on its dosage and a difference of more than 20-fold in activity exists between compounds utilized today in COCs. Initially, the estrogenic component was present only because it contaminated the first progestin utilized. It was soon found that an estrogen is necessary for proper cycle control. It was also found that the estrogen acts synergistically in inhibiting ovulation. For almost half a century, most COCs contained ethinyl estradiol. Today, also natural estrogens are being employed. Inhibition of ovulation was complete with all early high dose preparations. Decreasing dosage allowed some ovarian activity to occur, occasionally leading to a mature follicle. Even in this situation, defective corpus luteum formation assured contraceptive protection. [ABSTRACT FROM AUTHOR]

Multidrug resistance-associated protein 2 (MRP2) plays a key role in hepatic and intestinal disposition of endo - and xenobiotics. Several therapeutic agents modulate MRP2 activity resulting in pharmacological interactions. Nomegestrol acetate (NMGA) is a progestogen increasingly used in contraceptive formulations. The aim of this work was to evaluate the effect of NMGA on MRP2 activity in HepG2 and Caco-2 cells as models of human hepatocytes and enterocytes, respectively. NMGA (5, 50 and 500 nM; 48 h) decreased MRP2-mediated transport of 2,4-dinitrophenyl-S-glutathione in HepG2 cells, with no effect on MRP2 protein expression. Acute exposure (1 h) to the same concentrations of NMGA failed to affect MRP2 activity, ruling out an inhibitory action directly induced by the drug. In contrast, acute incubation with a lysate of HepG2 cells pre-treated with NMGA, containing potential metabolites, reproduced MRP2 inhibition. Preincubation of lysates with sulfatase but not with β-glucuronidase abolished the inhibitory action, strongly suggesting participation of NMGA sulfated derivatives. Western blot studies in plasma vs. intracellular membrane fractions ruled out internalization of MRP2 to be responsible for the impairment of transport activity. MRP2-mediated transport of 5(6)-carboxy-2′,7′-dichlorofluorescein was not affected in Caco-2 cells incubated for 48 h with either 5, 50 or 500 nM NMGA. Conversely, acute exposure (1 h) of Caco-2 cells to NMGA-treated HepG2 lysates decreased MRP2 activity, being this effect also prevented by pre-treatment of the lysates with sulfatase. Taken together, these findings demonstrate an inhibitory effect of NMGA sulfated metabolites on hepatic and intestinal MRP2 function. Extrapolated to the in vivo situation, they suggest the possibility of pharmacological interactions with coadministered drugs. [ABSTRACT FROM AUTHOR]

ABC transporters are key players in drug excretion with alterations in their expression and activity by therapeutic agents potentially leading to drug-drug interactions. The interaction potential of nomegestrol acetate (NMGA), a synthetic progestogen increasingly used as oral contraceptive, had never been explored. In this work we evaluated (1) the effect of NMGA on ABC transporters in the human hepatic cell line HepG2 and (2) the underlying molecular mechanism. NMGA (5, 50 and 500 nM) increased P-glycoprotein (P-gp) expression at both protein and mRNA levels and reduced intracellular calcein accumulation, indicating an increase also in transporter activity. This up-regulation of P-gp was corroborated in Huh7 cells and was independent of the classical progesterone receptor. Instead, using a siRNA-mediated silencing approach, we demonstrated the involvement of membrane progesterone receptor α. Moreover, we found that the activation of this receptor by NMGA led to a falling-rising profile in intracellular cAMP levels and protein kinase A activity over time, ultimately leading to transcriptional P-gp up-regulation. Finally, we identified inhibitory G protein and phosphodiesterases as mediators of this novel biphasic modulation. These results demonstrate the ability of NMGA to selectively up-regulate hepatic P-gp expression and activity and constitute the first report of ABC transporter modulation by membrane progesterone receptor α. If a similar regulation took place in vivo , decreased bioavailability and therapeutic efficacy of NMGA-coadministered P-gp substrates could be expected. This holds special importance considering long-term administration of NMGA and broad substrate specificity of P-gp. [ABSTRACT FROM AUTHOR]

Purpose: To identify at least one contraceptive vaginal ring that effectively inhibits ovulation and demonstrates cycle control that is non-inferior to NuvaRing® (Merck Sharp & Dohme B.V., The Netherlands) in terms of an unscheduled bleeding incidence, with a non-inferiority margin of 10%.Methods: This was a randomised, active controlled, parallel group, multicentre, partially blinded trial in healthy women 18-35 years of age. Subjects received one of six contraceptive vaginal rings with an average daily release rate of 300 µg 17β-estradiol (E2) and various rates of either etonogestrel (ENG; 75, 100, or 125 µg/day) or nomegestrol acetate (NOMAC; 500, 700, or 900 µg/day), or the active control NuvaRing® (ENG/ethinylestradiol 120/15 µg), for three 28-day cycles.Results: Ovulation inhibition was observed in all groups as confirmed by absence of progesterone concentrations compatible with ovulation (>16 nmol/L) and absence of ultrasound evidence of ovulation. All investigational rings provided good cycle control, with the ENG-E2 125/300 µg/day group being associated with the best cycle control based on the numerically lowest incidence of unscheduled bleeding and absence of scheduled bleeding. Non-inferiority to NuvaRing® with respect to the incidence of unscheduled bleeding could not be concluded for any of the investigational ring groups. The safety profile was consistent with the known safety profile of combined estrogen/progestin contraceptives and similar across all groups.Conclusions: Contraceptive rings releasing 300 µg E2 and 75-125 µg/day of ENG or 500-900 µg/day of NOMAC provided adequate ovulation inhibition and cycle control and are generally well-tolerated. While non-inferiority to NuvaRing® was not met, among the investigational rings, the ENG-E2 125/300 ring provided the best cycle control. [ABSTRACT FROM AUTHOR]

