Abstract
Background:
Published clinical practice guidelines have addressed antihypertensive therapy and sexual dysfunction (SD) in many different ways.
Objective:
In this systematic review, we evaluated guidelines that address antihypertensive drug-associated SD, guideline recommendations, and recent guideline trends.
Methods:
Thirty sets of guidelines for hypertension management in adults that had been published in the English language since 2000 were reviewed. The primary outcome measure was antihypertensive-associated SD potential, which was independently evaluated using specific questions by 2 authors in a nonblinded standardized manner.
Results:
Sexual dysfunctions associated with thiazide-class diuretics, β-blockers, and centrally acting sympathoplegics were addressed by half of the guidelines reviewed. There is no clarity on β-blockers and thiazide-class diuretics because one-third of the guidelines are vague about individual β-blockers and diuretics, and there is no statement on third-generation β-blockers and thiazide-like diuretics that can improve erectile function. The revised guidelines never use terms such as loss of libido, ejaculatory dysfunction, lack of orgasm, and priapism. Summary versions of guidelines are inadequate to reflect the key interpretation of the primary guidelines on SD associated with antihypertensives, even in the major guidelines that were updated recently. Therapeutic issues such as exploring SD in clinical history, assessing SD prior to and during treatment with antihypertensives, substituting the offending agents with alternatives that possess a better safety profile, intervening with phosphodiesterase-5 inhibitors, and avoiding the concomitant use of nitrovasodilators are superficially addressed by most guidelines, with the exception of 2013 European Society of Hypertension/European Society of Cardiology and Seventh Joint National Committee recommendations.
Conclusion:
Future guideline revisions, including both full and summary reports, should provide a balanced perspective on antihypertensive-related SD issues to improve the impact of hypertension treatment guidelines on patient care and quality of life.
Introduction
Cardiovascular disease is the leading cause of death, and public health efforts to improve lifestyles and risk factors can contribute to cardiovascular disease prevention. 1 Despite the significant progress made in improving drug therapies for hypertension and the promulgation of treatment guidelines over the past 2 decades, only a small proportion of patients with documented hypertension have had their condition controlled to target levels. Moreover, the complex interrelationship among hypertension, erectile dysfunction (ED), and antihypertensive drug therapy has become better understood in recent years. Erectile dysfunction has a high prevalence in individuals with multiple cardiovascular risk factors and patients with cardiovascular diseases. 2 –4 Hypertension is considered one of the most hazardous risk factors and is a frequent comorbidity in men with ED. 5 The prevalence of ED is higher in hypertensive men than in normotensives 6 –10 and is exacerbated by many older antihypertensive drugs. 10 –12 The deterioration of sexual function due to antihypertensive drug therapy can contribute to a poor quality of life (QOL) and, consequently, noncompliance with the therapy. 5,13 –16
Most of the recently revised guidelines for managing hypertension in adults, both comprehensive and abridged versions, do not satisfactorily address the complexity of hypertension and sexual dysfunction (SD). 17 –21 Only a minority of clinical practice guidelines stress the importance of ED or other sexual-related issues either as adverse outcomes or as factors to be considered when making treatment decisions. 22
The purpose of this systematic review is to critically evaluate how comprehensively ED associated with antihypertensive drug therapy is addressed by various national and international guidelines that were developed for managing arterial hypertension in adults, with reference to (1) recognizing antihypertensive drug-associated SD; (2) the potential differences in the guideline recommendations that were presented as complete or summary versions of international reports; and (3) comparisons between the guideline recommendations published at the end of the second millennium and those developed at the beginning of the third millennium.
Methods
The general methodology (literature search, inclusion/exclusion criteria, outcome measures, validity assessment, and definitions) used in this review has been described previously. 22,23
Literature Search
National and international guidelines for hypertension management were identified by searching for the following PubMed Medical Subject Heading terms: “guidelines” and “hypertension.” The World Wide Web via Google search engine and other effective search approaches were used with the following title: Guidelines on management of hypertension followed by name of countries (eg, Bahrain and Taiwan) or organizations (eg, National Institute for Health and Clinical Excellence [NICE], European Society of Hypertension [ESH], and National Heart, Lung, and Blood Institute [NHLBI]). The search was limited to studies that were published from January 2000 through January 2014. Based on the contact details retrieved from the International Society of Hypertension (ISH) Web site, e-mails were sent to several ISH-affiliated societies of Middle East, South East Asia, and Africa and requested these societies to provide the Web sites of their national guidelines for the management of arterial hypertension in adults, if available, in English.
