抗高血压药物的男性生殖风险
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摘要
目的探讨育龄期男性使用抗高血压药物时的生殖风险。方法以PubMed、Web of Science、EMbase、Scopus、中国知网(CNKI)、维普中文期刊数据库(VIP)和万方数据库(Wanfang Data)为数据源,计算机检索建库至2017年12月公开发表的有关抗高血压药物男性生殖风险的研究,手工检索纳入文章中的重要参考文献作为补充,概述抗高血压药物对男性生殖功能的影响及其机制。结果β受体阻断药和利尿药与男性性功能障碍的发生有一定相关性,血管紧张素转换酶抑制药、血管紧张素受体阻断药和钙通道阻滞药对男性性功能影响较小,甚或有正向影响。卡托普利和依那普利能改善精子质量参数,推荐育龄期高血压患者优先选择使用。β受体阻断药、利尿剂和钙通道阻滞剂在体外和动物实验中显示对精子质量有一定的负面影响,但缺乏进一步的临床研究。结论目前抗高血压药物生殖风险的相关研究较少,且多局限于动物研究和体外研究,尚需要长期和大规模临床研究进一步证实。育龄期男性在使用抗高血压药物时,建议医生或药师充分告知患者不同抗高血压药物的生殖风险,消除患者的顾虑,避免患者因考虑到药物的生殖风险而自行停药。服药期间出现生殖相关问题时,应该考虑到药物因素。
Objective To explore the reproductive risk of antihypertensive drugs in men of childbearing age.Methods PubMed,Web of Science,EMbase,Scopus,Chinese National Knowledge Infrastructure( CNKI),VIP Information and Wanfang Data were used as data sources. The studies on male reproductive risk of antihypertensive drugs published until December 2017 were collected by search strategy,and supplemented by manual retrieval of important references. Results The analysis showed that β receptor blockers and diuretics were related to the occurrence of male sexual dysfunction,however,angiotensin converting enzyme inhibitors,angiotensin receptor blockers and calcium channel blockers had little effect,or even a positive impact on male sexual function.Captopril and enalapril can improve sperm quality parameters and are recommended for use in hypertensive patients of child bearing age. The β-blockers,diuretics and calcium channel blockers have some negative effects on sperm quality in vitro and in animal experiments,but there is a lack of further clinical research. Conclusion Currently,there are few studies focused on reproductive risk of antihypertensive drugs,and most of them are based on animal or in vitro studies.It is still a problem need to further confirm by long-term and large-scale clinical studies. When male patients of childbearing age using antihypertensive drugs,it is recommended that doctors or pharmacists fully inform patients of the reproductive risks of different antihypertensive drugs,dispel patients' concerns,and prevent patients from stopping drugs on their own because of the reproductive risks. At the same time,drug factors should be taken into account when reproductive problems occur during these medications use.
Objective To explore the reproductive risk of antihypertensive drugs in men of childbearing age.Methods PubMed,Web of Science,EMbase,Scopus,Chinese National Knowledge Infrastructure( CNKI),VIP Information and Wanfang Data were used as data sources. The studies on male reproductive risk of antihypertensive drugs published until December 2017 were collected by search strategy,and supplemented by manual retrieval of important references. Results The analysis showed that β receptor blockers and diuretics were related to the occurrence of male sexual dysfunction,however,angiotensin converting enzyme inhibitors,angiotensin receptor blockers and calcium channel blockers had little effect,or even a positive impact on male sexual function.Captopril and enalapril can improve sperm quality parameters and are recommended for use in hypertensive patients of child bearing age. The β-blockers,diuretics and calcium channel blockers have some negative effects on sperm quality in vitro and in animal experiments,but there is a lack of further clinical research. Conclusion Currently,there are few studies focused on reproductive risk of antihypertensive drugs,and most of them are based on animal or in vitro studies.It is still a problem need to further confirm by long-term and large-scale clinical studies. When male patients of childbearing age using antihypertensive drugs,it is recommended that doctors or pharmacists fully inform patients of the reproductive risks of different antihypertensive drugs,dispel patients' concerns,and prevent patients from stopping drugs on their own because of the reproductive risks. At the same time,drug factors should be taken into account when reproductive problems occur during these medications use.
