Effect of Periodontitis on Erectile Function

Author: Roberto Tassone Davide Mirra
Date: 03/12/2012



Periodontitis is an extremely common chronic inflammatory disease in people over 30 years old, characterized by chronic bacterial infection of the gums leading to pain, allotriogeusia, easy bleeding, pyorrhea on pressing, periodontal atrophy and pocket formation, and odontoseisis.

There are evidences suggested that three species as Actinobacillus actinomycetem comitans,Porphyromonas gingivalis,and Tanerella forsythensis are causative factors for periodontitis because they are the responsible of the inflammation .

The figure shows how bacteria can settle in the area between the gums and the visible part of the tooth, called the crown, leading to the recall of pro-inflammatory agents that cause infection. For this the need to brush your teeth, avoiding the formation of plaque .

Erectile dysfunction is defined as the inability to attain, or maintaining, erection sufficient for satisfactory sexual performance.

The function of penile erection is impaired by periodontitis.

The expression of endothelial nitric oxide synthase (eNOS) in penile tissue has an important role in the mechanism of erection.
The decreased expression of eNOS or NOS activity in penile cavernous tissue, caused by mild systemic inflammatory status in periodontitis, may be one of the most important risk factors of ED.
Bacteria and inflammatory cytokines related to periodontitis, such as CRP and TNF-a ,into the blood may accelerate the process of cardiovascular disease .

Cardiovascular diseases have direct links to ED.

Common cardiovascular diseases, diabetes , and hypercholesterolemia have been shown to alter the function of endothelium-mediated relaxation of cavernous muscle of penis and impair erection.

( Association between chronic periodontitis and vasculogenic erectile dysfunction,2011 )


Periodontitis is estimated occurring in at least 35% adults over 30 years in the United States, approximately 22% in a mild form, and 13% in moderate to severe form.
Chronic periodontitis is the most common form of periodontal disease.

The risk of patients with periodontitis to suffer from coronary heart disease is 1.14 times higher than that of subjects without periodontitis :
therefore, periodontitis is an important risk factor of cardiovascular disease.

But, pay attention: the data shows that men with cardiovascular disease are significantly more likely to develop erectile dysfunction, 33–75% men with heart disease have the probabilities of ED .

On the other hand, epidemiologic data have suggested that ED may be an early marker for cardiovascular disease and for periodontitis.

ED is usually experienced at the age > 40 years.
In a random sample of 40- to 70-year-old men in Massachusets, the prevalence of ED is 52%, with the prevalence of complete impotence tripling from 5% to 15% in this age range.

ED resulting from organic causes comprises a few cases, whereas vascular disease is the most common pathophysiology of ED:
44~75% men with heart disease have the probabilities of ED.

In the table we can observe that for every age there is always a correlations between periodontitis and ED,in fact the Odds is always greater than one,so there is a real negative correlation as risk,and being p<0,001 it's statistically significant,then real .

Observing the Odds ratio for prior periodontitis (stratified by age group) we find that ED is consistently associated with prior CP (chronic periodontitis) at all age groups.
In particular, subjects aged >69 have the highest ORs (Odds ratio) for prior CP among cases when compared to controls .
In addition, among subjects aged <30, cases are 4.54 ( p < 0.001) times more likely to have had been previously diagnosed with CP than controls.

( A nationwide population-based study on the association between chronic periodontitis and erectile dysfunction,2012 )


• Methods

Comparing a group with periodontitis (group A) with a group not affected (group B) they exhibit peri-odontitis features including easy gum bleeding, periodontal pocket formation, alveolar bone absorption, and junctional epithelium moved to the apical root around the mandibular first molar tooth area.
This is physiophatologic.

We have done measurements of the count of hemoglobin ,red blood cell, and white blood cell in different groups to understand the possible effects induced by periodontitis, but we also have put our attention on the other data such as the ratio ICP/ MAP ,between the maximum intracaversonal pressure (ICP) and the mean arterial pressure (MAP),which is important to determine and obtain an erection.

• Laboratory Tests

We have certificated that there aren't significant difference in body weights and plasma glucose concentrations between group A (with periodontitis) and group without periodontitis:
the energetic homeostasis is preserved,and also the possible presence of cortisol caused by the periodontitis doesn't change the levels of plasma glucose concentration. (P > 0.05).

On the other side we certificate a real increasing of inflammation's factors as TNF (tumor necrosis factor),which is released with other cytokines as CRP (C reactive protein) during the periodontitis, and in general during an inflammation's process.
This increasing of cytokines is correlated with the higher levels of withe cells during the inflammation.

The hemoglobin count and red blood cells count show no statistically significant difference between group A and group B (P > 0.05).
The count of white blood cells is significantly increased in group A compared with group B
(P < 0.001).

