European Journal of Internal Medicine 81 (2020) 22–23
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European Journal of Internal Medicine
journal homepage: www.elsevier.com/locate/ejim
Commentary
Erectile dysfunction and arterial hypertension: Still looking for a scapegoat
Giovanni de Simone , Costantino Mancusi
⁎
Hypertension Research Center & Department of Advanced Biomedical Sciences, Federico II University Hospital, via S.Pansini 5, bld 1, 80131, Naples, Italy.
Hypertension awareness, treatment and control have improved
substantially in the past 40 years. However, control rates have pla-
teaued in the past decade in many countries, and a substantial pro-
portion of hypertensive patients remains uncontrolled [1].
Achievement of optimal BP control is a long process involving pa-
tients and physicians in a persistent bidirectional relationship.
Adherence to medications is a key factor for optimal blood pressure
(BP) control and contributes substantially to reduce related morbidity
and mortality [2]. Different factors can induce poor adherence to an-
tihypertensive treatment, including patients-physician-related factors
and drugs-related factors [2]. Careful titration of medications and
continuous assessment of side effects should be pursued at the begging
of the therapy and at each follow-up visits, to achieve optimal ad-
herence to treatment, also considering that some patients might be
reluctant in reporting some side effects. This reluctance explains at least
in part why sex differences exist in the adherence to antihypertensive
treatment: erectile dysfunction (ED) is an important reason to withdraw
therapy in men, whereas it does not affect adherence in women [7].
Hypertension and ED are patho-physiologically interrelated condi-
tions, which share common abnormalities, including endothelial dys-
function and vessel stiffening [3,4]. Stiffening of the vascular system
includes penile vasculature, and is likely to be the most important
mechanism paralleling ED and hypertension especially during the aging
process [5]. In a sub-analysis in male participants to the SPRINT study
[6], the International Index of Erectile Function Total Score was related
negatively to systolic and positively to diastolic BP and a persistent
sexual activity was not at all related to any class of anti-hypertensive
medications, confirming the importance of the hemodynamic pattern in
the hypertensive patient with sexual dysfunction.
No question that anti-hypertensive therapy can impact mechanisms
of induction and maintenance of adequate erection, but whether or not
this negative effect is related to single classes of medications, rather
than to short term consequences of reduction of blood pressure is not
completely clear [5,7]. All medications with potent vasodilator and no
counter-regulating activities (including ACE-inhibotors, Angiotensin
Receptor Blockers, Ca++-Channel Blockers and α-blockers) are not
reported to be associated with ED, and rather they might be protective,
as reported for doxazosin and Angiotensin Receptor Blockers. Other
medications reducing BP without direct vasodilator effect can worsen
⁎
Correspondence author.
E-mail address: simogi@unina.it (G. de Simone).
https://doi.org/10.1016/j.ejim.2020.09.004
Received 29 August 2020; Accepted 6 September 2020
Available online 16 September 2020
0953-6205/ © 2020 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.
T
sexual function [8]. The possible mechanism is related to the reduced
BP, not counterbalanced by vasodilation of penis arterioles and arteries,
with consequent reduction of blood flow, and lack of sufficiently trap of
incoming blood flow into sinusoids. These local hemodynamic altera-
tions blunt an efficient compression of subtunical venular plexuses and
occlusion of emissary veins, to minimize venuos outflow [7].
Not surprisingly, β-blockers are among the medications potentially
more involved in precipitation or aggravation of ED, though this asso-
ciation is not unanimously recognized [8,9]. The negative effect on
male sexual function is likely due to the decreased perfusion pressure
aggravated by the α-receptor unbalanced stimulation, tied with de-
creased levels of testosterone reported during therapy with both cardio-
selective and non cardio selective β-blockers [8]. These detrimental
effects are not reported with nebivolol, which rather increases expres-
sion of endothelial nitric oxide synthase (eNOS), enhancing blood flow
into the cavernous sinusoids, and decreases oxidative stress and col-
lagen content in penis [10,11]. In general, starting with low dose and
slow titration is reported to increase tolerability for β-blockers.
