| Objectives: With the increasing prevalence of hypertension and the tendency to become younger,many women of childbearing age suffer from hypertension.There is increasing evidence that the prevalence of sexual dysfunction in women with hypertension is higher than that in women with normal blood pressure at the same age.We reviewed the relationship between hypertension and antihypertensive drugs and female sexual function,performed a meta-analysis to compare the prevalence of sexual dysfunction and the score of female sexual function index(FSFI)scale with that of normotensive women.Methods: We search MEDLINE(1966-2022),Cochrane Clinical Trial Registration Center(Issue12022),EMBASE(1900-2022)and SCI(1974-2022)with the words "sexual function","sexual dysfunction","sexual orders","sexual activity","sexual desire","frigidity","hypertension","hypertensive","women" or "female".Studies providing prevalence of sexual function or sexual dysfunction in women with hypertension and women with normal blood pressure were included.The main outcome was to compare the prevalence of sexual dysfunction between hypertensive women and normotensive women.The secondary outcome was to compare the difference of total scores and scores for all of the domains of FSFI(including sexual desire,sexual arousal,orgasm,sexual satisfaction and pain)between hypertensive women and women with normal blood pressure after evaluation with FSFI scale.Then,we reviewed the current evidence of the impacts of antihypertensive therapy on female sexual function.The Cochrane systematic review management software Rev Man 5.3 was used for data analysis and synthesis.Results: Eight studies including a total of 1937 participants(1037 hypertensive women and 900 normotensive women)were included in meta-analysis.The prevalence of FSD was higher than that of normotensive women(OR 3.24 [2.23‐4.69],P<0.01).The total score of FSFI(-4.67 [95%CI—5.74,-3.60],P<0.01)and four domains including sexual desire(-0.90 [95%CI--1.23,-0.56],P<0.01),sexual arousal(-1.09 [95%CI--1.51,-0.67],P < 0.01),vaginal lubrication(-0.90 [95%CI--1.45,-0.35],P<0.01)and pain(-0.68 [95%C--0.87,-0.48],P<0.01)were lower than that of normotensive women.The effect of antihypertensive drugs on sexual function in women is not yet conclusive,but there is evidence that angiotensin receptor inhibitor(ARB)may have some effects on sexual function in hypertensive women.Angiotensin-converting enzyme inhibitor(ACEI)may have beneficial effects,or at least no adverse effects on sexual function in hypertensive women.Diuretics and beta-blockers may cause female sexual dysfunction.Conclusion: The prevalence of FSD is higher in women with hypertension.The scores for sexual desire,sexual arousal,vaginal lubrication,pain and the total scores for FSFI are lower in women with hypertension.The impacts of antihypertensive agents on female sexual function still lack evidence.ARB and ACEI might be beneficial.Objective: The role of renin angiotensin system inhibitors(RAS-I)in the prevention and treatment of hypertension mediated target organ damage(HMOD)is beyond doubt.Our previous research shows that the sexual organs are also target organs of hypertension,and sacubitril/valsartan can reduce the vascular remodeling and fibrosis of the lower genital tract caused by hypertension.For another two kinds of widely used renin angiotensin system(RAS)inhibitors: angiotensin converting enzyme inhibitor(ACEI)and angiotensin receptor blocker(ARB)on sexual function,studies generally tend to support that ARB are more superior than ACEI to the effects on sexual dysfunction in hypertensive patients.This research intends to compare the potential beneficial effects of ACEI and ARB on vascular remodeling and fibrosis in the myocardial and lower genital tract of females,and to explore whether hypertension has synchronous HMOD to sexual organs and heart,and the similarities and differences of the effects of these two types of RAS inhibitors on the remodeling of female sexual