Disorders of Ejaculation and Orgasm

Normal Ejaculatory Process

Phases (3)

1. Emission and bladder neck closure
2. Ejection (or penile expulsion)
3. Orgasm

Emission[1]

• Involves deposition of seminal fluid into the prostatic urethra
• Mediated by the sympathetic nervous system
• In response to cerebral stimulation, the thoracolumbar (T10-L2) sympathetic nerves stimulate contraction of
  • Prostatic smooth muscle
  • Seminal vesicles
  • Vas deferens
• Allows sperm and seminal fluid to be deposited into the prostatic urethra.
  • This results in swelling of the bulbar urethra
• Bladder neck closure occurs concurrently with emission in response to alpha-sympathetic stimulation by the sympathetic innervations
  • Sympathetic nerve fiber damage, such as that which can occur during a RPLND, can result in failure of the bladder neck to contract effectively allowing semen deposited into the prostatic urethra to pass in a retrograde fashion into the bladder (i.e., RE).§

Ejection/Expulsion[2]

• Antegrade flow of semen throw the urethral meatus
• Due to the combined action of sympathetic and somatic pathways
• Distension of the bulbar urethra stimulates the somatic pudendal nerve (S2-S4 nerve roots (Onuf's nucleus)) resulting in
  • Rhythmic contractions of the bulbocavernosus and pelvic floor muscles
  • Relaxation of the external urinary sphincter
  • This results in semen being projected in an antegrade fashion.
• Ejection also involves a sympathetic spinal cord reflex, on which there is limited voluntary control. The bladder neck closes to prevent retrograde flow; the bulbocavernous, bulbospongiosus, and other pelvic floor muscles contract rhythmically, and the external urinary sphincter relaxes. Intermittent contraction of the external urethral sphincter prevents retrograde flow into the proximal urethra
• Failure of emission is a condition whereby semen fails to be deposited into the prostatic urethra.
  • Differentiating between retrograde ejaculation and failure of emission §
    • Requires analysis of a urinalysis after the achievement of orgasm.
      • Patients should be instructed to urinate before masturbating to orgasm.
    • Can guide treatment
      • α-sympathomimetic agonists have been shown to improve bladder neck closure and may be of benefit to men with retrograde ejaculation after retroperitoneal surgery
        • Common oral treatment with α agonists involves 60 mg of pseudoephedrine given orally 4 times a day for two days prior to production of a sample.

Orgasm

• Orgasm is the result of cerebral processing of pudendal nerve sensory stimuli resulting from increased pressure in the posterior urethra, sensory stimuli arising from the verumontanum, and contraction of the urethral bulb and accessory sexual organs.

Ejaculatory reflex

• Involves central serotonergic and dopaminergic neurons, with secondary involvement of cholinergic, adrenergic, oxytocinergic, and γ-aminobutyric acid (GABA) neurons. Many neurotransmitters are involved in the control of ejaculation, however, dopamine and serotonin have emerged as essential neurochemical factors.
  • Dopamine promotes seminal emission/ejaculation via D2 receptors
  • Serotonin is inhibitory
    • Stimulation of the 5-HT2C receptor with 5-HT2C agonists results in delay of ejaculation in male rats, whereas stimulation of postsynaptic 5-HT1A receptors results in shortening of ejaculation latency, leading to the hypothesis that men with PE may have hyposensitivity of 5-HT2C and/or hypersensitivity of the 5-HT1A receptor

Spinal Cord Injury

Spinal Cord Injury Level	Ejaculation Potential	Notes
Above T12	No	May experience reflex ejaculation during other activities
T12-L1	Possible	May require manual or vibratory stimulation, potential for retrograde ejaculation
L2-L4	Likely	Reflex ejaculation with stimulation, possible normal antegrade ejaculate
Sacral (S1-S5)	High	Reflex ejaculation with stimulation, often normal antegrade ejaculate and erectile function

