Erectile dysfunction and its correlation with arterial hypertension and cardiovascular diseases

J Atherosclerosis Prev Treat. 2023 Jan-Apr;14(1):23-34 | doi:10.53590/japt.02.1044

REVIEW ARTICLE

Spyridon Tsoutsos, Vasilios Kotsis

3rd Department of Internal Medicine, Hypertension 24h ABPM ESH Center of Excellence, Papageorgiou Hospital, Aristotle University of Thessaloniki

 

Abstract

Nowadays many patients suffering from arterial hypertension appear to experience beforehand also erectile dysfunction (ED) which can be regarded as a risk factor for cardiovascular disease (CVD). Over the last years, various clinical trials have demonstrated a resilient correlation between CVD and ED, sharing common pathophysiology. Consequently, ED is highly perceived as an early marker for a patient to experience symptomatic CVD. Endothelial dysfunction, atherosclerosis, low plasma testosterone levels represent common pathophysiological phenomena that are encountered by hypertensive patients who are suffering from ED and CVD events. In every case that ED gets identified at an early stage, it usually precedes by two to five years to a CVD event. Furthermore, its identification represents a low cost-effective prognostic tool for primary and secondary prevention for both CVD and all-cause mortality. Diuretics and β-blockers and diuretics are some of the cardiovascular drugs that affect negatively in ED that physicians need to take seriously into account. Meanwhile nebivolol and renin–angiotensin–aldosterone system inhibitors are proved to affect positively when administered to a patient. PD5 inhibitors represent a breakthrough therapy when dealing with ED and are considered to be safe for the cardiovascular system. Additionally, PD5 inhibitors are beneficial to treat sexual dysfunction and they represent a safe solution for hypertensive patients who take or not antihypertensive drugs. Up to date conducted testosterone replacement therapy (TRT) studies lead to contradictory results related with CVD risks and when such a therapy is used, physicians should closely monitor for possible adverse effects.

Key words: Arterial hypertension, atherosclerosis, erectile dysfunction, sexual dysfunction, cardiovascular disease, cardiovascular drugs and treatment, risk factors, pathophysiology, inflammation, testosterone levels, phosphodiesterase type 5 inhibitors

Corresponding author: Spyridon Tsoutsos, 3rd Department of Internal Medicine, Hypertension 24h ABPM ESH Center of Excellence, Papageorgiou Hospital, Aristotle University of Thessaloniki, 564 29 Pavlos Melas, Greece, E-mail: tsoutsos@auth.gr

Abbreviations: ACE: Angiotensin Converting Enzyme, ADMA: Asymmetric Dimethylarginine, ARB: Angiotensin Receptor Blocker, cGMP: cyclic Guanosine MonoPhosphate, CAD: Coronary Artery Disease, CCB: Calcium-Channel Blocker, CVD: Cardiovascular Disease, CNP: C-type Natriuretic Peptide, CRP: C-Reactive Protein, ED: Erectile Dysfunction, eNOS: Endothelium Nitric Oxide Synthase, nNOS: Neuronal Nitric Oxide Synthase, ET-1: Endothelin-1, ICAM-1: Intercellular Adhesion Molecule, IIEF: International Index of Erectile Function, MCP: Monocyte Chemotactic Protein, NO: Nitric Oxide, PD5-i: Phosphodiesterase type – 5 inhibitors, PGI: Prostaglaandin, RF: Risk Factor, TRT: Testosterone Replacement Therapy, VCAM: Vascular Cell Adhesion Molecule

Submission: 22.03.2023, Acceptance: 26.04.2023

INTRODUCTION

Arterial hypertension is considered an important worldwide health problem with over a billion of adults being currently affected. High blood pressure levels provoke serious vascular malfunction; therefore, increased cardiac, cerebrovascular, and renal disease rates are connected with hypertension. One crucial factor to anticipate a cardiovascular disease in a hypertension patient is erectile dysfunction which is not systematically associated by physicians in order to proceed to a substantiated diagnosis1.

Many individuals with hypertension are affected by erectile dysfunction which is regarded nowadays as a common clinically meaningful problem. Therefore, identifying the problem of ED at an early stage, it could help physicians to gain a sufficient time frame quite in advance in order to anticipate additional future CVD-related risks and consequently diminish the risk for opposite cardiovascular results2. A considerable number of studies have revealed how prevalent factor is erectile dysfunction in individuals suffering from a CVD or patients risking to experience hypertension, dyslipidemia, diabetes, obesity and peripheral artery disease3. Although ED is explained due to the existence of same pathophysiological function with cardiovascular diseases, hypertension patients receive several medications in order to deal with CVD that may impact their sexual life4.

This article aims to highlight and bring to the physician’s attention the importance of ED as a prognostic factor when dealing with patients with hypertension and CVD. Erectile dysfunction, a well-known medical condition that is often coexists with hypertension, is the reason that contributes unevenly to the hypertensive patients and their sexual partners health well-being as well5. Consequently, it is extremely important to highlight that erectile dysfunction can truly be considered as a valuable indicator for asymptomatic or similar associated CVD events3. Outstandingly, it was shown that ED precedes the coronary artery disease (CAD) by two to five years. The successful management of ED has been particularly advanced by introducing phosphodiesterase-5 (PDE-5-i) inhibitors which effectively provided individuals with a simple and well-tolerated oral therapy6.

PREVALENCE OF ARTERIAL HYPERTENSION & ERECTILE DYSFUNCTION

According to recent assessments, arterial hypertension has affected an estimated 26.4% of the population worldwide in 2000. It is alarmingly important to highlight that by 2025, arterial hypertension is estimated to concern the 60% of the planet’s adults rising the number of affected cases up to 1.5 billion patients worldwide6,7. The prevalence of hypertension is growing substantially depending primary on age, estimated to touch up to 60% in older patients over 60 years. It goes without saying that arterial hypertension is prevalent to any population regardless of nationality, race or tribe or whether the concerned affected population comes from low, medium or high-income countries8,9.

Additionally, due to the fact that life expectancy has been continuously prolonged over the last years through medical advances along with the fact that hypertension and sexual dysfunction are both related to the age of a patient, it is expected that both arterial hypertension and ED are going to be prevalent within the world’s population in the future decades. Nonetheless, arterial hypertension is deeply connected with erectile dysfunction6. Recent studies have revealed that pathophysiology of ED implicates essential hypertension per se and their correlation and coexistence is unarguably a medical given fact7.