引文
[1]ALKHAJA K A,SEQUEIRA R P,ALKHAJA A K,et al.Antihypertensive drugs and male sexual dysfunction:a review of adult hypertension guideline recommendations[J].J Cardiovasc Pharmacol The,2016,21(3):233-244.
[2]PARTHASARATHY H K,JOEL M,WHITE W B,et al.Adouble-blind,randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism[J].J Hypertens,2011,29(5):980-990.
[3]SAMPLASKI M K,NANGIA A K.Adverse effects of common medications on male fertility[J].Nat Rev Urol,2016,12(7):401-413.
[4]MANOLIS A,DOUMAS M.Antihypertensive treatment and sexual dysfunction[J].Curr Hypertens Rep,2012,14(4):285-292.
[5]FRANZEN D,METHA A,SEIFERT N,et al.Effects of beta-blockers on sexual performance in men with coronary heart disease.a prospective,randomized and double blinded study[J].Int J Impot Res,2001,13(6):348-351.
[6]ALBERTO C,VICENTE B M,PILAR M,et al.Erectile dysfunction in high-risk hypertensive patients treated with beta-blockade agents[J].Cardiovasc Ther,2010,28(1):15-22.
[7]FOGARI R,ZOPPI A,POLETTI L,et al.Sexual activity in hypertensive men treated with valsartan or carvedilol:a crossover study[J].Am J Hypertens,2001,14(1):27-31.
[8]FERDINANDO F,MARCO F,NICOLA L,et al.The impact of non-urologic drugs on sexual function in men[J].Arch Ital Urol Androl,2014,86(1):50-55.
[9]钟翠玲,葛仁山.消旋普萘洛尔抑制豚鼠精子体外获能,顶体反应和精卵融合[J].中国药理学报,1990,2(11):169-172.
[10]HONG C Y,TURNER P.Influence of lipid solubility on the sperm immobilizing effect of beta-adrenoceptor blocking drugs[J].Br J Clin Pharmacol,2012,14(2):269-272.
[11]ABERG G,ADLER G,DUKER G,et al.Effects of adrenergic beta-blockers and a membrane stabilizing agent on ouabain-induced cardiac arrhythmias in anaesthetized guinea pigs[J].Acta Pharmacol Toxicol(Copenh),2010,45(2):102-106.
[12]HAYASHI T,MIYATA A,YAMADA T.The impact of commonly prescribed drugs on male fertility[J].Hum Fertil(Camb),2008,11(3):191-196.
[13]EID A H,ABDELKADER N F,EL-RAOUF O M A,et al.Carvedilol alleviates testicular and spermatological damage induced by cisplatin in rats via modulation of oxidative stress and inflammation[J].Arch Pharm Res,2016,39(12):1693-1702.
[14]EL-SAYED M G,EL-SAYED M T,EL S E A,et al.Effects of some beta-adrenergic blockers on male fertility parameters in rats[J].Dtsch Tierarztl Wochenschr,1998,105(1):10-12.
[15]SHALIUTINA O,GAZO I,SHALIUTINA-KOLEOVA,et al.The in vitro effect of nonylphenol,propranolol,and diethylstilbestrol on quality parameters and oxidative stress in sterlet(Acipenser ruthenus)spermatozoa[J].Toxicol In Vitro,2017,43(1):9-15.
[16]NUSIER M K,BATAINEH H N,DARADKA H M.Adverse effects of propranolol on reproductive function in adult male mice[J].Pak J Biol Sci,2007,10(16):2728-2731.
[17]LI-LI L,DONG W,WEI W,et al.Long-term treatment of clonidine,atenolol,amlodipine and dihydrochlorothiazide,but not enalapril,impairs the sexual function in male spontaneously hypertensive rats[J].PLoS One,2015,10(1):116-129.
[18]NUDELL D M,MONOSKI M M,LIPSHULTZ L I.Common medications and drugs:how they affect male fertility[J].Urol Clin North Am,2002,29(4):965-973.