Abstract: A highly sensitive and selective ultra‐performance liquid chromatography–tandem mass spectrometry method is described for the simultaneous determination of nomegestrol acetate (NOMAC), a highly selective progestogen, and estradiol (E2), a natural estrogen in human plasma. NOMAC was obtained from plasma by solid‐phase extraction, while E2 was first separated by liquid–liquid extraction with methyl tert‐butyl ether followed by derivatization with dansyl chloride. Deuterated internal standards, NOMAC‐d5 and E2‐d4 were used for better control of extraction conditions and ionization efficiency. The assay recovery of the analytes was within 90–99%. The analytes were separated on UPLC BEH C18 (50 × 2.1 mm, 1.7 μm) column using a mobile phase comprising of acetonitrile and 3.0 m m ammonium trifluoroacetate in water (80:20, v/v) with a resolution factor (Rs) of 3.21. The calibration curves were linear from 0.01 to 10.0 ng/mL for NOMAC and from 1.00 to 1000 pg/mL for E2, respectively. The intra‐ and inter‐batch precision was ≤5.8% and the accuracy of quality control samples ranged from 96.7 to 103.4% for both analytes. The practical applicability of the method is demonstrated by analyzing samples from 18 healthy postmenopausal women after oral administration of 2.5 mg nomegestrol acetate and 1.5 mg estradiol film‐coated tablets under fasting. [ABSTRACT FROM AUTHOR]

This observational study was conducted in healthy premenopausal women, who presented themselves for contraceptive advice at the outpatient Family Planning Clinics of the Department of Obstetrics and Gynecology of the University of Cagliari, Hospital–University of Cagliari (Italy). After a screening period of three menstrual cycles, 48 women without contraindications to estroprogestin contraceptives (OCs) were included in the study. The primary purposes of the study were to evaluate whether a 12-month-treatment with the combined OC containing micronized estradiol (1.5 mg, E2) plus nomegestrol acetate (2.5 mg, NOMAC) (E2/NOMAC) interfere on anthropometric indices (AI), body composition (BC) and psychological status (PS). In subjects with dysmenorrhea (#36), its intensity was evaluated using the visuo analogic scale (VAS), both before and during the 12-month-treatment with E2/NOMAC. E2/NOMAC did not modify neither AI nor BC in the 40 subjects who concluded the study. The PS and the VAS of dysmenorrhea were significantly (p < 0.0001) improved from the first cycle of treatment and throughout the E2/NOMAC treatment in comparison with basal values. The study suggests that E2/NOMAC is devoid of negative effects on AI and BC, with additional benefits on PS and dysmenorrhea. [ABSTRACT FROM AUTHOR]

This study investigated the effect of a novel progestin and its combination with metformin on the growth of endometrial cancer (EC) cells. Inhibitory effects of four progestins, including nomegestrol acetate (NOMAC), medroxyprogesterone acetate, levonorgestrel, and cyproterone acetate, were evaluated in RL95-2, HEC-1A, and KLE cells using cell counting kit-8 assay. Flow cytometry was performed to detect cell cycle and apoptosis. The activity of Akt (protein kinase B), mTOR (mammalian target of rapamycin) and its downstream substrates 4EBP1 (4E-binding protein 1) and eIF4G (Eukaryotic translation initiation factor 4G) were assayed by Western blotting. Nude mice were used to assess antitumor effects in vivo. NOMAC inhibited the growth of RL95-2 and HEC-1A cells, accompanied by arresting the cell cycle at G0/G1 phase, inducing apoptosis, and markedly down-regulating the level of phosphorylated mTOR/4EBP1/eIF4G in both cell lines (p < 0.05). Metformin significantly increased the inhibitory effect of and apoptosis induced by NOMAC and strengthened the depressive effect of NOMAC on activity of mTOR and its downstream substrates, compared to their treatment alone (p < 0.05). In xenograft tumor tissues, metformin (100 mg/kg) enhanced the suppressive effect of NOMAC (100 mg/kg) on mTOR signaling and increased the average concentration of NOMAC by nearly 1.6 times compared to NOMAC treatment alone. Taken together, NOMAC suppressing the growth of EC cells likely correlates to down-regulating the activity of the mTOR pathway and metformin could strengthen this effect. Our findings open a new window for the selection of progestins in hormone therapy of EC.