Based on the findings collected through various observation studies, erectile dysfunction prevalence is high both to men and women7,9. In particular, it has been specified that erectile dysfunction may concern a percentage of a maximum 74% in a specific population between 55- and 75-years old hypertension patients6. However, ED is mainly prevalent in the male population of the above age category, reflecting a percentage of 15-20%7. It should be noted though that sexual dysfunction affects more the female than the male individuals7,9.

Prevalence of ED is present especially in individuals with essential arterial hypertension. Several studies have underlined the correlation and interaction between these two diseases10. The first expanded trial, well known as the Treatment of Mild Hypertension Study (TOMHS) which revealed the extent to which ED is prevalent to patients with hypertension has been conducted in 19977. The study has revealed that sexual dysfunction has been claimed by 14.4% of men and 4.8% of women included in the assessment. However, it should be noted that TOMHS study has excluded patients suffering from diabetes or severe hypertension, and especially male or female population with age over 70 years old8. Furthermore, the means for assessing the population’s sexual function or erectile dysfunction were limited by asking only one related question and not with the later advanced and elaborated validated tools (specific number of item questionnaires, i.e. IIEF-5 or IIEF-15)6.

The study draws the attention to some additional qualitative characteristics that deserve to get high lightened. Patients with hypertension experience a more severe ED than those without hypertension. Secondly, the coexistence of other cardiovascular risk elements increases substantially the chances for a hypertension patient to experience a more prevalent ED. As more as the patient accumulates a number of comorbidities, the higher are the chances that ED appears to be more prevalent to that type of patient11.

Individuals who suffer from an overt cardiovascular disease are prone to get diagnosed with ED whose prevalence is increasingly high in this category of individuals6. Recent studies such as the ONgoing Telmisartan Alone together with Ramipril Global Endpoint Trial (ONTARGET) and Telmisartan Randomized Assessment Study in ACE intolerant subjects with cardiovascular disease (TRANSCEND) trials along with SPRINT, demonstrate that ED affects half of individuals suffering from acute and/or chronic coronary artery disease while the great majority of men who suffer from heart failure is detected with ED8,9. All in all, hypertensive individuals compared with normal blood pressure individuals appear double chances to experience a prevalent ED whose prevalence is expected to get established permanently12.

ED AND CVD SHARE A COMMON PATHOPHYSIOLOGY

Male erectile function involves a complex vascular process11. As far as their pathophysiology is concerned, endothelium of penis along with its smooth muscle tissue have great adherence with any change, functional and structural12. The damage of endothelium and its inflammation whether it is dependent or independent from the relaxation of the smooth muscle (this is what we call at an initial stage as functional vascular ED) or the obstruction of the cavernosal arteries due to atherosclerosis (this is what we call at a late stage as structural vascular ED) or both of the above combined result in vasculogenic erectile dysfunction13.

Based on current data, endothelial dysfunction interacts in a complex way with subclinical inflammation and androgen deficiency. This common pathophysiological base explains the correlation of ED with CAD at clinical level14. The “artery size” hypothesis reveals the reason that an individual suffering from CAD may experience often ED prior to their detection with CAD15. Consequently, that proves that the larger coronary arteries are getting obstructed at a later stage than the smaller penile arteries whose proper function seem to happen beforehand and at a considerably earlier stage16.

Non-obstructing atherosclerosis can also be explained with the same hypothesis: in comparison with other organs arteries, penile artery is smaller and its endothelial surface is greater, thus a large degree of vasodilation is necessary to occur for erection to happen17. These smaller vessels will experience the same endothelial dysfunction which will be simply symptomatic but subclinical in the larger vessels (i.e. coronaries). Similarly, arterial aging may also be the reason to have a similar outcome since, as measured by arterial stiffening large arteries of patients identified with erection dysfunction can be also affected.6,18.

Incremental inflammatory and endothelial pro-thrombotic activation is strongly associated with erectile dysfunction19. It is very interesting that CAD patients without erectile dysfunction may experience an equal prothrombotic activation, while when these two conditions are combined, then the patient has to deal with an additional trouble6,20. Last but not least, another element like the androgen deficiency may be also regarded the reason of implication within the shared ED and CVD pathogenetic pathways, nonetheless, such an assumption cannot be sustained without a further substantiate research13.

COEXISTENCE OF ED AND CVD

Clinical trials and physicians have concluded that ED serves as an independent factor and prognostic marker that may lead eventually to cardiovascular diseases and mortality6,21. Several researches and studies have demonstrated the tight interaction of these two comorbidities, specifying the association of ED of a hypertensive patient to experience certain risks for coronary artery disease, cardiovascular disease, cerebrovascular disease, and mortality of all cause3,6,22. Both ED and CVD appear to align with the same principal cardiovascular risk factors along with identical pathophysiological pathways13. Moreover, with regards to ED, various non-ordinary risk factors of psychological nature, like psychological depression, decreased mood for sexual activity, and feelings of love uncertainty from a partner, have led to the conclusion that a worse CVD prognosis is closely associated with that state of mind6,21 In relation with the above and what is interesting to highlight is that ED is accentuated in men where ED prevalence is dependent on the CVD severity and duration6,20,21. Below there is a schematic depiction of the ED and CVD shared pathways.

Studies have shown that ED usually precedes coronary artery disease with an average of 3 years22. Physicians may take advantage of this ‘’time window’’and take action as well in intervening and preventing CVD events in the future in favor of hypertensive patient. Regarding the male population suffering from chronic CAD, it has been proved that ED precedes CAD by 1–3 years6,23. The specific period can be specified based on how many diseased vessels have been affected (single-vessel disease is assessed with one year, two-vessel disease is assessed with two years, and three-vessel disease is assessed with three years)24. In order to substantiate further this correlation is the fact that the severity of symptoms can specify in which category of ED belong each patient and consequently these symptoms can further improve or predict a CVD and death in the future6,25. In case a patient does not present any cardiac symptoms, the ED can become a clear indicator or marker of CAD26.

The importance of ED as a prognostic role is remarkable even in the men who are categorized as patients with high risk for CVD events like diabetes, CAD or heart failure, so consequently ED is perceived as a credible biomarker in order to prevent secondarily any CVD27. Diabetes represents, among the above comorbidities, the best case that has been studied in men with ED. ED and CVD events correlation was assessed in four studies, especially referring to male individuals with both type of diabetes6,8. These studies have unanimously concluded that ED has been proven to be the ultimate element that predicts potential CVD events in these types of patients. Moreover, the ONTARGET/TRANSCEND trials have proved and underlined that ED plays a prognostic role while diagnosing men with high risk of CVD18,26. Last but not least, data stipulate also that there is a high tendency for men with HF and ED to be exposed to mortal outcomes in comparison with men who suffer from HF but not from ED26.

