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Male infertility during antihypertensive therapy: are we addressing correctly the problem?

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Review Article

267

Male Infertility during Antihypertensive Therapy: Are We

Addressing Correctly The Problem?

Antonio Simone Laganà, M.D.1*, Salvatore Giovanni Vitale, M.D.1, Paola Iaconianni, M.D.2,

Simona Gatti, M.D.2, Francesco Padula, M.D.3

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Abstract

Male fertility significantly decreased in the last 50 years, as showed in several stud-ies reporting a reduction of sperm counts per ml in the seminal fluid. Several “acute” pharmacological treatments, as antibiotics, could cause subclinical and temporary reduction of male fertility; conversely, long-term medical treatment may severely affect male fertility, although this effect could be considered transient in most of the cases. Thus, nowadays, several long-term pharmacological treatments may repre-sent a clinical challenge. The association between several kind of antihypertensive drugs and reduction of male fertility has been showed in the mouse model, although the modification(s) which may alter this fine-regulated machinery are still far to be elucidated. Furthermore, well-designed observational studies and randomized controlled trials are needed to accurately define this association in human model, meaning a narrative overview synthesizing the findings of literature retrieved from searches of computerized databases. We strongly solicit future human studies (both observational and randomized clinical trials) on large cohorts with adequate statisti-cal power which may clarify this possible association and the effects (reversible or permanent) of each drug. Furthermore, we suggest a close collaboration between general practitioners, cardiologists, and andrologists in order to choose the most appropriate antihypertensive therapy considering also patient’s reproductive desire and possible risk for his fertility.

Keywords: Andrology, Infertility, Antihypertensive

Citation: Laganà AS, Vitale SG, Iaconianni P, Gatti S, Padula F. Male infertility during antihypertensive therapy: are we addressing correctly the problem? Int J Fertil Steril. 2016; 10(3): 267-269.

Introduction

0DOHIHUWLOLW\VLJQL¿FDQWO\GHFUHDVHGLQWKHODVW 50 years, as showed in several studies reporting a reduction of sperm counts per ml in the seminal ÀXLG  7RGDWHPDOHIDFWRUVDFFRXQWIRUDOPRVW 35% of couple infertility. As widely accepted, sperm counts may vary among different ejaculates according to several pathological conditions, life-style and exposure to pollutants (2). In this regard, although well-known diseases such as cryptorchid-ism, varicocele, hypospadias, testicular tumors, Y chromosome microdeletion and endocrine

al-terations can cause azoospermia and/or oligozoo-spermia, iatrogenic risk factors may also play a detrimental role in male fertility. Several “acute” pharmacological treatments, as antibiotics, could cause subclinical and temporary reduction of male fertility; conversely, long-term medical treatment may severely affect male fertility, although this ef-fect could be considered transient in most of the cases. Thus, nowadays, several long-term pharma-cological treatments may represent a clinical chal-lenge. To the best of our knowledge, association between several kind of antihypertensive drugs and

Received: 4 Jan 2016, Accepted: 14 May 2016

*Corresponding Address: Unit of Gynecology and Obstetrics, De-partment of Human Pathology in Adulthood and Childhood “G. Bar-resi”, University of Messina, Via C. Valeria 1, 98125 - Messina, Italy

Email: antlagana@unime.it Royan InstituteInternational Journal of Fertility and Sterility Vol 10, No 3, Oct-Dec 2016, Pages: 267-269 Debate

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Int J Fertil Steril, Vol 10, No 3, Oct-Dec 2016 268

reduction of male fertility has been showed in the PRXVH PRGHO   DOWKRXJK WKH PRGL¿FDWLRQ V  ZKLFK PD\ DOWHU WKLV ¿QHUHJXODWHG PDFKLQHU\ are still far to be elucidated and human data are still lacking. Indeed, data from the following ani-mal studies are not robust: several studies (6-8) showed that verapamil, nimodipine, and lisinopril worsen semen quality and testicular morphology, ZKLOHRWKHUV  KDYHIRXQGWKDWQLIHGLSLQHDQG lisinopril improve these parameters.