Inclusion and Exclusion Criteria
Guidelines written in English and published from 2000 onward were included. However, guidelines written in languages other than English and those published prior to 2000 were excluded.
Outcome Measures
The primary outcome measures were the potential antihypertensives associated with SD. The guidelines were evaluated with research questions adapted from Karavitakis et al.
22
Does the guideline recognize the importance of SD as a component of patients’ clinical history? Does the guideline emphasize assessing sexual function prior to initiating or during treatment with antihypertensive drugs? Does the guideline specify antihypertensive drugs with potential sexual adverse effects? Does the guideline recommend that antihypertensive therapy in sexually active males be initiated with those drugs that are unlikely to affect sexual function (if the indication of the unlikely antihypertensive(s) associated with SD is/are not compelling) and to substitute the offending agent(s) with one(s) that possess a better safety profile? Does the guideline recommend intervention with phosphodiesterase-5 (PDE-5) inhibitors for antihypertensive-induced SD? Does the guideline specify that the use of PDE-5 inhibitors is contraindicated in patients with hypertension having ischemic heart disease who are on nitrovasodilators? Does the guideline recommend screening and treatment of hypertensive men with ED for low testosterone levels?
Validity Assessment
Assessment of outcome measures was independently carried out by the first 2 authors of this review in a nonblinded standardized manner. Any discrepancy between the reviewers was resolved by the fourth author based on consensus.
Operational Definitions
In the tables, the guidelines’ recommendations pertaining to the adverse effects of antihypertensives on sexual function in male patients are identified as (+) if they are available or addressed and as (−) if they are not available or not addressed. A superficially addressed guideline (SAG) means that data pertaining to hypertension- and antihypertensive-related ED were primarily derived from tables that list compelling and possible indications, contraindications, and cautions for major classes of antihypertensive drugs. A comprehensively addressed guideline (CAG) means that hypertension and antihypertensive-induced SD as a category has been explicitly addressed as one of the various headings under hypertension in special patient groups.
Results
A total of 30 national and international guidelines fulfilled the inclusion criteria used in this review for outcome measures, as summarized in Table 1. The recommendations related to the antihypertensive-associated SD (thiazide-class diuretics, β-blockers, and centrally acting sympathoplegics) were not addressed in 46.7% (14 of 30), superficially addressed in 43.3% (13 of 30), and comprehensively addressed in 10% (3 of 30) of the reviewed guidelines. Thiazide-class diuretics and β-blockers were identified as offending agents in 46.7% of the guidelines (14 of 30) each, whereas centrally acting sympathoplegics were identified in 20% (6 of 30). Sexual dysfunction induced by antihypertensives was recognized as an adverse effect, a major adverse effect and as a possible or absolute contraindication. Individual members of β-blockers and centrally acting agents that are associated with SD were not specified in 30% (9 of 30) and 13.3% (4 of 30) of the guidelines, respectively.
Antihypertensives With Predictable Sexual Dysfunction Addressed by National and International Guidelines.
Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed guideline; +, data are available; −, no data are available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; S, specified.
aSide effect/adverse effect.
bClonidine + methyldopa.
cPotential adverse effect.
dPossible contraindication in sexually active males.
eMethyldopa.
fMore prominent with old generations and not with new one such as nebivolol.
gNonspecified drug.
hAdverse effects were more prominent with old antihypertensive drugs, however in 2009 Guidelines 15 old antihypertensives were defined as diuretics, β-blockers, and centrally acting drugs.
iMajor adverse effects.
jOld generations of β-blockers.
kSpironolactone.
