Fig 2. PDE5 inhibition and the response to sexual stimulatio. cGMP, cyclic guanosine monophosphate; GTP, guanosine 5'-triphosphate; PDE5, phosphodiesterase 5.

Overview of Orally Active PDE5 Inhibitors: PDE5 and, to a much lesser extent, PDE2 & PDE3, are localized to the corpus cavernosum of the penis, where they catalyze the transformation of cGMP to 5-GMP. Sexual stimulation and attendant neural input cause a burst of nitric oxide (NO), which, under normal conditions, results in smooth-muscle dilatation in the penis and, ultimately, erection (Fig 2). Because cGMP serves as a second messenger for NO's intrinsic vasodilator effects, inhibition of PDE5 leads to increased levels of cGMP, which, in turn, potentiates the NO-mediated response to sexual stimulation through cGMP-specific protein kinases that diminish intracellular calcium.

CASE OF THE WEEK NOV 2015_CONITIVE CONCEPT MAP ON ERECTILE DYSFUNCTION (ED) Spider Model_Problem Based Learning (PBL) for Large Groups Medical Students: e-Problem Solving Test: ED

Dr Kumar Ponnusamy* and Dr Jegathambigai Rameshwar Naidu♫ *International Medical University (IMU), ♫ASIA Metropolitan University (MSU), Malaysia

Acknowledgements: The Authors Gratefully Acknowledeges All On-Line Resources Including Google.com, PubMed, Elsieviers’ Ltd, USMLE , Kaplan, BRS, Scribd.com., ect.,.

