Pathogenesis of DED
Detailed description of the physiology of erectile function (EF) is not an object
of this paper. In short, the erection is a complex process in which psychological, social, endocrine, paracrine, neural,
vascular and other factors take part. The penis is a hydraulic organ whose state –
from relaxation to different phases of erection is determined by the grade of fullness
with blood of corpora cavernosa. Their volume is defined by 2 variables – arterial
inflow and venous outflow. The capacity of the filling terminal helical arteries is
determined by NO-dependent smooth muscle relaxation. Different stimuli – psychogenic
(visual, auditory, olfactory, memory, fantasy) or reflectory (tactile) activate the
central and/or peripheral neuronal chains leading to synthesis and secretion of NO
from the non-adrenergic–non-cholinergic (NANC) neuronal terminals in the cavernosal
bodies through activation of neuronal nitric oxide synthase (nNOS). This small amount
of NO triggers initial smooth muscle relaxation starting the hemodynamic process of
erection. Further, receptor mechanisms and the shear stress in the vascular wall activate
phosphatidylinositol-3-kinase/protein kinase B (Akt) pathway leading to activation
of endothelial nitric oxide synthase (eNOS) and further NO release from the penile
endothelial cells. Binding of the released neural and endothelial NO to soluble guanylate
cyclase in the smooth muscle cells (SMC) increases cyclic guanosinemonophosphate (cGMP)
levels and cGMP-dependent protein kinase G (PKG) activity. As a consequence cell membrane
Ca-channels are closed decreasing the Ca++ influx in the cell and from the other side
cytosolic Ca++ is retained in the endoplasmic reticulum. The opening of the Ca-dependent
potassium channels on the membrane leads to potassium outflux and hyperpolarization.
Finally, the cytosolic Ca++ depletion causes cavernosal SMC relaxation leading to
increased blood inflow through the helical arteries, sinusoidal filling and cavernosal
dilation. The volume of corpora cavernosa increases and a compression of the draining
venous vessels (emissary veins) in subtunical venular plexus against the rigid tunica
albuginea occurs with a consequence – venous occlusion, decrease of outflow and further
increase of intracavernosal pressure. The process of erection needs an intact cavernosal
structure, characterized by abundant elastic fibers and less collagen.
The detumescence initiates with activation of the sympathetic neurons and liberation of norepinephrine
from the adrenergic terminals of the cavernosal nerve, as well as endothelins and
PgF2α from the endothelial cells covering the cavernosal sinusoids. An increase in intracellular
calcium activates myosin light chain (MLC) kinase and phosphorylation of MLC to generate
SMC contraction. Additional pathways such as RhoA/Rho-kinase lead to the sensitization
of the SMC contractile apparatus to calcium, promoting contraction. Activation of
Rho-kinase results in inhibition of MLC phosphatase and continued expression of phosphorylated
MLC. The RhoA/Rho-kinase pathway is a predominant calcium-sensitizing pathway to mediate
continuous smooth muscle tone in the penis. Protein kinase C (PKC) is also calcium
sensitizing and acts to inhibit MLC phosphatase, also promoting the contractile response
([Hidalgo-Tamola, Chitaley, 2009]).
Disturbances of each of the described consecutive stages from the erotic stimuli to
the venous drainage may compromise the process causing ED. The pathogenetic concept
about ED evolved from the mostly psychogenic in the past to the leading organic currently.
It should be mentioned that psychogenic and organic disturbances interplay in every
case of ED and cannot be separated absolutely even for didactic reasons. The similarities
of dilatation mechanisms in corpora cavernosa and the remaining arterial vessels in
the body, based on the key role of NO, explain the common mechanism of their deterioration
in endothelial dysfunction. The presence of cardio-vascular disease increases significantly
the likelihood for ED ([Martin-Morales et al., 2001]). From the other side, ED may be the first sign of existing but still undiagnosed
CVD ([Montorsi et al., 2003]).
The pathogenesis of DED is much more complex compared to non-diabetic men ([Fig. 3]). During the last years special attention has been paid to the importance of DM
as a vascular risk factor. It accelerates the development of endothelial dysfunction
– an earlier event of vascular disease, induces oxidative stress and dyslipidemia,
potentiates atherosclerotic process, aggravates arterial hypertension, etc. A vicious
pathogenetic circle between DM and hypogonadism perpetuates – men with DM have lower
levels of testosterone and men with hypogonadism have an increased risk of development
of obesity, metabolic syndrome and DM with the full spectrum of their unfavorable
cardiovascular consequences ([Mulligan et al., 2006]). This global vascular disorder takes place in the cavernosal bodies as well, where
other more DM-specific pathogenetic biochemical mechanisms develop:
Fig. 3 Pathogenesis of DED. AGEs – advanced glucation end products; PKC – protein kinase
C; NO – nitric oxide; MS – metabolic syndrome; SMS – smooth muscle cells; AH – arterial
hypertension.
Endothelial dysfunction
This is probably the most discussed aspect of DED in the literature. Investigating
the function of NO/cGMP signalling in human erectile tissues J. [Angulo et al. (2010)] used human corpus cavernosum (HCC) strips and penile resistance arteries (HPRA)
collected from penile specimens from organ donors (OD) and from diabetic and non-diabetic
men with ED undergoing penile prosthesis implantation ([Angulo et al. (2010)]). The relaxations to acetylcholine, electrical field stimulation, sodium nitroprusside,
and sildenafil were evaluated in phenylephrine-contracted HCC and norepinephrine-contracted
HPRA and cGMP content in HCC was also determined. The impairment of endothelium-dependent
relaxation in HCC and HPRA from ED patients was exacerbated by diabetes – E(max) 76.1,
62.9, and 49.3% in HCC and 73.1, 59.8, and 46.0% in HPRA from OD, non-diabetic and
diabetic ED, respectively. Hypertension, hypercholesterolemia, or aging did not exert
a further impairment of endothelial relaxation among ED patients. DM also caused a
further impairment of neurogenic relaxation in HCC and HPRA. The basal and stimulated
content of cGMP in HCC was significantly decreased in patients with ED, but specially
reduced in diabetic patients. Diabetes clearly impaired PDE5 inhibitor-induced vasodilation
of HPRA from ED patients. The authors concluded that ED is related to impaired vasodilation,
reduced relaxant capacity, and diminished cGMP content in penile tissue. These alterations
are more severe in diabetes and accompany reduced relaxant efficacy of PDE5 inhibition.
Thus, an exacerbated reduction of NO/cGMP signaling could be responsible for ED in
diabetic men and would explain their reduced response to treatment.