Premature Ejaculation

Definition

• ISSM Committee for the Definition of Premature Ejaculation (2013) defined PE (lifelong and acquired PE) as a male sexual dysfunction characterized by the following (3):
  1. Ejaculation that always or nearly always occurs before or within ≈1 minute of vaginal penetration (lifelong PE) or a clinically significant and bothersome reduction in latency time, often to ≈3 minutes or less (acquired PE) AND
  2. The inability to delay ejaculation on all or nearly all vaginal penetrations AND
  3. Negative personal consequences, such as distress, bother, frustration, and/or the avoidance of sexual intimacy

Classification (4):

1. Lifelong: characterized by a cluster of core symptoms, including early ejaculation at nearly every intercourse within 30-60 seconds in the majority of cases (80%) or between 1-2 minutes (20%), with every or nearly every sexual partner and from the first sexual encounters onward
2. Acquired: men develop early ejaculation at some point in their life, which is often situational, having previously had normal ejaculation experiences
3. Variable: occasionally experience an early ejaculation; should not be regarded as a disorder, but as a natural variation of the ejaculation time in men
4. Subjective: patients report premature ejaculation but actually have normal or even extended ejaculation time

Epidemiology

• Most common sexual dysfunction in males aged 18-59 years
• Prevalence difficult to characterize given varying definitions
  • One study reported overall PE prevalence as 19.8% comprising (most common to least common):
    • Variable PE (8.5%)
    • Subjective PE (5.1%)
    • Acquired PE (3.9%)
    • Lifelong PE (2.3%)
• ≈2.5% in general population of intravaginal ejaculation latency time (IELT) ≤1 minute, a substantially higher percentage of men with normal IELT report premature ejaculation
  • Distribution of the IELT is positively skewed, with a median of 5.4 minutes (range 0.55-44.1 minutes), decreases with age, varies across countries
    • 21-23 minutes represents about 2 standard deviations above the mean
  • IELT is lower in men with lifelong PE compared with acquired PE and highest in men with subjective PE.

Causes

• Lifelong: in some men, neurobiologic and genetic variations could contribute to the pathophysiology of lifelong PE
• Acquired:
  1. Sexual performance anxiety: anxiety activates the sympathetic nervous system and reduces the ejaculatory threshold
  2. Psychological or relationship problems
  3. Erectile dysfunction: as many as half of subjects with ED also experience PE
  4. Prostatitis/CPPS: PE can be the main sexual disorder symptom in men with chronic prostatitis or CPPS
  5. Hyperthyroidism
  6. Withdrawal/detoxification from prescribed or recreational drugs

Diagnosis and Evaluation

• Inclusion of the partner in the evaluation and management process is important but not mandatory
• PE is associated with negative psychological consequences, including distress, bother, and frustration that may affect quality of life, partner relationships, self-esteem, and self-confidence and can act as an obstacle to single men forming new partner relationships

History and Physical Exam

• History (medical and sexual)
  • Recommended questions (related to definition above):
    • What is the time between penetration and ejaculation?
      • Self-estimation by the patient and partner of IELT should be used; studies have indicated that patient or partner self-report of ejaculatory latency correlate relatively well with objective stopwatch latency and might be useful as a proxy measure of IELT
    • Can you delay ejaculation?
    • Do you feel bothered, annoyed, and/or frustrated by your PE?
  • Optional questions:
    • Differentiate Lifelong and Acquired PE
      • When did you first experience PE? Have you experienced PE since your first sexual experience on every/almost every attempt and with every partner?
    • Assess Erectile Function
      • Is your erection hard enough to penetrate? Do you have difficulty in maintaining your erection until you ejaculate during intercourse? Do you ever rush intercourse to prevent loss of your erection?
    • Assess Relationship Impact
      • How upset is your partner with your PE? Does your partner avoid sexual intercourse? Is your PE affecting your overall relationship?
    • Previous Treatment of PE
    • Impact on Quality of Life
      • Do you avoid sexual intercourse because of embarrassment? Do you feel anxious, depressed, or embarrassed because of your PE?
• Physical exam
  • Screen for cardiovascular and gender-specific diseases
  • In men with acquired PE, a physical examination is mandatory in an effort to identify the cause of the PE and to alleviate its possible cause
  • Digital rectal examination, routine in an andrologic setting for all men age ≥ 40 years, is useful in identifying possible evidence of prostatic inflammation or infection.