[19]陈义珊,蓝朝廷.氢氯噻嗪合ACEI致性功能障碍37例[J].浙江中西医结合杂志,2008,18(6):390-391.
[20]OPIE L H.Diuretic downsides-but in low doses they still seem among the best authenticated antihypertensives[J].Cardiovasc Drugs Ther,2000,14(4):407-409.
[21]刘培君,余静,康秀峰,等.不同药物联合对男性高血压患者勃起功能的影响[J].中华高血压杂志,2010,4(18):365-369.
[22]MILLSOP J W,HELLER M M,ELIASON M J,et al.Dermatological medication effects on male fertility[J].Dermatol Ther,2013,26(4):337-346.
[23]贺汉军.螺内酯小剂量短期治疗引起男性乳房肿大及性功能低下[J].药物不良反应杂志,2010,12(1):41.
[24]WONG P Y,LEE W M.Effects of spironolactone(aldosterone antagonist)on electrolyte and water content of the cauda epididymidis and fertility of male rats[J].Biol Reprod,1982,27(4):771-777.
[25]JENKINS A D,LECHENE C,HOWARDS S S,et al.The effect of spironolactone on the elemental composition of the intraluminal fluids of the seminiferous tubules,eete testis and epididymis of the rat[J].J Urol,1983,129(4):851-854.
[26]KHN F M,MLLER C,DRESCHER D,et al.Effect of angiotensin converting enzyme(ACE)and angiotensins on human sperm functions[J].Andrologia,1998,30(4-5):207-215.
[27]CHRYSANT S G.Antihypertensive therapy causes erectile dysfunction.[J].Curr Opin Cardiol,2015,30(4):383-390.
[28]SCHILL W B,PARSCH E M,MISKA W.Inhibition of angiotensin-converting enzyme:a new concept of medical treatment of male infertility?[J].Fertil Steril,1994,61(6):1123-1128.
[29]姚华雄,刘继红.卡托普利体外对人精子运动参数的影响[J].中华男科学杂志,2006,12(5):435-437.
[30]NAGAOKA S,KAWASAKI S,KAWASAKI H,et al.The angiotensin converting enzyme(ACE)inhibitor,captopril disrupts the motility activation of sperm from the silkworm,Bombyx mori[J].J Insect Physiol,2017,2017(103):18-28.
[31]SOMLEV B,SUBEV M.Effect of kininase II inhibitors on bradykinin-stimulated bovine sperm motility[J].Theriogenology,1998,50(4):651-657.
[32]K HLER-SAMOUILIDIS G,SCHMIDT-ADAMOPOULOUB,SAMOUILIDIS S,et al.Effects of captopril on the male reproductive organs and various semen parameters of rabbits[J].Berl Munch Tierarztl Wochenschr,1997,110(6):201-205.
[33]OKEAHIALAM B N,AMADI K,AMEH A S.Effect of lisnopril,an angiotensin converting enzyme(ACE)inhibitor on spermatogenesis in rats[J].Arch Androl,2006,52(3):209-213.
[34]SAHA L,GARG S K,BHARGAVA V K,et al.Role of angiotensin-converting enzyme inhibitor,lisinopril,on spermatozoal functions in rats[J].Methods Find Exp Clin Pharmacol,2000,22(3):159-162.
[35]BECHARA G R,SOUZA D B D,MICHELE S,et al.Testicular morphology and spermatozoid parameters in spontaneously hypertensive rats treated with enalapril[J].JUrol,2015,194(5):1498-1503.
[36]KUSHWAHA S,JENA G B.Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat:investigation on possible mechanisms[J].Naunyn Schmiedebergs Arch Pharmacol,2012,385(2):111-124.
[37]BAUMH KEL M,SCHLIMMER N,KRATZ M,et al.Cardiovascular risk,drugs and erectile function:a systematic analysis[J].Int J Clin Pract,2015,65(3):289-298.
[38]DING J,SHANG X,ZHANG Z,et al.FDA-approved medications that impair human spermatogenesis[J].Oncotarget,2016,8(6):10714-10725.
