Evaluation, Etiology and Management Louis Plzak, M.D. Erectile Dysfunction Evaluation, Etiology and Management Louis Plzak, M.D.

Goals Review erectile physiology Anatomy Mechanism of Erection and Detumescence Neuroanatomy and Neurophysiology of Erection. Pathophysiology of E.D. Discuss modern evaluation and management

Approach to Erectile Dysfunction PE Laboratory assessment Advanced testing: NPT, arterial evaluation, veno-occlusive evaluation Pharmacotherapy SURGERY

Epidemiology Between age 40-70: 52% report some ED Mild 17% Moderate 25% Complete 10% Age 40: 5% complete. Age 70: 15% complete. Other sexual dysfunction (men aged 18-59) Premature ejaculation: 28.5% Decreased libido: 15.8% Anxiety: 17%

ANATOMY Tunica Albuginea: Bilayer; inner-circumferential, outer-longitudinal. Outer layer deficient at 6 o’clock. Intercavernosal pillars (ICPs) radiate inward to provide support. These act as struts. Spongiosum does not have outer layer or ICPs: Allows for low pressure during erection.

Cross Section of Penis ICPs

Arterial Supply Hypogastric->Internal Pudendal artery. Runs through Alcock’s canal, lateral to levator muscles. Within Alcock’s canal, the PERINEAL artery branches off of the Pudendal. The continuing artery is then the PENILE. Penile artery gives off three branches: Bulbourethral, Cavernous (or Central, Deep) and the Dorsal artery (multiple collaterals)

Arterial System

Venous Drainage Venules in sinusoidal spaces merge to become subtunical venous plexus which become emissary veins piercing through the albuginea. 100 microns-several mm diameter. Form circumflex, deep dorsal (drains the glans), cavernous and crural veins. Skin is drained by superficial dorsal vein.

Venous Drainage

Cavernosum-Erection Sinsusoids become dilated for rapid transport of blood. Arterioles (which open directly into sinusiods) become dilated and straighten. Increase from 15-30 to 100 microns. Resistance to incoming blood flow drops. Subtunical venous complex compressed against the tunica. Uneven stretch of the inner and outer tunica further occludes the emissary veins.

Molecular Mechanism: Contraction Ca++ concentration increases. Binds calmodulin, which changes its conformation and exposes sites of interaction with myosin light chain kinase. This catalyzes phosphorylation of myosin light chains and triggers cycling of myosin cross bridges along actin filaments. Also activates myosin ATPase which hydrolyzes ATP to provide energy for contraction.

Smooth Muscle Relaxation Decrease in Ca++ cAMP and cGMP are secondary messengers and phosphorylate proteins and ion channels. Open potassium channels (hyperpolarization). Sequestration of intracellular calcium in the endoplasmic reticulum. Inhibit Ca++ channels, blocking influx.

Signal Transduction NO: cGMP PGE1: cAMP Both induce relaxation by activating protein kinases and modifying the activity of ion channels. cAMP activates calcium sensitive K-channel. Degradation of cGMP and cAMP is mediated by specific phosphodiesterases. This is PDE5 for cGMP (but there are 11 isozymes families).

Neurophysiology of Erection “The penis does not obey the order of its master, who tries to erect or shrink it at will. Instead, the penis erects freely while its master is asleep. The penis must be said to have its own mind, by any stretch of the imagination.” Leonardo Da Vinci

Neurophysiology Central: Paraventricular and Medial preoptic area (MPOA) of hypothalamus control sex drive and erection. Dopaminergic and Adrenergic receptors enhance. Serotoninergic receptors inhibit. Peripheral Neurotransmitter: Nitric Oxide

Peripheral Neuroanatomy Parasympathetic S2-4. Sympathetic T10-12. Form pelvic plexus, which form the cavernous nerves (next to prostate). This splits medial bundle is close to membranous urethra and enters penis at hilum. lateral bundle innervates the crura and some fibers join the dorsal nerve to innervate the distal penis.

7 Phases of Erection Flaccid Initial filling: max inflow, no change pressure. Tumescence: increasing pressure with decreasing arterial flow Full erection: small inflow and outflow, pressure plateaus aroung MAP. Initial Detumescence: transient increase in pressure due to smooth muscle contraction against closed system. Slow detumescence: slow decrease in pressure from slowly opening venous channels Fast detumescence: completely reopened sinusoids cause fast decrease in pressure.

Classification Psychogenic: previously 90% of ED. “With few exceptions, the causes of sexual difficulties in the male are psychic, ie., based on guilt, anxiety, jealousy, or frigidity on the part of the wife. . . Many of these men are tense and nervous. . . Unless the patient’s difficulties are of short duration, he should be referred to a psychiatrist.” Smith’s General Urology, 1966.

Classification Psychogenic factor now rarely identified as a “pure” cause. Exaggerated suprasacral inhibition? Excessive sympathetic outflow/elevated catacholamine levels? Inadequate release of neurotransmitters?