-
NO bioavailability may be decreased by suppressed eNOS expression and/or activity or by increased NO
scavenging. Jesmin et al. (2004) reported reduction of eNOS mRNA expression suggesting
an eNOS deficient expression at transcriptional level in OLETF diabetic rats ([Jesmin et al., 2003]). In the same study decreased vascular endothelial growth factor (VEGF) expression
and mRNA transcription in penile tissues was also found. It should be mentioned that
the Akt-dependent pathway mediates both shear stress and VEGF phosphorylation of eNOS
([Musicki et al., 2004]). The effects of VEGF include endothelial cell proliferation, migration, angiogenesis,
and anti-apoptosis, increased eNOS phosphorylation and expression of anti-apoptotic
proteins. There is strong evidence that VEGF is a survival factor for endothelial
cells ([Dimmeler, Zeiher, 2000]). At the molecular level, VEGF can upregulate eNOS expression in endothelial cells
([Papapetropoulos et al., 1997]). Furthermore, increased expression of eNOS has been reported in the rat penis after
intracavernosal injection with VEGF ([Lin et al., 2002]). These findings support the importance of VEGF as an eNOS inducer. It would be
logical to assume that the reduced expression of eNOS shown by Jesmin et al. (2004)
in the OLETF rat penis may be causally related to the decrease in VEGF expression
in the tissue. Unlike eNOS, nNOS does not appear to be inducible by VEGF ([Sheehy et al., 1997]). The penile expression level of nNOS has been documented to remain unchanged in
VEGF-treated rats ([Lin et al., 2002]). Thus, the VEGF-triggered biochemical events probably have no targets in the nNOS
gene, which continues to produce nNOS transcripts at a steady level.
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Oxidative stress is a key pathogenic factor in the development of diabetic complications. Chronic
hyperglycemia induces free radical (reactive oxygen species – ROS) production through
formation of advanced glycation end-products (AGE), lipid peroxidation, polyol pathway
activation, superoxide production, and the activation of protein kinase C. ROS participate
in most studied mechanisms for the initiation and maintenance of functional and structural
deterioration. Increased oxidative activity and the expression of inflammatory markers
are seen in patients with DED. Circulating monocyte activity and expressions of inflammatory
markers such as endothelin-1 (ET-1) and intracellular adhesion molecule-1 (ICAM-1)
are used as markers for ROS and inflammation ([Hidalgo-Tamola, Chitaley, 2009]).
-
Advanced Glycation End-products (AGEs). Normally with aging every tissue in the body is glycated in some extent.
In hyperglycemic conditions the glycation process is more active and leads to micro-structural
changes on a molecular level, which can further compromise the function of the tissue
and finally lead to macro-structural deterioration. AGEs bond covalently to the vascular
collagen leading to thickening of the vascular wall, deceased elasticity, endothelial
dysfunction and atherosclerosis ([Bucala et al., 1991]; [Singh et al., 2001a]). Interaction between AGEs and endothelial cells up-regulates adhesion molecules
that mediate vascular damage. AGE also stimulates cytokine expression on monocytes
and macrophages ([Yan et al., 2008]). AGEs are increased in corpora cavernosa of rats and men with DM and cause impaired
cavernosal smooth muscle relaxation and ED in diabetic rats ([Seftel et al., 1997]; [Cartledge et al., 2001b]; [Usta et al., 2003]). One important mechanism for decreasing of cavernosal compliance and smooth muscle
relaxation is through the generation of free radicals which react with NO and decrease
its availability. Increased penile levels of ROS were found in diabetic rats. The
resultant most reactive peroxinitrite is involved in cell damage and death. Summarizing,
AGEs contribute to the development of DED by generating free radicals leading to oxidative
cell damage and by quenching NO ([Cartledge et al., 2001b]; [Bivalacqua et al., 2005]; [Khan et al., 2001]).
-
Endothelins. Endothelin has 3 isopeptides (1, 2 and 3) and 2 receptors bound to G-protein (ETA
and ETB). ET-1 is a powerful vasoconstrictor released from the vascular endothelium
in the penis [Moore, Wang (2006)]. There is evidence that DED is related to a disturbed balance towards increased
vasoconstriction, caused by endothelin and its receptors ([Bivalacqua et al., 2003]; [Christ et al., 1995]). The plasma levels of ET-1 are increased in diabetic men ([Clozel et al., 1992]). ETA-receptors are located on the SMC and induce vasoconstriction and cell proliferation.
ETB-receptors are presented mostly on the vascular endothelium and induce vasodilatation
through NO and prostacyclin release ([Bivalacqua et al., 2003]; [Sima et al., 1996]). On the contrary, these receptors mediate vasoconstriction in some arteries like
coronary in dogs and mammary in men ([Clozel et al., 1992]; [Teerlink et al., 1994]). It was found that ETB-receptors are up-regulated in the cavernosal bodies of diabetic
rabbits where it is supposed to have constrictive role. In this way an increase in
ETB receptors and their ligands may cause disbalance and vasoconstriction ([Sima et al., 1996]). It is considered that the mitogenic effect of ETB causes early ultrastructural
atherosclerotic changes in diabetics ([Lu et al., 2004]).
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RhoA-Rho kinase. RhoA is a GTB-binding protein affected by Rho-kinase. The ET1 induced vasoconstriction
is related to the RhoA-Rho kinase pathway ([Park et al., 2002]; [Wang et al., 2002]; [Buyukafsar, Un, 2003]) the activation of which suppresses eNOS ([Ming et al., 2002]). Rho-kinase is found in the cavernosal tissue of rats, rabbits and men and is activated
in diabetic rats. It is considered that the RhoA-Rho kinase pathway potentiates ED
by the decreased production of NO in the penis ([Rees et al., 2002]; [Bivalacqua et al., 2004]; [Chua et al., 2006]).
Several other mechanisms have been described in which hyperglycemia leads to functional
and structural changes in cavernosal bodies and arteries. The described complex pathogenetic
attack decreases the capacity of SMC relaxation and functional dilatation of cavernosal
structures, but also limits the penile arterial inflow through atherosclerotic changes.
Diabetic neuropathy (DN)
DN is the most common diabetic complication, affecting 10–90% of people with diabetes,
depending of the diagnostic criteria and the age and duration of DM ([Vinik et al., 1992]; [Young et al., 1993]; [Dyck et al., 1993]; [Tesfaye et al., 1996]). Some studies showed an earlier development of DN in men, compared to women ([Aaberg et al., 2008]; [Kamenov et al., 2010]). Neuropathy is a very important pathogenetic factor in the development of DED.
Because DN affects all levels of the neural system, disturbances could also happen
on all levels in the complex process of erection – from the central initiation to
the penis. In the literature much more attention is paid to the vascular aspects of
DED compared to the neural ones ([Kamenov, Traykov, 2012]).