[39]KANWAR U,ANAND R J,SANYAL S N.The effect of nifedipine,a calcium channel blocker,on human spermatozoal functions[J].Contraception,1993,48(5):453-470.
[40]LATIF R,ASLAM M,MEHMOOD T.Spermatogenesis following discontinuation of calcium channel blocker amlodipine in rats[J].J Ayub Med Coll Abbottabad,2009,21(1):25-27.
[41]MORAKINYO A O,IRANLOYE B O,ADEGOKE O A.Antireproductive effect of calcium channel blockers on male rats[J].Reprod Med Biol,2009,8(3):97-102.
[42]KATSOFF D,CHECK J H.A challenge to the concept that the use of calcium channel blockers causes reversible male infertility[J].Hum Reprod,1997,12(7):1480-1482.
[43]ANAND R J K,KANWAR U,SANYAL S N.Calcium channel antagonist verapamil modulates human spermatozoal functions[J].Res Exp Med(Berl),1994,194(1):165-178.
[44]MEHDI S,ALI N,SAIED K D,et al.Comparison of the protective effects of papaverine,lidocaine and verapamil on the sperm quality of the testis after induced torsion-detorsion in rats[J].Scand J Urol Nephrol,2010,44(3):133-137.
[45]IRANLOYE B O,MORAKINYO A O,UWAH J,et al.Effect of nifedipine on reproductive functions in male rats[J].Nig Q J Hosp Med,2009,19(3):165-168.
[46]AYODELE M,BOLANLE I,OLUFEYISIPE A.Calcium antagonists modulate oxidative stress and acrosomal reaction in rat spermatozoa[J].Arch Med Sci,2011,7(4):613-618.
[47]MORAKINYO A O,IRANLOYE B O,DARAMOLA A O,et al.Antifertility effect of calcium channel blockers on male rats:association with oxidative stress[J].Adv Med Sci,2011,56(1):95-105.
[48]SHIMIZU S,TSOUNAPI P,HONDA M,et al.Effect of an angiotensin II receptor blocker and a calcium channel blocker on hypertension associated penile dysfunction in a rat model[J].Biomed Res,2014,35(3):215-221.
[2]PARTHASARATHY H K,JOEL M,WHITE W B,et al.Adouble-blind,randomized study comparing the antihypertensive effect of eplerenone and spironolactone in patients with hypertension and evidence of primary aldosteronism[J].J Hypertens,2011,29(5):980-990.
[3]SAMPLASKI M K,NANGIA A K.Adverse effects of common medications on male fertility[J].Nat Rev Urol,2016,12(7):401-413.
[4]MANOLIS A,DOUMAS M.Antihypertensive treatment and sexual dysfunction[J].Curr Hypertens Rep,2012,14(4):285-292.
[5]FRANZEN D,METHA A,SEIFERT N,et al.Effects of beta-blockers on sexual performance in men with coronary heart disease.a prospective,randomized and double blinded study[J].Int J Impot Res,2001,13(6):348-351.
[6]ALBERTO C,VICENTE B M,PILAR M,et al.Erectile dysfunction in high-risk hypertensive patients treated with beta-blockade agents[J].Cardiovasc Ther,2010,28(1):15-22.
[7]FOGARI R,ZOPPI A,POLETTI L,et al.Sexual activity in hypertensive men treated with valsartan or carvedilol:a crossover study[J].Am J Hypertens,2001,14(1):27-31.
[8]FERDINANDO F,MARCO F,NICOLA L,et al.The impact of non-urologic drugs on sexual function in men[J].Arch Ital Urol Androl,2014,86(1):50-55.
[9]钟翠玲,葛仁山.消旋普萘洛尔抑制豚鼠精子体外获能,顶体反应和精卵融合[J].中国药理学报,1990,2(11):169-172.
[10]HONG C Y,TURNER P.Influence of lipid solubility on the sperm immobilizing effect of beta-adrenoceptor blocking drugs[J].Br J Clin Pharmacol,2012,14(2):269-272.