*International Medical University (IMU), ST Matthew’s School of Medicine (SMU),

AIMST-U, MSU, Vinayaka Mission’s Med School

Erectile Dysfunction (ED):Incidence & Prevalence: ED is defined by a National Institutes of Health consensus panel as the inability to achieve or maintain an erection sufficient for satisfactory sexual performance (1). Worldwide estimates of ED prevalence range from 2% in men younger than 40 yr to 86% inmen 80 yr or older. ED prevalence has been reported as 7% among men aged 18 to 29 yr, 2 to 9% among men aged 30 to 39 yr, 9 to 11% among men aged 40 to 49 yr, 16 to 18% among men aged 50 to 59 yr, 34% among men aged 60 to 69 yr, and 53% among men aged 70 to 80 yr. ED: The inability to achieve or maintain an erection sufficient for satisfactory sexual performance. Prevalence increases with age, cardiovascular disease, diabetes mellitus, and hyperlipidemia. Diabetes is the most common cause of sexual dysfunction in men. It has been estimated that up to 50-60 % of diabetic men have erectile dysfunction. [1] . The primary risk factors are smoking, lack of physical exercise and obesity. Erectile dysfunction is strongly correlated with depressive symptoms and negatively impacts a man’s quality of life. The pharmaceutical industry for treatment of erectile dysfunction is worth nearly 6 billion dollars! . Factors that cause the onset of Erectile Dysfunction: Psychological causes include, but are not limited to: fatigue, stress, performance anxiety, poor self image or lack of communication with sexual partner/s. Major Depressive Disorder (MDD) also has a strong correlation with sexual dysfunction in men and women. Physical causes include: Urological, Vascular, neural, Endocrine (hypogonadism or Hyperprolactinaemia), Iatrogenic, Pelvic trauma or dietary. History of Treatment for Erectile Dysfunction: 1930s: Dr. John R. Brinkley experimented with goat glands to treat impotence. 1948: Masters and Johnson published the book Sexual Behavior in the Human Male and five years later when they published Sexual Behavior in the Human Female. Up until the 1970's it was generally believed that the majority of male impotence was psychological in nature and that the mind must be treated and the sexual situation counseled in order to treat and effectively cure the problem. But Penile vacuums were also used to erect the penis by drawing blood into the penile tissue. 1973: American Medical Devices developed inflatable prosthetic devices. 1980: intracorporal injections developed such as alprostadil. Early 90s an herbal supplement, Yohimbine created but advised against. 1999: Pfzier introduced VIAGRA (sildenafil). 2000: TAP Pharmaceutical Products, developed the first oral centrally acting drug: Apomorphine HCL, marketed under the brand name Uprima. 1999-2003: vardenafil and tadalafil created. PDE5 Inhibitors: Sildenafil, tadalafil, vardenafil: Men who have erectile dysfunction often produce insufficient amounts of NO. So although they are producing a small amount of cGMP, it is being broken down at the same rate, so they cannot maintain an erection. Viagra, Tadalafil, and Vardenafil work by selectively inhibiting PDE5, by binding with PDE5's active site. This prevents the hydrolysis of cGMP to inactive GMP, allowing cGMP to accumulate and prolong the vasodilation effect, resulting in a stronger and longer erection. All 3 drugs work regardless of the cause of ED, but all require sexual stimulation for activation. Contraindications: Since PDE5 inhibitors such as sildenafil, tadalafil, and Vardenafil may cause transiently low blood pressure (hypotension), organic nitrates should not be taken for at least 48 hours after taking the last dose of tadalafil. Using organic nitrates within this timeframe may increase the risk of life-threatening hypotension. A role in fighting infection: In addition to its role as a vasodilator and neurotransmitter, NO is produced by macrophages. These phagocytic cells of the immune system use NO to impair DNA synthesis and metabolism in microorganisms. NO● and in Septic Shock: Massive bacterial infections are known to cause septic shock, the hallmark characteristic of which is a dramatic lowering of blood pressure. This is due to the release of massive amounts of NO directed against the bacteria; the unfortunate side effect is the extreme vasodilation that occurs in response to NO. The discovery of Viagra: Pfizer accidentally fell upon Viagra as a treatment of erectile dysfunction. They were initially searching for a vasodilator to treat angina pectoris. Their goal was to find a molecule that would bind to PDE's active site, so that it wouldn’t be able to convert cGMP to the inactive GMP form. They studied the structure of the substrate cGMP. Compare cGMP and Viagra. Similarities: The sulfur dioxide (SO2) group of sildenafil mimics the phosphate in cGMP. Both have similar 4-piperidone rings (six-membered ring with N at one end and C=O at the other. Although similar, they are obviously not a perfect match. But, an inhibitor doesn't have to bind in exactly the same way as substrate. It just has to bind tightly enough so that it inhibits the substrate (PDE5) from getting into the active site. Comparison of sildenafil, vardenafil, tadalafil: They all are all PDE5 inhibitors with the same mechanism of action and similar adverse effects. They all require sexual stimulation as a prerequisite and are effective regardless of the cause of erectile dysfunction. Viagra has been around the longest and thus has the benefit of having long-term safety data. It also has the highest use and lowest discontinuity of the three drugs. However, Viagra is also administered in higher doses than the others. Tadalafil has the longest period of onset (2 hours) and lasts up to 36 hours, whereas as sildenafil is effective up to 12 hours and vardenafil is only effective 4-5 hrs after administration. Vardenafil, however, is the most potent (lowest maximal concentration) and binds to PDE5 more rapidly than the others, thus it has a potential time of onset of 10 minutes. Centrally Acting Oral Drugs: Apomorphine HCL (Urima): Apomorphine is a centrally acting drug that improves erectile dysfunction by enhancing the central natural erectile signals that normally occur in the brain during sexual stimulation. It is a non-selective dopamine receptor agonist and acts mainly on dopamine D2-like receptors in the brain. Dopamine (DA): DA functions in the brain as a neurotransmitter, activating dopamine receptors, and also it is a neurohormone released by the hypothalamus. Dopamine acts on the sympathetic nervous system, producing effects such as increased heart rate and blood pressure. Male orgasm and ejaculation are under the control of the sympathetic nervous system. Apomorphine, as a dopamine receptor agonist specifically activates the oxytocinergic neurons in the paraventricular nucleus of the hypothalamus, releasing erectogenic signals and thus facilitating an erection. Efficacy rates for erections that are hard enough for intercourse, range from 48%-55% for patients receiving apomorphine. It is fast acting and 71% of erections are achieved within 20 minutes of administration. Side Effect: nausea. 96% of men surveyed preferred sildenafil over apomorphine as a treatment for erectile dysfunction. Intracavernous Pharmacotherapy: Patients that are not responding to oral drugs may be offered intracavernous injections. Papaverine and alprostadil are the main drugs used for intracavernous treatment. Drugs to treat… SEXUAL DYSFUNCTION (SD): SD: Sexual Dysfunction is estimated to effect 30-40% of men and women. Its prevalence increases with age. Drug treatment of male sexual dysfunction has been given significantly more attention than that of women. Sexual Dysfunction in MEN: Sexual problems in men include: an inability to acquire or maintain an erection satisfactory for sexual intercourse (impotence or erectile dysfunction (ED)); a lack of interest in sex (diminished libido); premature ejaculation; and delayed or inhibited ejaculation. Erectile dysfunction is the most common physiological sexual disorder for men. It was estimated that in 2005, three-hundred and twenty two million men world wide would be affected by erectile dysfunction. Physiological mechanisms of normal penile erections: http://www.healthcentral.com/animation/408/17/Erectile_Dysfunction.html . Stimulation of penile shaft by the nervous system leads to the secretion of nitric oxide (NO), causing the creation of cyclic guanosine monophosphate (cGMP) which functions to relax blood vessels (vasodilatation) so erectile tissues in the corpus cavernosa can fill with blood, and subsequently cause a penile erection. Phosphodiesterase type 5 (PDE5) is always present in the penis and functions to destroy cyclic GMP, causing vasoconstriction of erectile tissues and resulting in the loss of erection. In normal males, the loss of an erection occurs after orgasm and ejaculation of sperm.   