However, the problem of lack of adherence to antihypertensive
therapy because of potentially β-blocker-induced ED is a limited pro-
blem in terms of general adherence to antihypertensive therapy.
Although listed among the main therapeutic options, the ESC/ESH
2018 guidelines implicitly suggest using this class of meds as first line
treatment only for specific indications, similar to the recommendations
of the American guidelines. As the ESC/ESH guidelines underline, in
addition to the higher rate of discontinuation, β-blockers present a
number of additional disadvantages, compared to the other classes of
antihypertensive meds, including less efficacy in prevention of stroke
and in regression of hypertension-mediated organ damage, and poten-
tial deleterious effect on glucose metabolism when combined with
diuretics. Vasodilator β-blockers present attenuated, albeit still detect-
able, effects on glucose metabolism [12], but there is scarce informa-
tion on the combination with thiazides.
Thus, in the setting of arterial hypertension, β-blockers are used in
the context of other severe associated conditions, such as coronary
heart disease and heart failure, per sé associated with ED, which makes
assumption on cause-effect relationship even more difficult.
In this issue of the journal, in the context of a review on adherence
to antihypertensive therapy, Manolis et al. [13] specifically analyze the
G. de Simone and C. Mancusi
effect of β-blockers on ED, with a particular focus on nebivolol. The
authors confirm that for its peculiar characteristics nebivolol should be
a preferred choice in hypertensive patients, consistent with the in-
dications of the European guidelines that recommend nebivolol or
carvedilol when a β-blocker needs to be prescribed in the context of
anti-hypertensive strategy.
Nebivolol is the most cardio selective beta-blocker, with potent
vasodilator properties, promoting increasing secretion of nitric oxide
form endothelial cells, a mechanism that, however, has fundamental
assumption in the integrity of endothelial cells. Nebivolol exerts a sy-
nergic effect with type 5 phosphodiesterase inhibitors (PD5-i) in the
treatment of ED [14], with reported beneficial effects on adherence, as
Manolis et al. underline [13].
Although in vivo and in vitro studies have demonstrated that ne-
bivolol activates the NO/cGMP pathway, enhancing erectile response,
and potentiates relaxation of erectile tissue, an affect that was not
present with atenolol [15], whether this effect is maintained in the
presence of endothelial dysfunction is not clear. Three small rando-
mized control trials have demonstrated beneficial effect of nebivolol
compared to other β-blockers on erectile function [16–18].
Other observational studies have reinforced the concept that nebi-
volol has no detrimental effect on ED: data from a Spanish study de-
monstrated that the effect of nebivolol was enhanced in young hy-
pertensive patients, being the main protective factors against ED, but in
older patients BP control was the main protective factors against ED
[19]. Thus, the effect of nebivolol might be maximized when integrity
of endothelial cells is preserved as it is in younger hypertensive patients
compared to older. The protective mechanism of PD5-inhibitors is dif-
ferent and active also in a condition of endothelial dysfunction and,
when associated with any β-blockers, PD5-inhibitors improve ad-
herence to therapy [20]. However, nebivolol remains the sole β-blocker
with a direct potential protective effect on sexual function, being ED
reported also during therapy with carvedilol [21].
Overall, our knowledge about the impact of the different anti-
hypertensive drugs on the development of ED is currently based either
on small clinical studies or sub-analyses of large studies with inherent
limitations. Although robust clinical conclusions cannot be drawn,
when a β-blockers is indicated for treatment of arterial hypertension,
based on the present evidence, it is reasonable to prefer nebivolol to
other β-blockers also to prevent the development of ED [20]. It is im-
portant to underline that β-blockers should not be considered as a first
line anti-hypertensive therapy in the absence of compelling indications.
Larger and finalized randomized controlled trials would be needed
to confirm whether nebivolol reduces the incidence of ED compared to
other beta-blockers and independently of endothelial function, espe-
cially irrespective of age, and whether switching from other β-blockers
to nebivolol might still improve erectile function.
Declaration of Competing Interest
None.
23
European Journal of Internal Medicine 81 (2020) 22–23
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