Introduction: The pharmacodynamic effects of various combined oral estrogen-progestin combinations (COC) are examined for their components alone or in the various combined formulations. Special emphasis is given to products containing natural estrogens. Areas covered: Recent information on the effect of androgens, estrogens, progestins, as well as various COC combinations on the coagulation cascade will be reviewed aiming at providing an updated picture. The present article reviews hemostatic changes occurring during use of classic and modern combinations of estrogens (ethinyl estradiol, estradiol, estradiol valerate and estetrol) and new progestins (desogestrel, gestodene, dienogest, drospirenone, nomegestrol acetate), compared to classic compounds, such as levonorgestrel. Both pro- and anti-coagulatory effects of COC in healthy women are detailed and possible links with incidence of thromboembolic events are discussed. Expert commentary: Overall, the picture is reassuring: the use of natural estrogens and of new generation progestins has reduced pro-coagulatory changes in healthy subjects, although the observed differences in the risk of venous thromboembolism between second and third generation progestins is still incompletely understood. At the same time, there still is a need for large comparative and surveillance studies before firm conclusions can be drawn. At any rate, available evidence indicates that hemostatic effects of the newer COC, especially those utilizing natural estrogens, are minimal and often remain with the normal range. [ABSTRACT FROM PUBLISHER]

Objectives: To investigate the effects of a combined oral contraceptive (COC) containing 17 β-estradiol (E2) 1.5 mg and nomegestrol acetate 2.5 mg (NOMAC/E2) on the sexual health of women affected by low sexual desire due to COCs containing ethinylestradiol. Materials and Methods: Eighty-three women (age range 19-32) participated in the study. Sex hormone-binding globulin (SHBG), total testosterone (TT), and free androgen index (FAI) were measured. The Female Sexual Function Index (FSFI) and the Female Sexual Distress Scale (FSDS) questionnaires were used to assess sexual function and distress, respectively. Hormonal levels were measured and questionnaires were administered before the women switched COC NOMAC/E2 usage (baseline) and at the 3-month (first) and 6-month (second) follow-ups. Results: SHBG reduction ( p < 0.001), TT ( p < 0.05), and FAI increases ( p < 0.001) were observed during the first and second follow-ups with respect to baseline values. Sexual desire increased from baseline to the first and second follow-ups ( p < 0.001). At baseline, the total FSFI score was 22 ± 1.5 and the FSDS score was 16.6 ± 1.3, both indicating sexual dysfunction with sexual distress. At the first follow-up, the total FSFI score and the FSDS score increased toward sexual health values, being 28.3 ± 1.6 and 12.1 ± 1.5, respectively ( p < 0.001). At the second follow-up, the FSFI score had risen to 30.6 ± 1.3 ( p < 0.001) and the FSDS score had dropped to 8.3 ± 1.4 ( p < 0.001). Conclusions: COCs containing E2 are an innovation that could help women to not suffer from low sexual desire during hypoandrogenic COC usage. [ABSTRACT FROM AUTHOR]

Nomegestrol acetate (NOMAC) has been successfully used for the treatment of some gynecological disorders, and as a combined oral contraceptive with approval in many countries. In this study, we investigated the effects of NOMAC on human endometrial cancer cells in vitro and in vivo. The proliferation of human endometrial cancer cells (RL95-2 and KLE) were assessed using CCK-8 and EdU incorporation assays. Whole-genome cDNA microarray analysis was used to identify the effects of NOMAC on gene expression profiles in RL95-2 cells. RL95-2 xenograft nude mice were treated with NOMAC (50, 100, and 200 mg/kg) or medroxyprogesterone acetate (MPA; 100 and 200 mg/kg) for 28 consecutive days. The results showed that NOMAC significantly inhibited the growth of RL95-2 cells in a concentration-dependent manner, but not in KLE cells. Further investigation demonstrated that NOMAC produced a stronger inhibition of tumor growth (inhibition rates for 50, 100, and 200 mg/kg NOMAC were 24.74%, 47.04%, and 58.06%, respectively) than did MPA (inhibition rates for 100 and 200 mg/kg MPA were 41.06% and 27.01%, respectively) in the nude mice bearing the cell line of RL95-2. NOMAC altered the expression of several genes related to cancer cell proliferation, including SUFU and Wnt7a. The upregulation of SUFU and Wnt7a was confirmed using real-time quantitative polymerase chain reaction and Western blotting in RL95-2 cells and RL95-2 xenograft tumor tissues, but not in KLE cells. These data indicate that NOMAC can inhibit the proliferation of RL95-2 cell in vitro and suppress the growth of xenografts in the nude mice bearing the cell line of RL95-2 in vivo. This effect could be related to the upregulating expression of SUFU and Wnt7a. [ABSTRACT FROM AUTHOR]

Objectives: Oral hormonal contraception is an effective contraceptive method as long as regular daily intake is maintained. However, a daily routine is a constraint for many women and can lead to missed pills, pill discontinuation and/or unintended pregnancy. This article describes the frequency of inconsistent use, the consequences, the risk factors and the possible solutions.Methods: The article comprises a narrative review of the literature.Results: Forgetting one to three pills per cycle is a frequent problem among 15-51% of users, generally adolescents. The reasons for this are age, inability to establish a routine, pill unavailability, side effects, loss of motivation and lack of involvement in the initial decision to use oral contraceptives. The consequences are 'escape ovulations' and, possibly, unintended pregnancy. Solutions are either to use a long-acting method or, for women who prefer to take oral contraceptives, use a continuous or long-cycle regimen to reduce the risks of follicular development and thus the likelihood of ovulation and unintended pregnancy. A progestogen with a long half-life can increase ovarian suppression.Conclusions: For women deciding to use oral contraceptives, a shortened or eliminated hormone-free interval and a progestogen with a long half-life may be an option to reduce the negative consequences of missed oral contraceptive pills. [ABSTRACT FROM AUTHOR]