[11]ABERG G,ADLER G,DUKER G,et al.Effects of adrenergic beta-blockers and a membrane stabilizing agent on ouabain-induced cardiac arrhythmias in anaesthetized guinea pigs[J].Acta Pharmacol Toxicol(Copenh),2010,45(2):102-106.
[12]HAYASHI T,MIYATA A,YAMADA T.The impact of commonly prescribed drugs on male fertility[J].Hum Fertil(Camb),2008,11(3):191-196.
[13]EID A H,ABDELKADER N F,EL-RAOUF O M A,et al.Carvedilol alleviates testicular and spermatological damage induced by cisplatin in rats via modulation of oxidative stress and inflammation[J].Arch Pharm Res,2016,39(12):1693-1702.
[14]EL-SAYED M G,EL-SAYED M T,EL S E A,et al.Effects of some beta-adrenergic blockers on male fertility parameters in rats[J].Dtsch Tierarztl Wochenschr,1998,105(1):10-12.
[15]SHALIUTINA O,GAZO I,SHALIUTINA-KOLEOVA,et al.The in vitro effect of nonylphenol,propranolol,and diethylstilbestrol on quality parameters and oxidative stress in sterlet(Acipenser ruthenus)spermatozoa[J].Toxicol In Vitro,2017,43(1):9-15.
[16]NUSIER M K,BATAINEH H N,DARADKA H M.Adverse effects of propranolol on reproductive function in adult male mice[J].Pak J Biol Sci,2007,10(16):2728-2731.
[17]LI-LI L,DONG W,WEI W,et al.Long-term treatment of clonidine,atenolol,amlodipine and dihydrochlorothiazide,but not enalapril,impairs the sexual function in male spontaneously hypertensive rats[J].PLoS One,2015,10(1):116-129.
[18]NUDELL D M,MONOSKI M M,LIPSHULTZ L I.Common medications and drugs:how they affect male fertility[J].Urol Clin North Am,2002,29(4):965-973.
[19]陈义珊,蓝朝廷.氢氯噻嗪合ACEI致性功能障碍37例[J].浙江中西医结合杂志,2008,18(6):390-391.
[20]OPIE L H.Diuretic downsides-but in low doses they still seem among the best authenticated antihypertensives[J].Cardiovasc Drugs Ther,2000,14(4):407-409.
[21]刘培君,余静,康秀峰,等.不同药物联合对男性高血压患者勃起功能的影响[J].中华高血压杂志,2010,4(18):365-369.
[22]MILLSOP J W,HELLER M M,ELIASON M J,et al.Dermatological medication effects on male fertility[J].Dermatol Ther,2013,26(4):337-346.
[23]贺汉军.螺内酯小剂量短期治疗引起男性乳房肿大及性功能低下[J].药物不良反应杂志,2010,12(1):41.
[24]WONG P Y,LEE W M.Effects of spironolactone(aldosterone antagonist)on electrolyte and water content of the cauda epididymidis and fertility of male rats[J].Biol Reprod,1982,27(4):771-777.
[25]JENKINS A D,LECHENE C,HOWARDS S S,et al.The effect of spironolactone on the elemental composition of the intraluminal fluids of the seminiferous tubules,eete testis and epididymis of the rat[J].J Urol,1983,129(4):851-854.
[26]KHN F M,MLLER C,DRESCHER D,et al.Effect of angiotensin converting enzyme(ACE)and angiotensins on human sperm functions[J].Andrologia,1998,30(4-5):207-215.
[27]CHRYSANT S G.Antihypertensive therapy causes erectile dysfunction.[J].Curr Opin Cardiol,2015,30(4):383-390.
[28]SCHILL W B,PARSCH E M,MISKA W.Inhibition of angiotensin-converting enzyme:a new concept of medical treatment of male infertility?[J].Fertil Steril,1994,61(6):1123-1128.
[29]姚华雄,刘继红.卡托普利体外对人精子运动参数的影响[J].中华男科学杂志,2006,12(5):435-437.
[30]NAGAOKA S,KAWASAKI S,KAWASAKI H,et al.The angiotensin converting enzyme(ACE)inhibitor,captopril disrupts the motility activation of sperm from the silkworm,Bombyx mori[J].J Insect Physiol,2017,2017(103):18-28.
