Premature Ejaculation

Premature Ejaculation

Monday, February 15, 2010

Ejaculation Physiology Ejaculation is a complex reflex that consists of two distinct phases: emission and expulsion. The emission phase is characterized by the secretion of seminal fluids from the accessory sex glands, as well as closure of the bladder neck to ensure expulsion of semen from the urethral meatus as opposed to retrograde transport into the bladder. During the expulsion phase, stereotypic rhythmic contractions of the smooth muscle of the urethra, as well as striated perineal muscles such as the ischiocavernosus and bulbocavernosus muscles, result in the forceful expulsion of semen. This response consists of 10 to 15 contractions. Monday, February 15, 2010

Diagnostic and Statistical Manual of Mental Disorders (DSM-IV-TR) American Psychiatric Association (APA)

‘‘persistent or recurrent ejaculation with minimal sexual stimulation before, on, or shortly after penetration and before the person wishes it’’. ‘‘The clinician must take into account factors that affect duration of the excitement phase, such as age, novelty of the sexual partner or situation, and recent frequency of sexual activity’’. PE can only be diagnosed when ‘‘the disturbance causes marked distress or interpersonal difficulty’’. Monday, February 15, 2010

The International Classification of Diseases (ICD-10) PE is defined as ‘‘the inability to delay ejaculation sufficiently to enjoy lovemaking, which is manifested by either an occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 s of the beginning of intercourse) or ejaculation occurs in the absence of sufficient erection to make intercourse possible’’

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The ISSM Definition of Premature Ejaculation Constructs that are necessary to define PE are • time from penetration to ejaculation • inability to delay ejaculation • negative personal consequences from PE.

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The ISSM Definition of Premature Ejaculation Lifelong PE is a male sexual dysfunction characterized by

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ejaculation that always or nearly always occurs prior to or within about one minute of vaginal penetration; the inability to delay ejaculation on all or nearly all vaginal penetrations; and negative personal consequences such as distress, bother, frustration, and/or the avoidance of sexual intimacy.

Types of Premature Ejaculation •

Lifelong PE

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Acquired PE

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Natural variable PE

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Premature-like ejaculatory dysfunction

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Life long PE • Ejaculation occurs too early nearly every time intercourse takes place • With (nearly) every woman • From about the first sexual encounters onwards • In the majority of cases (80%) within 30–60 seconds or between 1 minute and 2 minutes (20%) • Remains rapid throughout the lifetime of the subject

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Acquired PE •

Early ejaculation occurs at some point in a man’s life

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The man had normal ejaculation experiences before

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The onset is either sudden or gradual

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The dysfunction may be a result of urological, neurological, or thyroid dysfunctions

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The dysfunction may be because of psychological or relationship problems

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Natural Variable PE •

Early ejaculations are inconsistent and occur irregularly

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This type of PE should not be regarded as a symptom a real pathology but rather a normal variation in sexual performance

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The ability to delay ejaculation may be diminished or lacking

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the impression of diminished control of ejaculation, are accompanied by either a short or normal ejaculation time

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Premature-like ejaculatory dysfunction Men with premature-like ejaculatory dysfunction experience or complain of PE while the ejaculation time is in the normal range •

subjective perception of consistent or inconsistent rapid ejaculation during intercourse;

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preoccupation with an imagined early ejaculation or lack of control of ejaculation;

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The actual intravaginal ejaculation latency time is in the normal range or may even be of longer duration

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Ability to delay ejaculation may be diminished or lacking

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The preoccupation is not better accounted for by another mental disorder

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Prevalence •

Most estimates from general population prevalence studies fall between 22% and 38%, with ranges from 4% to 39%. The wide variability in the reported ranges is mirrored in the variability and lack of standardized definitions for PE.

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In spite of the high prevalence rates, PE is the disorder for which patients are least likely to seek professional assistance, raising the distinct possibility that the problem may be more prevalent than currently estimated.

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It has also been suggested that the prevalence of PE may vary between racial groups

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The recurrent emerging pattern appears to be that PE is a largely underdiagnosed condition

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Prevalence

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Etiology •

Psychogenic causes include anxiety, an unpleasant introductory or early sexual experience, infrequent sexual intercourse, poor ejaculatory control techniques, and evolutionary as well as psychodynamic factors.