Neurogenic ED Stroke, Alzheimer’s, Trauma, Tumor, Diabetes, Alcoholism (and pelvic surgery, trauma)

Hormonal Hypothalamic-pituitary axis dysfunction. Hypogonadotropic hypogonadism: congenital or tumor in pituitary or hypothalamus. Hypergonadotropic hypogonadism: testicular tumor, surgery or mumps orchitis. Hyperthyroid: diminished libido (increased estrogens) Hypothyroidism: low testosterone secretion, elevated prolactin.

Hyperprolactinemia-Causes Hypothalamic: tumors (craniopharyngioma), granuloma (sarcoidosis, histiocytosis X) Pituitary: micro/macroadenoma (acromegaly), meningioma, surgical trauma Miscellaneous: chronic renal failure, liver failure, stress, idiopathic. Drugs

Drug-Related Hyperprolactinemia Drugs which decrease synthesis of or inhibit release of dopamine cause overproduction of prolactin. Deplete central dopamine stores: methyl-dopa, reserpine. Dopamine-receptor blocking agents: chlorpromazine, haloperidol, metoclopramide) Block effects of endogenous dopamine: metoclopramide, verapamil, cocaine, cimetidine, opiods.

Hyperprolactinemia Suspect in patients that present with both ED and decreased libido. Low incidence of prolactin secreting tumors, but Of patients with a prolactin secreting tumor, 90% presented with decreased libido and ED. High Prolactin levels (>22ng/ml) suppress LHRH secretion from the hypothalamus.

Arteriogenic Component of the generalized atherosclerotic process. HTN Smoking (Odds ratio of 1.5 in 31-49 year olds) DM Pelvic irradiation (obliterative arteritis) Hyperlipidemia. Trauma (including biking).

Cavernosal (Venogenic) Abnormal veins Degeneration of tunica albuginea (Peyronies’s, DM, aging) Shunting (trauma, iatrogenic) Alteration of erectile tissue (increased collagen deposition, smooth muscle atrophy, aging, DM) Medications

Drug Induced Drugs which interfere with central neurotransmitter pathways: antipsychotics, tranquilizers, antidepressants and antihypertensives. Centrally acting sympatholytics: clonidine, methyldopa, reserpine. Peripheral sympatholytics: Guanethidine. Alpha blockers: Ejaculatory inhibition. Beta blockers: Decrease libido. Spironolactone: Decrease libido, gynecomastia (4-30%) Estrogens and Antiandrogens.

Evaluation Psychosexual history: differentiate changes in libido, ejaculation and orgasm from ED. Presence of morning erections. Underlying psychological conflict. Medical History: esp. medications, trauma. PE: phallus: Peyronie’s, chordee, micropenis. Testicles: small, softendocrine workup Breasts: Gynecomastia Neurological: sensation, bulbocavernosus reflex.

Lab Studies (?) CBC, UA, Renal and Liver Function, Lipid profile, morning testosterone and PSA in older men. Prolactin, FSH, LH?

Diagnostic Studies Choice of study, if any, is directed by the patient’s goals and overall health. Impact of Sildenafil

Diagnostic Tests Therapy Tests Oral, Intraurethral or VED None, CIS or Doppler US Intracavernous Injection CIS (Duplex U/S optional) Penile Prosthesis Nocturnal Penile Tumescence or CIC or U/S Venous Surgery CIS+U/S+cavernosography+NPT Arterial Surgery CIS+ U/S

Nocturnal Penile Tumescence NPT or sleep-related erection is a recurring cylce of erections associated with REM sleep in virtually all potent men. Rigiscan: normal result rules out significant vascular insufficiency. Results can be confirmed with formal sleep lab study with polysomnography.

Biothesiometry Designed to measure the sensory perception threshold to various amplitudes of vibratory stimulation. Test pulp of fingers, both sides of penis, and the glans.

Vascular Evaluation Penile Brachial Pressure Index (PBPI) Penile systolic BP divided by the brachial systolic BP. Less than 0.7 is abnormal (arteriogenic impotence).

Duplex Ultrasonography U/S of flaccid penis: arterial diameter and calcifications. Intracavernous injection, then repeat U/S 3-5 minutes later. Self stimulation and possibly a second injection if necessary. Normal= peak systolic flow velocity more than 30cm/sec in both cavernous arteries and strong phasic pulsations of the cavernous arteries. Normal veno-occlusive mechanism characterized by sustained erection and absence of end-diastolic flow after self-stimulation.

Vascular Evaluation Combined Intravcavernous Injection and Stimulation (CIS). Alprostadil (10mcg) or papaverine injected intracavernouly, and self-stimulation. Full erection (>90 degrees and firm) should be achieved in 15 minutes and last longer than 15 minutes. Normal finding rules out venous leak. 20% of men with arterial insufficiency may achieve erection. Heightened fear of injection may cause false positive (sympathetic response).

Cavernous Artery Occlusion Pressure Injection of vasodilators (30mg papaverine +2mg of phentolamine) followed by infusion of saline into corpora. Bring intracavernous pressure above the systolic blood pressure. Doppler placed at penile base, and infusion is stopped. Measure pressure at which arterial blood flow becomes detectable. Normal is gradient less than 35 mmHg and equal left/right.