Other

Questionnaires

• Standardized assessment measures such as validated questionnaires (Premature Ejaculation Profile (PEP) and the Index of Premature Ejaculation (IPE)) and PRO measures can be used as an adjunct to a full medical and sexual history and self-estimation of ejaculatory latency in the evaluation of males presenting with self-reported PE. These measures are all relatively new and were developed primarily for use as research tools.

Assessment of erectile function

• Possible comorbid ED should be evaluated using a validated instrument such as the International Index of Erectile Function (IIEF) or the IIEF-5 (SHIM).
  • Normal erectile function should be defined as an IIEF Erectile Function Domain of ≥26 or IIEF-5 > 21

Management

• Patients with ED and premature ejaculation should have their ED addressed first.
• Based on subtype
  • Lifelong PE: pharmacotherapy alone or in combination with graded levels of patient and couple psychosexual therapy
  • Acquired PE: cause-specific treatment (e.g., psychosexual counseling or ED pharmacotherapy, alone or in combination with PE pharmacotherapy).
  • Variable PE or PE-like ejaculatory dysfunction: psychosexual education and graded patient and couple psychotherapy

First-line: Psychosexual therapy

• All men seeking treatment for PE should receive basic psychosexual education or coaching
• Most frequently used treatments are the squeeze or stop-start techniques
• At least moderately successful in alleviating the dysfunction in the short term, but long-term outcome data are limited and suggest a significant relapse rate

Second-line: Pharmacologic treatment

Options

• PASTA (5):

1. PDE5 inhibitors (only if comorbid erectile dysfunction)
2. Anesthetic, topical
3. Selective serotonin reuptake inhibitors (SSRIs)
4. Tramadol
5. Alpha-blockers

• All are considered off-label

Phosphodiesterase type 5 (PDE5) inhibitors

• In males with comorbid erectile dysfunction, erectile dysfunction pharmacotherapy alone or in combination with PE pharmacotherapy is recommended for the treatment of lifelong PE or acquired PE
• In males with normal erectile dysfunction and
  • Lifelong PE, PDE5 inhibitors (off-label on-demand or daily dosing) are not recommended
  • Acquired PE, most often secondary to comorbid ED, hyperthyroidism, chronic lower urogenital infection, prostatodynia, or CPPS, appropriate cause-specific treatment alone or in combination with an SSRI is recommended

Anesthetic, topical

• Efficacy
  • Moderately effective in delaying ejaculation
• Drugs and Dosages
  • Available as cream, gel, or spray
  • 2.5% lidocaine and/or 2.5% prilocaine

Selective serotonin reuptake inhibitors (SSRIs)

• Mechanism of Action: block pre-synaptic axonal reuptake of serotonin from the synaptic cleft of central serotonergic neurons by 5-HT transporters, resulting in enhanced 5-HT neurotransmission and stimulation of postsynaptic membrane 5-HT receptors.
• Ejaculation delay usually occurs within 5-10 days of starting treatment, but the full therapeutic effect may require 2-3 weeks of treatment and usually is sustained during long-term use.
• Drugs and Dosages
  • Daily dosing
    • Options: paroxetine, clomipramine, sertraline, fluoxetine, or citalopram.
      • Paroxetine
        • 10-40mg daily
        • Exerts the strongest ejaculation delay, increasing IELT approximately 8.8x over baseline
  • On-demand
    • Options: dapoxetine (not available in Canada) or off-label paroxetine, clomipramine, sertraline, and fluoxetine
      • On-demand administration 3-6 hours before intercourse is modestly efficacious and well tolerated but is associated with substantially less ejaculatory delay than daily treatment
• Adverse effects
  • Usually minor, start in the first week of treatment, and may gradually disappear within 2-3 weeks.
  • Includes
    • Fatigue
    • Yawning
    • Mild nausea
    • Diarrhea
    • Perspiration
    • Hypomania
      • Can occur infrequently; treatment with SSRIs should be avoided in men with a history of bipolar depression
        • SSRIs are associated with a small increase in the risk for suicidal ideation or suicide attempts in youth but not adults.
          • Caution is suggested in prescribing SSRIs to young adolescents with PE age ≤ 18 years, and to males with PE and a comorbid depressive disorder, particularly when associated with suicidal ideation.
    • Upper GI bleeding
      • Platelet serotonin release has an important role in hemostasis and SSRIs, especially with concurrent use of aspirin and NSAIDs, may be associated with increased risk for upper GI bleeding
    • Priapism; rare adverse effect of SSRIs
    • Weight gain and increased risk of type 2 diabetes associated with long-term SSRI use
    • Abnormal semen parameters
      • In males with normal semen parameters, paroxetine has been reported to induce abnormal sperm DNA fragmentation in a significant proportion of patients, without a measurable effect on other semen parameters.
        • Fertility potential of a substantial number of men on paroxetine may be adversely affected by these changes in sperm DNA integrity
• Patients should be advised to avoid sudden cessation or rapid dose reduction of daily dosed SSRIs, which may be associated with an SSRI withdrawal syndrome

