Review

Antihypertensive Drugs and Male

Sexual Dysfunction: A Review of Adult
Hypertension Guideline Recommendations

Journal of Cardiovascular
Pharmacology and Therapeutics
2016, Vol. 21(3) 233-244
The Author(s) 2015
Reprints and permission:
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DOI: 10.1177/1074248415598321
cpt.sagepub.com

Khalid A. J. Al Khaja, PhD1, Reginald P. Sequeira, PhD, FCP1,

Alwaleed K. Alkhaja, PhD2, and Awatif H. H. Damanhori, MBBCh, FP3

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, b-blockers, and centrally acting
sympathoplegics were addressed by half of the guidelines reviewed. There is no clarity on b-blockers and thiazide-class diuretics
because one-third of the guidelines are vague about individual b-blockers and diuretics, and there is no statement on thirdgeneration b-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.
Keywords
hypertension, guidelines, antihypertensive drugs, sexual dysfunctions, treatment, revisions, adult male

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 normotensives6-10 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

Department of Pharmacology & Therapeutics, College of Medicine & Medical

Sciences, Arabian Gulf University, Manama, Kingdom of Bahrain
2
Qatar Foundation, Doha, Qatar
3
Primary Care, Ministry of Health, Manama, Kingdom of Bahrain
Manuscript submitted: January 15, 2015; accepted: June 21, 2015.
Corresponding Author:
Khalid A. J. Al Khaja, Department of Pharmacology & Therapeutics, Arabian
Gulf University, PO Box 22979, Kingdom of Bahrain.
Email: khlidj@agu.edu.bh

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Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

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

1.
2.

3.
4.

5.

6.

7.

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

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

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,
b-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

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SAG
NA
NA
SAG
SAG
NA
SAG
NA
NA
NA
SAG
NA
SAG
SAG
CAG
CAG
NA
NA
SAG
NA
SAG
SAG
SAG
NA
NA
SAG
NA
CAG
NA
SAG

GHA
MOH, Bahrain
MOH, Malaysia
MOH, Singapore
SHMS
TSC
KSC
TFCPP-HK
HF
LASH
PAHO/CHRC
BHS
ESH
ESH/ESC
NICE
SIGN
ASH/ISH
WHO/ISH
WHO
AACE
ACCF/AHA
CCS
DVA/DoD
ICSI
ISHIB
NHLBI
NHLBI
RNAO

Guidelines
Presentation

EHS
SAHS

Acronym

2006
2011
2011
2004
2010
2010
2003
2014
2005

2014
2003
2007

2004
2009
2013
2011
2007

2009
2007

2008

2010
2008
2008
2005
2011
2010
2006
2010

2004
2011

Year


c,I
a,ED

d



c,ED

d
a,ED
a,ED
h,SD




i,I

k,SD


c,ED

a,SD

a,ED

26

34
35

37

38

40

47

46

45

44

43

42

21

41

39

20

19

18

16

15

36

33

32

31

30

29

28

27

25

a,I


Diuretics

24

Ref #

a,ED,j
a,SD,f


c,ED,NS


a,ED,NS

a,ED,j

a,SD,NS

i,I,NS

a,ED,NS
a,ED,f
h,SD,f






c,ED,NS


c,I,NS
a,ED,NS






a,I,NS


b-Blockers

a,g,ED










g,i,SD





a,g,ED
g,h,SD





a,e,I










a,b,I


CASDs

Predictable Antihypertensives
Associated With Sexual Dysfunction

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.
a
Side effect/adverse effect.
b
Clonidine methyldopa.
c
Potential adverse effect.
d
Possible contraindication in sexually active males.
e
Methyldopa.
f
More prominent with old generations and not with new one such as nebivolol.
g
Nonspecified drug.
h
Adverse effects were more prominent with old antihypertensive drugs, however in 2009 Guidelines15 old antihypertensives were defined as diuretics, b-blockers, and centrally acting drugs.
i
Major adverse effects.
j
Old generations of b-blockers.
k
Spironolactone.