Studying the data we understand that the periodontitis is able to induce an increasing of the withe cells causing an inflammatory state, probably related also with ED.

• Oral Situation

The values of alveolar bone loss and pocket depth are significantly increased in group A compared with in group B (P < 0.05)

• Penis Situation

• The pressure:

The ICPmax/MAP X 100 in group with periodontitis is significantly less than in group B, this is important because it shows that during periodontitis the quantity of blood which arrive in penil tissue is higher, but that the cavernou's pressure is not enable to increase loosing the capacity in erection , the physiopathology's chapter we're seeing the matters of it linked to NO pathway.

• The structure:

The results of this study indicate that there are no significant ultrastructural changes including endothelial cells, smooth muscles cells, and peripheral nerve fibers occurred in the penile cavernous tissue,because the inflammation,probably,induced by periodontitis is not enough important in order to compromise the anatomical and histologic structure of the tissue.

Periodontitis mainly impairs the function of penile cavernous endothelial cells and less affects its structure, however, chronic endothelial dysfunction may lead to a cascade of events that lead to the structural changes that result in refractory ED;
but a chronic endothelial dysfunction is certificated only when the inflammation is able,thanks his hight level,to induce a releasing of a great number of cytokines which as we see in the section of pathogenesis are the guilty of the endothelial's dysfunction.

( Effect of periodontitis on erectile function and its possible mechanism,2011 )


• The erection

To understand this paragraph is necessary to know the anatomical structure of penis .

In the picture we are able to observe the anatomical structure of penis with its important cavernous tissue in which are present lots of arterioles witch can fill themselves with blood producing and maintaining the erection thanks to the forbidden venous outflow .

Erectile mechanism is a complex physiological process that mainly depends on the functional and structural integrity of nerve and blood vessel in cavernous tissues, it occurs when two tubular structures, called the corpora cavernosa that run the length of the penis, become engorged with venous blood.

At the beginning there is a dilatation of the arterioles and arteries by increased blood flow in both the diastolic and the systolic phases, but starts a trapping of the incoming blood by the expanding sinusoids.

A compression of the subtunical venular plexuses,between the tunica albuginea and the peripheral sinusoids,reduces the venous outflow,so,in according with what we have seen in the section "penis pressure" if the process is physiologyc the ICP is able to increase permitting the erection.
Stretching of the tunica to its capacity, which occludes the emissary veins between the inner circular and the outer longitudinal layers and further decreases the venous outflow to a minimum.

An increase in pressure O2 (to about 90 mmHg) and intracavernous pressure (ICP,around 100 mm Hg), which raises the penis from the dependent position to the erect state.

( Physiology of Penile Erection and Pathophysiology of Erectile Dysfunction,2005 )

• physiopathology

In the figure we see how it's important the metabolism of NO in order to induce the Guanylate cyclase,which using the production of cGMP,induces the cGMP-specific protein kinase that permits the enter of Calcium which is segregated in Endoplasmatic Reticulum decreasing the concentration of Calcium (in the citosol) and relaxing the smooth muscle .
If there isn't No there isn't production of cGMP and there isn't relaxation of the muscle .

NO,synthesized and released from cavernous endothelial cells by eNOS is an important factor to maintain an erection.
Various causes that result in endothelial dysfunction of the cavernous tissue may contribute to impair the NO signal pathway.

CRP and TNF-a are important cytokines and markers of inflammation,which,as we studied in the diagnostic part,are increased during the periodontitis.

The role of CRP and TNF-a includes inhibiting the expression of eNOS in endothelial cells and reducing its biological activity and others.
TNF-a also inhibits NOS activity by impeding degradation of asymmetric dimethylarginine , the endogenous inhibitor of NOS.

There was often an increase of serum CRP and TNF-a level in cardiovascular disease patients.

Periodontitis generate a systemic response and made the body in a statues of long-term low-intensity inflammatory response. The results of the cytokine measurements confirm that mild systemic inflammation impairs endothelium-dependent vascular dilatation in humans.

Therefore, periodontitis may directly or indirectly inhibit the expression and activity of eNOS at least in part by CRP, TNF-a,
and other cytokines produced by inflammatory stress.

Periodontitis, known to induce endothelial dysfunction, caused ED by decreasing the total NOS activity in corpus cavernosum, resulting in reducing NO production and decreasing cGMP activity, and thus inhibition of endothelial dependent corpus cavernosum smooth muscle relaxation ( cGMP dependent) .
CRP levels was significantly associated with the severity of penile vascular disease.
The impairment of erectile function in periodontal disease is possible through the mechanisms of damaging endothelium-dependent smooth muscle .