Erectile Dysfunction (ED): Epidemiology, Anatomy, Biochemistry & Molecular Basis of ED, Physiology & Pathophysiology, History, Examination, Lab Investigations, Pathology, Physical Examination, Laboratory Investigations, Treatment-Pharmacology, Behavioural Issues & Ethics, Preventive Medicine, e-Resourse for Large Group Medical Students

Fig 1. Illustrates how the binding of Phosphodiesterase 5Inhibits the functioning of cGMP. PDE5’s active site fits exactly (A lock

& key mechanism) with molecules of cGMP to make them break down

The above fig shows the mechanism of action of Viagra, and the other PDE5

inhibitors, on the nitric oxide (NO•) cycle

Sildenafil (VIAGRA)

•Viagra is the most popular of the PDE5 inhibitors. It is estimated that it has worked for 20 million men worldwide. It is administered in 25, 50 and 100mg doses. •Taken 1 hour before sexual intercourse•Maximum dose is once daily•Window of opportunity: 30 minutes to 4-5 hrs.•But can be effective for up to 12 hrs.•side effects, such as: headache, facial flushing, dyspepsia, dizziness, rhinitis and abnormal vision.

Tadalafil (Cialis): Aadministered orally in 10mg and 20mg doses . Instructed to take Tadalafil two hours before sexual intercourse. Its efficacy is maintained for at least 36 hours. The maximum dosing frequency is once every other day . Improved erections were reported by 82.8% of treated men. Thirty-six hours after administration of Tadalafil, 59.2% of intercourse attempts were successful. Side effects: headache, flushing, rhinitis and back pain/myalagia. Safety concern: it also serves as an inhibitor of PDE11, an enzyme in the testes, so there is concern on the effect that it has one sperm and spermatogenesis Vardenafil (Levitra): higher in vitro potency, more rapid binding to

PDE5, and slower dissociation from this enzyme than Sildenafil and Tadalafil. •Administered orally on demand in 5, 10 and 20mg doses •Maximum dose administration frequency is once daily. •There is a window of opportunity from 30 minutes to 4-5 hours after administration. But, the earliest time to onset of action leading to successful intercourse can be just 10 minutes! •75% of intercourse attempts were successful for patients using vardenafil compare with the 40% success in the placebo group •Treatment with vardenafil in patients with erectile dysfunction that were previously unresponsive to sildenafil produced significant improvements in erectile function domain score and maintenance of an erection. Side effects: headache, flushing and rhinitis .

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Apomorphine is a D1 and D2 Dopamine agonistAlso used as anti-Parkinsonian, and as emetic agent

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PapaverineNon-specific inhibitor of phosphodiesterase (PDE)

Smooth muscle relaxant and vasodilatorFound in opium

HO N

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Phentolamine-Adrenergic Antagonist

(alpha-blocker)vasodilator

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Alprostadil (MUSE, Caverject, Befar)•Alprostadil causes blood vessels to expand, increasing blood flow throughout the body. Thus, by increasing blood flow to the penis, alprostadil helps facilitate an erection. •Alprostadil is a vasoactive prostaglandin E1.•It is more effective when used in combination with phentolamine and papaverine; this is considered a tri-mix combination therapy. This tri-mix has an extremely high rate of efficacy at 92% •However, alprostadil is normally administered by itself. Sexual activity is reported after 94% of injections, a figure that no other sexual dysfunction treatment option has reached. It also has an almost immediate onset of action. •Side Effects: penile pain, prolonged erections, priapism, and fibrosis • alprostadil is also now available in a cream, under the brand name Befar .