Nonetheless, it has been observed through various studies and time-length clinical trials that male population who are exposed to a low risk for CVD appear to belong at a younger age and hold no factors for an overt cardiovascular risk6,26. This category of men is most probable to experience psychogenic ED and not vasculogenic ED, thus it is not implied that these men suffer from vascular aging6,19. In such cases, the concerned population needs to be treated properly when psychogenic ED is identified19,26.

Figure 1. ED and CVD sharing the same pathways. The image depicts that erectile dysfunction (ED) and cardiovascular disease (CVD) share similar risk factors and pathophysiological mechanisms. ED manifestation may precede from 2-5 years before the CVD events appearance, a ‘’window’’ timeframe during which physicians may take measures for prevention like hsCRP, high-sensitivity C-reactive protein.

DIAGNOSIS OF ERECTILE DYSFUNCTION

ED is regarded to be the hard binder during the diagnosis of a patient through his medical and sexual history. Physicians need to take into account thoroughly the medical record of a patient when they proceed to the diagnosis of ED6,21. The alarming aspects of a patient’s medical history may contain probable cardiovascular symptoms, various risk factors and comorbidities like obesity, hypertension, diabetes, dyslipidemia. Additional factors like family record of premature atherothrombotic cardiovascular disease, lifestyle and medications that have been previously administered need also to be included during the ED assessment22. Further useful information might be also revealed by individual’s sexual record. Especially when the diagnosis is to be determined between psychogenic ED and organic/vasculogenic ED, physicians possess simple but tangible indicators to concretize successfully their diagnosis6,23.

Specifically, psychogenic ED is determined by various reasons like the presence of acute onset, intermittent course, normal erections in the morning, and a history of psychosexual problems6. On the other hand, constant symptoms, the gradual onset and non regular morning erections lead to the conclusion that the patient is suffering from organic/vasculogenic ED19. Additional elements that may lead a physician to diagnose a predominant vasculogenic ED is when the patient experiences a cardiovascular disease or is exposed to high risk factors like advanced age and metabolic abnormalities6,27.

Two specialized questionnaires have been used to assess the sexual history of a patient and identify potential ED6. The most common one is the International Index of Erectile Function (IIEF-15) questionnaire which is comprised of fifteen validated questions for self-evaluation. IIEF-15 is widely used and focuses its questions in order to assess penile function, desire, satisfaction, orgasmic function, and the general sexual fulfilment28. Likewise, IIEF-5, including only 5 questions, is also widely used to rapidly assess the sexual activity of concerned individuals.

In order to identify ED, six questions out of 15 of IIEF-15 questionnaire aim to reveal whether scoring less than 25 is an indication for ED diagnosis. Likewise, scoring 21 or below than score in the IIEF-5 questionnaire indicates an ED28,29. Both questionnaires are widely used by all general practitioners and clinical doctors like internists, cardiologists, diabetologists and nephrologists, and not only by andrologists and urologists exclusively. Furthermore, physicians need to perform thorough clinical tests of the individual’s heart and peripheral circulation6,26. Urinary protein, fasting plasma glucose and an estimation of glomerular filtration rates represent some of the performed laboratory exams that may lead a physician to precisely assess whether a patient is exposed to any cardiovascular risk6. Additionally, calculating the cardiovascular risk score (SCORE or Framingham) to all concerned patients would stratify what is their level for cardiovascular risk24,30. Last but not least, it is also recommended to quantify the levels of testosterone in all relevant individuals suffering from organic ED, particularly when sexual function of patients has not been improved with the PDE-5 inhibitor therapy6.

For patients who do not suffer from any cardiovascular disease and having no symptoms as well, it is important to determine various cardiovascular biomarkers who may provide with useful information in order to assess if the patient is exposed to any cardiovascular risk. Coronary artery calcium, central intima-media thickness, albuminuria, ankle–brachial index and aortic stiffness are associated with ED diagnosis and cardiovascular events6,21. It has been proven that especially albuminuria and aortic stiffness19 are certainly leading a patient who suffers form ED to experience a cardiovascular event13,22. Lastly, organic/vasculogenic ED is also identified by using a penile Doppler31,32.

MANAGEMENT OF ERECTILE DYSFUNCTION

Since ED is an indicator for potential CVD risk, all physicians should question their patients with vasculogenic ED about their sexual and medical history which will the baseline of assessment in order to anticipate whether these patients were initially exposed to any cardiovascular disease risk33. These patients need to be investigated by their physician in order to define the initial risk stratification which will defined according to the Framingham Risk Score24,30. This method helps physicians to identify within their concerned patients any potential risk for cardiovascular event or death, occurring within a 10-year timeframe34. Specifically, the Framingham Risk Score method takes into account various risk factors like the total and high-density lipoprotein cholesterol, sex, age, smoking, systolic blood pressure and the use of antihypertensive medications as well35.

Male population who appears ED symptoms are expected to experience a cardiovascular disease and they can be considered themselves as being patients at high risk for any CVD event6,27. According to the Framingham Risk Score assessment, some of the tests that can be used by physicians in order to define which male population is exposed to a cardiovascular risk are the following ones: a complete and extensive medical history, the physical examination of the patient that includes measuring of visceral adiposity, evaluation of the ED duration and severity, resting electrocardiogram, assessing the fasting plasma glucose and serum creatinine (glomerular filtration rate) and albumin: ratio of creatinine and the metabolic syndrome attitude (presence or absence)24. Last but not least, sleep apnea should be also considered for examination of patients by their physician6. The physician should also determine whether the patient may respond to stress testing and the ability to exercise so as to assess the CVD risks and stratification30.

According to the SCORE or Framingham Risk Score assessment, patients who are not exposed to overt CVD or any type of diabetes (type 1 or type 2) need to undergo an evaluation by their physician in order to identify if they run any risk for future cardiovascular events24,30. Patients who have been detected with a cardiovascular disease or any type of diabetes are classified as being in increased risk category6,34. Patients who demonstrate sufficient exercise ability or perform a negative stress test, they can initiate sexual activity and get access to ED treatment36. On the other hand, patients who perform a positive stress test or are considered to be in high risk to produce a positive stress test, they need to delay any sexual activity until the moment they treat and stabilize their cardiac condition6,35. In any case, it is recommended that patient ought to follow up his physicians’ advices for reassessment6.