The differences between the primary full reports and secondary summary publications pertaining to antihypertensive-related SD (either as a potential adverse effect or as a major adverse effect) are shown in Table 2. The issue of SD (as a potential adverse effect) has been overlooked completely in summary or quick reference guide compared with primary full report publications. This clinical issue has been inconsistently recognized by guidelines and recommendations that were updated in the third millennium compared with those published at the end of second millennium. It was only superficially updated by the 2004 Fourth Working Party of British Hypertension Society (BHS-IV), fully ignored by 2003 World Health Organization (WHO)/ISH, and comprehensively addressed by the 2003 Seventh Joint National Committee (JNC-7; Table 3).
Antihypertensive-Induced Sexual Dysfunction as Presented by Full and Summary Reports.
Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed guideline; +, data are available; −, no data are available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; BHS-IV, 2004 Fourth Working Party of British Hypertension Society; HF, Heart Foundation; NHLBI, National Heart, Lung, Blood Institute; WHO, World Health Organization.
aSide effect/adverse effect.
bPotential adverse effect.
cNonspecified drug.
dMajor adverse effects.
Comparison Between Old and Updated Full Guideline Reports.
Abbreviations: CAG, comprehensively addressed guideline; CASDs, centrally acting sympathoplegic drugs; NA, not addressed; SAG, superficially addressed guideline; +, data are available; −, no data are available; ED, erectile dysfunction; I, impotence; NS, not specified; SD, sexual dysfunction; BHS, Working Party of British Hypertension Society; NHLBI, National Heart, Lung, Blood Institute; WHO, World Health Organization; ISH, International Society of Hypertension.
aSide effect/adverse effect.
bNonspecified drug.
In this review, the guidelines were evaluated based on 7 author-specified research questions. The rate of addressing these questions by practice guidelines was as follows: 30% (9 of 30) considered SD to be a component of a patient’s clinical history; 10% (3 of 30) emphasized the assessment of SD prior to initiating or during treatment with antihypertensive drugs; 53.3% (16 of 30) specified antihypertensives with potential SD; 10% (3 of 30) recommended the importance of initiating treatment with an antihypertensive that is unlikely to cause SD (if the antihypertensive indication is not compelling) or substituting the offending agent with better alternatives; 10% (3 of 30) recommended an intervention with PDE-5 inhibitors to treat SD due to antihypertensive medications; 6.7% (2 of 30) specified that the use of PDE-5 inhibitors with vasodilators is contraindicated; and finally, none of these guidelines recommended screening and treatment of hypertensive men with ED for low testosterone levels (Table 4).
Guideline Profile in Terms of Research Questions.a
Abbreviations: +, data are available; −, no data are available.
aQ1, Does the guideline recognize the importance of sexual dysfunction as a component of patients’ clinical history? Q2, Does the guideline emphasize on assessment of sexual function prior to initiating or during any antihypertensive drug treatment? Q3, Does the guideline specify antihypertensive drugs with predictable sexual adverse effects? Q4, Does the guideline recommend when commencing antihypertensive therapy in sexually active males to initiate erectile dysfunction-free agent(s) (if the indication of unlikely antihypertensive is not compelling)? and to substitute the offending agent(s) with one(s) that possess a better safety profile? Q5, Does the guideline recommend a special drug management as administration of phosphodiesterase-5-inhibitors in case of antihypertensive-induced sexual dysfunction? Q6, Does the guideline contraindicate the use of phosphodiesterase-5-inhibitors in patients with hypertension having ischemic heart disease receiving nitrates? Q7, Does the guideline recommend screening and treatment men with ED for low testosterone levels?
bSee Table 1 for details of organizations’ acronym.
cWas not absolutely specified under clinical “medical” history.