Objectives: To obtain more precise and detailed information regarding the bleeding patterns of nomegestrol acetate (NOMAC)/17β-estradiol (E2) and drospirenone/ethinyl estradiol (DRSP/EE) and to identify whether baseline demographic characteristics were associated with unscheduled bleeding, absent scheduled bleeding, or amenorrhea.Study Design: This analysis pooled results from two pivotal open-label, randomized trials that compared bleeding patterns of NOMAC/E2 and DRSP/EE. In the two studies 4317 women aged 18-50 years from 24 countries across the Americas, Europe, and Asia underwent treatment.Results: 2835 women taking NOMAC/E2 (2.5 mg/1.5 mg) in a 24/4-day regimen and 938 women taking DRSP/EE (3 mg/30 μg) in a 21/7-day regimen had at least 1 evaluable cycle for vaginal bleeding analyses. The frequency of absent scheduled bleeding was higher (p<.0001) for women using NOMAC/E2 than DRSP/EE across all 11 cycles (cycles 2-12), ranging between 17.6% and 31.6% and between 3.4% and 5.8%, respectively. For women who had absent scheduled bleeding in cycles 2, 3, or 4 the incidence of absent scheduled bleeding in subsequent cycles was high and ranged between approximately 50%-60% for NOMAC/E2 and approximately 40%-50% for DRSP/EE. Amenorrhea increased over time with both regimens, being higher with NOMAC/E2. Both absent scheduled bleeding and amenorrhea with NOMAC/E2 were more common in older women, overweight women, switchers, and smokers; unscheduled bleeding was more common in starters, but had no association with age, body mass index, and smoking.Conclusions: NOMAC/E2 is associated with a higher prevalence of absent scheduled bleeding compared with DRSP/EE. Absent scheduled bleeding and amenorrhea were associated with age, body weight, switching and smoking. Unscheduled bleeding was more common in starters.Implications: Information about the factors associated with bleeding patterns may help clinicians provide guidance to women considering use of the NOMAC/E2 oral contraceptive. [ABSTRACT FROM AUTHOR]

Cachexia, a complex disorder that results in depletion of adipose tissue and skeletal muscle, is driven by anorexia, metabolic abnormalities and inflammation. There are limited therapeutic options for this syndrome. Previous evidence has demonstrated that increasing adipose tissue may improve quality of life and survival outcomes in cachexia. Cisplatin, as a chemotherapy drug, also causes cachexia during antitumor therapy due to its adverse effects. To establish a rat model of cachexia, the animals were intraperitoneally treated with cisplatin at doses of 1, 2 and 3 mg/kg, and the rats that responded to cisplatin at the optimal dose were used to test the effect of nomegestrol acetate (NOMAc). Rats that were assessed to be sensitive to cisplatin were randomly grouped and intragastrically administered vehicle, 5 or 10 mg/kg megestrol acetate (MA) or 2.5, 5 or 10 mg/kg NOMAc. The body weights and food consumption of the rats were assessed. Serum IL-6 and TNF-α levels were assessed using ELISA. The protein expression levels of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), peroxisome proliferator activated receptor γ (PPARγ), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1) from inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) were evaluated using western blotting. The optimal way to establish a chemotherapy-induced rat model of cachexia demonstrated in the present study was to intraperitoneally administer the rats with 2 mg/kg cisplatin for 3 consecutive days. NOMAc (2.5, 5 mg/kg) and MA (10 mg/kg) were able to significantly ameliorate the loss of body weight in the cisplatin-induced cachectic rats. NOMAc significantly reduced the serum levels of TNF-α at 10 mg/kg. Morphologically, iWAT atrophy, with a remarkable reduction in adipocyte volume, was observed in the cisplatin-induced cachectic rats, but the effects were reversed by administering 5, 10 mg/kg NOMAc or 10 mg/kg MA. Furthermore, 2.5 mg/kg NOMAc markedly reduced the protein expression levels of the lipolysis genes HSL and ATGL, and 5 mg/kg NOMAc markedly enhanced the protein expression levels of adipogenesis genes, including FASN, SREBP-1 and PPARγ in iWAT but not in eWAT. NOMAc was demonstrated to improve cachexia at lower doses compared with MA. Overall, NOMAc is likely to be a promising candidate drug for ameliorating cancer cachexia induced by cisplatin. [ABSTRACT FROM AUTHOR]

Objective: Numerous studies have confirmed a strong association between progestins and meningiomas and the regression and/or stabilization of meningiomas after discontinuation of treatment. Osteomeningiomas represent a small subgroup of meningiomas that appear to be more common among progestin-related meningiomas. However, the specificity of the behavior of this subset of meningiomas after discontinuation of progestin has not yet been assessed., Methods: Thirty-six patients (mean age 49.5 years) who presented with at least one progestin-related osteomeningioma (48 tumors total) were identified from a prospectively collected database of patients and had been referred to our department for meningioma and had documented use of cyproterone acetate, nomegestrol acetate, and/or chlormadinone acetate. Hormonal treatment was stopped at the time of diagnosis for all the patients, and the clinical and radiological evolution of this subgroup of tumors was evaluated., Results: For half of the 36 patients, treatment was prescribed for signs of hyperandrogenism, such as hirsutism, alopecia, or acne. Most lesions were spheno-orbital (35.4%) or frontal (31.2%). Although the tissular part of the meningioma shrank in 77.1% of cases, the osseous part exhibited discordant behavior with 81.3% showing volume progression. The combination of estrogens, as well as the prolonged duration of progestin treatment, seems to increase the risk of progression of the osseous part after treatment discontinuation (p = 0.02 and p = 0.028, respectively). No patient required surgical treatment at diagnosis or during the study., Conclusions: These results show that while the soft intracranial part of progestin-related osteomeningioma tumor is the most likely to regress after treatment discontinuation, the bony part is more likely to increase in volume. These findings suggest the need for careful follow-up of these patients, especially those with tumors near the optical apparatus.