The central aspects of erection have been investigated in some studies, from fundamental investigations
of sexual behavior to functional MRI imaging and PET in the phase of REM sleep, associated
with nocturnal penile tumescences, as well as the whole sexual cycle in men ([Nofzinger, 1997]). It should be mentioned that central aspects of DN and DED have been much less
investigated probably because of the insufficient options for diagnostic methods and
selective therapeutic influence. Recently, MRI for structural ([Frøkjær et al., 2013]) and functional MRI for structural and functional changes and other methods have
been used for investigating the central aspects of DN ([Selvarajah et al., 2014]; [Wilkinson et al., 2013]).
In the clinical classification of DN traditionally DED is positioned in the genito-urinary
autonomic DN. The initial stage of the erection process at penile level – NANC nerve
endings nNOS activation and NO release has been shown to be impaired in animal models
of DM1 and (although less convincingly) in DM2 ([Hidalgo-Tamola, Chitaley, 2009]). Otsuka Long-Evans Tokushima fatty (OLETF) rats represent an appropriate model
for spontaneously developed DM2 with its late complications ([Kawano et al., 1992]), including DN ([Kamenov et al., 2006]). OLETF rats showed decreased immunofluorescent staining for nNOS in dorsal nerves
and 40% decrease in nNOS 160 kDa protein expression relative to that of non-diabetic
controls (P<0.01), thus supporting an impaired nNOS effectiveness in DM2 ([Jesmin et al., 2003]).
By applying different neurological tests it has been shown that diabetics with ED
present more commonly with abnormal NCV, sphincter electromyography and vibration
sensitivity compared to those without ED ([Hakim, Goldstein, 1996]; [Hecht et al., 2001]). The combination of sensory and autonomic disturbances leads to decreased sensory
afferentation necessary for the initiation and maintenance of the erection, but also
limits the effect of the critically necessary for the erection NO from the intracavernosal
nerve terminals. In most studies no separate evaluation of the macro- and microvascular
(including DN) complications is presented. We found that microangiopathy and in particular
DN is a more important risk factor for DED than macroangiopathy ([Kamenov et al., 2007]). The presence of ED increased the likelihood to have macrovascular but in higher
degree microvascular diabetic complications. These data support the crucial negative
role of DN in the complex pathogenesis of DED and may explain why men with diabetes
are more prone to ED compared to men with same degree of macrovascular disease but
without DN.
Hypogonadism
is frequently associated with DM2 ([Yagihashi et al., 2007]; [Bartolini et al., 2004]; [Corrales et al., 2004]; [Corona et al., 2007]). There are strong causal links between the metabolic syndrome, ED and late onset
hypogonadism. Even shortly after the diagnosis of DM2 the prevalence of hypogonadism
(symptoms+TT<3.2 ng/ml) is 17.6%, but only 0.2% of the subjects in this study reported
occasional use of testosterone and none a current therapy of frequent use ([Corona et al., 2014]). Later-on in the evolution of the disease, in the average diabetic population,
choosing a cut-off of total testosterone (TT)<10.4 nmol/l for evaluation of 2 165
men aged≥45 years, visiting primary care practices in the United States, the investigators
of HIM study reported that half of diabetic men were hypogonadal=50.0% (45.5–54.4),
OR(95%CI)=2.09 (1.70–2.58) ([Mulligan et al., 2006]). Hypogonadism was also very common in other co-morbidities included in the metabolic
syndrome: obesity=52.4% (47.9–56.9); OR=2.38 (1.93–2.93), arterial hypertension=42.4%
(39.6–45.2); 1.84 (1.53–2.22), hyperlipidemia=40.4% (37.6–43.3); 1.47 (1.23–1.76)
respectively. Many studies support the weight-increasing effect of hypogonadism and
the testosterone lowering effect of obesity. It is difficult to answer which one is
the initial event – hypogonadism or the metabolic syndrome. Even if the cause-consequence
dilemma is still not definitely solved, the treatment should be directed to both problems.
Against the older opinion that testosterone is mostly a trigger of desire with limited
importance for the lower levels of erection, a growing body of evidence supports its
active participation and importance on all levels of the above described hierarchic
structure of the erectile process ([Fig. 4]).
Fig. 4 Effects of hypogonadism on ED. MS – metabolic syndrome; DM2 – diabetes type 2; ED
– erectile dysfunction. (modified from [Kamenov, Frederique Courtois 2013]).
On the cerebral level testosterone acts by itself, but also as its metabolites after
appropriate enzymatic transformations to estradiol (via aromatase) and to dihydrotestosterone
(via 5-alpha reductase). It stimulates the synthesis, storage and release of pro-erectogenic
neurotransmitters and modulates the neuronal activity, receptor sensitivity, neurotransmitter
liberation, the socio-sexual behavior (increasing libido) and positively influencing
dopamine, NO, oxytocine, etc. On the spinal level testosterone activates the androgen-sensitive
motoneurons of mm. bulbo- and ischiocavernosi and the androgen receptors in parasympathetic
erectile area S2–4.
It is generally accepted that androgens are critical for the development, growth,
and maintenance of penile erectile tissue. Animal studies showed testosterone dependency
of the eNOS-containing cavernosae parasympathetic fibers ([Baba et al., 2000]). In animal models, androgen deprivation produces penile tissue atrophy concomitant
with alterations in dorsal nerve structure, endothelial morphology, reduction in trabecular
smooth muscle content, and an increased deposition of extracellular matrix. Further,
androgen deprivation results in the accumulation of adipocytes in the subtunical region
of the corpus cavernosum ([Traish, Kim, 2005]). Testosterone deprivation is followed by the programmed cell death of cavernosal
SMC ([Porst, 2007]). Interestingly, testosterone stimulates both the initiator of the erection (NOS)
and its terminator (PDE-5), thus fine balancing the whole process. Androgen deficiency
diminishes protein expression and the enzymatic activity of nitric oxide synthases
(eNOS and nNOS) and PDE-5. The androgen-dependent loss of erectile response is restored
by androgen administration but not by administration of PDE-5 inhibitors alone. These
data suggest that androgens regulate trabecular smooth muscle growth and connective
tissue protein synthesis in the corpus cavernosum. Further, androgens may stimulate
the differentiation of progenitor cells into SMC and inhibit their differentiation
into adipocytes. Clinical and preclinical studies have suggested that venoocclusion
is modulated by the tone of the vascular smooth muscle of the resistance arteries
and the cavernosal tissue and a balance between trabecular smooth muscle content and
connective tissue matrix. In men with ED, venous leakage is thought to be a common
condition among non-responders to medical management and is attributed to penile smooth
muscle atrophy. Summarizing, [Traish and Kim (2005)] concluded that androgens exert a direct effect on penile tissue to maintain EF and
that androgen-deficiency produces a metabolic and structural imbalance in the corpus
cavernosum, resulting in venous leakage and erectile dysfunction ([Traish and Kim (2005)]). The testosterone level necessary for normal EF still needs exact determination.