Discussion
Thiazide-class diuretics are one of the most widely used class of antihypertensives. They are used both as fixed-dose formulations and as individual agents in complementary combination therapy and can be further classified into thiazide-type diuretics (ie, hydrochlorothiazide) and thiazide-like diuretics (ie, chlorthalidone and indapamide). Some of thiazide-class diuretics have been reported to be associated with potentially detrimental adverse effects on male sexual function. 10 –12,16,55 –59 Nonetheless, SD induced by this class of antihypertensives has not been addressed by several clinical practice guidelines, 18 –21,25,26,29,31 –33,35,38,42,44,46 either as an adverse effect or as a factor to be considered by physicians when prescribing antihypertensive agents. However, ED and SD were deemed to be potential adverse effects, 27,34,43 definite side effects, 15,16,24,28,37,45,47 and major adverse effects 39 on male sexual function by some sets of guidelines. Some treatment guidelines such as Saudi Hypertension Management Society 30 and Pan America Health Organization 36 considered thiazide-class diuretics to be possibly or absolutely contraindicated in sexually active hypertensive males, respectively. Of note, the term “thiazide-class diuretics” 60 has never been used by any of the guidelines reviewed. Instead, the term “thiazide diuretics” has been commonly used by most guidelines, 27,30,34,36,43,45,47 whereas thiazide and thiazide-like diuretics have been used in other guidelines. 24,28,37 Diuretics, as a generic term, has been used by the ESH. 15 We suggest that an explicit categorical term such as thiazide-class diuretics 60 be used in future guideline revisions to avoid ambiguity.
It has been reported that thiazide-like diuretics, such as indapamide, decrease the risk of worsening of sexual function by lowering blood pressure in men 61 and that switching to indapamide-based therapy improves SD due to other antihypertensives. 62,63 Indapamide is rarely associated with an adverse effect on male sexual function, 61 –64 and indapamide-related SD has been addressed only by the Registered Nurses Association of Ontario (RNAO). 47
Although β-blockers are one of the most widely used antihypertensive classes of drugs for the prevention and treatment of cardiovascular diseases, the use of some first-generation β-blockers has occasionally been associated with SD in males. 59 β-Blockers are distinguished based on several properties, such as their relative affinity to β1 and β2 receptors, difference in lipid solubility, capacity to induce vasodilatation, and pharmacodynamic and pharmacokinetic parameters. 65 Some of these characteristics are clinically relevant for selecting the appropriate β-blocker for individual patients with hypertension. 65 Propranolol, a first-generation nonsubtype selective β-blocker, has the potential to impair sexual function in males; this adverse effect appears to be dose related and often occurs at doses in excess of 120 mg/d. 66,67 Second-generation β1-selective blockers such as atenolol have less of a tendency to produce ED than do nonsubtype selective β-blockers. 68,69 However, β1-selectivity is dose related 66,67 and tends to diminish at higher drug concentration 69,70 ; thus, the incidence of SD may rise. 69 Nebivolol, a third-generation β1-blocker, has the highest cardioselectivity of any of the currently available β-blockers. 71 Additionally, nebivolol produces an endothelium-derived nitric oxide-dependent vasodilatation that results in the reduction of systemic vascular resistance and facilitates penile erection. Hence, nebivolol may offer the additional benefit of precluding ED in male patients with hypertension. 72 –74 Of note, the Hawthorne effect of ED with β-blockers should also be considered; knowledge and prejudice about ED as a side effect of β-blockers can produce anxiety, which may adversely influence erectile function in hypertensive men. 75 Because the etiology of the ED is largely psychological, it is not surprising that placebo is as effective as PDE-5 inhibitors in reversing this side effect. 75,76
Of the 30 reviewed national and international guidelines, 46.7% (14 of 30) focused on the potential implications of β-blockers on impairing male sexual function (Table 1). β-Blocker-associated SD has been deemed as a potential adverse effect by some of these guidelines 27,34,43 as either a major side effect 39 or a definite adverse effect. 15,16,24,28,37,38,40,41,45,47 Individual β-blockers were not specified by approximately 30% (9 of 30) of guidelines, 24,27,28,34,37 –39,43,45 though they were specified by a mere 16.7% (5 of 30) of the treatment guidelines. 15,16,40,41,47 The ESH guidelines state that “older β-blockers exert negative effects on ED, whereas newer drugs such as nebivolol have neutral or beneficial effects.” 15(p2146) The SD as an adverse effect of β-blockers was more commonly associated with other β-blockers. 16 Moreover, atenolol-related ED, based on the outcomes of United Kingdom Prospective Diabetic Study, 77 has been addressed as a prototype for β-blockers by the American Association of Clinical Endocrinologists. 40 The American College of Cardiology Foundation/American Heart Association 41 state that “older β-blockers have been associated with depression, SD, dyslipidemia, and glucose intolerance, and these side effects are less severe or unlikely with newer agents.” The RNAO 47(p2439) precisely specified that first-generation nonsubtype-selective β-blockers (nadolol, pindolol, propranolol, and timolol), second-generation selective β1-blockers (acebutolol, atenolol, bisoprolol, and metoprolol), and third-generation labetalol are all associated with ED.