The expression of eNOS mRNA by real time PCR suggests that there is no significant change on the expression of mRNA of eNOS in the course of periodontitis.

However, the expression of eNOS protein has significantly decrease:

we deduces that is not implicated a cytokine which can work as factor of transcription ,because the expression of mRNA is constant,but we must think that there is a molecule which could inhibit eNOS,and in the next paragraph we're discovering that this molecule is ...

asymmetrical dimethylarginine .

It is speculated that periodontitis may interfere with the course of post-translation in eNOS mRNA expression by CRP, TNF-a, and others to decrease the expression of eNOS and NOS bioactivity.
Moreover, superoxide occurred in oxidative stress may response with NO and impaired NO activity.

( Effect of periodontitis on erectile function and its possible mechanism,2011 )

• Dimethylarginine pathway

Asymmetrical dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase (NOs) which has now fully emerged as a risk marker in a variety of pathological conditions including end-stage renal disease,liver insufficiency, heart failure, diabetes, pre-eclampsia, and atherosclerotic complications,because it's the most important marker of the endothelial dysfunction .

The ADMA (asymmetric dimetil arginine) is synthesized when the arginine residues are methylated by the action of specific enzymes of methylation said arginine methyltransferases, or PRMTs .
The PRMTs use the S-adenosyl-methionine ( SAM ), synthesized from methionine and ATP, as a methyl group donor.

The synthesis of a molecule of ADMA requires therefore two methyl groups and therefore each of it shall be produced two of homo-cysteine.

There are two classes of PRMTs :

• those of type I catalyze the formation of:

- dimethyl arginine asymmetric ADMA
- N, N-dimethyl-L-arginine
- N-monomethyl-L-arginine NMA

PRMTs type II produce a symmetrical dimethyl arginine SDMA.

It is also seen that the expression of type I PRMTs increases as a result of increased expression of lipoprotein low density (LDL), an effect which is also correlated with altered production of ADMA,so we understand that a condition in witch the levels of LDL are changed,for example in a patient with hypercholesterolemia where the level of LDL are higher,we find an important endothelial dysfunction which raising as atherosclerosis but also as an erectile dysfunction.

The modified proteins by PRMTs are involved in the interaction with nucleic acids and are involved in processes such as RNA splicing messenger, in its transcription, nuclear transport in the cytoplasmatic and in signal transduction.

To prevent the accumulation of ADMA the cell has two elimination pathways, an enzymatic and a excretory:

• 80% of ADMA is accumulated and enzymatically degraded by dimethylarginine dimethylaminohydrolase ( DDAH ) that breaks down ADMA in citrullina and dimethylamine .

• remaining 20% is transported from the cell into plasma through a cationic amino acid transporter ( CAT ) and then excreted in the urine.

The inhibition of eNOS is correlated with levels of plasmatic ADMA .

Furthermore, the concentration of ADMA is inversely correlated with the endothelium-dependent vasodilation .

It's has also been suggested that accumulation of ADMA increases renal vascular resistance, decreases renal plasma flow and increases the blood pressure.
It is also demonstrated that in humans the infusion of ADMA reduces heart rate, cardiac output and the increase mint blood pressure.

In conclusion the pathway shows that oxidative stress of oxidized LDL or TNF-α decreases the activity of DDAH,so decreasing the activity of DDHA is higher the level of ADMA which is able to inhibit eNOS:

if decreased the activity of DDAH will increase the levels of AMDA which inhibits the activity of eNOS,there isn't production of NO and we assist at a decreasing of Intra Cavernosal Pressure (ICP) which DOESN'T permit the erection.

The DDAH is also inactivated by S-nitrosylation, suggesting the existence of a regulatory mechanism to feedback in which high levels of NO are increased levels of ADMA.

Then, the ADMA is continuously produced from protein turnover and eliminated by DDAH, therefore altered enzyme activity contributes to an increase in plasma levels of ADMA in different pathologies,and in our case the ED.

( Dimetilarginina asimmetrica,2006 )


There are several risk factors such as diabetes mellitus, coronary artery diseases , atherosclerosis , hypertension , and smoking associated with ED and periodontitis.

These kind of pathologies in general lead to an inflammation's process which activates white cells leading to the release of proteolytic enzymes, cytokines, chemokines and growth factors that can lead to damage and possibly cause a focal necrosis within the lesion.

In fact, inflammatory mediators such as tumor necrosis factor TNF-alpha, interleukin 1 , the factor stimulating the growth of macrophage colonies M-CSF and the protein monocyte chemotactic MCP 1 favor the binding of LDL to the endothelium and to smooth muscle and induce the transcription of the gene for the LDL receptor, leading to a further stimulus in arteriosclerotic sense,so a patient who has an important hypercholesterolemia if had an important inflammation's process,thanks cytokines and other, he will worsen his personal situation in aterosclerotic,heart decease ore ED,sense.