Africa
Egyptian Hypertension Society
Southern African Hypertension Society
Asia
Gulf Heart Association
Ministry of Health, Bahrain
Ministry of Health, Malaysia
Ministry of Health, Singapore
Saudi Hypertension Management Society
Taiwan Society of Cardiology
The Korean Society of Circulation
The Task Force on Conceptual and Preventive Protocols (Hong Kong)
Australia
Heart Foundation
Caribbean and Latin America
Latin America Society of Hypertension
Pan America Health Organization/Caribbean Health Research Council
Europe
British Hypertension Society
European Society of Hypertension-reappraisal
European Society of Hypertension/European Society of Cardiology
National Institute of Health and Clinical Excellence (United Kingdom)
Scottish Intercollegiate Guidelines Network
International
American Society of Hypertension/International Society of Hypertension
World Health Organization/International Society of Hypertension
World Health Organization
North America
American Association of Clinical Endocrinologist Hypertension Task Force
American College of Cardiology Foundation/American Heart Association
Canadian Cardiovascular Society
Dept of Veterans Administration/Dept of Defense (United States)
Institute of Clinical Systems Improvement (United States)
International Society on Hypertension in Blacks
National Heart, Lung, Blood Institute (United States)
National Heart, Lung, Blood Institute (United States)
Registered Nurses Association of Ontario

Organizations

Table 1. Antihypertensives With Predictable Sexual Dysfunction Addressed by National and International Guidelines.

236

Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

Table 2. Antihypertensive-Induced Sexual Dysfunction as Presented by Full and Summary Reports.

Organizations
(Publication Year)
BHS-IV (2004)
HF (2008)
NHLBI (2003)
WHO (2007)

Guideline format (Reference No.)

37

Full Report
Summary Version48
Full Report34
Quick Reference Guide49
Full Report, 200345
JNC-7 Express, 200350
Full Report39
Pocket Guidelines51

Guidelines
Presentation
SAG
NA
SAG
NA
CAG
NA
SAG
NA

Antihypertensive-Induced
Sexual Dysfunction
No. of Pages
46
7
38
18
48
12
92
20

Diuretics
a,ED


b,ED

a,SD

d,I


b-Blockers

CASDs

a,ED,NS







b,ED,NS

a,ED,NS

d,I,NS


a,c,ED

c,d,SD


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.
a
Side effect/adverse effect.
b
Potential adverse effect.
c
Nonspecified drug.
d
Major adverse effects.

Table 3. Comparison Between Old and Updated Full Guideline Reports.

Predictable Antihypertensive-Induced Sexual Dysfunction

Organizations
(Reference #)

Publication
Year

Guideline
Presentation

Diuretics

b-Blockers

CASDs

BHS-III52
BHS-IV37
NHLBI-VI53
NHLBI-VII45
WHO/ISH54
WHO/ISH20

1999
2004
1997
2003
1999
2003

NA
SAG
NA
CAG
SAG
NA


a,ED

a,SD
a,I



a,ED,NS

a,ED,NS






a,b,ED



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.
a
Side effect/adverse effect.
b
Nonspecified drug.

and b-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 b-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.
The differences between the primary full reports and secondary summary publications pertaining to antihypertensiverelated 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).
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 patients
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

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237

Table 4. Guideline Profile in Terms of Research Questions.a

Research Questions
Organizationsb
Africa
EHS
SAHS
Asia
GHA
MOH, Bahrain
MOH, Malaysia
MOH, Singapore
SHMS
TSC
KSC
TFCPP-HK
Australia
HF
Caribbean and Latin America
LASH
PAHO/CHRC
Europe
BHS
ESH
ESH/ESC
NICE
SIGN
International
ASH/ISH
WHO/ISH
WHO
North America
AACE
ACCF/AHA
CCS
DVA/DoD
ICSI
ISHIB
NHLBI
NHLBI
RNAO
Rate of addressing each research questions, %