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Biogenic causes include penile hypersensitivity, hyperexcitable ejaculatory reflex, hyperarousability, endocrinopathy, genetic predisposition, and 5-hydroxy tryptamine (5-HT)-receptor dysfunction.

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Risk factors of lifelong PE •

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Genetic predisposition (Race, fi rst-degree relatives, twins, other factors) Psychosomatic disorder Behavioral or cognitive disorder from early experience Greater sexual arousal Evolutionary natural selection Penile hypersensitivity & reflex hyperexcitability Ejaculation distribution theory with dysregulation of 5 HT receptor subtypes Oxytocin release theory

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5-HT Transporter •

The 5-HTT is a membrane bound protein transporter that facilitates serotonin re-uptake from the synapse

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The 5-HTT protein is encoded for and its functioning determined by promoter region of polymorphic 5HTT gene (5-HTTLPR)

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5-HTT gene is located on the long arm of chromosome 17 (17q11.1)

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Serotonergic Basis of Ejaculation Male rat studies demonstrate that serotonin and 5-HT receptors and to a lesser extent oxytocin, are involved in the ejaculatory process. Selective serotonin re-uptake inhibitors (SSRIs) block 5HT transporters, resulting in higher synaptic cleft levels of 5-HT and delay of ejaculation. Stimulation of 5-HT2C receptors with non-selective 5HT2C agonists delays ejaculation in male rats. Stimulation of 5-HT1A receptors facilitates ejaculation. Monday, February 15, 2010

SERT Gene The 5-HTTLPR gene has two variant alleles: a short (S) and a long (L) allele. The genotypes of these alleles are called LL, SS, and SL The S allele of the 5-HTT genotype reduces transcriptional efficiency of the 5-HTT gene promoter, resulting in a 50% reduction 5-HTT protein expression and reduced serotonin reuptake compared with the L allele S allele is associated with increased vulnerability for mood disorders, reduced response to SSRIs and less side-effects Men with LL genotypes have shorter IELTs than men with SS and SL genotypes

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Risk factors of Aquired Psychorelational Functional (experiences, education) Constitutive (psychological constitution) Stress-induced (acute or chronic) Psychosexual skill deficit Neurological

Multiple sclerosis Spina bifida Spinal cord tumors Traumatic brain injury Cerebrovascular accidents

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Risk factors of Aquired Psychorelational Factors 

Functional (experiences, education)

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Constitutive (psychological constitution)

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Stress-induced (acute or chronic)

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Psychosexual skill deficit

Neurological

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Multiple sclerosis Spina bifida Spinal cord tumors Traumatic brain injury Cerebrovascular accidents

Risk factors of Aquired Endocrinological and metabolic

Hyperthyroidism Diabetes mellitus? Metabolic syndrome? Higher fasting leptin levels Haemodialysis? Hypoactive sexual desire Erectile dysfunction Relative hypogonadism (respect to non-PE patients) Hyperprolactinaemia?

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Etiology Urologic causes, including chronic prostatitis, or post. urethrtis. Early animal studies revealed that nonselective agonists of the 5-HT2C receptors delay ejaculation, but selective 5-HT2A agonists do not have a similar effect, and selective 5-HT1A agonists cause a shorter ejaculatory latency compared with 5-HT2C agonists. PE may be secondary to relative hyposensitivity of the 5-HT2C and/ or 5-HT1A hypersensitivity.

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Diagnosis: The Sexual History Frequency and duration of PE Proportion of sexual attempts with PE Relationship to specific partners Frequency and nature of sexual activity Aggravating or alleviating factors Impact of PE on sexual activity Effect on relationships and QoL Relationship to drug use/abuse Other considerations ➡ Lifelong vs. acquired ➡ Situational vs. universal/global ➡ Because of psychological or combined psychological/ biological factors ➡ Any links to ED?