The relation between centrally acting sympathoplegic drugs, such as α-methyldopa and clonidine, and the incidence of SD has been noted by only 20% (6 of 30) of the reviewed guidelines. 15,16,24,36,39,45 The plausible explanation for paying less attention to these antihypertensive agents may be attributed to several reasons: (1) α-methyldopa is reserved as the drug of choice for nonsevere hypertension in pregnancy 25,35 –37,45 ; (2) α-methyldopa is no longer recommended for the treatment of uncomplicated hypertension and has been superseded by newer antihypertensive classes; and (3) in addition to SD, centrally acting antihypertensives are associated with numerous unpleasant adverse effects. 48,54
Clinical practice guidelines are systematically developed statements that assist clinicians, consumers, and policy makers in making appropriate health-related decisions. Potential guideline deficits and the need for guideline appraisal tools have been proposed by Siering et al. 78 To reach the widest possible audience, these guidelines are developed as primary “full reports” and as “secondary summary” publications in a prearranged process that is accepted by both authors and the editors of journals. 79 A full report is deemed as an evidence-based approach that provides a broader and more detailed review of recommendations and is based on observational studies and major clinical trials. 18,45 However, secondary publications such as the summary version, 48 quick reference guide, 49 express report, 50 and pocket guide 51 are abridged versions that are intended to provide recommendations for busy primary care physicians and should be used for educational purposes. Secondary publications are considered justifiable if their contents are sufficiently abbreviated and faithfully reflect the data and interpretation of the primary version. 79 As a recommendation, SD associated with hypertension per se and the use of antihypertensive medications have been completely excluded from the summary versions of several full report guidelines 48 –51 (Table 2). The omission of such pivotal recommendations may lead to undesired consequences: (1) inappropriate attention to SD as an adverse effect may result in a negative impact on patients’ QOL, compliance with drug therapy and discontinuation of the antihypertensive medications 58,66 ; (2) an inadvertent departure from the evidence-based approach recommended by full report clinical guidelines; and (3) confusion and misleading of practicing physicians and researchers. 79 For instance, Viigimaa and his colleagues 3 (the ESH Working Group on SD) inadvertently cited the JNC-7 full report that comprehensively addressed the SD issue instead of the JNC-7 Express Report as a reference for guidelines that ignore or superficially address the important association between cardiovascular risk factors and SD. We opine that despite their usefulness, guideline summary versions should faithfully reflect the data and interpretations of the primary full report versions. We suggest that the issue of antihypertensive-related SD should be prudently addressed and appropriately considered in future guideline revisions.
Some of the widespread guideline recommendations developed at the end of the second millennium 52 –54 were compared with those updated at the third millennium 20,37,45 to identify the scope of the changes and updates that have occurred in published clinical guidelines on antihypertensive-associated SD (Table 3). From this perspective, the importance of iatrogenic SD due to antihypertensives has been rather superficially updated by the report of the BHS-IV 37 compared with BHS-III. 52 This issue has been completely overlooked by WHO/ISH updated clinical practice guidelines. 20 However, the recognition of antihypertensive-induced SD and its management in patients with hypertension has been comprehensively addressed by the updated complete report of the JNC-7—NHLBI 45 (Tables 3 and 4). Our observations suggest that antihypertensive-related SD is inconsistently recognized by clinical practice guidelines that were developed for managing primary hypertension in adults, even among those that were published more recently. We believe that this clinical issue is an area that needs further attention to improve the quality and impact of the guidelines and, ultimately, patient care and QOL.