Year

Ref #

Q1

Q2

Q3

Q4

Q5

2004
2011

24







2010
2008
2008
2005
2011
2010
2006
2010

26





















2008

34

2009
2006

35




2004
2009
2013
2011
2007

37

2014
2003
2007

38

2006
2011
2011
2004
2010
2010
2004
2014
2005

40

25

27
28
29
30
31
32
33

36

15
16
18
19

20
39

41
21
42
43
44
45
46
47

Q6

Q7






























































c























































c


30










10




53.3










10










10










6.7










0

Abbreviations: , data are available; , no data are available.

a
Q1, 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 antihypertensiveinduced 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?
b
See Table 1 for details of organizations acronym.
c
Was not absolutely specified under clinical medical history.

recommended screening and treatment of hypertensive men

with ED for low testosterone levels (Table 4).

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 thiazidelike 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

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Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

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 effects39
on male sexual function by some sets of guidelines. Some
treatment guidelines such as Saudi Hypertension Management Society30 and Pan America Health Organization36 considered thiazide-class diuretics to be possibly or absolutely
contraindicated in sexually active hypertensive males, respectively. Of note, the term thiazide-class diuretics60 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 diuretics60 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 men61 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 b-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
b-blockers has occasionally been associated with SD in
males.59 b-Blockers are distinguished based on several properties, such as their relative affinity to b1 and b2 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 b-blocker for individual patients with hypertension.65 Propranolol, a first-generation nonsubtype selective
b-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
b1-selective blockers such as atenolol have less of a tendency
to produce ED than do nonsubtype selective b-blockers.68,69
However, b1-selectivity is dose related66,67 and tends to diminish at higher drug concentration69,70; thus, the incidence of SD
may rise.69 Nebivolol, a third-generation b1-blocker, has the
highest cardioselectivity of any of the currently available
b-blockers.71 Additionally, nebivolol produces an endotheliumderived 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 b-blockers should also be considered; knowledge and prejudice about ED as a side effect of
b-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
b-blockers on impairing male sexual function (Table 1).
b-Blocker-associated SD has been deemed as a potential adverse
effect by some of these guidelines27,34,43 as either a major side
effect39 or a definite adverse effect.15,16,24,28,37,38,40,41,45,47 Individual b-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 b-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 b-blockers was more commonly associated
with other b-blockers.16 Moreover, atenolol-related ED, based
on the outcomes of United Kingdom Prospective Diabetic
Study,77 has been addressed as a prototype for b-blockers by the
American Association of Clinical Endocrinologists.40 The
American College of Cardiology Foundation/American Heart
Association41 state that older b-blockers have been associated
with depression, SD, dyslipidemia, and glucose intolerance, and
these side effects are less severe or unlikely with newer agents.
The RNAO47(p2439) precisely specified that first-generation
nonsubtype-selective b-blockers (nadolol, pindolol, propranolol, and timolol), second-generation selective b1-blockers
(acebutolol, atenolol, bisoprolol, and metoprolol), and thirdgeneration labetalol are all associated with ED.
The relation between centrally acting sympathoplegic drugs,
such as a-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) a-methyldopa is reserved as the drug
of choice for nonsevere hypertension in pregnancy25,35-37,45;
(2) a-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 guide51 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

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239

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 guidelines48-51 (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
medications58,66; (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 colleagues3 (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 millennium52-54 were compared
with those updated at the third millennium20,37,45 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-IV37 compared with BHSIII.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-7NHLBI45 (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 SD5,12,80 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 guidelines15,16,24,27,34,39,42,44,45
(Table 4). Nonetheless, SD has not been explicitly specified
under patients clinical history by ESH15 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 diseases82 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 se5,12 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 b-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 b-blockers or centrally acting medications) have
been addressed by approximately half (16 of 30) of the revised
guidelines15,16,24,27,28,30,34,36-41,43,45,47 (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 abovementioned 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

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Journal of Cardiovascular Pharmacology and Therapeutics 21(3)

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
therapy3,4,85 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, a-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 NHLBI45 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/ESC16 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 a-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 ED88 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.
Acknowledgments
We acknowledge the assistance given to us by Ina DSouza 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.

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