The effect of 17ß-estradiol plus norethisterone acetate on blood pressure and inflammation markers: A meta-analysis of randomized controlled trials.

OBJECTIVE: Several randomized controlled trials (RCTs) have explored the impact of 17ß-estradiol plus norethisterone acetate administration on blood pressure and inflammation markers, however, their findings have often been contradictory. Thus, we conducted a systematic review and meta-analysis of RCTs to assess the effects of this drug combination on systolic blood pressure (SBP), diastolic blood pressure (DBP) and C-reactive protein (CRP) concentrations. METHODS: The Cochrane Library, PubMed/Medline, Scopus, and Google Scholar were searched to identify relevant published RCTs. The pooled mean change and standard deviation (SD) of the outcomes were calculated using the STATA software (version 14) for Statistical Computing. RESULTS: A total of 18 publications were included in the current meta-analysis. In total, there were 12 RCT arms on SBP, 12 RCT arms on DBP, and 6 RCT arms on CRP levels. The administration of 17ß-estradiol plus norethisterone acetate intake increased SBP (WMD: 3.48 mmHg, 95% CI: 0.73, 6.23, P = 0.013), particularly in subjects aged ≥ 60 years (WMD: 5.89 mmHg, 95% CI: 1.71, 10.07, P = 0.006) or with a body mass index (BMI) < 30 kg/m2 (WMD: 6.55 mmHg, 95% CI: 2.64, 10.46, P = 0.012), as well as in the RCTs which lasted ≥ 6 months (WMD: 6.47 mmHg, 95% CI: 3.03, 9.90, P < 0.001),when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 4.12 mmHg, 95% CI: 1.03, 7.22, P = 0.009; I2 = 99%, P < 0.001) and in RCTs conducted on healthy postmenopausal women (WMD: 4.22 mmHg, 95% CI: 0.43, 8.01, P = 0.02; I2 = 94%, P < 0.001). DBP decreased following this drug combination in the RCTs which lasted < 6 months (WMD: -1.42 mmHg, 95% CI: -2.27, -0.57, P = 0.001). CRP concentrations increased following the use of this drug combination (WMD: 1.01 mg/L, 95% CI: 0.62, 1.41, P < 0.001), especially in participants aged < 60 years (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001) or with a BMI < 30 kg/m2 (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001), as well as in RCTs with a duration of ≥ 6 months (WMD: 1.15 mg/L, 95% CI: 0.57, 1.73, P < 0.001), when 17ß-estradiol dosages were ≥ 2 mg/day (WMD: 0.97 mg/L, 95% CI: 0.67, 1.27, P < 0.001; I2 = 55%, P = 0.107) and in RCTs conducted on healthy postmenopausal women (WMD: 1.22 mg/L, 95% CI: 0.77, 1.68, P < 0.001; I2 = 90%, P < 0.001). CONCLUSION: The administration of 17ß-estradiol plus norethisterone acetate increases SBP and CRP concentrations and, when prescribed for less than 6 months, decreases DBP. However, despite being statistically significant, the impact of this drug combination on SBP and DBP is not clinically relevant as the variation in blood pressure values was low.

The effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a), atherogenic and anti-atherogenic apolipoproteins levels in postmenopausal women: A meta-analysis of randomized controlled trials.

BACKGROUND AND AIM: The administration of 17ß-estradiol plus norethisterone acetate seems to confer women cardioprotection, however, its impact on lipoprotein (a) and apolipoproteins' concentrations remains unclear. Thus, we conducted a meta-analysis of randomized controlled trials (RCTs) to investigate the effect of 17ß-estradiol plus norethisterone acetate treatment on lipoprotein (a) and apolipoproteins' values in females. METHODS: We systematically searched four databases (PubMed/MEDLINE, Scopus, Embase, and Web of Science) to identify relevant publications published until March 9th, 2022. No language restrictions were applied. The random-effects model (the DerSimonian and Laird methods) was employed to calculate the weighted mean difference (WMD). RESULTS: The administration of 17ß-estradiol plus norethisterone acetate resulted in a significant decrease of lipoprotein (a) (WMD: -67.59 mg/L, 95 % CI: -106.39 to -28.80; P < 0.001) and apolipoprotein B concentrations (WMD: -3.71 mg/dL, 95 % CI: -6.68 to -0.75; P = 0.014), respectively. No effect of 17ß-estradiol plus norethisterone acetate on apolipoprotein AI (WMD: 0.23 mg/dL, 95 % CI: -3.99 to 4.46; P = 0.91) or AII (WMD: 0.21 mg/dL, 95 % CI: -2.24 to 2.68; P = 0.86) concentrations was detected. In the stratified analysis, there was a notable reduction in lipoprotein (a) levels in the RCTs with a duration of ≥6 months (WMD: -73.34 mg/L), in postmenopausal women with a BMI ≥25 kg/m2 (WMD: -69.85 mg/L) and in postmenopausal women aged ˂60 years (WMD: -61.93 mg/L). CONCLUSION: The present meta-analysis of RCTs demonstrates that 17ß-estradiol plus norethisterone acetate treatment reduces lipoprotein (a) and apolipoprotein B levels in postmenopausal women.