organs and heart.Methods: Sixteen-week-old female spontaneously hypertensive rats(SHRs)and Wistar-Kyoto(WKY)rats were allocated to four groups: SHR + Irb(N = 13),which received irbesartan;SHR + Ben(N = 13),which received benazepril;control SHR(N = 13),which received vehicle;and control WKY(N = 13),which received vehicle.After 12 weeks,the left ventricular myocardium and vaginal tissues of the rats were excised for analysis by real-time PCR and Western blot to detect the expression of RAS components including ACE,ACE2,ATl R,AT2 R,Mas R and e NOS,α-SMA and Col III.Immunohistochemistry was also performed on myocardium and lower genital tract tissues to detect the expression of α-SMA and Col III and TGF-β1.The collagen fiber deposition in vaginal tissue was measured by Masson trichrome staining.Results: At the 12 th week,the mean SBP in SHR group was 190.5 ± 10.4 mm Hg,that in SHR + Irb group was 131.7 ± 7.2 mm Hg,and that in SHR + Ben group was 133.0 ± 8.1 mm Hg.The mean SBP were lower in SHR + Irb and SHR + Ben group than in SHR group(P<0.05 for all),and there was no statistical difference between SHR + Irb and SHR + Ben group(P>0.05).The mean DBP in SHR group was 108.5 ± 4.8 mm Hg,the mean DBP in SHR + Irb group was 81.4 ± 6.5 mm Hg,and in SHR + Ben group was 80.6 ± 6.2 mm Hg.The mean DBP were lower in SHR + Irb and SHR + Ben group than in SHR group(all P<0.05),and there was no statistical difference between SHR + Irb and SHR + Ben group(P>0.05).SHR group showed left ventricular hypertrophy and decreased diastolic function.Compared with WKY group,SHR group had increased IVSd(1.83 ± 0.14 mm vs.1.28 ± 0.14 mm,P<0.05)and LVPWd(2.19 ± 0.32 mm vs.1.21 ± 0.16 mm,P<0.05).IVSd and LVPWd in SHR + Irb group decreased compared with SHR group(1.46 ± 0.15 mm vs.1.83 ± 0.14 mm,1.55 ± 0.20 mm vs.2.19 ± 0.32 mm,P<0.05 respectively).IVSd and LVPWd in SHR + Ben group were lower than those in SHR group(1.42 ± 0.13 mm vs.1.83 ± 0.14 mm,1.51 ± 0.18 mm vs.2.19 ± 0.32 mm,P<0.05 respectively).IVSd,LVPWd,LVEDd,EF and FS in SHR + Irb group were not statistically different from those in SHR+Ben group(all P>0.05).Compared with WKY group,E/E’ in SHR group increased(28.35 ± 1.80 vs.20.06 ± 1.09,P<0.05),E’/A’ decreased(0.57 ± 0.10 vs 1.42 ± 0.11,P<0.05).E/E’ in SHR+Irb group was lower than that in SHR group(22.76 ± 2.67 vs.28.35 ± 1.80,P<0.05),E’/A’ was higher than that in SHR group(1.40 ± 0.12 vs.0.57 ± 0.10,P<0.05).E/E’ in SHR+Ben group was lower than that in SHR group(23.29 ± 2.10 vs.28.35 ± 1.80,P<0.05),E’/A’ was higher that in SHR group(1.35 ± 0.09 vs.0.57 ± 0.10,P<0.05).There was no significant difference in E/E’ and E’/A’ between SHR + Irb group and SHR + Ben group(P>0.05 for all).SHR showed left ventricular hypertrophy and decreased diastolic function.Western blot analysis indicated that the expression of Col III,TGF-β1 increased(P<0.05 for all),while the expression of e NOS decreased(P<0.05)in myocardium of SHR.Irbesartan and benazepril both reduced the expression of TGF-β1 and Col III in myocardium(P<0.01 for all)and enhance the expression of e NOS(P<0.01).Benazepril decreased Col III and TGF-β1 and up-regulate e NOS expression in myocardium slightly superior than irbesartan(P<0.05).Vaginal RAS components expression were changed in the control SHRs compared to that in the WKYs(P<0.01 for all).A reduction in the AT1 R expression was observed in the SHR + Irb and SHR + Ben groups(P<0.01 for all).Irbesartan upregulated the AT2 R,Mas R and ACE expressions(P<0.05 for all)and remarkably increased the ACE2 expression(P<0.01).In contrast,the AT2 R,Mas R and ACE expressions were downregulated in the SHR + Ben group(P<0.01,P<0.01,P<0.05).Results of western blot analysis showed that a significant increase in vaginal α-SMA(P<0.01),as well as a reduction in e NOS(P<0.01),was observed in the control SHRs compared with that in the WKYs.Both irbesartan and benazepril elicited a marked decrease in vaginal α-SMA expression(P<0.01 for all)as well as decrease in Col III