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PE and Hyperthyroidism Established link between thyroid hormones, central 5-HT and depression Chronic treatment with thyroxine (T4) is an effective therapy of depression The 5-HT2A receptor is up-regulated in the cortex of suicide victims, downregulated by antidepressant drugs and seems to be under thyroid hormone regulation The majority of patients with thyroid hormone disorders experience sexual dysfunction Corona et al. reported a significant correlation between PE and suppressed TSH values of hyperthyroidism Carani et al. subsequently reported a PE prevalence of 50% in men with hyperthyroidism which fell to 15% after treatment with thyroid hormone normalization Waldinger et al. failed to demonstrate an increased incidence of thyroid dysfunction in lifelong PE, consistent with the notion that hyperthyroidism appears to be a cause of only acquired PE Monday, February 15, 2010

PE and Chronic Prostatitis Acute and chronic prostatitis and Chronic Pelvic Pain Syndrome (CPPS) are associated with painful ejaculation, ED and PE In 3700 men with benign prostatic hypertrophy (BPH), painful ejaculation, ED and PE were reported by 18.6%, 72% and 75% and were all associated with more severe lower urinary tract symptoms (LUTS) Several studies report PE as the main sexual disorder symptom in men with chronic prostatitis or chronic pelvic pain syndrome with a prevalence of 26-77%. Monday, February 15, 2010

PE and Chronic Prostatitis Prostatic inflammation and prostatitis have been reported as common findings in men with both lifelong and acquired PE Shamloul and El-Nashaar reported prostatic inflammation and chronic bacterial prostatitis in 64% and 52% of men with PE The exact pathophysiology of the link between chronic prostatitis, ED and PE is unknown Although physical and microbiological examination of the prostate in men with painful ejaculation or LUTS is mandatory, there is insufficient evidence to support routine screening of men with PE Monday, February 15, 2010

Diagnosis: The Sexual History How well are you enjoying your sex life? Do you ejaculate too soon or earlier than desired? If so, can you estimate the amount of time before you ejaculate? Do you feel you have control over the timing of your ejaculation? Does ejaculating early bother/distress you and/or your partner?

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Medical History and Examination To rule out an acute or chronic illness or identify injuries or surgeries that might interfere with healthy sexual functioning. In particular, the clinician should focus on any physical signs of neurological impairment, chronic systemic illness, and endocrine dysfunction. Infection in the urethra, prostate, or epididymis should also be ruled out. Current medications that might influence sexual functioning. laboratory assessments to identify drug or alcohol use/abuse, as PE has been reported to result from opiate withdrawal

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PE Medical Treatment Psychotherapy/Behavioural Therapy Pharmacotherapy ➡ Daily Dosing SSRI drugs and clomipramine Daily alpha-adrenoreceptor antagonists

➡ On-demand Dosing

SSRI drugs, dapoxetine and clomipramine Tramadol Topical anesthetic sprays or gels PDE-5 inhibitors

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Central Serotonergic Neuron Multiple 5-HT receptors Synaptic cleft 5-HT is regulated by the 5-HT transporter re-uptake system and several autoreceptors As 5-HT is released, the transporter system is activated, removes 5-HT from the synaptic cleft, preventing over-stimulation of postsynaptic 5-HT2C receptors Monday, February 15, 2010

Effect of SSRIs on Ejaculation

McMahon CG (1998) J Urol 59:1935-8 Monday, February 15, 2010

Selective Serotonin Reuptake Inhibitors (SSRIs) Treatment with an SSRI activates the 5-HT2C receptor and delays ejaculation The ability of SSRIs to delay ejaculation was first uncovered during the use of these medications in the treatment of depressed men in the 1970s. Fluoxetine was next shown to be helpful in the intentional treatment of PE SSRIs may cause an increase in latency time as early as 2–3 days after the initiation of oral therapy. This effect tends to plateau after 3–4 weeks, with a six- to eightfold increase in IELT. In order of clinical response,Paroxetine is the most effective, followed by fluoxetine, then sertraline, and lastly fluvoxamine Monday, February 15, 2010

Pharmacological Treatment Level 1 evidence to support the efficacy of SSRIs citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline Serotonergic tricyclic, clomipramine Meta-analysis of all drug treatment studies has demonstrated that paroxetine exerts the strongest ejaculation delay (mean IELT fold increase of 8.8) Monday, February 15, 2010

Daily SSRI Treatment Usually well tolerated Adverse effects of SSRIs ➡ Fatigue, yawning, mild nausea, loose stools or perspiration ➡ Start in the first week after intake ➡ Attenuate within 2-3 weeks ➡ Occasionally hypoactive sexual desire and mild ED ➡ Occasional agitation - avoid in men with history of bipolar depression Suspend gradually over 3-4 weeks to avoid withdrawal symptoms Monday, February 15, 2010

On-Demand Intervention SSRIs ➡

Dapoxetine, an SSRI structurally related to fluoxetine, is the first SSRI developed with a short half-life, convenient for the on-demand treatment of PE

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When taken 3 hours prior to intercourse, increased the IELT 3.0–3.7 times over baseline.