Effects of ultra-low dose hormone therapy on biochemical bone turnover markers in postmenopausal women: A randomized, placebo-controlled, double-blind trial.

OBJECTIVE: Evaluate the effects of ultra-low-dose hormone therapy (Ultra-LD HT) with 17ß-estradiol 0.5 mg and norethisterone acetate 0.1 mg (E2 0.5/NETA 0.1) versus placebo on bone turnover markers (BTM) in postmenopausal women. STUDY DESIGN: A multicenter, double-blind, randomized, placebo-controlled study was performed with 107 participants who received one tablet daily of E2 0.5/NETA 0.1 or placebo for 24-weeks. Bone formation markers-N-terminal propeptide of type I procollagen (PINP) and Bone-specific alkaline phosphatase (BSAP), and bone resorption markers-C-telopeptide of type I collagen (CTX-I) and N-telopeptide crosslinked of type I collagen (NTX) were assessed before and at 12 and 24-weeks of treatment. RESULTS: Women treated with E2 0.5/NETA 0.1 had a significant reduction in the PINP marker from baseline (58.49 ± 21.12 µg/L) to week 12 (48.31 ± 20.99 µg/L) and week 24 (39.16 ± 16.50 µg/L). Placebo group, the PINP marker did not differ significantly. The analysis of the BSAP indicated a significant increase in the placebo group (13.8 ± 5.09 µg/L and 16.29 ± 4.3 µg/L, at baseline and week 24, respectively), whereas in the treatment group the values did not change. The analysis of the NTX marker showed a significant reduction only in the treatment group (43.21 ± 15.26 nM/mM and 33.89 ± 14.9 nM/mM, at baseline and week 24, respectively). CTX-I had a significant decrease in the treatment group from baseline (0.3 ± 0.16 ng/L) to week 12 (0.21 ± 0.14 ng/L) and week 24 (0.21 ± 0.12 ng/L). CONCLUSION: Women receiving E2 0.5/NETA 0.1 experienced reductions in bone resorption and formation markers, an expected effect during the anti-resorptive therapy, suggesting a protective bone effect with the Ultra-LD HT.

Effects of drospirenone and norethisterone acetate combined with estradiol on mammographic density and proliferation of breast epithelial cells-A prospective randomized trial.

OBJECTIVE: There are no previous data on the influence of drospirenone (DRSP) in combination with estradiol (E2) on the breast in postmenopausal women. The objective of this study was to evaluate the effect of DRSP or norethisterone acetate (NETA) in continuous combination with E2 on two surrogate markers for breast cancer - mammographic breast density and proliferation of breast epithelial cells - in healthy postmenopausal women. STUDY DESIGN: 120 healthy, naturally postmenopausal women were randomized to either 2 mg of DRSP or 0.5 mg of NETA in continuous combination with 1 mg of oral E2. The women underwent mammography and fine-needle aspiration biopsy of the breast at baseline and after six months of treatment. MAIN OUTCOME MEASURES: Digitized mammographic breast density and breast cell proliferation. RESULTS: There was a significant increase in mammographic breast density after treatment in both groups (median increase 5.5% for E2/DRSP and 2.3% for E2/NETA, respectively, p < 0.001), but with no significant difference between groups. The proliferation of breast epithelial cells also increased in both groups (p < 0.001, respectively), with a significantly larger increase in the E2/DRSP group than in the E2/NETA group (2.5% versus 0.7%, respectively, p < 0.05). Systolic blood pressure had decreased significantly after 6 months of treatment in the E2/DRSP group (p < 0.05) but not in the E2/NETA group. CONCLUSIONS: Breast density increased to a similar degree with E2/DRSP and E2/NETA. Proliferation of breast epithelial cells also increased significantly in both groups but was slightly more pronounced in the E2/DRSP group.