Of note, an association has been documented between arterial hypertension and SD 5,12,80 and other cardiovascular risk factors. 2 –4,80,81 Recently, the revised appraisal of European guidelines on hypertension management stressed that ED is a prevalent condition in patients with hypertension and is a predictor of future cardiovascular diseases; the screening and treatment of ED, therefore, improve the management of cardiovascular risk factors. 15 Thus, SD should be explored while taking the clinical history from patients with arterial hypertension. Such an approach has been recommended by 30% (9 of 30) of the treatment guidelines 15,16,24,27,34,39,42,44,45 (Table 4). Nonetheless, SD has not been explicitly specified under patients’ clinical history by ESH 15 or NHLBI. 45 The ESH is implicit that screening and treatment of ED improve the management of cardiovascular risk factors, whereas NHLBI recommends that a clinician be willing to discuss SD problems. Although SD is frequently encountered in patients with cardiovascular diseases 82 and in cardiology practice, there may be an overall lack of attention to exploring sexual problems (Table 4).
It should be noted that sexual function in male patients with hypertension may be impaired by hypertension per se 5,12 and by the use of some older antihypertensives as a drug-related side effect. 10 –12 The practicing physicians should therefore carefully explore and assess the sexual sequelae in patients with hypertension. The typical initial evaluation of a man complaining of ED is conducted in person and includes sexual, medical, and psychosocial histories as well as laboratory tests that are sufficiently thorough to identify comorbid conditions that may predispose the patient to ED or contraindicate certain drug therapies. History may reveal causes or comorbidities such as cardiovascular disease (including hypertension, atherosclerosis, or dyslipidemia), diabetes mellitus, depression, and alcoholism. 83 Emphasis on the assessment of sexual function prior to initiating or during antihypertensive drug treatment has been stressed only by ESH, 15 ESH/European Society of Cardiology [ESC] 16 and NHLBI, 45 which represent a mere 10% (3 of 30) of all national and international guidelines.
Antihypertensive drug regimens should be tailored to the age and gender of individual patients and should consider SD as a potential adverse effect. 16,66 Such a therapeutic strategy is necessary to achieve the objectives of treatment of hypertension: ensuring good compliance and QOL, achieving optimal control of blood pressure, and reducing the risk of cardiovascular events. 66 It is extremely important to take a complete drug history, particularly with regard to antihypertensives and other offending medications. Antihypertensive drugs, such as diuretics, first- and second-generation β-blockers, and centrally acting drugs can be discontinued or switched (if the indication is not compelling) to alternatives with a better sexual safety profile, such as angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and calcium channel blockers. 59 Despite its importance, such a recommendation has been stressed by only NHBLI, 45(p1236) which states “if SD appears after institution of antihypertensive drug therapy, the offending agent should be discontinued and treatment restored with another agent.”
Sexual dysfunctions associated with antihypertensives (diuretics or β-blockers or centrally acting medications) have been addressed by approximately half (16 of 30) of the revised guidelines 15,16,24,27,28,30,34,36 –41,43,45,47 (Tables 1 and 4). Overall, 10% (3 of 30) and 43.3% (13 of 30) of the guidelines have presented data pertaining to antihypertensive-related SD in CAG and SAG, respectively (Table 1). Male SD refers to a problem during any phase of the sexual response cycle that prevents achieving satisfaction from sexual activity. The most common problems related to male SD include ED (impotence), loss of libido (loss of sexual interest or desire), ejaculatory dysfunction, and priapism. Other than ED, none of the above-mentioned terms have been stated in the revised guidelines.