Furthermore, patients need to be urged by their physicians for lifestyle changes by introducing a healthier diet, motivation for physical exercise and quitting smoking which are widely considered to decrease cardiovascular risks and reestablish erectile function26. Male population which is classified as being at high risk for CVD events need to be also consulted by cardiologist33. Patients of intermediate risk with vasculogenic ED and no overt CVD need to undertake additional non-invasive assessment of cardiovascular risk though various available methods like exercise stress testing, ankle-brachial index, intima-media thickness or determination of coronary artery calcium scores6,35. There is no proof that any order of testing is adequate and it has not been established that any of these tests is more important one over the other in order to proceed to prognosis24. Physician who run the patients’ tests need to select and customized tests according to patient’s clinical profile, physician’s judgment along with availability of test and cost involved30.

Last but not least, the physician may examine the patient for testosterone levels in order to define the ED6,33,34. Testosterone constitutes a vital element and contributor in the physiological mechanism of erectile function. Testosterone contributes in stimulating the sexual desire, arousal and behavior6,26. Clinical trials have demonstrated that testosterone levels appear to be in lower levels of concentration especially in patients with ED who experience decreasing levels of sexual desire33. It should be highlighted that corporeal expression and activity of endothelial and neuronal NOS are regulated by testosterone while it enhances NO production6. Given the fact that testosterone is connected with CVD, physicians are encouraged to measure the levels of testosterone in all patients who are identified with vasculogenic ED, particularly in those cases of patients who responded unsuccessfully to phosphodiesterase type 5 (PDE5) inhibitor therapy6,32.

CVD DRUGS IMPACT ON ERECTILE FUNCTION

While lifestyle changes like body training, healthier diet (particularly the Mediterranean diet), weight loss and quitting smoking are recommended to men with CVD as an additional prevention strategy, drugs related to CVD therapies or prevention may cause a decrease of sexual performance of an individual, thus consequently experiencing ED6,37. Although this is a common reality for men with CVD, this holds a close relation with the disease mechanism, various other factors of risk, sentimental state of mind like fear and anxiety, comorbidities, and methods of therapy especially to patients who have stable CAD, chronic heart failure (HF) or hypertension as well as patients who have undergone cardiac intervention like defibrillator implant, bypass graft surgery of coronary artery or heart transplantation36.

 Undoubtfully, individuals who suffer from a CVD and have been undergone a treatment are more probable to experience ED compared to those who have not undergone any treatment. This status implies that the treatment of a CVD event may contribute to an undesired and negative effect on erectile function. Earlier studies conclude that individuals who have undergone a treatment against hypertension are keen on experiencing a prevalent ED compared to those whose hypertension remained untreated6,37. The main explanation of such an event is because of the impact after β-blockers and/or diuretics use against patients with hypertension38. The above outcome confirms that although several antihypertensive medications like angiotensin-receptor blockers (ARBs), calcium-channel blockers and angiotensin-converting enzyme inhibitors are considered to be “erection-friendly”, ED appears to be more prevalent in individuals who have undergone treatment against hypertension in comparison to the patients whose hypertension has not been identified6,38. However, the severity of ED remains the same in both cases39. Patients may experience a negative effect in penile blood flow because of the antihypertensive medications especially in cases where patients show low levels of blood pressure33. It is more alarming that when a patient is administered with a large number of CVD drugs, he is more probable to experience a more important ED deleterious effect6,34. A CVD therapy implies considerable effects on patient with ED, thus appropriate management of CVD drugs is recommended for its adherence38.

Antihypertensive drugs demonstrate a resilient interaction between hemodynamic factors (like heart rate and/or blood pressure) and erectile dysfunction, so these drugs are considered as the best researched CVD drugs with an impact on men who suffer from erectile dysfunction38. It can be stated that physicians are getting genuinely challenged by the impact of the antihypertensive drugs on ED where they need to assess what strategy to follow in order to eliminate these side effects by offering to patients with ED a sustainable and solid therapy against ED while improving the quality of their sex life6,35. Given the fact that these antihypertensive drugs may negatively affect men with ED, physicians need to support with insightful clinical assessment and as per patient’s needs and profile by urging them to share these undesired side effects on the erectile function35. Categorizing antihypertensive drugs in classes, it can be clearly stated that some of them may have a neutral effect, some may have a beneficial one while others affect negatively patients with ED38. Consequently, according to each case of a patient with ED, physicians need to revise their decision to alter antihypertensive drugs of one class into the equivalent of another class6. Alternatively, by changing agents belonging in the same class of antihypertensive medications might be proved useful and successful to deal with a patient’s erectile dysfunction38.

All in all, antihypertensive medications of older generations (like first and second generation β-blockers, diuretics and methyldopa that is considered to be a central-acting agent) provoke a negative impact on erectile function38. Nonetheless, calcium-channel blockers, α-blockers and angiotensin-converting enzyme inhibitors represent a newer generation of antihypertensive medications with neutral impact on erectile function. Lastly, nebivolol and ARBs are the ones who affect in a beneficial way to men with ED38.

It is quite complicated to explain precisely diuretics negative impact that may lead to erectile dysfunction. Sympathetic nervous system is mainly believed to get inhibited with the mediation of β-blockers since nervous system is also responsible for provoking erection and stimulate the release of testosterone38. Anxiety is the main outcome that β-blockers may produce as an adverse effect and consequently that may lead a patient to experience erectile dysfunction39. However, the use of selective β-blocker nebivolol, which blocks β1-adrenergic receptors, seems to contribute in a beneficial manner and against erectile dysfunction in comparison with non-selective β-blockers6,38. Especially with regards to non-selective β-blockers, it is important to underline that they reduce the sympathetic tone in the body causing an unproper vasodilatation38. This means that the levels of testosterone in plasma are getting reduced since these non-selective β-blockers affect the luteinizing hormone which ultimately would lead to sleepiness or depression, thus a libido is getting weaker38.

As far as the renin-angiotensin-aldosterone system is concerned, angiotensin II plays also a major role, thus endothelial function is improved by ARBs who are also responsible for the promotion of adequate vasorelaxation, thus erectile function is improved considerably6. Concerning α-blockers, early studies that have been conducted with controlled administration of a placebo in random samples of patients suffering from benign prostatic hyperplasia, they demonstrate that therapy with a-blockers has at least a neutral effect on erectile function7,37. Nevertheless, the Treatment of Mild Hypertension Study (TOMHS) has shown that using the α-blocker doxazosin as an antihypertensive agent, erectile dysfunction still occurs almost at the same level, if not below, with the sample of patients who received a placebo24,30.