Delayed ejaculation (DE), anejaculation, and anorgasmia

• Any psychological or medical disease or surgical procedure that interferes with either central control of ejaculation or the peripheral sympathetic nerve supply to the vas and bladder neck, the somatic efferent nerve supply to the pelvic floor, or the somatic afferent nerve supply to the penis can result in delayed ejaculation, anejaculation, retrograde ejaculation, and/or anorgasmia.
• Ejaculation is considered delayed in men with latency times >25-30 minutes who report distress or simply cease sexual activity because exhaustion or irritation
• Failure of ejaculation
  • Can be a lifelong problem (25%) or an acquired problem (75%)
  • Can be global and happen in every sexual encounter or be intermittent or situational
• DE is associated with high levels of relationship distress, sexual dissatisfaction, anxiety about their sexual performance, and general health issues

Causes of retrograde ejaculation, delayed ejaculation, anejaculation, and anorgasmia

• Psychogenic
  • Often described as inhibited ejaculation
  • Usually related to sexual performance anxiety; in some men, may be associated with orthodoxy of religious belief; guilt and anxiety about “spilling seed”
  • Disparity between the reality of sex with the partner and the sexual fantasy used during masturbation may inhibit sexual arousal and thus represent another contributor to DE
• Aging male
  • Degeneration of penile afferent nerves and Pacinian corpuscles
• Endocrine
  • Diabetes
  • Hypogonadism and low testosterone are associated with DE or anejaculation
  • Hypothyroidism is strongly associated with delayed ejaculation, hyperthyroidism is rarely associated with premature ejaculation
  • Hyperprolactinemia, via inhibition of hypothalamic GnRH is associated with low testosterone, reduced sexual desire, ED, and DE. The effect of prolactin on ejaculation is possibly mediated via its action on the serotinergic system
• Neurogenic
  • Radical prostatectomy, proctocolectomy, bilateral sympathectomy, abdominal aortic aneurysmectomy, para-aortic lymphadenectomy, radiotherapy, diabetic autonomic neuropathy, multiple sclerosis, spinal cord injury
  • After RP/RALP, men no longer ejaculate, but maintain a sense of orgasm
  • RPLND: anejaculation occurs in the majority of the patients in non–nerve-sparing techniques. With nerve sparing techniques, antegrade ejaculation is maintained in 80-100% of patients
    • The superior hypogastric plexus, a fenestrated network of fibers anterior of the lower abdominal aorta, is responsible for ejaculation and is mediated by the sympathetic system. The hypogastric nerves exit bilaterally at the inferior pole of the superior hypogastric plexus and have connections with the S1 to S2 roots. Normal emission requires integrity of this system. During RPLND, these nerves are difficult to recognize and might be damaged, resulting in decreased semen volume or dry ejaculation.
  • Radiotherapy: pathways for ejaculation are included in the RT fields for rectal and prostate carcinomas.
  • Stroke
  • Spinal cord injury:
    • Unlike erectile capacity, the ability to ejaculate increases with descending levels of spinal injury; < 5% of patients with complete upper motor neuron lesions retain the ability to ejaculate.
    • Several techniques for obtaining semen in men with SCI with ejaculatory dysfunction have been reported including vibratory stimulation and electroejaculation, both of which are associated with a significantly high risk of autonomic dysreflexia (see Surgery for Infertility Chapter Notes).
• Medication:
  • SSRIs, antipsychotics, tricyclic antidepressants, thiazide diuretics, α-Methyldopa, phenothiazine, alcohol abuse
    • 60% of patients on SSRIs report some form of treatment-related sexual dysfunction, most commonly ejaculatory dysfunction
    • Antipsychotics can cause either a direct and/or indirect dopamine antagonism or increased prolactin levels and are commonly associated with DE and retrograde ejaculation.
    • Retrograde ejaculation associated with antipsychotics is thought to be due to antagonistic effects on the α-adrenergic system at the level of the bladder neck
• Anatomic
  • Transurethral resection of prostate, bladder neck incision
    • TURP carries a high incidence of retrograde ejaculation
• Congenital
  • Müllerian duct cyst, Wolffian duct abnormality, Prune belly syndrome
• Infection (causing obstruction)
  • Urethritis, genitourinary tuberculosis, schistosomiasis
  • Sexually transmissible infections such as gonorrhea or nonspecific urethritis can produce cicatrization and obstruction anywhere in the male reproductive tract, especially if treatment is delayed.
  • Urinary infection, especially if complicated by epididymitis, also can produce obstruction that may be situated at the ejaculatory duct level.