It is well known that SD compromises the QOL of both the patient and the partner. Management of ED thus not only improves QOL but also substantially enhances adherence to antihypertensive drug therapy. 3,4 Oral PDE-5 inhibitors are generally effective and safe as a first-line treatment of patients with hypertension having SD, unless contraindicated. 12,83 In addition to the potential blood pressure lowering effect, which does not appear to be a major problem, 12,84 PDE-5 inhibitors improve patients’ adherence to antihypertensive drug therapy 3,4,85 and allow the implementation of antihypertensive add-on approach to the existing antihypertensive therapy. 12,86 It should be noted that PDE-5 inhibitors are absolutely contraindicated in patients on short- and long-acting nitrovasodilators because of an unpredictable synergistic decline in blood pressure. 3,4,12 In patients with hypertension having lower urinary tract symptoms, α-blocker and PDE-5 inhibitor therapy should be cautiously used, and the lowest effective dose of these medications should be considered. 83,87 The role of PDE-5 inhibitors in ameliorating SD induced by either hypertension or certain antihypertensive drugs has been emphasized by the ESH, 15 ESH/ESC, 16 and NHLBI 45 guidelines. However, the life-threatening symptomatic hypotension in some patients that results from the concurrent use of PDE-5 inhibitors and nitrovasodilators has been addressed only by ESH/ESC 16 and NHLBI. 45 According to the ESH/ESC guidelines, PDE-5 inhibitors may be safely administered to hypertensive, even to those who are on multiple drug regimens (with the possible exception of α-blockers and nitrovasodilators). The NHLBI declared that sildenafil or other PDE-5 inhibitors may be prescribed, without a significant likelihood of adverse reactions, to those with concomitant antihypertensive therapy, provided that nitrovasodilators are avoided.
Low testosterone levels may contribute to ED 88 and are prevalent in men with hypertension, 89 –91 diabetes mellitus, 92 and metabolic syndrome. 93 Men with ED should, therefore, be screened for testosterone because hypotestosteronemia-related dysfunction can be improved by exogenous testosterone therapy. 94 –96 It is evident that none of the revised guidelines have recommended the importance of testosterone screening and supplementation in hypogonadal men with hypertension (Table 4). The combination of testosterone therapy, unless contraindicated, with PDE-5 inhibitors may be beneficial for treating ED in men with a low level of total testosterone (<8 nmol/L) or in those with borderline levels (8-12 nmol/L), who did not adequately respond to prior treatment with PDE-5 inhibitors alone. 94 –97
A strong link between ED and endothelial dysfunction has been postulated. 98 –100 Moreover, there is an emerging body of evidence that endothelial dysfunction due to gene polymorphisms may be linked with hypertension. A recent study has identified a single-nucleotide polymorphism of the human calcium/calmodulin-dependent protein kinase type 4 gene, which plays a role in blood pressure regulation by controlling endothelial nitric oxide synthase activity. 101 Given the wide array of G-protein-coupled receptors (GPCRs), it is reasonable to speculate that gene polymorphism related to GPCRs may play a critical role in regulating vascular smooth muscle function. 102 In view of these findings, it is imperative that the choice of antihypertensive drug should also consider the pivotal role of endothelial function as an important target. There is also a need to understand whether gene polymorphisms determine the susceptibility of patients to the adverse effects of antihypertensive medications, which may result in ED.
Conclusion
In this systematic review, there may be a discrimination bias because only English-language guidelines were included in the analysis. Notwithstanding this limitation, hypertension treatment guidelines have placed less emphasis on the issue of antihypertensive drug-associated SD. Most of the national or international guidelines are less explicit concerning preexisting or treatment-induced SD in patients with hypertension, with the exception of the 2003 NHLBI, 2009 ESH and the more recently revised 2013 ESH/ESC guidelines. The future guideline revisions, including both full and summary report versions, should provide a balanced perspective on antihypertensive-related SD issues to improve the QOL of patients with hypertension, bearing in mind that QOL is a more serious issue than hypertension for many men during midlife.
Footnotes
Acknowledgments
We acknowledge the assistance given to us by Ina D’Souza in preparing this manuscript.
Authors’ Contribution
K. A. J. Al Khaja contributed to conception and design; acquisition, analysis, and interpretation; drafted the manuscript; critically revised the manuscript; gave final approval; and agrees to be accountable for all aspects of work ensuring integrity and accuracy. R. P. Sequeira, A. K. Alkhaja contributed to acquisition, analysis, and interpretation; critically revised the manuscript; gave final approval; and agree to be accountable for all aspects of work ensuring integrity and accuracy. A. H. H. Damanhori contributed to analysis and interpretation, critically revised the manuscript, gave final approval, and agrees to be accountable for all aspects of work ensuring integrity and accuracy.
Authors’ Note
This article has not been submitted or presented elsewhere. In preparing this manuscript, the authors have not received financial support from any drug companies or organizations.
Declaration of Conflicting Interests
The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The author(s) received no financial support for the research, authorship, and/or publication of this article.