Statins are presented to possible affect in a beneficial way and in favor of erectile function obstructing premature vascular aging (endothelial function is getting improved like arterial stiffness as well) which is very common in male population with erectile dysfunction40. Consequently, physicians may administer either statins alone or together with phosphodiesterase type 5 (PDE5) inhibitors as a therapy against ED32.

As far as medications against arrhythmia are concerned, it seems that they have no effect to erectile function, however, β-blockers as well as digoxin do have an effect23,41. As an alternative solution to β-blockers, Ivabradine may act in favor of erectile function especially in male population who suffer from heart failure23,41. Last but not least, antiplatelet, anticoagulant agents and nitrates act mostly in a neutral way on erectile function7,42.

Limited data exist for the new antidiabetic medications in favor of erectile function (dipeptidyl peptidase 4 inhibitors, glucagon-like peptide 1 receptor agonists, and sodium–glucose cotransporter 2 inhibitors). However, few findings show that erectile function can be improved with glucagon-like peptide 1 receptor agonists action. Given the limited results of these agents limited results for erectile function, physician need to customize cardiovascular medications therapy according to each patient’s profile that may have ED symptoms43.

ED TREATMENT and ITS EFFECT ON CVD EVENTS

Changes in lifestyle (i.e., constant body exercise, losing weight, avoiding salt, adopting a healthier diet like the Mediterranean one, quitting smoking, restricting alcohol), avoiding medication associated with erectile dysfunction and counseling on sex activity represent important pillars for managing ED6. Similar strategies are implemented in order to deal with CVD events; however, the outcomes may vary and changes need to be applied to the concerned patients. Although different systemic and local treatments have been put forward by physicians in order to manage erectile dysfunction, these treatments are also linked with the risk of CVD events42,43. The most common systemic treatments against ED are the administration of PDE5 inhibitors and appliance of testosterone-replacement therapy (TRT)6.

PDE5 INHIBITORS

Introducing PDE5 inhibitors (PDE5-i) in order to manage ED in men, it was a historic breakthrough in modern drug development. However, the fact that it has not been introduced a similar treatment for women over the last years, it creates an unequal perception in the treatment of sexual and erectile dysfunction between the two genders32.

The cGMP escapes from getting degraded with the blocking help of PDE5 inhibitors, who subsequently promote the blood flow into the penile body and reestablish the erectile function. PDE5 inhibitors have a mild hypotensive effect, since PDE5-i appears present in smooth muscle cells of blood vessels44. The process of the cGMP–nitric oxide also regulates the blood pressure38. In the rare scenario that the administration of PDE5 inhibitors has failed, this is due to the fact that endothelial has been extensively damaged which consequently decreases the nitric oxide bioavailability. In that case, an alternate therapy option has to be envisaged by physicians6,45.

For the time being, sildenafil, avanafil, vardenafil and tadalafil represent the four worldwide approved drugs for extensive use PDE5 inhibitors while mirodenafil, udenafil and lodenafil are three additional drugs that are approved and administered in a small number of countries45. Sildenafil was the first drug that has obtained the approval as a therapy tool against ED with an approximate 20 min onset of action, also a 4-h half-life and a 12-h duration of long action46. Vardenafil appears to have the same profile like sildenafil. Tadalafil holds an impressive half-life of 17.5-h and a 36-h long duration of action47. On the contrary, Avanafil holds the shortest onset of action but it stays active for more than 6-h, which is considered at least a preferable safe alternative drug to be administered by physicians48.

Based on individual’s needs, a customized and individual therapy approach is possible to be implemented by physicians because of its pharmacokinetic and pharmacodynamic properties. Many clinical researches have examined the safety of PDE5 inhibitors in favor of cardiovascular events6,46-47. It has been confirmed that particularly sildenafil in comparison with placebo gives no sign of a potential risk for myocardial infraction or death48. Most of the mild side effects are like headache, dizziness, facial flushing, rhinitis, palpitation, nausea and dyspepsia while individuals with hypertension tolerate generally the above medications against ED49.

The PDE5-i act in blood pressure without any synergy with the rest antihypertensive agents like calcium-channel blockers, β-blockers, angiotensin-converting enzyme inhibitors, diuretics or ARBs6,37. It is strongly recommended not to administer jointly PDE5-i and nitrates since there is an increased risk for the concerned individuals to experience symptomatic hypotension47. PDE5 inhibitors can be jointly administered with α-blockers that physicians may prescribe to manage benign prostatic hyperplasia, however, they need to be precautious in order to eliminate the chance for their patients to experience orthostatic hypotension47. For that reason, it is suggested that the two drugs need to be administered with a 6-h interval48. Physicians may also administer uroselective α-blockers but physician need to urge patients to report any side effect concerning ejaculation49. When administering a treatment whether with a PDE5 inhibitor or with an α-blocker, physicians should make sure that patients have followed their previous therapy on a stable pace for more than a month while the initial dose must be half of the typical dose and careful with gradual titration upscale6,32,50.

There is growing evidence that PDE5 inhibitors act benignly on the cardiovascular system32. Some of them is that PD5-i foster the endothelial function, reverse the vascular aging based on the condition of patient’s arterial stiffness and decrease active inflammation and oxidative stress51. Additionally, PDE5-i improve pulmonary and exercise hemodynamics while offer protection to penile from adverse side effects of any injury due to ischemia-reperfusion49-51. The administration of PDE5 inhibitors offers numerous advantages in a number of comorbidities like protection against probable CVD events while they offer benefits for survival of patients suffering from HF, peripheral artery disease and CAD6,32,52. Furthermore PDE5-i reduce considerably mortality risks in male population suffering from diabetes53. Nonetheless, depending on age and comorbidities of an individual, PDE5-i beneficial effects might not be similar to all patients and additional researches need to be conducted to substantiate this type of argumentation32.

Testosterone Replacement Therapy (TRT)

The close relation and interaction between low testosterone levels and CVD events has been revealed in many recent research6,26. ED was proved to be the outcome of low testosterone levels which are prevalent in male population suffering from hypertension, or any type of diabetes, and metabolic syndrome33. Men experiencing erectile dysfunction need to undergo testosterone tests since exogenous testosterone replacement therapy (TRT) can improve dysfunction which is related to hypotestosteronemia54.