Objective: Nomegestrol acetate (NOMAC), a selective progestogen, and 17β-estradiol (E2), which is identical to endogenous oestrogen, are components of a new monophasic combined oral contraceptive--NOMAC/E2. This study aimed to compare pharmacokinetics (PK) of NOMAC in adolescent and adult women following a single dose of NOMAC/E2.Study Design: Healthy postmenarcheal adolescent (14-17years) and adult (18-50years) women received a single dose of NOMAC/E2 (2.5mg/1.5mg) in this single-centre, open-label, parallel-group Phase 1 study (EudraCT# 2008-002142-38). Blood samples were obtained for PK analysis, and concentrations of NOMAC, E2 and its metabolite estrone (E1) were determined for up to 129h following dosing to obtain PK data. An independent whole-body physiology-based pharmacokinetic (WB-PBPK) simulation model of NOMAC based on an independent Phase 3 dataset was used to scale NOMAC concentration-time plots to adolescents.Results: Overall, 52 women were screened, of whom 30 (15 adolescents and 15 adults) were enrolled. No statistically significant differences were observed between the adolescent and adult groups for the clinically evaluated NOMAC PK parameters [maximum concentration (Cmax), area under the curve (AUC) and half-life (t1/2)]. The PK of E2 and E1 showed extensive overlap between both age groups. The WB-PBPK model accurately predicted NOMAC AUC and Cmax values in both groups.Conclusions: No differences were observed in the clinically evaluated PK parameters for NOMAC between adolescent and adult women after a single dose of NOMAC/E2. The WB-PBPK model accurately predicted NOMAC PK data (EudraCT# 2008-002142-38).Implications: PK studies in adolescents are challenging because of ethical considerations. The whole-body physiology-based model described here complements classic noncompartmental and population PK approaches. The utility of this method is its ability to expand to adolescent postmenarcheal girls by using virtual postmenarcheal adolescent population data and applying physiological scaling. [ABSTRACT FROM AUTHOR]

Nomegestrol acetate (NOMAC), a synthetic progestogen derived from 19-norprogesterone, is an orally active drug with a strong affinity for the progesterone receptor. NOMAC inhibits ovulation and is devoid of undesirable androgenic and estrogenic activities. The aim of this study was to evaluate the pharmacokinetics, tissue distribution, and excretion of NOMAC in female rats. Sprague-Dawley female rats were orally administered a single dose of NOMAC (10, 20 or 40 mg/kg) and drug plasma concentrations at different times were determined by RP-HPLC. Tissue distribution at 1, 2, and 4 h and excretion of NOMAC into bile, urine, and feces after dosing were investigated. The results showed that NOMAC was rapidly absorbed after oral administration, with $$t_{ \hbox{max} }$$ of 1-2 h. The plasma concentration-time curves were fitted in a two-compartment model. The exposure to NOMAC ( $$C_{ \hbox{max} }$$ and $${\text{AUC}}$$ ) increased dose proportionally from 10 to 40 mg/kg. The average CL and $$t_{1/2\beta }$$ were 5.58 L/(h·kg) and 10.8 h, respectively. The highest concentrations of NOMAC in ovary, liver, kidney, lung, heart, brain, spleen, muscle, and uterus were observed at 2 h, whereas the highest concentrations in stomach, pituitary, and hypothalamus appeared at 1 h. The total cumulative excretion of NOMAC in feces (0-72 h), urine (0-72 h), and bile (0-48 h) was ~1.06, 0.03, and 0.08 % of the oral administered dose, respectively. This study indicated that NOMAC had a widespread distribution in tissues, including ovary, pituitary, and hypothalamus, which are main target tissues where NOMAC inhibits ovulation. NOMAC was excreted via both feces and urine with few unchanged NOMAC excreted. Enterohepatic circulation was found in the drug elimination; however, it did not significantly affect $$t_{ \hbox{max} }$$ . [ABSTRACT FROM AUTHOR]

