שפיכה מהירה

1. שפיכה מהירה ד"ר נעם כתרי המחלקה לאורולוגיה המרכז הרפואי ע"ש שיבא, תל-השומר

2. Premature Ejaculation • Premature, early or rapid ejaculation • PE is the most common male sexual disorder. 9-31 % of the male population.

3. Definition • (DSM-IV) : “Persistent or recurrent ejaculation with minimal sexual stimulation before, on or shortly after penetration and before the person wishes it” associated with “marked distress or interpersonal difficulty”. • (ICD-10) : “An inability to delay ejaculation sufficiently to enjoy lovemaking, manifest as either of the following: occurrence of ejaculation before or very soon after the beginning of intercourse (if a time limit is required: before or within 15 sec of the beginning of intercourse); occurrence of ejaculation in the absence of sufficient erection to make intercourse possible. The problem is not the result of prolonged absence from sexual activity”. IVELT (stopwatch / estimation) < 15s < 1m < 2m Three essential criteria short ejaculatory latency lack of control sexual dissatisfaction

4. Etiology Psychogenic Anxiety Early sexual experience Infrequent sexual intercourse Poor ejaculatory control techniques Evolutional Psychodynamic Biogenic Penile hypersensitivity Hyperexcitable ejaculatory reflex Hyperarousability Endocrinopathy Genetic predisposition 5-HT receptor dysfunction Campbell-Walsh Urology, 9th edition, 2007

5. Etiology • Lower biothesiometric vibration perception thresholds • Shorter somatosensory evoked potential latency times of the penis Xin et al. 1996, 1997 • No significant difference from controls Paick et al. 1998, Rowland 1993

6. Etiology • Higher amplitude of cortical somatosensory evoked potentials in response to penile electrostimulation Fanciullacci et al. 1988 • Larger cortical distribution of the dorsal nerve of penis Yang & Bradley 1998 • Hyposensitivity of 5-HT2c / Hypersensitivity of 5-HT1a receptors Waldinger et al. 1998

7. Physiology of ejaculation • Highly coordinated physiological process controlled by sympathetic, parasympathetic and somatic nervous systems Sympathetic Parasympathetic Somatic • expulsion • emission

8. The emission phase • The ejection of spermatozoa into the posterior urethra with secretions of accessory sexual glands • Organs of emission: • Epididymis (<1%) • vasa deferentia • seminal vesicles (50-80%) • prostate gland (15-30%) • Bulbourethral (Cowper’s) Glands Mann et al. 1981

9. The emission phase • sympathetic • parasympathetic • Contraction of the seminal tract from the epididymis to the prostate • Closure of the bladder neck • Secretion of seminal fluids from the accessory sex glands

10. The expulsion phase The ejection of sperm out of the urethral meatus • sympathetic • somatic • Closure of the bladder neck • External sphincter relaxation • Contraction of pelvic floor • Bulbospongiosus m. • Ischiocavernosus m. • Levator ani m.

11. Neuroanatomy of Ejaculation

12. T10-L2 Hypogastric n. Afferents S2-S4 Bladder neck Pudendal n. Afferents Ext sphincter Bulbospongiosus

13. T10-L2 DCN IML Hypogastric n. S2-S4 Bladder neck Ext sphincter IML Pelvic n. Bulbospongiosus SV and vas deferens Pelvic plexus

14. T10-L2 S2-S4 Bladder neck Ext sphincter Onuf n. Bulbospongiosus SV and vas deferens Pudendal n.

15. Spinal control of ejaculation • Ejaculation is a spinal reflex • paraplegic humans • able to ejaculate • animals with spinal cord lesion Thoracolumbar Sympathetic Nuclei Spinal Control center Sacral Parasympathetic Nuclei Peripheral Stimuli Somatic (Onuf’s nucleus)

16. Spinal control of ejaculation • Lumbar Spinothalamic (LSt) • group of interneurons • located in the central gray of L3-L4 • critical part of the ejaculation center • lesions of the LSt in male rats completely ablate ejaculation w/o effect on other sexual aspects LSt

17. Cerebral inputs LSt Peripheral inputs sensory afferents from pudendal n. terminate closely to LSt (McKenna et al. 1986) Sympathetic centres (DGC, IML) T12-L1 L3-L4 HN PN BS motoneurones (Onuf’s nucleus) Parasympathetic centre (SPN) PP L5-S3 Seminal tract PudN BS muscle Adapted from Giuliano et al. 2006

18. Cerebral inputs LSt Peripheral inputs projections of LSt cells to sympathetic & parasympathetic nuclei (Truit et al. 2002) projections of LSt fibers to sympathetic & parasympathetic nuclei (Truit et al. 2002) Sympathetic centres (DGC, IML) T12-L1 L3-L4 HN PN BS motoneurones (Onuf’s nucleus) Parasympathetic centre (SPN) PP L5-S3 Seminal tract PudN BS muscle Adapted from Giuliano et al. 2006

19. Cerebral inputs LSt Peripheral inputs projections of LSt cells to Onuf’s n. (Xu et al. 2005) Sympathetic centres (DGC, IML) T12-L1 L3-L4 HN PN BS motoneurones (Onuf’s nucleus) Parasympathetic centre (SPN) PP L5-S3 Seminal tract PudN BS muscle Adapted from Giuliano et al. 2006