expression(P<0.05 for all),and caused increments of e NOS expression(P<0.01 for all).There was no significant difference in the vaginal α-SMA,Col III and e NOS expression levels in the SHR + Irb and SHR + Ben groups(P>0.05).Masson trichrome staining showed that the collagen fibers in the vaginal tissue in the SHR group increased(P < 0.01).Both irbesartan and benazepril decreased the collagen fibers(p < 0.05 for all)without group differences(P>0.05).Immunohistochemical results showed that the clitoral glands,inferior genital arterioles and arterioles,and paraurethral erectile tissues of female SHR had undergone morphological changes at 28 weeks including vascular remodeling and fibrosis,and the clitoral glands showed characteristics similar with aging rats.Irbesartan and benazepril both reduced wall/lumen ratio(P<0.05)and α-SMA expression(P<0.05)of vaginal arterials,alleviated morphological changes in clitoral glands,reduced α-SMA and Col Ⅲ expression of clitoral glands(P<0.05 for all)and reduced Col Ⅲ expression of paraurethral erectile tissues(P<0.05)equally.Conclusions: In this study,we observed that irbesartan and benazepril had different effects on RAS expression in myocardium and female lower genital tract.Compared with irbesartan,benazepril has better effects on indicators of left ventricular myocardial vascular remodeling and fibrosis in female hypertensive rats.However,ACEI and ARB have similar positive effects against vascular and structure remodeling and fibrosis in the female lower genital tract in female hypertensive rats.Objectives: A better control of blood pressure to the target level is necessary to prevent cardiovascular and cerebrovascular events.Antihypertensive combination therapy is an important method to raise the blood pressure control rate.The aim of this study was to evaluate the impacts of two antihypertensive combination regimens: angiotensin receptor blocker irbesartan combined with calcium channel blocker felodipine,and felodipine combined with a β blocker metoprolol succinate(a combination therapy recommended by the Chinese hypertension guidelines and widely used in China),on blood pressure,sexual function,sex hormones and indicators of oxidative stress in women with hypertension.Methods: Total of 160 women,aged 18-60 years,with newly diagnosed,previously untreated no less than one month,mild or moderate hypertension(systolic blood pressure[SBP] ≥140 mm Hg and<180 mm Hg,and/or diastolic blood pressure [DBP] ≥90 mm Hg and<110 mm Hg)were randomized to a treatment with irbesartan150 mg +felodipine 5-10 mg once daily(I+F,n=80),or felodipine 5-10 mg + metoprolol 47.5 mg once daily(F+M,n=80)for 2 years.At baseline,the first year and the 2nd year,office blood pressure measurement and ambulatory blood pressure monitoring were performed.Patients’ sexual function was evaluated using a female sexual function index(FSFI)questionnaire.Concentrations of sex hormones including serum estradiol,testosterone,FSH and SHBG,and indicators of oxidative stress including levels of serum 8-Hydroxy-2’-deoxyguanosine(8-OHd G),4-hydroxynonenal(HNE)and malondialdehyde(MDA)were measured in the meantime.The differences in the office blood pressure,ambulatory blood pressure,FSFI scores,serum sex hormone concentrations and oxidative stress indicators of the two groups of hypertensive participants before and after treatment were analyzed.The research was approved by the Ethics Committee of Lanzhou University Second Hospital and registered on the Clinical Trial.gov website.Results: Of the 160 female hypertensive participants,141 completed the first year of follow-up,and 124 completed the second year of follow-up.All the normotensive female participants completed the first year of follow-up,and 43 completed the second year of follow-up.The mean blood pressure at baseline was 157.4/101.6 mm Hg in the I+F group and 156.1/102.3 mm Hg in the F+M group.There was no statistical difference between the two groups(both SBP and DBP P>0.05).At the first year of