OBJETIVOS: estudar o efeito de um único implante de acetato de nomegestrol (Uniplant) sobre função ovariana, produção do muco cervical e penetração espermática, quando inserido na fase pré-ovulatória. MÉTODOS: estudo clínico aberto, comparativo, incluindo 20 mulheres com ciclos menstruais regulares que foram estudadas durante um ciclo menstrual antes (controle) e um ciclo menstrual depois da inserção do implante. Dosagens de hormônio luteinizante (LH), estradiol e progesterona, ultra-sonografia vaginal, coleta de muco cervical e teste de penetração espermática foram realizados. Para comparação estatística, foi utilizado o Student t-test para grupos pareados e o teste Wilcoxon não paramétrico. Os valores estão mostrados como médias ± erro padrão. RESULTADOS: todos os ciclos controles foram ovulatórios com parâmetros normais. Os níveis pré-ovulatórios de estradiol e LH diminuíram significativamente de 603,2 ± 78,0 pmol/l e 22,5 ± 6,5 UI/l na pré-inserção do implante para 380,7 ± 51,9 pmol/l e 4,9 ± 1,3 UI/l 48 horas após a inserção (p < 0,05 e p < 0,01, respectivamente). Os níveis de progesterona mantiveram-se sem variação significativa após a inserção do implante (ciclo controle = 49,8 ± 3,3 nmol/l e ciclo tratado = 43,2 ± 5,2 nmol/l). Muco cervical e penetração espermática foram profundamente afetados em 10,5% das usuárias após 20 horas da inserção do implante, em 68,5% das usuárias após 24 horas e em 100% após 48 horas. Ruptura folicular ocorreu na maioria dos ciclos tratados após 48 horas da inserção. CONCLUSÕES: o uso de um único implante de acetato de nomegestrol inserido na fase pré-ovulatória afetou os picos pré-ovulatórios de estradiol e LH, a produção do muco cervical e a penetração espermática, mas não foi capaz de impedir a ovulação, o que reforça a necessidade da inserção do implante nos 5 primeiros dias do ciclo menstrual.OBJECTIVE: to study the effect of a single contraceptive implant of nomegestrol acetate (Uniplant) on the ovarian function, cervical mucus production and sperm penetration, when inserted in women in the preovulatory phase. METHODS: twenty women with regular menstrual cycles were included in an open comparative study. All participants were investigated during one menstrual cycle before (control) and one menstrual cycle after implant insertion. Measurements of estradiol, LH, and progesterone, as well as transvaginal sonography, cervical mucus examination and sperm penetration test, were carried out. Statistical analysis was performed with the paired t-test and the non-parametric test of Wilcoxon. RESULTS: all control cycles were ovulatory and presented normal parameters. Preovulatory estradiol and LH peak decreased significantly from 603.2 ± 78.0 pmo/l and 22.5 ± 6.5 IU/l at pre-insertion to 380.7 ± 51.9 pmol/l and 4.9 ± 1.3 IU/l 48 hours after implant insertion (p < 0.05 and p < 0.01, respectively). Progesterone levels did not vary significantly (control cycle = 49.8 ± 3.3 nmol/l and treated cycle = 43.2 ± 5.2 nmol/l). Cervical mucus and sperm penetration tests were profoundly affected in 10.5% of the users 20 h after implant insertion, in 68.5% after 24 h and in 100% after 48 h. Follicular rupture occurred in the majority of the cycles 48 h after implant insertion. CONCLUSIONS: the use of a single implant of nomegestrol acetate affected estradiol and LH preovulatory peaks and disrupted the process of cervical mucus production and sperm penetration, but it was unable to prevent ovulation when inserted at the preovulatory phase, which reinforces the need to insert the implant during the first five days of the menstrual cycle.

Objective: To study the three cycles effect on primary dysmenorrhea of the monophasic 24/4 estradiol/nomegestrol acetate (E2/NOMAC) and of the 21/7 ethinyl-estradiol/chlormadinone acetate (EE/CMA) oral contraceptive. The tolerability and the effect of both preparations on metabolism and health-related quality of life were also evaluated. Design: Prospective observational cohort study. Setting: Tertiary gynecologic center for pelvic pain. Patients: Subjects with primary dysmenorrhea requiring an oral contraceptive, who spontaneously selected either E2/NOMAC (n = 20) or EE/CMA (n = 20). Main outcome measures: Visual Analogue Scale (VAS) score for dysmenorrhea, Short Form-36 questionnaire for health-related quality of life, lipoproteins and days of menstrual bleeding (withdrawal bleeding during oral contraceptive). Results: Mean age and body mass index (BMI) were similar between the two groups. The final analysis was performed on 34 women, 15 in E2/NOMAC and 19 in EE/CMA group. Compliance with treatment was significantly higher with EE/CMA (100%) than E2/NOMAC (75%) (p = 0.02). Both treatments significantly (p < 0.0001) reduced VAS of primary dysmenorrhea, similarly (E2/NOMAC by a mean of 74.7%, EE/CMA by a mean of 78.4%;p = 0.973). Only E2/NOMAC significantly increased SF-36 score (p = 0.001), both in physical (p = 0.001) and mental domains (p = 0.004). The mean number of days of menstrual bleeding was significantly reduced in E2/NOMAC group (from 4.86 ± 1.20 d to 2.64 ± 1.59 d,p = 0.0005 versus baseline,p = 0.007 versus EE/CMA group). BMI did not vary in either group. E2/NOMAC did not change lipoproteins and apoproteins while EE/CMA increased total cholesterol (p = 0.0114), HDL-cholesterol (p = 0.0008), triglycerides (p = 0.002), apoprotein-A1 (Apo-A1;p = 0.0006) and apopoprotein-B (Apo-B;p = 0.008), decreasing LDL/HDL ratio (p = 0.024). Conclusions: Both oral contraceptives reduced similarly primary dysmenorrhea, with E2/NOMAC also reducing withdrawal bleedings and being neutral on lipid metabolism. 目的：研究服用单相24/4 雌二醇/醋酸诺美孕素（E2/NOMAC）与21/7 炔雌醇/醋酸氯地孕素（EE/CMA）口服避孕药三个周期对原发性痛经的治疗作用。且评估药物的耐药性及两种剂型对代谢和健康相关生活质量的影响。 设计：前瞻性观察性队列研究。 机构：第三妇科盆腔疼痛中心。 患者：需服用口服避孕药的原发性痛经患者，自发选择E2/NOMAC（n = 20）或EE/CMA（n = 20）。 主要评估方法：原发性痛经用视觉模拟量表（VAS），简版-36（SF-36）生活质量问卷，脂蛋白及月经经期（服用口服避孕药期间的撤退性出血）。 结果：两组患者的平均年龄与体质量指数（BMI）相似。研究最终分析了34名女性的数据，E2/NOMAC组15名，EE/CMA组19名。EE/CMA组（100%）的治疗依从性显著高于E2/NOMAC组（75%）（p= 0.02）。两种治疗方法均能显著降低患者的原发性痛经VAS评分（p＜ 0.0001），且效果近似（E2/NOMAC组平均为74.7%，EE/CMA组平均为78.4%；p= 0.973）。E2/NOMAC治疗显著升高患者SF-36评分（p= 0.001），无论在生理维度（p= 0.001）还是心理维度（p= 0.004）。E2/NOMAC组的平均月经经期显著缩短（从4.86 ± 1.20天降至2.64 ± 1.59天，p= 0.0005与基线水平相比，p= 0.007与EE/CMA组相比）。两组的BMI均无变化。E2/NOMAC组患者的脂蛋白与载脂蛋白未发生变化，而EE/CMA可升高患者总胆固醇（p= 0.0114）、HDL（p= 0.0008）、甘油三酯（p= 0.002）、载脂蛋白-A1（Apo-A1；p= 0.0006）及载脂蛋白-B（Apo-B；p= 0.008），降低LDL/HDL（p= 0.024）。 结论：两种口服避孕药对于原发性痛经的缓解作用相似。E2/NOMAC可减少撤退性出血，且对血脂代谢没有影响。 [ABSTRACT FROM PUBLISHER]