Interventional studies in men have demonstrated the favorable effect of testosterone
replacement therapy (TRT) on EF in men with organic hypogonadism, mostly in cases
when it is the only reason for ED (Shabsigh, 2006). Other structural changes related
to DM include the loss of normal cavernosal endothelium and SMC ([Burchardt et al., 2000]) and an increased deposition of collagen and thickening of the basal lamina leading
to fibrosis ([Jevtich et al., 1990]).
Treatment Options for DED
The already described mixed pathogenesis of DED requires a complex treatment which
can be divided into general and specific measures.
The general measures include the improvement and control of the main pathogenetic factors leading to DED.
The therapeutic approach does not differ from the currently accepted options for reaching
the appropriate for the particular patient targets for blood glucose, lipids and blood
pressure control as well as the cessation or limitation of unhealthy lifestyle habits
like smoking, alcohol overconsumption, immobilization, stress, use of recreational
drugs, etc.
Although the data about the beneficial effect of life style modification on ED are limited diet and physical activity changes should always be recommended
for diabetic men with ED ([Giugliano et al., 2010]). Nevertheless studies investigating the effect of weight loss on DED are scarce ([Stoian et al., 2014]). The Look AHEAD (Action for Health in Diabetes) trial examined 1-year changes in
EF, measured by the IIEF in 372 overweight/obese men aged 45–74 with DM2 randomly
assigned to diabetes support and education or to intensive lifestyle intervention
involving group and individual sessions to reduce weight and increase physical activity.
At 1 year, the intensive group lost a greater percent of initial body weight (9.9
vs. 0.6%), had greater improvements in fitness (22.7 vs. 4.6%) and EF improved more
(17.3±7.6 at baseline; 18.6±8.1at 1 year) than the control group (18.3±7.6 at baseline;
18.4±8.0 at 1 year); P=0.04 and after adjusting for baseline differences P=0.06. According to the results of the 82% of men who finished the study the authors
concluded that in this sample of older overweight/obese diabetic men, weight loss
intervention was mildly helpful in maintaining EF ([Wing et al., 2010]).
Strict glycemic control is the cornerstone in the treatment of DM and prevention of its complications like
DED. Poor control increases the risk for ED 2–5-fold compared to good control ([Fedele et al., 1998]; [Klein et al., 2005]). C-C. [Lu et al., (2009)] concluded in a study including 792 subjects with 83.6% of them having ED and 43.2%
– severe ED that better glycemic control probably would reduce the prevalence of ED
and its severity among the younger men with DM2, but aging is the major determinant
for ED risk for the older group ([Lu et al., 2009]). Although new options are proposed ([Hidmark et al., 2014]), until now the results of pathogenetic treatment of DN have been generally disappointing,
most probably because of the late initiation of the treatment. There are some exceptions
from this non-optimistic conclusion like alpha-lipoic acid (review in [Ziegler 2006]; [Boulton et al., 2013]), and benfothiamine ([Stracke et al., 2008]).
The specific measures
include the psychotherapy, oral treatment, intracavernosal injections and intraurethral
application of PgE1, vacuum constrictor devices and penile implants. Summarizing the
results in the literature it should be mentioned that:
-
There are not many studies designed wich focus on diabetic patients. Usually diabetics
are sub-groups of larger patient populations. In some trials DM is even an exclusion
criterion.
-
In most series diabetes (type, duration, control, etc.) and its macro- and microangiopathic
complications including DN (presence, stage and treatment) are not described in detail.
-
In most cases oral treatment should be applied in the highest dose – sildenafil 100 mg,
vardenafil 20 mg, tadalafil 20 mg, avanafil 200 mg, udenafil 200 mg, mirodenafil 100 mg.
-
The effectiveness of the treatment in diabetic men is lower compared to non-diabetic
([Price, Hackett, 2008]). This difference is even underestimated because commonly poor glycemic control
is an exclusion criterion at enrollment in the randomized clinical trials (RCT).
-
Patients with DED require more often switching to a higher line of treatment like
intracavernosal injections, vacuum constrictor devices and implants, compared to healthy
men.
-
Vascular reconstruction operations for ED are very rarely performed in diabetic patients.
Psychological aspects of ED in DM
Although there is a growing number of studies on the association between DED and psychological
factors, the dominant scientific interest is focused on the organic pathology of DED.
Some authors draw attention to the individual and marital pathology in diabetic men
and the significance of psychological dimensions on the sexual impact of this illness
([Siddiqui et al., 2012]). ED is associated with higher levels of diabetes-specific health distress and worse
psychological adaptation to DM, which in turn worsens metabolic control ([Berardis et al., 2002]). Diabetic men are more likely to consider their ED to be severe and permanent,
compared with non-diabetic ([Eardley et al., 2007]). ED contributes to poorer overall quality of life in diabetic patients ([Avasthi et al., 2011])
PDE-5 inhibitors
A new era in “erectology” began about 15 years ago with the introduction of the first
inhibitor of PDE-5 – sildenafil. The members of this group of drugs inhibit the main
PDE isoform in the cavernosal smooth muscle – type 5 responsible for the degradation
of cGMP ([Wallis et al., 1999]) whose level increases and leads to improvement of the erection. Later PDE-5 inhibitors
– vardenafil, tadalafil and avanafil – have higher specificity to the target iso-enzyme
([Saenz de Tejada et al., 2001a]). Further avanafil and udenafil were also introduced on the market. Currently available
PDE-5 inhibitors are very effective and safe and represent the first line therapy
for treatment of ED, including DED, although less effective in diabetic men ([Ng et al., 2002]; [Padma-Nathan, 2003]; [Goldstein et al., 2003]). Only 56% of DM2 patients respond to PDE5, compared to 87% response in normal patients
([Rendell et al., 1999]). Even when a good response to treatment has been reported initially in DM2 patients,
the effect is not sustainable overtime. After 1 year of treatment of men with DED,
IIEF scores reverted to baseline values ([Penson et al., 2003]).
Sildenafil
Sildenafil is the most studied PDE-5i with an enormous data base. It has been successfully
used in doses 25, 50 and 100 mg in the general population as well as in difficult-to-treat
subgroups, particularly in DED. In one of the first trials – multicenter, randomized,
double-blind, placebo-controlled study (RCT) 268 men with DED were randomized to sildenafil
in a flexible escalating dose or placebo for a period of 12 weeks. In the active arm
56% of the patients had improvement of erections compared to 10% on placebo ([Rendell et al., 1999]).