According to the recent updated guidelines, there is no indication that it is important to check hypogonadal men suffering from hypertension for testosterone screen or to provide testosterone supplement. Only if it is recommended by the physicians, men with erectile dysfunction may get beneficial results through a combined therapy of TRT with PDE5 inhibitors55. Yet, such a therapy can take place exclusively to men with ED showing decreased total testosterone level (<8nmol/L) or to men with intermediate total testosterone levels (8-12nmol/L) and whose prior treatment only with PDE5 inhibitors did not give successful results or sufficient progress6,55.

TRT has been proved to have beneficial effects in boosting muscle mass, fosters corporal strength and enhances erythropoiesis55. There are various methods for administrating testosterone such as through injection, transdermal and subdermal preparations or simply by oral and buccal routes56. However, adverse cardiovascular events, prostate cancer or exacerbation, sleep apnea or erythrocytosis are some of the potential side effects that a patient may experience afterwards and in the long-run.

A number of reports in the recent years claimed that TRT has caused raise in cardiovascular events in hypertensive men, thus remaining skeptical about TRT efficiency and raising concerns about TRT as a therapy approach which might against cardiovascular health57. However, it should be mentioned that these reports lack credibility, since the methodology used, was not in line with scientific standards like the volume of participants, sample, and period conducted6. On the other hand, different reports underline that TRT as a treatment approach offers substantial cardiovascular benefits to patient with hypertension, thus considering TRT as a safe method in favor of cardiovascular well-being56-57. In any case, further studies have to be conducted so as to reach more concrete assessments, with the examination of TRT effects on cardiovascular health or mortality in relation to a pre or post-treatment of testosterone levels in an hypertension patient suffering from erectile dysfunction6,55.

CONCLUSION

Cardiovascular disease events and erectile dysfunction share common pathophysiological characteristics, while and they are subject to common risk factors like inflammation and dysfunction of the endothelium6. Furthermore, erectile dysfunction represents itself an independent risk factor leading to potential cardiovascular events in the future for a hypertensive individual17. It is certain and clinically approved that erectile dysfunction can be considered as an important tool of prognosis that can be used in order to predict any potential CVD risk especially for men over 40 years old19.

However, identifying and treating ED is not always a priority for physicians and the issue remains partially unaddressed to patients with hypertension and CVD. Patients who appear to have arterial hypertension may also develop ED due to the administration of antihypertensive medications7. All in all, antihypertensive medications of older generations (like first and second generation β-blockers, diuretics and methyldopa that is considered to be a central-acting agent) provoke a negative impact on erectile function23,41. Nonetheless, calcium-channel blockers, α-blockers and angiotensin-converting enzyme inhibitors represent a newer generation of antihypertensive medications with neutral impact on erectile function7-37. Lastly, nebivolol and ARBs are the ones who affect in a beneficial way to men with ED. Statins, antiplatelet and anticoagulant agents have mostly neutral effect to the erectile function of hypertensive patients40.

Additionally, introducing important changes in lifestyle habits coupled with ED drugs therapy can contribute to foster cardiovascular drug therapy and help men suffering from CVD to achieve a better quality of life. It is of paramount importance that physicians keep raising awareness especially within male hypertensive population to identify and report erectile dysfunction; that would enable physicians to better monitor the evolution or erectile dysfunction within a hypertensive individual. Administering PDE5 inhibitors constitutes an effective and safe solution for hypertensive patients with ED32. Additionally, TRT, alone or in combination with PD5 inhibitors forms an alternative therapy management for patients with ED but further substantiated and appropriate randomized studies would unveil the real relation between TRT and cardiovascular results and safety55.

Acknowledgements

I would like to express my gratitude to Dr. Vasilios Kotsis who allowed me to discover a new search path in the field of arterial hypertension. Dr. Spyridon Tsoutsos got entire access to all findings and data of the study and bears responsibility for the accuracy and integrity of the data.

Conflict of interest

There is no conflict of interest.