These pathologies are related by a commune endothelial dysfunction .

Functional alteration of endothelia occurs with changes in haemostatic properties and endothelial permeability to plasma proteins.
Although the dysfunction relates to all endothelial functions, endothelial dysfunction is evaluated clinically mainly as impaired endothelium-dependent vasodilation at the level of the coronary circulation or the brachial artery.

Nitric oxide NO is involved in a wide range of regulatory mechanisms of the cardiovascular system: it mediates endothelium-dependent vasodilation, inhibits the proliferation of smooth muscle cells, platelet aggregation and leukocyte, the adhesion of monocytes, the oxidation of LDL, and inhibits the formation of free radicals(chemistry) maintaining the homeostasis of the endothelium ...

it is clear therefore that an altered production of NO impairs endothelial function.

Poor bioavailability of NO is due to endothelial dysfunction and this plays a central role in the process of cardiovascular diseases. Once the NO enters inside the cell activates a series of cascade reactions in which the protein is activated cGMP.

Increased levels of cyclic GMP decreases the entry of Ca ions thus inhibiting the formation of the Ca-calmodulin complex causes a reduced phosphorylation of myosin light chain resulting in a reduced contraction of smooth muscle cells,but if the NO was not available the reduced contraction it will not possible,as it will not possible the inhibition of proliferation of smooth muscle cell,platelet aggregation and leukocyte and others,so it will be possible engage a pathological situation as atherosclerosis,ED or cardiovascular disease .

( The relationship of plasma ADMA levels with cardiac functions and metabolic parameters in peritoneal dialysis patients,27th of November 2012 )

ADMA as a marker of endothelial dysfunction

It seems that there is an important relationship between levels of ADMA and severity of endothelial damage ( see the chapter of physiophatology to understand the inhibition of NOS by ADMA):

in a study of subjects undergoing hemodialysis levels of ADMA are predictive of cardiovascular events and mortality.
This finding supports the hypothesis that the ADMA is a marker of the risk of cardiovascular disease in these patients as an inhibitor of NOS.
Increased levels of ADMA has also been studied in relation to traditional cardiovascular risk factors such as hypercholesterolemia, hypertension, diabetes, and hyperhomocysteinemia in patients with atherosclerotic disease.
The concentration of ADMA increases in hypercholesterolemic rabbits that fed a diet enriched with 1% cholesterol showed an increase in only 4 weeks compared with controls.
The ADMA also increases in human subjects with hypercholesterolemia or aterosclerosi.

Nowadays ADMA is commonly measured by enzyme immunoassays , which besides being expensive can not be determined simultaneously also the arginine or the SDMA which can give additional important clinical indications.

( Sviluppo di strategie analitiche per la misurazione delle arginine metilate libere ed incorporate nelle proteine,2009 and State of the science: chronic periodontitis and systemic health,2012

CONCLUSIONS of the authors

The authors,Roberto Tassone and Davide Mirra,at the end of their research think that periodontal decease represents an important pathology in order to have a systematic disorder :
the periodontitis putting the organism under a long-term low-intensity state of inflammation (confirmed by the increasing of withe cells studied in the paragraph "diagnosis") witch is able to conduce the person under a generalized,important, endothelial dysfunction that can interests the erectile tissue,but also the blood tissue bringing to atherosclerosis and hypertension which induce a cardiovascular disease.

They,studying the data of the modern literature,have find as the principal guilt TNF-a released during the inflammation,which is important to "preserve" the ADMA which is able to inibiths the activity of NOS forbidding the relaxation of the smooth muscle,so the erection,but also promoting the platelets aggregation and the proliferative state of smooth muscle cells (caused by the absence of the NO signal) which is at the origin of atherosclerosis.

In conclusion they want put in evidence the importance of ADMA as a marker of endothelial dysfunction,then the necessity to improve the clinical instrumentation which can notice the levels of ADMA.
About the curative treatment they have known the use of Interferon that can,emulating the physiologic response,reduces the inflammation:
they believe that its efficiency it's famous,but not his systematic response after treating the patients for many years,as in the case of a chronic inflammation as CP,so it will be show in future some problems.

An advice?
Prevention is betten than cure ,
so the solution is ...

remove,cancel,eliminate,the unnecessary risk's factors of periodontitis ( witch it's possible to eliminate) as SMOKING and you pay attention to your ORAL HYGIENE,so do not allow the formation of plaque and tartar!

Davide Mirra, Roberto Tassone

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