Sildenafil has also been shown to be effective vs. placebo in DM1 patients. Significant
improvements in the ability to achieve erections evaluated by IIEF (35.7 vs. 19.9%)
and to maintain erections (68.4 vs. 26.5%), improved erections with treatment (GAQ
66.6 vs. 28.6%), and successful attempts at intercourse (63 vs. 33%) were reported
([Stuckey et al., 2003]).
In a RCT a total of 282 men were randomized to fixed-dose sildenafil or placebo. А
significant improvement from baseline in IIEF Q3 (55 vs. 29%) and IIEF Q4 (61 vs. 25%) lead to the conclusion that sildenafil is a moderately
effective treatment for ED in men with diabetes. The response rate was lower and cardiovascular
events were higher than previously reported in non-diabetic patients ([Safarinejad, 2004]).
Sildenafil has been investigated for potential benefits in different diabetic areas.
After one dose of 50 mg an improvement of cerebrovascular reactivity, assessed using
breath holding-hyperventilation test with trans-temporal ultrasound examination on
the middle cerebral artery, was observed in diabetic, but not in non-diabetic men
([Al-Amran et al., 2012]). A. [Burnett et al. (2009)] evaluated the changes of biomarkers of vascular function serum cGMP, 8-isoprostane,
IL-6 and IL-8 in men with DM2 with ED after use of sildenafil for 12 weeks ([Burnett et al., 2009]). They concluded that short-term continuous sildenafil treatment causes improvement
in systemic endothelial function remaining for a period after its discontinuation.
However, they did not mentioned any influence of this treatment on systemic oxidative
stress or inflammation, or a long-term beneficial effect on EF. [Grover-Páez et al. (2007)] determined the levels of hs-CRP, microalbuminuria, homocysteine, HbA1c and EF at
baseline and after 30 days sildenafil 50 mg daily or placebo. Men on sildenafil had
a significant decrease of microalbuminuria vs. baseline (p<0.01) and vs. placebo (p<0.02)
and of HbA1c (p<0.01 and p<0.01 respectively) ([Grover-Páez et al., 2007]). To evaluate the endothelial function 24 DM2 men were randomized to daily sildenafil
50 mg or placebo for 10 weeks. At the end of the trial, those who received sildenafil
had significantly improved erectile rigidity as captured by IIEF-5 (p<0.001) and increased
endothelial function via brachial artery flow-mediated dilation (p<0.01) ([Deyoung et al., 2012]).
Tadalafil
Tadalafil is an effective drug for treatment of ED of different severity and etiology.
The most important difference compared to other available currently approved PDE-5
inhibitors is its long half-life (17.5) hours allowing (1) a long-lasting clinical
effect of 36 h by on demand dosing with 5, 10 or 20 mg, and (2) full diurnal therapeutic
coverage by daily use in lesser dose (2.5 and 5 mg). Besides the evidence in the general
population ([Brock et al., 2002]; [Carson et al., 2004]) the drug has been successfully used in difficult-to-treat patients with severe
organic ED ([Carson et al., 2005]), DED ([Saenz de Tejada et al., 2002]; [Fonseca et al., 2004]), after radical prostatectomy ([Carson et al., 2005]; [Montorsi et al., 2004]) or radiation therapy ([Incrocci et al., 2007]). Tadalafil 10 and 20 mg on demand resulted in 56 and 64% improvement of the erections
compared to 25% in the placebo arm in a study with 191 diabetic men ([Saenz de Tejada et al., 2002]). Based on the significant benefit of low dose daily tadalafil ([McMahon, 2004]; [Porst et al., 2008]) the FDA approved this regimen in 2008. Tadalafil 5 mg once daily is used also for
lower urinary tract symptoms suggestive of benign prostatic hyperplasia ([Porst et al., 2013]).
In the diabetic arm (726 men with DED with minimal duration of 3 months) of the randomized
crossover, open study with 4 262 patients from 392 centers in 14 European countries
The Scheduled Use vs. on-demand Regimen Evaluation (SURE) study tadalafil 20 mg was
used regularly 3 times a week irrespective of sexual activity or on demand [(Buvat J et al., 2006)]. The patients were divided into 2 groups according to the used regimen and after
a 5–6 weeks period the 2 arms were crossed using the alternative dose regimen for
the same period of time. Regarding DM, patients were considered having type 1 or 2
according to current insulin use and the age of onset of DM – before or after 40 years
of age with no pre-selection for diabetic complications. At the end point on both
regimens, the mean IIEF EF domain score was 22, and >40% of the patients had a normal
EF domain score (≥26). The proportion of “yes” responses was ≥73% for SEP2 (penetration),
≥58% for SEP3 (successful intercourse), >46% for SEP4 (hardness of erection), and
≥45% for SEP5 (overall satisfaction). Efficacy was maintained up to 36 h post-dosing.
More than 70% of sexual attempts while on the 3-times-per-week regimen and approximately
50% of the attempts with on-demand treatment occurred >4 h post-dosing. Treatment
preference was 57.2% for on demand and 42.8% for 3 times per week. The authors concluded
that tadalafil, when taken on demand or 3 times per week, is efficacious and safe
in men with DED.
[Schulman et al. (2004)] studied the differences in effectiveness of the fixed dose tadalafil over time ([Schulman et al., 2004]). They combined the data from five12-week RCTs including 3 groups of 308, 321 and
258 men on placebo, 10 and 20 mg tadalafil respectively. The very first dose lead
to significant improvement of SEP2 – 47, 74, 79%; SEP3 – 31, 56, 67% and SEP5 (satisfied
overall with their sexual experience) −15, 36, 47% respectively. Later on the effect
increased reaching a plateau of 95% (SEP2), 90% (SEP3), and 81% (SEP5) between the
4th and 8th dose.
In a meta-analysis of 12 RCTs with tadalafil [Fonseca et al. (2004)] included 637 men of mean age 57 years with DM and mean baseline IIEF 12.6 ([Fonseca et al., 2004]). The use of tadalafil 10 or 20 mg lead to an improvement of 7.4 points vs. 0.9
points in the placebo group. In men with DM 53% of the sexual attempts were successful
vs. 22% in the placebo group. Baseline IIEF showed a negative correlation with HbA1c,
but the response to tadalafil treatment was not related to the glycemic control, type
of treatment or previous use of sildenafil. No analysis was made on the pathogenic
factors for ED. Comparison of this population with 1 681 men of mean age 56 years
with ED (baseline IIEF=15) without diabetes demonstrated more severe ED in DM but
independently equal therapeutic effect to tadalafil.