Diagnosis and Evaluation

• History and Physical Exam
  • Assessment begins by determining whether DE is lifelong or acquired, global or situational
• Labs: serum testosterone
• Any additional investigations suggested by the above findings.

Management

• Treatment may include patient/couple psychoeducation and/or psychosexual therapy, lifestyle changes, pharmacotherapy, or integrated treatment
• Psychological strategies
  • If organic and pharmacologic causes have been eliminated, referral to an expert psychosexual therapist is usually indicated to evaluate the causative psychological and behavioral issues.
• Lifestyle changes
  • Changes include enjoying more time together to achieve greater intimacy, minimizing alcohol consumption, having sex when not tired, and practicing techniques that maximize penile stimulation such as pelvic floor training
• Pharmacotherapy
  • Options include pseudophedrine (alpha-agnonist), reboxetine (SNRI), carbegoline, amantadine, oxytocin, burpropion, buspirone, and cyrohetadine.
    • These drugs facilitate ejaculation by either a central dopaminergic, antiserotonergic, or oxytocinergic mechanism of action or a peripheral adrenergic mechanism of action. However, no drugs have been approved by regulatory agencies for this purpose and most drugs that have been identified for potential use have limited efficacy, impart significant side effects, or are as yet considered experimental in nature.
  • Results are relatively poor in men with psychogenic DE and neuropathic DE.

Retrograde ejaculation

Risk factors

• Surgical procedures that compromise the bladder neck closure mechanism, such as TURP
• Diabetes

Diagnosis and Evaluation

• Retrograde ejaculation and failure of emission can be distinguished by examination of a post-masturbatory specimen of urine for the presence of spermatozoa and fructose.

Management

• Pharmacological
  • Options
    • α-agonists (pseudophedrine, ephedrine, midodrine)
      • α-adrenergic sympathetic nerves mediate both bladder neck closure and emission
    • Imipramine
    • Phenylpropanolamine (selective norepinephrine releasing agent)

Painful ejaculation

Risk factors

• Urethritis, BPH, acute or chronic prostatitis, CPPS, seminal vesiculitis, seminal vesicular calculi, or ejaculatory duct obstruction

Treatment

• Based on underlying cause

Post-orgasmic illness syndrome (POIS)

• Collection of symptoms that include severe myalgia and fatigue associated with a flu-like state that occurs within 30 minutes of orgasm
• Symptoms commence within 30 minutes of ejaculation in 87% of men and increase in intensity to a peak on day 2.
• A type 1 hypersensitivity immunogenic reaction has been proposed as the underlying mechanism.
• A prolonged hyposensitization program with multiple subcutaneous injections of autologous semen has been suggested as a possible treatment

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 29