Objectives To compare premenstrual and menstrual symptoms in healthy women using nomegestrol acetate/17β-estradiol (NOMAC/E2) and drospirenone/ethinylestradiol (DRSP/EE) via the Moos Menstrual Distress Questionnaire Form C (MDQ-C). Methods Women completed the MDQ-C at baseline and after completion of cycles 1, 3, 6 and 13, for the premenstrual (four days before most recent flow) and menstrual (most recent flow) phases in two randomized controlled trials. Treatment effects of NOMAC/E2 and DRSP/EE on the t-scores of eight MDQ-C symptom domains from 3522 women were examined, and the effects of both treatments on the score for cramps from 1779 women with moderate to severe cramps at baseline. Longitudinal data analysis methods were applied in both analyses. Results NOMAC/E2 users experienced a significant improvement in Pain, Water Retention, Negative Affect, Impaired Concentration and Behaviour Change domain scores in the menstrual phase compared with DRSP/EE users ( p < 0.001 for all comparisons). However, Arousal (emotional and mental) scores worsened with NOMAC/E2 but not with DRSP/EE. Women with moderate to severe cramps experienced an improvement in the cramps score with NOMAC/E2 and DRSP/EE. Conclusions NOMAC/E2 was effective in reducing most premenstrual and menstrual symptoms, and was associated with significantly greater improvements in many MDQ-C domain scores compared with DRSP/EE. (: NCT00413062 and NCT00511199). [ABSTRACT FROM AUTHOR]

Nomegestrol acetate (NOMAC) 2.5 mg with 17-beta estradiol (E2) 1.5 mg is a new combined oral contraceptive (COC) formulation and is the first monophasic E2 pill to be marketed, having been licensed for use in Europe in 2011. It is available to be taken daily in a regimen of 24 active pills followed by four placebo pills. NOMAC is a highly selective 19-nor progestogen derivative with specific binding to progesterone receptors, anti-estrogenic activity and no androgenic, mineralocorticoid nor glucocorticoid effects. E2 is an estrogen that is identical to endogenous estrogen. While it has been in use for only a short period of time, current evidence suggests that NOMAC/E2 is just as effective, safe, and acceptable as existing COC preparations. Two large Phase III trials conducted in the Americas and across Europe, Australia, and Asia showed lower cumulative pregnancy rates in the NOMAC/E2 groups compared to the drospirenone (DRSP) 3 mg in combination with ethinyl estradiol (EE) 30 µg (DRSP/EE) groups but this difference was not statistically significant. NOMAC/E2 exhibits a good safety profile and has less effects on cardiovascular risk, hemostatic, metabolic, and endocrine factors in comparison to COCs containing EE in combination with levonorgestrel (LNG) or DRSP . NOMAC/E2 has also been found to cause less breast cell proliferation when compared to E2 alone and has some anti-proliferative effect on human breast cancer cells. NOMAC/E2 is considered acceptable as its compliance, continuation rates, and bleeding patterns were similar to COCs containing DRSP/EE and LNG 150 µg combined with EE 30 µg or LNG 100 µg combined with EE 20 µg (LNG/EE). However, discontinuation was found to be slightly higher in the NOMAC/E2 groups in the two large Phase III trials comparing NOMAC/E2 use with DRSP/EE. As the scientific literature has limited information on NOMAC/E2, further experience with NOMAC/E2 is required. [ABSTRACT FROM AUTHOR]