REFERENCES

  1. Imprialos KP, Stavropoulos K, Doumas M, Tziomalos K, Karagiannis A, Athyros VG. Sexual Dysfunction, Cardiovascular Risk and Effects of Pharmacotherapy. Curr Vasc Pharmacol. 2018 Jan;16(2):130-42.
  2. Vlachopoulos C, Jackson G, Stefanadis C, Montorsi P, et al. Erectile dysfunction in the cardiovascular patient. Eur Heart J 2013; 34: 2034-46.
  3. Viigimaa M, Vlachopoulos C, Lazaridis A, Doumas M. Management of erectile dysfunction in hypertension: Tips and tricks. World J Cardiol 2014 Sep; 6(9): 908-15.
  4. Jackson G, Boon N, Eardley I, Kirby M, Dean J, Hackett G, et al. Erectile dysfunction and coronary artery disease prediction: evidence-based guidance and consensus. Int J Clin Pract. 2010 Jun;64(7):848-57.
  5. Chrysant SG, Chrysant GS. The pleiotropic effects of phosphodiesterase 5 inhibitors on function and safety in patients with cardiovascular disease and hypertension. J Clin Hypertens (Greenwich) 2012 Sep;14:644-9.
  6. Viigimaa M, Vlachopoulos C, Doumas M, Wolf J, Imprialos K, Terentes-Printzios D, for the European Society of Hypertension Working Group on Sexual Dysfunction.Update of the position paper on arterial hypertension and erectile dysfunction. J Hypertens. 2020 Jul;38(7):1220-34.
  7. Grimm RH, Grandits GA, Prineas RJ, McDonald RH, Lewis CE, Flack JM, et al. Long-term effects on sexual function of five antihypertensive drugs and nutritional hygienic treatment in hypertensive men and women: Treatment of MildHypertension Study (TOMHS). Hypertension. 1997 Jan;29(1 Pt 1):8-14.
  8. Bohm M, Baumhakel M, Teo K, Sleight P, Probstfield J, Gao P, et al. ONTARGET/TRANSCEND Erectile Dysfunction Substudy Investigators. Erectile dysfunction predicts cardiovascular events in high-risk patients receiving telmisartan, ramipril, or both: The ONgoing Telmisartan Alone and in combination with Ramipril Global Endpoint Trial/ Telmisartan Randomized Assessment Study in ACE iNtolerant subjects with cardiovascular Disease (ONTARGET/TRANSCEND) Trials. Circulation. 2010 Mar;121(12):1439-46.
  9. Thomas HN, Evans GW, Berlowitz DR, Chertow GM, Conroy MB, Foy CG, et al. SPRINT Study Group. Antihypertensive medications and sexual function in women: baseline data from the SBP intervention trial (SPRINT). J Hypertens. 2016 Jun;34(6):1224-31.
  10. Doumas M, Douma S. Sexual dysfunction in essential hypertension: Myth or reality? J Clin Hypertens (Greenwich). 2006 Apr;8(4):269-74.
  11. Vlachopoulos C, Ioakeimidis N, Terentes-Printzios D, Stefanadis C. The triad: Erectile dysfunction– endothelial dysfunction–cardiovascular disease. Curr Pharm Des. 2008;14(35):3700-14.
  12. Montorsi P, Montorsi F, Schulman CC. Is erectile dysfunction the ‘tip of the iceberg’ of a systemic vascular disorder? Eur Urol. 2003 Sep;44(3):352-4.
  13. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: A systematic review and meta-analysis. J Am Coll Cardiol. 2010 Mar;55(13):1318-27.
  14. Vlachopoulos C, Aznaouridis K, Ioakeimidis N, Rokkas K, Tsekoura D, Vasiliadou C, et al. Arterial function and intima- media thickness in hypertensive patients with erectile dysfunction. J Hypertens. 2008 Sep;26(9):1829-36.
  15. Vlachopoulos C, Aznaouridis K, Ioakeimidis N, Rokkas K, Vasiliadou C, Alexopoulos N, et al. Unfavourable endothelial and inflammatory state in erectile dysfunction patients with or without coronary artery disease. Eur Heart J. 2006 Nov;27(22):2640-8.
  16. Terentes-Printzios D, Ioakeimidis N, Rokkas K, Vlachopoulos C. Interactions between erectile dysfunction, cardiovascular disease and cardiovascular drugs. Nat Rev Cardiol. 2022 Jan;19(1):59-74.
  17. Vlachopoulos C, Rokkas K, Ioakeimidis N, Stefanadis C. Inflammation, metabolic syndrome, erectile dysfunction, and coronary artery disease: common links. Eur Urol. 2007 Dec;52(6):1590-600.
  18. Böhm M, Baumhäkel M, Probstfield JL, Schmieder R, Yusuf S, Zhao F, et al. Sexual function, satisfaction, and association of erectile dysfunction with cardiovascular disease and risk factors in cardiovascular high-risk patients: substudy of the ONgoing Telmisartan Alone and in Combination with Ramipril Global Endpoint Trial/Telmisartan Randomized AssessmeNT Study in ACE-INtolerant Subjects with Cardiovascular Disease (ONTARGET/TRANSCEND). Am Heart J. 2007 Jul;154(1):94-101.
  19. Vlachopoulos C, Rokkas K, Ioakeimidis N, Aggeli C, Michaelides A, Roussakis G, et al. Prevalence of asymptomatic coronary artery disease in men with vasculogenic erectile dysfunction: A prospective angiographic study. Eur Urol. 2005 Dec;48(6):996-1002; Discussion 1002-3.
  20. Montorsi P, Ravagnani PM, Galli S, Rotatori F, Veglia F, Briganti A, et al. Association between erectile dysfunction and coronary artery disease. Role of coronary clinical presentation and extent of coronary vessels involvement: the COBRA trial. Eur Heart J. 2006 Nov;27(22):2632-9.
  21. Terentes-Printzios D, Vlachopoulos C, Ioakeimidis N, Aznaouridis K, Stefanadis C. Erectile dysfunction severity and prediction of cardiovascular events and all-cause mortality: A systematic review and meta-analysis of cohort studies. Eur Heart J. 2013 Aug; 34(Supp 1):95-8.
  22. Rastrelli G, Yannas D, Mucci B, Corona G, Maggi M. Family history for cardio-metabolic diseases: A predictor of major adverse cardiovascular events in men with erectile dysfunction. J Sex Med. 2020 Dec;17(12):2370-81.
  23. Terentes-Printzios D, Vlachopoulos C, Xaplanteris P, Ioakeimidis N, Aznaouridis K, Baou K, et al. Cardiovascular risk factors accelerate progression of vascular aging in the general population: results from the CRAVE study (Cardiovascular Risk Factors Affecting VascularAge). Hypertension. 2017 Nov;70(5):1057-64.
  24. Araujo AB, Hall SA, Ganz P, Chiu GR, Rosen RC, Kupelian V, et al. Does erectile dysfunction contribute to cardiovascular disease risk prediction beyond the Framingham risk score? J Am Coll Cardiol. 2010 Jan;55(4):350-6.
  25. Climie RE, Bruno RM, Hametner B, Mayer CC, Terentes-Printzios D. Vascular age is not only atherosclerosis, it is also arteriosclerosis. J Am Coll Cardiol. 2020 Jul;76(2): 229-30.
  26. Gandaglia G, Briganti A, Jackson G, Kloner RA, Montorsi F, Montorsi P, et al. A systematic review of the association between erectile dysfunction and cardiovascular disease. European association of urology. Eur Urol. 2014 May;65(5):968-78.
  27. Montorsi P, Ravagnani PM, Vlachopoulos C. Clinical significance of erectile dysfunction developing after acute coronary event: Exception to the rule or confirmation of the artery size hypothesis? Asian J Androl. 2015 Jan-Feb;17(1):21-5.