Cavernosometry and Cavernosography Saline infusion and intracavernous pressure monitoring after injection of vasodilators. Measure infusion rate required to maintain the erection and the pressure drop 30 seconds after cessation of infusion. Normal is less than 5ml/min with a pressure decrease from 150mmHg of less than 45 mmHg in 30 seconds. Cavernosography: infuse dilute contrast to see radiographically where the leak is located.

Arteriography Limited usefulness Pre-op evaluation of young man with traumatic arterial disruption or pelvic steal syndrome.

Medical Treatment Testosterone: Need to evaluate for occult prostate cancer with PNBx. DRE and PSA q6 months. Hepatotoxicity is the largest risk (esp orally). Increases libido, decreases osteoporosis Only 10-20% get a better erection. In patients with hyperprolactinemia with or without hypogonadism, testosterone doesn’t work. Bromocriptine (Dopamine agonist) lowers prolactin, increases Testosterone. Androgel 5mg apply to skin daily.

Sildenafil (Viagra) PDE 5 inhibitor which prolongs the relaxant effects of Nitric Oxide on penile smooth muscle. During stimulation, NO is released from nonadrenergic/noncholinergic neurons in penile smooth muscle. NO activates guanylyl cyclase leading to increased levels of cGMP which relaxes cavernous smooth muscle. Breakdown of cGMP is blocked by sildenafil. No effect in absence of sexual stimulation because NO and cGMP are at basal levels.

Sildenafil In initial studies, effect was dose-related: 63% at 25 mg 82% at 100mg Taking with high fat meals decreased peak serum levels by 29% and increased the absorption time by 60 minutes. Does not increase libido. Metabolized by cytochrome P450 3A4 and 2C9. Drugs which inhibit these will retard the metabolism.

Sildenafil: Side Effects Headache 16% Flushing 10% Dyspepsia 7% Abnormal vision 3% (color tinge or light sensitivity) These are dose dependent (at 100mg, 11% have vision changes). Priapism: 25 cases Death: >500. Most had severe cardiac issues.

Sildenafil: Contraindications Long or short acting nitrates. “If the patient has stable coronary disease and does not need nitrates on a consistent basis, the risks of sildenafil should be carefully discussed with him.” Pre-sildenafil treadmill test may be appropriate. Use of nitrates 24 hours after sildenafil may be hazardous.

Sildenafil Interactions Cytochrome P450 3A4 Inhibitors: Cimetidine Erythromycin Ketoconazole Patients with liver damage Patients with borderline hypotension.

Sildenafil Start off at 50mg tabs. 1 tab 1 hour before sex on an empty stomach. No alcohol! Do not exceed 1 tab in 24 hours. It may not be covered by insurance.

Yohimbine Alpha-2 adrenergic antagonist which might work at the paraventricular and pre-optic brain centers. 18mg daily Not harmful, but not effective either.

Phentolamine (Vasomax) 45 % response rate. Not approved or available.

Apomorphine Potent emetic which acts on central dopaminergic (D1/D2) receptors Sublingual form has been developed, but did not gotten approval due to syncope. Nausea 17%.

Trazadone Serotonin antagonist and reuptake inhibitor. Sedative effect renders sexual activity more difficult. (Un)common cause of priapism.

Muse Intraurethral alprostadil Penile Pain (11%) Urethral Burning 7% Lower response rate compared to injections (65%). Less fibrosis/scarring (about 1%) Less invasive and local administration minimizes side effects.

Injection Therapy Papaverine: inhibits PDE. Increasing cAMP and cGMP Blocks calcium channels Dose of 15-60mg; response 35-55% Side effects: fibrosis 1-33%, occasional increase in LFTs.

Alprostadil PGE 1. Derivitive of arachidonic acid. Rapidly inactivated; half-life of less than 1 minute. 70-80% response rate. Most frequent side effect is pain at injection sight: 16.8-34% of patients.

Trimix Papaverine, Phentolamine, Alprostadil 77-92% effective Lower incidence of painful erections.

VED Satisfaction rates of 68-83% High partner satisfaction rate. Should not be left on for more than 30 minutes. May prevent penile shortening after removal of prosthesis. Pain and numbness 5-45%.

Surgery Vascular v. Malleable v. Inflatable Penile prosthesis. Prosthetics: 11% of men complained of penile pain after malleable and needed to have prothesis removed. 5-15% failure rate in first 5 years. Majority of devices will fail in 10-15 years and need to be replaced.

Surgery- IPP Most common complaint post-op is penile shortening (?2 cm) Ejaculatory dysfunction- men need to be aroused too.

Pearls Premature ejaculation: 90% effectively treated with sex therapy. Otherwise use Zoloft. Peyronie’s orginates in the albuginea of the cavernosum-no intracavernosal fibrosis. If device fails more than 5 years after implant, replace entire device instead of simple revision.

Pearls: IPP selection Normal: Ultrex (expand in length and girth) Peyronie’s: implant AMS CX (expand in girth only). These patients tend to not have intracorporal fibrosis. Small or fibrotic (from previous implant) : CXM cylinders. Never tell your patient “we used the CXM cylinders.”