[31]SOMLEV B,SUBEV M.Effect of kininase II inhibitors on bradykinin-stimulated bovine sperm motility[J].Theriogenology,1998,50(4):651-657.
[32]K HLER-SAMOUILIDIS G,SCHMIDT-ADAMOPOULOUB,SAMOUILIDIS S,et al.Effects of captopril on the male reproductive organs and various semen parameters of rabbits[J].Berl Munch Tierarztl Wochenschr,1997,110(6):201-205.
[33]OKEAHIALAM B N,AMADI K,AMEH A S.Effect of lisnopril,an angiotensin converting enzyme(ACE)inhibitor on spermatogenesis in rats[J].Arch Androl,2006,52(3):209-213.
[34]SAHA L,GARG S K,BHARGAVA V K,et al.Role of angiotensin-converting enzyme inhibitor,lisinopril,on spermatozoal functions in rats[J].Methods Find Exp Clin Pharmacol,2000,22(3):159-162.
[35]BECHARA G R,SOUZA D B D,MICHELE S,et al.Testicular morphology and spermatozoid parameters in spontaneously hypertensive rats treated with enalapril[J].JUrol,2015,194(5):1498-1503.
[36]KUSHWAHA S,JENA G B.Enalapril reduces germ cell toxicity in streptozotocin-induced diabetic rat:investigation on possible mechanisms[J].Naunyn Schmiedebergs Arch Pharmacol,2012,385(2):111-124.
[37]BAUMH KEL M,SCHLIMMER N,KRATZ M,et al.Cardiovascular risk,drugs and erectile function:a systematic analysis[J].Int J Clin Pract,2015,65(3):289-298.
[38]DING J,SHANG X,ZHANG Z,et al.FDA-approved medications that impair human spermatogenesis[J].Oncotarget,2016,8(6):10714-10725.
[39]KANWAR U,ANAND R J,SANYAL S N.The effect of nifedipine,a calcium channel blocker,on human spermatozoal functions[J].Contraception,1993,48(5):453-470.
[40]LATIF R,ASLAM M,MEHMOOD T.Spermatogenesis following discontinuation of calcium channel blocker amlodipine in rats[J].J Ayub Med Coll Abbottabad,2009,21(1):25-27.
[41]MORAKINYO A O,IRANLOYE B O,ADEGOKE O A.Antireproductive effect of calcium channel blockers on male rats[J].Reprod Med Biol,2009,8(3):97-102.
[42]KATSOFF D,CHECK J H.A challenge to the concept that the use of calcium channel blockers causes reversible male infertility[J].Hum Reprod,1997,12(7):1480-1482.
[43]ANAND R J K,KANWAR U,SANYAL S N.Calcium channel antagonist verapamil modulates human spermatozoal functions[J].Res Exp Med(Berl),1994,194(1):165-178.
[44]MEHDI S,ALI N,SAIED K D,et al.Comparison of the protective effects of papaverine,lidocaine and verapamil on the sperm quality of the testis after induced torsion-detorsion in rats[J].Scand J Urol Nephrol,2010,44(3):133-137.
[45]IRANLOYE B O,MORAKINYO A O,UWAH J,et al.Effect of nifedipine on reproductive functions in male rats[J].Nig Q J Hosp Med,2009,19(3):165-168.
[46]AYODELE M,BOLANLE I,OLUFEYISIPE A.Calcium antagonists modulate oxidative stress and acrosomal reaction in rat spermatozoa[J].Arch Med Sci,2011,7(4):613-618.
[47]MORAKINYO A O,IRANLOYE B O,DARAMOLA A O,et al.Antifertility effect of calcium channel blockers on male rats:association with oxidative stress[J].Adv Med Sci,2011,56(1):95-105.
[48]SHIMIZU S,TSOUNAPI P,HONDA M,et al.Effect of an angiotensin II receptor blocker and a calcium channel blocker on hypertension associated penile dysfunction in a rat model[J].Biomed Res,2014,35(3):215-221.
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