Anatomy & Physiology of Erection

Veno-Occlusive Mechanism

Psychogenic ED

PDE5 PhysiologyIntracavernosal Injections

Sildenafi l (SDF): SDF Works Via Inhibitionof cGMP Phosphodiesterase, Not cAMP

Phosphodiesterase.

Amrinone, a phosphodiesterase inhibitor, causes an increase in cardiac inotropy but also causes vasodilation. Thus, its use would be inappropriate in this hypotensive patient.

Examination: BP, Peripheral pulses, palpate for AAA. Testes size & consistency, 2○sexual characteristics, Penis for Peyronie’s plaques, phimosis.

Pathology: ED and Coronary Artery Disease: Generalised atherosclerosis.• Penile arteries smaller than coronary arteries, ED pre-dates coronary artery disease• Man with ED and no cardiac symptoms is a cardiac patient until proven otherwise. Investigations: Fasting glucose and lipids., Morning testosterone and SHBG. If testosterone is

Low or borderline repeat with Prolactin, FSH & LH. Thyroid function, PSA.Specialised Investigations: Vascular studies: Young patients with primary ED. History of

trauma e.g. penile fracture, Patients unresponsive to medical therapies. Treatment of ED General Measures: Smoking cessation, Reduce alcohol, Weight loss, Exercise.

Endocrine Disorders: Hypogonadism, Hyperthyroidism, Hyperprolactinaemia, Endo referral.Psychosexual therapy: Even if cause of ED is physical the patient will develop psychosexual

issues, Performance anxiety, Sensate focus exercises, Relationship counselling. Drugs for ED: Oral Agents: Centrally acting dopamine-receptor agonist Apomorphine

(discontinued in UK). Phosphodiesterase type 5 inhibitors• Intra-cavernosal. Prostaglandin E1 Alprostadil. Intra-urethral-AlprostadilPDE5 inhibitorss: Sildenafil (Viagra) 25mg, 50mg, 100mg, 1 hour before sexual activity

4-6 hour window, Absorption delayed by fatty mealTadalafil (Cialis) 10mg, 20mg, 30 minutes before sexual activity, 36 hr window, Absorption not

affected by food. Tadalafil (Cialis) 5mg daily. Vardenafil (Levitra) 5mg, 10mg, 20mg

30-60 min before sexual activity, 4-6 hr window, Absorption delayed by fatty meal .PDE5 Inhibitors Side Effects: Facial flushing, Headache, Nasal congestion, Dizziness,

Dyspepsia, Visual disturbance (blue halo), Priapism. Non-arteritic anterior ischaemic optic neuropathy

PDE5 Contraindications: Recent cardiovascular (CVD) event, Nitrates, Hypotension, Anatomical deformity, Angulation, cavernosal fibrosis, Peyronie’s . Predisposition to prolonged erection, Sickle cell disease, Multiple myeloma, Leukaemia

PDE5 Drug Interactions: Nitrates: Glyceryl trinitrate, isosorbide mono or dinitrate.Chest pain after taking Sildenafil/Vardenafil no nitrates 24 hours, Tadalafil no nitrates 48 hrs. Recreational amyl nitrate (Poppers)

Cytochrome P450 inhibitorss: Protease inhibitors especially Ritonavir use very small dose, Cimetidine, Ketoconazole, Erythromycin Alpha blockers.

Intracavernosal Injections: Alprostadil (Caverject, Viridal) 5-40 mcg, -Independent of intact nervous system, -Manual dexterity, adequate vision, training, Contraindicated: bleeding disorders, sickle cell anaemia, multiple myeloma, leukaemia

-Side effects: penoscrotal pain, haematoma, fibrosis at injection sites, priapismPapaverine, Phentolamine, Aviptadil (vaso-intestinal peptide) been used sole or with Alprostadil Intraurethral: Alprostadil (Muse) 125mg, 250mg, 500mg,1g.