We assessed the efficacy of biodegradable microspheres (MSs) containing nomegestrol acetate (NOMAC) for treatment of endometriosis in a rat model and investigated its preliminary mechanism of action. Sprague-Dawley rats with surgically implanted endometrial autografts were divided randomly into four groups of thirteen rats each, and subcutaneously injected twice (10 d apart) with either empty MSs or MSs containing nomegestrol acetate (NOMAC-MS; 27–800 mg per kg of rat body weight). Twenty-one days after the first injection, blood and endometriotic tissues were collected and assayed for changes in endometriotic tissue, serum hormone, liver function parameters, and apoptotic protein. No remarkable irritation was observed at the site of injection. NOMAC-MS treatment significantly reduced the volume of the endometrial autografts, decreased serum levels of estradiol, progesterone, triiodothyronine, and alanine aminotransferase, and decreased levels of estrogen receptor alpha protein. Furthermore, NOMAC-MS at the highest dose significantly reduced serum aspartate aminotransferase and endometrial antibody, reduced the Bcl-2/Bax protein ratio, and increased caspase-3 and caspase-9 proteins. There was no pronounced difference observed in alkaline phosphatase, carbohydrate antigen 125, progesterone receptor, or vascular endometrial growth factor receptor 2 (VEGFR2) in any of the tested groups relative to the control. NOMAC-MS significantly changed the expression of apoptotic protein only at the highest dose. Our findings warrant the further investigation of sustained application of steroid hormone via microspheres for the treatment of endometriosis. [ABSTRACT FROM AUTHOR]

Objective Combined oral contraceptives (COCs) containing ethinyl-estradiol are known to increase blood pressure (BP). We evaluated whether COCs containing estradiol (E2) influence 24-h ambulatory BP and heart rate (HR) in normotensive and normal-weight women. Study design Twenty-four-hour BP and HR were measured every 30 min with an ambulatory BP device in 18 normotensive healthy non-smoking women prior to (Days 3–6 of menstrual cycle) and after 6 months of use (Days 20–24 of cycle 6) of a COC containing either a quadriphasic combination of E2 valerate plus dienogest ( n =11) or a monophasic association of micronized E2 plus nomegestrol acetate ( n =7). Results Mean age and body mass index of the final sample were 32.50±7.49 years and 22.87±4.08, respectively. E2-based COCs induced no modification of 24-h systolic BP (+ 1.65±8.34 mmHg; p=.41), diastolic BP (+ 0.04±7.36 mmHg; p=.98), mean BP (+ 0.64±6.42 mmHg; p=.68) or HR (− 0.72±5.86 beats/min; p=.61). Differences were not observed even when daytime or nighttime values were separately considered. Though this was not a comparative study, we did not find differences between the effects of the two formulations (24-h mean BP; p=.699). Conclusions These data suggest a neutral effect of estradiol-based COCs on independent risk factors for cardiovascular diseases such as BP or HR. Implications BP and HR of normotensive women are not increased by E2-based COCs. [ABSTRACT FROM AUTHOR]

Cachexia, a complex disorder that results in depletion of adipose tissue and skeletal muscle, is driven by anorexia, metabolic abnormalities and inflammation. There are limited therapeutic options for this syndrome. Previous evidence has demonstrated that increasing adipose tissue may improve quality of life and survival outcomes in cachexia. Cisplatin, as a chemotherapy drug, also causes cachexia during antitumor therapy due to its adverse effects. To establish a rat model of cachexia, the animals were intraperitoneally treated with cisplatin at doses of 1, 2 and 3 mg/kg, and the rats that responded to cisplatin at the optimal dose were used to test the effect of nomegestrol acetate (NOMAc). Rats that were assessed to be sensitive to cisplatin were randomly grouped and intragastrically administered vehicle, 5 or 10 mg/kg megestrol acetate (MA) or 2.5, 5 or 10 mg/kg NOMAc. The body weights and food consumption of the rats were assessed. Serum IL-6 and TNF-α levels were assessed using ELISA. The protein expression levels of adipose triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), peroxisome proliferator activated receptor γ (PPARγ), fatty acid synthase (FASN) and sterol regulatory element-binding protein-1 (SREBP-1) from inguinal white adipose tissue (iWAT) and epididymal white adipose tissue (eWAT) were evaluated using western blotting. The optimal way to establish a chemotherapy-induced rat model of cachexia demonstrated in the present study was to intraperitoneally administer the rats with 2 mg/kg cisplatin for 3 consecutive days. NOMAc (2.5, 5 mg/kg) and MA (10 mg/kg) were able to significantly ameliorate the loss of body weight in the cisplatin-induced cachectic rats. NOMAc significantly reduced the serum levels of TNF-α at 10 mg/kg. Morphologically, iWAT atrophy, with a remarkable reduction in adipocyte volume, was observed in the cisplatin-induced cachectic rats, but the effects were reversed by administering 5, 10 mg/kg NOMAc or 10 mg/kg MA. Furthermore, 2.5 mg/kg NOMAc markedly reduced the protein expression levels of the lipolysis genes HSL and ATGL, and 5 mg/kg NOMAc markedly enhanced the protein expression levels of adipogenesis genes, including FASN, SREBP-1 and PPARγ in iWAT but not in eWAT. NOMAc was demonstrated to improve cachexia at lower doses compared with MA. Overall, NOMAc is likely to be a promising candidate drug for ameliorating cancer cachexia induced by cisplatin., Competing Interests: The authors declare that they have no competing interests., (Copyright: © Zhong et al.)