,QWKLVUHJDUGV%HFKDUDHWDO  KDYHVWXGLHG the effects of an angiotensin-converting enzyme (ACE) inhibitor (Enapril) on hypertension-induced morphological changes in the testis and sperma-tozoid production in spontaneously hypertensive rats. According to their data analysis, sperm con-centration was greater in the treated group than in the nontreated group, testicular vascular volumet-ric density decreased in the nontreated group and, last but not least, volumetric density of the semi-niferous epithelium in the treated group was high-er than in the nontreated group. Although these results could not be de facto translated in humans, they have suggested a possible pivotal role of ACE LQKLELWRUV DV ¿UVWOLQH WUHDWPHQW ZKHQ IHUWLOLW\ LV a relevant concern. Even if well-designed obser-vational studies and randomized controlled trials DUHQHHGHGWRDFFXUDWHO\GH¿QHWKLVDVVRFLDWLRQLQ human model, daily clinical experience seems to FRQ¿UP WKDW LQ FDVH RI DQWLK\SHUWHQVLYH WKHUDS\ with concomitant male infertility, the substitution of the drug with another one which does not affect semen parameters may improve male fertility.

In particular, beta blockers and calcium-channel blockers (CCBs) seem to play a detrimental role on male fertility, causing in several cases azoo-spermia and/or oligozooazoo-spermia. On the other hand, inhibitors of the funny channel, such as oral ivabradine, seem not to be associated with reduc-tion of male fertility. In this regard, it was already demonstrated in the mouse model that CCBs, like amlodipine, can cause a reduction of testosterone, luteinizing hormone (LH) and follicular stimulat-ing hormone (FSH), leadstimulat-ing to affect spermato-JHQHVLVDQGVSHUPSDUDPHWHUV  +RZHYHU these data do not seem to be surprising, since ac-cumulating evidence have already suggested that

Ca2+ plays a prominent role during fertilization in

all animal species. On one hand, in mice, rats, pigs,

hamsters and bovines, extracellular Ca2+ is

neces-sary for epididymal acquisition of sperm motility  

Furthermore, it is known to regulate both acti- YDWHGDQGK\SHUDFWLYDWHGPRWLOLW\  ,QDG-GLWLRQ ÀDJHOODU PRWLOLW\ LV FRQWUROOHG E\ FDOFLXP through the regulation of dynein-driven microtu-EXOHVOLGLQJDQGPRGXODWLRQRIWKHVSHUPÀDJHOODU waveform (22, 23). Finally, calcium has a pivotal role during the acrosome reaction in invertebrates, VXFKDVHFKLQRGHUPVDQGVXSHULRUYHUWHEUDWHV  25). Also, in this case, although these data demon-strated that it does have a direct impact on humans, they may underlie the possible detrimental effect of calcium antagonists administered for hyperten-sion on male fertility.

Conclusion

The average life expectancy is increasing and even more older male patients refer to fertility experts, the association between antihypertensive therapy and male infertility is a growing area of interest. Based on this scenario, we strongly so-licit future human studies (both observational and randomized clinical trials) on large cohorts and with adequate statistical power which may show this possible association and the effects (reversible or permanent) of each drug. Furthermore, we sug-gest a close collaboration between general prac-titioners, cardiologists, and andrologists in order to choose the most appropriate antihypertensive therapy considering also patient’s reproductive de-sire and possible risk for his fertility.

Acknowledgements

7KHDXWKRUVKDYHQRSURSULHWDU\¿QDQFLDOSUR-fessional or other personal interest of any nature in any product, service or company. The authors alone are responsible for the content and writing RIWKHSDSHU7KHUHLVQRFRQÀLFWRILQWHUHVWLQWKLV article. References 1. :LQWHUV%5:DOVK7-7KHHSLGHPLRORJ\RIPDOHLQIHUWLO-LW\8URO&OLQ1RUWK$P   2. 1XGHOO'00RQRVNL00/LSVKXOW]/,&RPPRQPHGLFD-WLRQV DQG GUXJV KRZ WKH\ DIIHFW PDOH IHUWLOLW\ 8URO &OLQ 1RUWK$P  

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