Pellet inserted with applicator, Massage penis to aid absorption.. Side effects: Penile pain, dizziness, priapism rare. Vacuum Devices: Blood trapped in intracorporal and extracorporal compartments of penis, Constricting ring at base of penis, Cyanosis, oedema, cold, Pivots at base below ring, Maximum time 30 minutes. Penile Prostheses: Semi-rigid rods, 2 piece inflatable prosthesis, 3 piece inflatable prosthesis with abdominal reservoir, Risks: Infection, Destroys corpora cavernosa, Erosion and extrusion, Mechanical failure.

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History: Medical, Surgical, Psychiatric, Medication, Smoking, Alcohol. Recreational drug use. Detailed description of problem, is it ED?. Causative factors, Sexual desire/libido. Ejaculatory disorders, Impact on quality of life & on relationship, Expectations of treatment.

Behavioural Science: Relationship issues: Current relationship status. Length of relationship, Previous sexual partners and relationships, Partner issues e.g. menopause/pain/cancer. Psychogenic and Psychiatric Causes : Anxiety, Loss of attraction to partner, Relationship difficulties, Stress, Depression.

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11. A 56-year-old man presents to his family doctor for a regular check-up visit. His past medical history is signifi cant for long-standing hypertension and coronary artery disease. He had a myocardial infarction and percutaneous angioplasty 1 year ago. The patient initially reports no complaints, but as his physician is heading toward the door, the patient states with some embarrassment that he has had problems achieving erections since he was released from the hospital last year. He says that he has morning erections. His current medications include simvastatin and lisinopril. Which of the following is a likely cause for this man’s acquired erectile dysfunction?(A) Decreased interest in sexual activity(B) Fear of another myocardial infarction√(C) Increasing age of the patient(D) Medication side effects(E) Physical inability after the heart attack 11. The correct answer is B. There is a temporal association between this man’s myocardial infarction and his subsequent erectile dysfunction (ED). The presence of morning erections indicates that the cause of this patient’s ED is psychological rather than physical. The patient should be reassured that if he can tolerate climbing two flights of stairs, he can tolerate sexual activity.

17. A 57-year-old man with erectile dysfunction has cavernosography prior to surgery. Cavernosography demonstrates a leak from the dors al vein to the saphenous vein. Which of the following is the most likely cause of this patient’s impotence?(A) Arterial insuffi ciency(B) Hormonal impotence(C) Psychogenic impotence(D) Somatosensory defect(E) Venous outfl ow. √17. The correct answer is E. A leak into the dorsal and saphenous vein, demonstrating venous outflow, is typically due to insuffi cient relaxation of the smooth muscle resulting from excessive adrenergic tone or damaged parasympathetic innervation.

12. A 27-year-old healthy man presents because he and his wife have been repeatedly unsuccessful in conceiving a child. His wife has been tested and determined to be fertile. Upon questioning, the patient denies coronary or lipid abnormalities but admits to having multiple sinus infections and a chronic productive cough. Further analysis of his semen shows a normal number of sperm. Which of the following is the most likely etiology for the patient’s infertility? (A) Age-related increase in estradiol with possible prostate dihydrotestosterone sensitization(B) Autosomal recessive dysfunction of a chloride ion channel(C) Failure of testicles to descend into the scrotum(D) Familial disease causing early atherosclerosis leading to erectile dysfunction(E) Lack of dynein ATPase arms in microtubules of cilia. 12. The ans is E. This patient has Kartagener’s syndrome, which is caused by a lack of dynein arms in microtubules in cilia, rendering them immotile. It results in infertility due to immotile sperm, as well as recurrent sinusitis due to defi cient removal of bacteria and other infectious particles. It is also associated with situs invertus, in which the major organs are reversed or mirrored from their original locations.