  28. Nehra A, Jackson G, Miner M, Billups KL, Burnett AL, Buvat J, et al. The Princeton III Consensus recommendations for the management of erectile dysfunction and cardiovascular disease. Mayo Clin Proc. 2012 Aug; 87(8):766-78.
  29. Vlachopoulos C, Ioakeimidis N, Stefanadis C. Biomarkers, erectile dysfunction, and cardiovascular risk prediction: the latest of an evolving concept. Asian J Androl. 2015 Jan-Feb;17(1):17-20.
  30. Araujo AB, Hall SA, Ganz P, Chiu GR, Rosen RC, Kupelian V, et al. Does erectile dysfunction contribute to cardiovascular disease risk prediction beyond the Framingham risk score? J Am Coll Cardiol. 2010 Jan;55(4):350-6.
  31. Batty GD, Li Q, Czernichow S, Neal B, Zoungas S, Huxley R, et al. Erectile dysfunction and later cardiovascular disease in men with type 2 diabetes: Prospective cohort study based on the ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified-Release Controlled Evaluation) trial. J Am Coll Cardiol. 2010 Nov;56(23):1908-13.
  32. Seidu S, Cebrián A, Kunutsor SK, Khunti K. Erectile dysfunction, phosphodiesterase-5 inhibitor use and risk of cardiovascular disease and mortality in people with diabetes: A systematic review and meta-analysis. Prim Care Diabetes. 2022 Oct;16(5):601-13.
  33. Rundblad L, Dorthe Zwisler A, Palm Johansen P, Holmberg T, Schneekloth N, Giraldi A. Perceived sexual difficulties and sexual counseling in men and women across heart diagnoses: a nationwide cross-sectional study. J Sex Med. 2017 Jun;14(6):785-96.
  34. Korhonen PE, Ettala O, Kautiainen H, Kantola I. Factors modifying the effect of blood pressure on erectile function. J Hypertens. 2015 May;33(5):975-80.
  35. Ioakeimidis, N, Rokkas K, Terentes-Printzios D, Angelis A, Dima I, Gardikioti V, et al. Association between office blood pressure, antihypertensive medication use and male sexual dysfunction: a penile Doppler study. Eur Heart J. 2020 Nov; 41(Supp 2).
  36. Scranton RE, Goldstein I, Stecher VJ. Erectile dysfunction diagnosis and treatment as a means to improve medication adherence and optimize comorbidity management. J Sex Med. 2013 Feb;10(2):551-61.
  37. Thomopoulos C, Parati G, Zanchetti A. Effects of blood-pressure-lowering treatment in hypertension: 9. Discontinuations for adverse events attributed to different classes of antihypertensive drugs: meta- analyses of randomized trials. J Hypertens. 2016 Oct;34(10):1921-32.
  38. Doumas M, Tsakiris A, Douma S, Grigorakis A, Papadopoulos A, Hounta A, et al. Beneficial effects of switching from beta-blockers to nebivolol on the erectile function of hypertensive patients. Asian J Androl. 2006 Mar;8(2):177-82.
  39. De Oliveira AA, Nunes KP. Hypertension and erectile dysfunction: Breaking down the challenges. Am J Hypertens. 2021 Mar;34(2):134-42.
  40. Elgendy AY. et al. Statin use in men and new onset of erectile dysfunction: a systematic review and meta-analysis. Am J Med. 2018 Apr;131(4):387-94.
  41. Vlachopoulos C, Aznaouridis K, Ioakeimidis N, Rokkas K, Tsekoura D, Vasiliadou C, et al. Arterial function and intima- media thickness in hypertensive patients with erectile dysfunction. J Hypertens. 2008 Sep;26(9):1829-36.
  42. Nicolai MP, Liem SS, Both S, Pelger RCM, Putter H, Schalij MJ, et al. A review of the positive and negative effects of cardiovascular drugs on sexual function: a proposed table for use in clinical practice. Neth Heart J. 2014 Jan;22(1):11-9.
  43. Corona G, Isidori AM, Aversa A, Bonomi M, Ferlin A, Foresta C, et al. Male and female sexual dysfunction in diabetic subjects: focus on new antihyperglycemic drugs. Rev Endocr Metab Disord. 2020 Mar;21(1):57-65.
  44. Chung EA. Review of current and emerging therapeutic options for erectile dysfunction. Med Sci (Basel). 2019 Aug;7(9):91.
  45. Chrysant SG. Effectiveness and safety of phosphodiesterase 5 inhibitors in patients with cardiovascular disease and hypertension. Curr Hypertens Rep. 2013 Oct;15(5):475-83.
  46. Kloner RA, Goldstein I, Kirby MG, Parker JD, Sadovsky R. Cardiovascular safety of phosphodiesterase type 5 inhibitors after nearly 2 decades on the market. Sex Med Rev. 2018 Oct;6(4):583-94.
  47. Kloner RA, Goggin P, Goldstein I, Hackett G, Kirby MG, Osterloh I, et al. A new perspective on the nitrate- phosphodiesterase type 5 inhibitor interaction. J Cardiovasc Pharmacol Ther. 2018 Sep;23(5):375-86.
  48. Vlachopoulos C, Ioakeimidis N, Rokkas K, Stefanadis C. Cardiovascular effects of phosphodiesterase type 5 inhibitors. J Sex Med. 2009 Mar;6(3):658-74.
  49. Vlachopoulos C, Tsekoura D, Alexopoulos N, Panagiotakos D, Aznaouridis K, Stefanadis C, et al. Type 5 phosphodiesterase inhibition by sildenafil abrogates acute smoking- induced endothelial dysfunction. Am J Hypertens. 2004 Nov;17(11 Pt 1):1040-4.
  50. Vlachopoulos C, Hirata K, O’Rourke MF. Effect of sildenafil on arterial stiffness and wave reflection. Vasc Med. 2003 Nov;8(4):243-8.
  51. Vlachopoulos, C, Ioakeimidis N, Rokkas K, Angelis A, Terentes-Printzios D, Stefanadis C, et al. Acute effect of sildenafil on inflammatory markers/mediators in patients with vasculogenic erectile dysfunction. Int J Cardiol. 2015 Mar;182:98-101.
  52. Tzoumas N, Farrah TE, Dhaun N, Webb DJ. Established and emerging therapeutic uses of PDE type 5 inhibitors in cardiovascular disease. Br J Pharmacol. 2020 Dec;177(24):5467-88.
  53. Anderson SG, Hutchings DC, Woodward M, Rahimi K, Rutter MK, Kirby M, et al. Phosphodiesterase type-5 inhibitor use in type 2 diabetes is associated with a reduction in all-cause mortality. Heart. 2016 Nov;102(21):1750-6.
  54. Hackett G, Heald AH, Sinclair A, Jones PW, Strange RC, Ramachandran S. Serum testosterone, testosterone replacement therapy and all-cause mortality in men with type 2 diabetes: retrospective consideration of the impact of PDE5 inhibitors and statins. Int J Clin Pract. 2016 Mar;70(3):244-53.
  55. Onyeji IC, Clavijo RI. Testosterone replacement therapy and erectile dysfunction. Int J Impot Res. 2022 Nov;34(7):698-703.
  56. Vigen R, O’Donnell CI, Barón AE, Grunwald GK, Maddox TM, Bradley SM, et al. Association of testosterone therapy with mortality, myocardial infarction, and stroke in men with low testosterone levels. JAMA. 2013 Nov;310(17):1829-36.
  57. Cheetham TC, Ann JJ, Jacobsen SJ, Sidney S, Quesenberry CP, VanDenEeden SK. Association of testosterone replacement with cardiovascular outcomes among men with androgen deficiency. JAMA. Intern Med. 2017 Apr;177(4):491-9