Vardenafil
Vardenafil is a powerful PDE5 inhibitor whose efficacy and tolerability at doses 5,
10 and 20 mg were shown in RCTs including large populations of men with ED ([Porst et al., 2001]; [Hellstrom et al., 2002]; [Hatzichristou et al., 2004]), and men presenting difficult-to-treat groups like DM, after prostatectomy etc.
([Goldstein et al., 2003]; [Brock et al., 2003]). The reliability of vardenafil was determined in a retrospective analysis of 2
clinical studies showing an increased probability for penetration, maintenance of
erection and higher general satisfaction compared to placebo. Most of the patients
who responded to the first dose of vardenafil reported success during the whole 12-week
treatment period ([Montorsi et al., 2004]). In one open study with 398 non-preselected men the efficacy and tolerability of
vardenafil used at initial dose of 10 mg and titrated to 5 or 20 mg were investigated
([Potempa et al., 2004]). At the end of the 10-week therapeutic period an improvement in EF domain of IIEF
from 13.9 to 25.9 points, successful penetration SEP2 in 89%, maintenance of erection
SEP3 in 78% and general satisfaction of the treatment (GAQ) in 92% were reported.
[Goldstein et al. (2003)] conducted in the USA and Canada a multicenter RCT with 452 men with DM1 and DM2
with HbA1c<12% ([Goldstein et al., 2003]). Patients were randomized in 3 groups – vardenafil 10 or 20 mg or placebo over
a 12 week period. The drug was taken 1 h before intercourse no more than once a day.
After the end of this period the patients received 10 or 20 mg vardenafil for another
12 weeks. Treatment efficacy was assessed using IIEF, GAQ, SEP2 and SEP3. Sub-analyses
of the data was made according to the baseline severity of ED, HbA1c (<6, <8 and >8%),
and dose-response effect. Special focus was placed on the registration of possible
side effects. At the end of the trial for the different doses vardenafil 57 and 72%
оf the men reported an improvement in EF according to GAQ compared to 13% improvement
in the placebo group. On the twelfth treatment week IIEF increased by 19.0 points.
Successful penetration (SEP2) was achieved by 64%, and successful coitus (SEP3) by
54% of men. The results of this study were summarized in 3 major conclusions: (1)
Vardenafil has a favorable dose-dependent treatment profile on DED. (2) The efficacy
of vardenafil is present irrespective of the baseline severity of ED and glycemia.
(3) The drug has no serious side effects and has very good tolerability. No disturbances
of color vision were reported.
Patient satisfaction with the treatment for ED is critical for his long term compliance ([Dean et al., 2006]). In one international trial with 3 291 men with ED 47% of them pointed the “constant
efficacy” as the most important feature of the treatment ([Eardley et al., 2003]; [Meuleman et al., 2003]). This is extremely important in men with DM, who report their ED to be severe and
permanent, seek medical help more often and are more prone to discontinuation of the
treatment because of an unsatisfactory result, than are men without diabetes ([Eardley et al., 2007]). Most of the above mentioned research suggests that responsiveness to PDE5i drugs
increases with sequential dosing from initiation; 8 doses are generally considered
an adequate trial of therapy to establish efficacy. The effect of the first intake
of a PDE5 inhibitor is a prognostic factor for its treatment efficacy. It can be stated
that the initial success and further reliability of the treatment for ED are crucial
for patient satisfaction with the treatment that directly affects compliance. L.[Valiquette et al. (2005)] evaluated the efficacy of the first intake of 10 mg vardenafil vs. placebo in non-selected
population of 600 men of mean age 54±11 years (20–79), of whom 30% had hypertension,
15% DM and 16% dyslipidemia ([Valiquette et al. (2005)]). Baseline EF domain of IIEF is 14.6±5 points, and ED duration about 5.6±5.2 years.
Efficacy regarding SEP2 is 87%=520 of total 600 men reported successful penetration
and 85% of them maintained their erection to the end of the intercourse (SEP3), which
equals the 74% success of the first intake of vardenafil regarding SEP3 in the general
population. Although head-to-head comparisons are scarce the data about the effectiveness
of the PDE-5 inhibitors in diabetic men suggest a similar degree. Recently, wе compared
the effect of the first intake of tadalafil 20 mg and vardenafil 20 mg in men from
the difficult-to-treat group with DED and proven DN ([Kamenov, 2011]). To synchronize the therapeutic windows, sexual intercourse should have been initiated
in the interval of 1–6 h after the drug intake. In this time frame the effectiveness
(IIEF-EF, SEP2, SEP3, GAQ) of both medications was comparable.
Avanafil
Avanafil was recently approved by the US Food and Drug Administration (2012) and European
Medicine Agency (2013) for the management of ED. It was studied in over 1 300 patients
during clinical trials, including patients with DM and those who had undergone radical
prostatectomy, and was found to be more effective than placebo in all men who were
randomized to the drug. The medication was studied with on-demand dosing as 50, 100,
or 200 mg that may occur after food and/or alcohol. Avanafil has a very quick onset
of action and higher specificity for phosphodiesterase type 5 vs. other phosphodiesterase
subtypes ([Burke, Evans, 2012]).
In a 12-week, multicenter RCT 390 men with DED were randomized 1:1:1 to receive avanafil
100 or 200 mg, or placebo. Compared with placebo IIEF-EF domain, SEP2 and SEP 3 improved
with both doses avanafil – 100 mg (P≤0.002), and 200 mg (P<0.001). The authors concluded
that avanafil was safe and effective for treating ED in men with diabetes and was
effective as early as 15 min and more than 6 h after dosing. The adverse events seen
with avanafil were similar to those seen with other PDE-5 inhibitors ([Goldstein et al., 2012]).
In a 52-week open-label extension phase of two 12-week RCTs 686 patients with mild
to severe ED with or without diabetes were assigned to avanafil 100 mg, but could
request 200 mg (for increased efficacy; 100/200-mg group) or 50 mg (for improved tolerability).
SEP2 and SEP3 success rates improved from 44 to 83% and from 13 to 68% (100-mg group)
and from 43 to 79% and from 11 to 66% (100/200-mg group), respectively. Mean IIEF-EF
domain scores improved from 13.6 to 22.2 (100-mg group) and from 11.9 to 22.7 (100/200-mg
group). Based on the the long-term tolerability and improvement in sexual function,
coupled with rapid onset, the authors concluded that avanafil is well suited for the
on-demand treatment of ED ([Belkoff et al., 2013]).
Recently, [Yilmaz et al. (2014)] injected intracavernosally 1 μM avanafil for 10 weeks in rats with streptozotocin
induced diabetes. Avanafil partially restored the diminished intracavernosal pressure
responses in diabetic rats. After the application of different stimuli on corpus cavernosal
strips from the diabetic group the relaxation responses were enhanced and contractile
responses diminished. The authors suggested that intracavernosal administration of
avanafil might also be beneficial for the treatment of ED in patients with DM2 ([Yilmaz et al., 2014]).