follow-up,the mean blood pressure was 127.9/80.3 mm Hg in I+F group and 127.0/79.2 mm Hg in F+M group,and there was no statistical difference between the two groups(SBP and DBP P>0.05).By the second year of follow-up,the mean blood pressure was 129.4/81.5 mm Hg in I+F group and 130.2/80.7 mm Hg in F+M group,and there was no statistical difference between the two groups(both SBP and DBP P>0.05).The blood pressure control rate in the 4th week,8th week,12 th week,24 th week,the first and second year were 72.7%,79.3%,83.3%,84.7%,85.6% and 83.3% respectively in I+F group and 75.3%,81.7%,84.4%,85.8%,86.2%,83.8% respectively F+M group.At baseline,60.4%(96/160)of hypertensive participants had FSD,which was higher than that of normotensive participants(60.4% vs.26%,P<0.01).The results of ambulatory blood pressure monitoring in I+F group and F+M group at 1 and 2 years of follow-up showed that there was no significant difference 24 h SBP,24 h DBP,d SBP,d DBP,n SBP and n DBP between the I+F group and F+M group(all P>0.05).In the I+F group,the scores of sexual desire,sexual arousal,and sexual satisfaction were higher than those at baseline(P<0.01,P<0.01,P<0.05)at the first year of follow-up,and the total FSFI score was higher than the baseline(P<0.01).At the second year of follow-up,the scores of sexual desire,sexual arousal,lubrication and sexual satisfaction were higher than those at baseline(all P<0.01),and the total score of FSFI was higher than baseline(P<0.01).In the F+M group,the score of the vaginal lubrication level decreased from baseline at the first year of follow-up(P<0.01).At the second year of follow-up,the scores of sexual desire and sexual arousal were higher than those at the baseline(P<0.05,P<0.01,respectively),and the total score of FSFI was higher than the FSFI score at baseline(P<0.05).The improvement of total FSFI score was higher in I+F group(P<0.01).In the I+F group,serum Er levels were higher than baseline at the first and second years of follow-up(P<0.01 for all),and serum T levels were lower than baseline at the first and second years of follow-up(P<0.01 for all).Serum FSH levels were lower than baseline at the first and second years of follow-up(P<0.01,P<0.05),and serum SHBG levels were higher than baseline at the first and second years of follow-up(P<0.01 for all).In the F+M group,serum Er levels were lower at the first year and second year of follow-up(P<0.01 for all).Serum T levels were higher than baseline at the first year and second year of follow-up(P<0.01 for all).Serum FSH levels were not significantly different from baseline at the first and second year of follow-up(P<0.01 for all).Serum SHBG levels were lower than baseline at the first year of follow-up(P<0.05),and had no statistical difference compared with baseline at the second year of follow-up(P>0.05).At the first year of follow-up and the second year of follow-up,serum 8-OHd G levels in the I+F group decreased compared with baseline(P<0.01 for all).Serum HNE levels decreased compared with baseline(P<0.01 for all),Serum MDA levels also decreased compared with baseline(P<0.01 for all).Serum 8-OHd G levels in the F+M group decreased compared with baseline at the second year of follow-up(P<0.05).Serum HNE levels decreased compared with baseline at the first and second year of follow-up(P<0.05 for all).Serum MDA levels decreased compared with baseline at the first and second year of follow-up(P<0.01 for all).The levels of 8-OHd G,HNE and MDA decreased more significantly in the I+F group than F+M group(P<0.05 for all).Conclusion: These results suggest that irbesartan-felodipine combination regiment improves sexual function more in hypertensive women than the felodipine-metoprolol regiment,despite of the similar blood pressure reductive effects.Reasons for the different influences of these two combination regimens on female sexual function might be their different impacts on oxidative stress and hormone levels. |
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