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Nausea was the most frequently noted side effect reported in up to 20.1% of patients on the higher (60mg) dose of dapoxetine; other commonly observed side effects in the 30- and 60-mg doses, respectively, were diarrhea (3.9%, 6.8%), headache (5.9%, 6.8%), and dizziness (3.0%, 6.2%).

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Behavioral Therapy and Psychotherapy Squeeze technique Behavioral therapy has long been a mainstay of treatment for PE and remains, in the absence of anything better, a common approach today. This technique involves withdrawal of the penis during intercourse and prior to the moment of ejaculatory inevitability. The sexual partner is instructed to give a very sharp and hard squeeze to the glans penis to abort the ejaculation. However, many practitioners and patients report that this technique is unpractical. Monday, February 15, 2010

Behavioral Therapy and Psychotherapy The stop–start technique has been used, with variations, for some three decades and was particularly popularized by Kaplan in 1983. This method requires the man to pause during sexual stimulation, just prior to impending ejaculation. The pause allows the patient to acclimatize to the sensation and eventually to condition himself to increased ejaculatory control. Monday, February 15, 2010

Medical Treatment Decreasing sensory perception in the penis has been the goal of most topical agents aimed at treating PE Prilocaine-lidocaine cream (EMLA, eutectic mixture of local anesthetics) Aerosol TEMPE formulation (topical eutectic mixture for PE)

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TEMPE - IELT

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Topical Agents - Side effects Anesthetic creams require a somewhat messy application within a condom, and the entire shaft is anesthetized. Aerosol TEMPE formulation, on the other hand, requires a decreased time for prior application, and only the glans penis is anesthetized Significant penile hypoanesthesia and risk of transvaginal absorption with vaginal numbness, unless a condom is utilized. Irritating topical reactions, both penile and vaginal, can occur, and systemic reactions are also possible. Efforts to wash off the medication prior to intercourse may reduce the risk of these side effects, but also reduce the spontaneity of the coital experience

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Clomipramine Clomipramine is a tricyclic antidepressant used in the treatment of obsessive compulsive disorders. Although it is not an SSRI, it does inhibit 5-HT transport. A 25-mg dose has effected delay in ejaculation, when taken as a one-time treatment 5 hours before intercourse by men with lifelong PE Side effects include dry mouth, fatigue, nausea, and dizziness. Tricyclic antidepressants seem to share with the SSRIs the risk of increased suicide, when initiated in men under age 24. At higher doses (75mg for more than 3 months), clomipramine may have an adverse effect on sperm function Monday, February 15, 2010

Tramadol Tramadol, a centrally acting synthetic opioid analgesic Effective on-demand agent The ejaculatory-delaying mechanism of tramadol has not been fully understood

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Binds to µ-opioid receptors Weak GABA, norepinephrine, serotonin re-uptake inhibitors

Occasionally associated with serotonin syndrome especially when co-administered with SSRI anti-depressant Dependance occurs but appears minimal

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PDE5 Inhibitors PE may be seen in up to a third of patients with ED In cases of PE associated with ED, treatment of ED by using PDE5 inhibitors may have a salutary effect on ejaculatory dysfunction PDE5 inhibitors may exert a secondary benefit for patients with PE when they (i) allow for a sustained penile erection, even after ejaculation; (ii) facilitate a second intercourse after the initial ejaculation, which is often less prone to PE; and/or (iii) help the patient to overcome performance anxiety, which often exacerbates PE Monday, February 15, 2010

Future PE Drugs 5_HT1A receptor antagonists ➡

The superior ejaculatory delay seen with daily SSRIs due to desensitization of 5-HT1A receptors, increased activation of postsynaptic 5-HT2C and the resultant higher increase in synaptic 5-HT neurotransmission can be achived by blockage of 5-HT1A receptors with c0administered 5-HT1A receptor antagonists

Oxytocin receptor antagonists ➡

Plasma oxytocin is elevated during erection and orgasm

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Electrical stimulation of the dorsal penile nerve produced excitation in 1/2 of oxytocin cells in the PVH and SON of rats

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