Udenafil
Udenafil is a potent novel PDE-5 inhibitor approved for use in Korea. Udenafil has
a T max of 1.0–1.5 h and a T 1/2 of 11–13 h. Therefore, both on-demand and once-daily
use of udenafil have been reported. Udenafil's efficacy and tolerability in doses
100 or 200 mg have been evaluated in several studies, and recent and continuing studies
have demonstrated udenafil's promise in both dosing regimens. Presently, tadalafil
is the only FDA-approved drug for daily dosing, but udenafil can be used as a once-daily
dose for erectile dysfunction patients who cannot tolerate tadalafil due to phosphodiesterase
subtype selectivity ([Kang, kim, 2013]). Recently [Park et al. (2014)] proved the equal efficacy and safety of 200 mg on-demand or 50 mg once-daily dosing
udenafil for 8 weeks on IIEF, SEP Q2 and Q3, GAQ, and vascular endothelial markers
in a multi-center, randomized, open-label, parallel-group, 12-week study with 161
DM2 patients. The authors concluded that both regimens were well-tolerated with flushing
and headache being the most frequent adverse events and further studies are needed
to assess the effect of daily udenafil treatment in diabetic patients ([Park et al. (2014)]).
Udenafil as an on-demand or once-daily dose is effective and tolerable, but more studies
are needed in patients of other ethnicities and with comorbid conditions such as DM,
hypertension, and benign prostate hyperplasia ([Kang, Kim, 2013]).
In a multicenter, fixed-dose RCT with 174 Korean patients with DED randomized to placebo,
100 or 200 mg of udenafil for 12 weeks were evaluated by IIEF (Q3 and Q4), the rate
of achieving normal EF (IEEF≥26), SEP2, SEP3, and GAQ. Compared with the placebo,
patients receiving both doses of udenafil showed statistically significant improvements
in the IIEF-EFD score. However, a statistically significant difference was not observed
between the udenafil 100 and 200 mg groups. Similar results were observed in the comparison
of Q3 and Q4 of IIEF, SEP diary, and GAQ. The percentages of subjects experiencing
at least one adverse event related to the study drugs were 3.6, 15.8, and 22.4% for
the placebo, udenafil 100 and 200 mg groups, respectively. Major adverse events were
flushing, headache, nausea, and conjunctival hyperemia. The study concluded that udenafil
was significantly effective for the treatment of ED, demonstrating significant improvement
in EF in patients with DM. The incidence of adverse events was relatively low and
well tolerated in patients with DM ([Moon du et al., 2011]).
Mirodenafil
A multicenter, parallel-group, fixed-dose RCT was conducted with 112 subjects who
were randomized to either placebo or mirodenafil 100 mg on demand for 12 weeks. The
active group showed significantly greater change from the baseline compared with the
placebo group in the following indicators: IIEF-EF (9.3 vs. 1.4, P<0.0001), IIEF Q3
(1.7 vs. 0.4, P<0.0001) and Q4 (1.7 vs. 0.3, P<0.0001), SEP2 (82.0 vs. 55.2%, P=0.0003),
SEP3 (68.9 vs. 22.3%, P<0.0001), GAQ (76.9 vs. 19.1%, P<0.0001). Normal EF domain
scores (≥ 26) at the study end were achieved by 32.7% and 9.4% in the mirodenafil
and placebo groups respectively (P=0.0031). As for the Life Satisfaction Checklist
scores, the mirodenafil group showed significantly greater improvements in sexual
life and partner relationship than the placebo group. Most treatment-associated AEs
were mild that resolved spontaneously. The conclusion of this study was that mirodenafil
is an effective and well-tolerated agent for the treatment of diabetic patients with
ED in Korea ([Park et al., 2010]).
Adverse events of PDE-5 inhibitors
The tolerance and safety of PDE-5 inhibitors is very good. Recent studies have even
shown several pleiotropic beneficial effects of PDE-5 inhibitors in patients with
CAD, hypertension, heart failure, pulmonary arterial hypertension, DM and Raynaud's
phenomenon (recent reviews in [Chrysant, 2013], [Giagulli et al., 2013]). Side effects and interactions of PDE-5 inhibitors with other drugs have been minimal,
with the exception of their co-administration with nitrates, which could lead to severe
vasodilation and hypotension and therefore, their co-administration is prohibited.
A Cochrane Database Report analyzing the randomized placebo-controlled studies did
not find any lethal case in men with DED. Only in one study have cardiovascular adverse
events been reported. The most common side effects (with a decreasing rate) are: headache,
flush, respiratory tract complaints and flu-like symptoms, dyspepsia, myalgia, vision
disturbances and back pain ([Vardi, Nini 2007]).
More concise data about the adverse events are available for the “older” PDE-5 inhibitors.
After a systematic review and meta-analysis ([Tsertsvadze et al., 2009]) the following conclusions about (1) vs. placebo and (2) head-to-head comparisons
were made: (1) A greater proportion of men treated with PDE-5i than placebo had at
least 1 adverse event. The most commonly reported adverse events were headache, flushing,
rhinitis, and dyspepsia. Other reported events were visual disturbances, myalgia,
nausea, diarrhea, vomiting, dizziness, and chest pain. In general, these events were
mild to moderate and were transient. Serious adverse events were reported in fewer
than 2.0% of participants, and the incidence did not differ between PDE-5 inhibitor
recipients and placebo recipients. (2) Differences in the incidence of any adverse
events among men treated with sildenafil (range, 24.0–34.0%), tadalafil (range, 28.0–35.0%),
and vardenafil (27.0%) were not statistically significant. Discontinuation due to
adverse effects ranged from 0.5–3.8% during tadalafil treatment, 0.5–3.8% during sildenafil
treatment, and 1.0% during vardenafil treatment. The frequency of specific adverse
events (headache, flushing, dyspepsia, and nasal congestion) seemed similar among
treatments. Data about the currently available PFE-5 inhibitors worldwide are presented
on [Table 2].