10. A 74-year-old man comes to the physician complaining of increased urinary frequency along with difficulty starting and stopping urination. Assuming a benign underlying cause, which of the following is the mechanism of action of a common medication used to treat this condition?(A) Formation of superoxide radicals that attack DNA bonds(B) Gonadotropin-releasing hormone analog(C) Inhibition of cyclic guanosine monophosphate–specifi c phosphodiesterase type 5(D) Inhibition of cytochrome P450 enzymes(E) Inhibition of 5α-reductase√(F) Inhibition of testosterone’s negative feedback on gonadotropin secretion. 10. The ans is E. This man has the symptoms of benign prostatic hypertrophy, which include diffi culty starting and maintaining a urine stream, feeling as though the bladder is never emptied, having the urge to urinate again soon after voiding, and pain on urination or dysuria. Finasteride is most commonly used to treat this condition. Finasteride acts by inhibiting the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase. This leads to a reduction in the size of the prostate, providing symptomatic relief.

36. A 45-year-old man presents to his physician complaining of erectile dysfunction. Which of the following is the mechanism of action of the oral agents approved for the treatment of erectile dysfunction?(A) Androgen supplementation(B) Antiandrogen action via receptor site interference(C) Binding to G proteins to stimulate adenylyl cyclase(D) Inhibition of cAMP phosphodiesterase(E) Inhibition of cGMP phosphodiesterase. 36. The ans is E. Sildenafil acts by inhibiting cGMP phosphodiesterase, which increases cGMP levels and thereby leads to smooth muscle relaxation in the corpus cavernosum. The muscle relaxation allows increased headache, fl ushing, and disturbances in color vision.

Conclusions: ED is a common problemImpact on patient and partner/sOverlap of psychological and physicalMay be initial presentation of diabetes or coronary artery diseaseGood range of safe and effective therapiesIf YOU don’t ask your patient may be too embarrassed to tell you..

NHS Prescription for ED: Diabetes (DM), Multiple sclerosis, Parkinson’s Disease, Poliomyelitis

Prostate cancer, Prostatectomy incl TRPRadical pelvic surgery, Severe pelvic injury Renal failureOn dialysis., Transplant, Single gene neurological disease

Spinal cord injury, Spina bifida, Receiving NHS Rx 14/9/1998

Private Prescription: Pharmacy costs vary Sildenafil 100mgX4 £25-£40

Pharmacy2U £25

Intracavernosal InjectionsIntraurethral AlprostadilVacuum Devices Penile Prosthesis

Research Component on ED

Arteriogenic Cause of ED• Hypertension,

Smoking, DM, Hyperlipidaemia

• Peripheral vascular disease

• Blunt perineal or pelvic trauma

• Pelvic irradiation.

Neurogenic causes of ED: Lesions of medial preoptic nucleus, paraventicular nucleus, hippocampus, Spinal trauma

• Myelodisplasia (spina bifida)• Pelvic surgery/radiotherapy• Multiple sclerosis, Intervertebral disc lesion• Peripheral neuropathies: Alcohol, Diabetes,

HIV

Endocrine Causes of ED• Hypogonadism: Low testosterone,

Raised SHBG, Raised Prolactin , Thyroid disease.

Drugs associated with ED• Antihypertensive

s– Thiazides– B blockers– Centrally acting drugs

• Antidepressants– Tricyclics– MAO inhibitors– SSRI

• Anticholinergics– Atropine

• Antipsychotics– Phenothiazines

• Anxiolytics– Benzodiazepines

• Psychotropic drugs

– Alcohol– Opiates– Amphetamines– Cocaine

Differential Diagnosis / Causes / Etiology of ED

Note & Disclaimer: The content in this e-Cognitive Concept Map on BIO-GEN is based on the knowledge that I acquired studying regular reference books and On-Line Learning Resources in Google, PUBMed ect., and after years of teaching biochemistry-Genetics to Medical and Allied Health Science students in PBL Based Integrated Med Curriculum. The sourvce of the figures, animation used in this Map is mentioned where ever applicable, and they are used purely for teaching Biochemistry-Genetics to audience and no monetary benefit intended out of it. If copyright owner of the figures used in this Map do not agree with this disclaimer, they are welcome to contact me about it and, I will delete their content and source from my presentation. Thanking You!.

Clues Differentiating Psychogenic From Organic Causes

Psychogenic–Sudden onset–Situational, Normal waking and nocturnal erections, Normal erection with masturbation–Relationship problems, Life event–Anxiety, fear, depression

Organic–Gradual onset, All situations–Reduced or absent waking and nocturnal erections, No erection with masturbation, Penile pain.

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L-CARNITINE PREVENTS ED

Research Component on ED