Table 2 Currently available PDE-5 inhibitors.
|
Drug
|
Dose (mg)
|
t
1/2 (h)
|
Frequency
|
Advantages
|
Side effects
|
|
sildenafil
|
25, 50*, 100
|
4.6
|
On demand or daily
|
safe; available on demand as well as continuous low dose (tadalafil 2.5 and 5 mg)
|
headache, myalgia, back pain, blurred vision, facial flushing, nasal congestion, dizziness
|
|
tadalafil
|
2.5, 5, 10,20
|
17–21
|
|
|
|
|
vardenafil
|
2.5, 5, 10*, 20
|
4–5
|
|
|
|
|
avanafil
|
50, 100, 200
|
5–10
|
|
|
|
|
udenafil #
|
100, 200
|
11–13
|
|
|
|
|
mirodenafil #
|
50, 100
|
2.5
|
|
|
|
t
1/2: plasma half-life time; h: hours; * also available in orodispersable formulation
(supralingual); #not approved in Europe ([Gareri et al., 2014]; [Park et al., 2014]; [Kang, kim, 2013]; [Ryu et al., 2013])
In real non-responders to a particular PDE-5 inhibitor the following could be attempted: (1) test for low
testosterone level (if not already done at the initiation of the treatment) and if
hypogonadal – TRT should be started (more details in [Nieschlag et al., 2006]); (2) metabolic optimization (also an earlier target); (3) escalation of the dose
of the PDE-5 inhibitor ad maximal; (3) change of the PDE-5 inhibitor; (4) daily dosing
of tadalafil; (5) second and third line treatment.
Second and third line treatment options
Second line treatment options include intracavernosal injections of individual or
combined (bimix, trimix) drugs and vacuum constrictor devices. Third-line therapy
are the penile prostheses (implants).
Intracavernosal injections (ICI)
Since 1983, ICI has become a staple therapeutic option and high success rates have
been reported ([Coombs et al., 2012]). ICI of vasoactive drugs – prostaglandin E1 (also used transurethral), phentolamine, vasoactive intestinal peptide
(VIP), papaverine. PGE1 stimulates adenylate cyclase, thereby increasing levels of cAMP, which results
in smooth muscle relaxation and vasodilatation. Erection appears after 5–15 min and
lasts for a period that depends on the dose injected. The patient should be enrolled
in an office-based training programme (requiring 1 or 2 visits) to learn the correct
injection procedure ([Phé, Rouprêt, 2012]). Intracavernosal injections remain safe, and a highly effective treatment option
in men with DED ([Redrow et al., 2014]). The efficacy rate is approximately 70%, with reported sexual activity after 94%
of injections, and satisfaction rates are high ([Moore, Wang, 2006]). However, dropout rates of 41–68% have been reported, with most dropouts occurring
within the first 2–3 months ([Vardi et al., 2000]). Complications with intracavernous alprostadil include penile pain (50% of patients
after 11% of injections), prolonged erections (5%), priapism (1%) and fibrosis (2%)
([Hatzimouratidis, Hatzichristou, 2005]). Drug combinations such as alprostadil plus papaverine, a non-specific PDE inhibitor
resulting in increased levels of cAMP and/or cGMP, and alprostadil plus phentolamine,
a competitive antagonist of alpha-1 and alpha-2 adrenoreceptors, may increase efficacy
by up to 90%.
Vacuum constriction devices (VCDs)
apply negative pressure to draw blood into the penis that is then retained by the
application of a visible constricting band at the base of the penis. This method appears
to be more acceptable to older patients ([Levine, Dimitriou, 2001]). There are few recognized complications with this low-cost treatment option for
selected diabetic ED patients. It was reported that VCDs achieved satisfactory erections
in more than 70% of diabetic men ([Price et al., 1991]). Recently, [Sun et al. (2014)] reported that combined use of sildenafil and VCD for 3 months significantly enhances
erectile function, and is well tolerated by DM patients not responding to first-line
sildenafil 100 mg alone ([Sun et al., 2014]). Problems with VCDs include pain from the constriction ring, lack of spontaneity,
decrease in the quality of orgasm and ejaculatory discomfort. In addition, up to 30%
of patients discontinue use as the result of inadequate rigidity, penile pain, failure
to ejaculate and the appearance of the penis while using the device ([Price et al., 1991]; [Sidi et al., 1990]).
Penile implants
When pharmacotherapy fails, surgical implantation of a penile prosthesis may be considered.
Penile implants provide a predictable and reliable erection, and have the highest
satisfaction rate among both patients and their partners of all the available treatments
for waning erections ([Phé, Rouprêt, 2012]; [Redrow et al., 2014]). Prostheses are either malleable (semirigid) or inflatable (2- or 3-pieces). In
a study of 224 Chinese men patient satisfaction was higher (P<0.05) in the 3-pieces
inflatable than in the malleable prosthesis group ([Song et al., 2013]). Men with DM are more likely to require more aggressive treatments for ED. In a
recent study including 19 236 diabetics it was shown that they were more than 50%
more likely to be prescribed secondary ED treatments, and more than twice as likely
to undergo penile prosthesis surgery compared to non-diabetics ([Walsh et al., 2014]). DED is among the 2 main reasons for implantation of an implant. [Segal et al. (2014)] developed a prediction tool based on a patient's clinical history to determine likelihood
of ultimately receiving a penile prosthesis ([Segal, 2014]). Inclusion criteria were18 years of age with 1 year of continuous enrollment at
the first diagnosis of ED. Analyzing the data from the Commercial (N+=+310 303) and
Medicare (N+=+74 315) supplemental databases they found approximately 1%/N=3 928 patients
of the dataset's population (0.78%/2 405 and 2.05%/1 523, respectively) underwent
penile prosthesis implantation during the study period. Factors with the greatest
predictive strength of penile prosthesis implantation included prostate cancer diagnosis
(relative risk: 3.93, 2.29; 95% CI, 3.57–4.34, 2.03–2.6) and DM (2.31, 1.23; 2.12–2.52,1.1–1.37)
(both P<0.01).
The 2 main complications associated with penile prostheses are mechanical failure
(< 5% after a 5-year follow-up with the currently available 3-pieces prostheses) and
infection. Since the introduction of a 3-pieces inflatable penile implant impregnated
with the antibiotics minocycline and rifampin, there has been a significant reduction
in infection rates and currently, the infection rate is 1% ([Carson et al., 2011]). The "no touch" enhancement to the surgical procedure further decreases the rate
of infection to 0.46% ([Eid et al., 2012]). For non-impregnated implants, the infection risk rate is around 2.5% (Montague
et al., 2001). Some research has indicated that diabetics have an increased risk of
infection vs. non-diabetics, but most studies observed no differences in infection
rates ([Wilson, Delk, 1995]; [Jarow, 1996]; [Wilson et al., 1998]; [Montague et al., (2001)]; [Chung et al., 2013]). A penile prosthesis infection may be either treated with explantation of the prosthesis
with a possible delayed reimplantation or a salvage procedure with an immediate reimplantation
of the prosthesis. In a total of 1 557 patients treated with an explantation only
(82.7%) or salvage (17.3%) comorbid diabetes did not independently affect the salvage
rate of penile prosthesis infection ([Zargaroff et al., 2014]).