20. Cerebral inputs LSt Peripheral inputs projections of LSt cells to thalamus – parvocellular subparafascicular n. (SPFp) (Coolen et al. 2003) Thalamus Sympathetic centres (DGC, IML) T12-L1 L3-L4 HN PN BS motoneurones (Onuf’s nucleus) Parasympathetic centre (SPN) PP L5-S3 Seminal tract PudN BS muscle Adapted from Giuliano et al. 2006

21. Cerebral control of ejaculation McKenna et al.

22. Cerebral control of ejaculation

23. Cortex Adapted from Giuliano et al. 2006 SPFp Thalamus Hypothalamus MeApd MPOA BNSTpm PNpd PVN Brain Stem PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

24. Cortex • Expression of Fos protein during ejaculation • (Hamson et al. 2004, Heeb et al. 2001) • Reciprocal connections prooved in anatomical and functional studies • (Coolen et al. 1998, Heeb et al. 2001) SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

25. Cortex • Pivotal role of MPOA • Increased Activity during copulation and ejaculation • electrophysiological studies • (Shimura et al. 1994) • Fos protein immunoreactivity studies • (Baum et al. 1992) • Abolishment of ejaculation after lesion • (Arendash et al. 1983) • Elicitation of ejaculation after chemical stimulation • Apomorphine (Pehek et al. 1989) • Quinelorane (Hull et al. 1992) SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

26. Cortex • Pivotal role of MPOA • Elicitation of ejaculation after electrical stimulation • (Larsson et al. 1970, Malsburyet al. 1972, Marson et al. 1994) • Connection to spinal centers has not been found SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

27. Cortex • MPOA projections to: • PVN - paraventricular hypothalamic n. • (Simerly et al. 1988) • PAG - periaquaductal grey • (Rizvi et al. 1992) • nPGi – paragigantocellular n. • (Murphy et al. 1999) SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

28. Cortex • PVN • Key site for neuroendocrine function • Bilateral lesions of PVN impairs ejaculation • (Ackerman et al. 1997) • Projections to autonomic nuclei in lumbosacral segments • (Saper et al. 1976, Luiten et al. 1985) • Projections to pudendal motoneurons • (McKenna et al. 1986) SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

29. Cortex • SPFp • Anatomic connection (by axonal tracing studies) • to BNST and MeA • (Johnson et al. 1991, Canteras et al. 1995) • to MPOA and LSt • (Coolen et al. 2003) • No functional investigation SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

30. Cortex • nPGi • Strong inhibitory effect on ejaculation • (Marson et al. 1990, 1992) • Projections to lumbosacral segments • (Marson et al. 1992, 1996) • PAG • relay between MPOA and nPGi • (Coolen et al. 1992, Murphy et al. 2001) SPFp MeApd MPOA BNSTpm PNpd PVN PAG nPGi Sensory Input LSt Onuf’s n. Sacral Autonomic Centers

31. Neurochemistry of Ejaculation • Very complex – many neurotransmitters play different roles in different sites • Several receptors with opposite effect • serotonin (5-HT) • dopamine (DA) • adrenaline • Acetyl Choline • NANC (Oxytocine, ATP, NPY, VIP, NO, SP, Enkephalin, etc.)

32. 5-HT & Ejaculation • Over 20 years of experience with crSSRI for depression and anxiety disorders • Up to 19% of ejaculation side effects (delayed ejaculation or anejaculation) • PE side-effect after 1-2 weeks of daily use • Other side effects: fatigue, decreased libido • Rebound rapid ejaculation in withdrawal Clinical Experience Lab

33. 5-HT & Ejaculation “off-label” use for treatment of PE (Mechanism ?)

34. 5-HT & Ejaculation • Overall inhibitory effect on ejaculation • 15 5-HT receptor subtypes in 7 subgroups: • All are postsynaptic. Only 5-HT1 subtype (5-HT1A and 5-HT1B) are presynaptic as well • 5-HT1A, 5-HT1B,5-HT2C are related to ejaculation • 5-HT1A autoreceptors proejaculatory • 5-HT1B autoreceptors inhibitory • 5-HT2C heteroreceptors inhibitory

35. 5-HT & Ejaculation • 5-HT in high concentration in MPOA, PAG, nPGi and in lumbosacral spinal cord • Most neurons descending from nPGi to spinal cord are serotoninergic • 5-HT receptors are abundant in the vas deferens and seminal vesicles

36. 5-HT & Ejaculation • Trying to prescribe conventional SSRI “on demand”: • Paroxetine ~5 hours before intercourse • 30 pts • Mean IELT ~ 20 sec →36 sec Vs. • Paroxetine daily for six weeks • Mean IELT ~ 20 sec →146 sec (Waldinger et al., 2004) Disappointing 

37. 5-HT & Ejaculation • Dapoxetine (Short acting SSRI) • Peak plasma levels within 60 min, short half life • Dapoxetine 30 mg / 60 mg / placebo • “on demand” for 3 months • ~600 pts in each group • Efficient IELT x 2-3 (60 mg > 30 mg) • Safe: Nausea, Dizziness, Headache, Diarrhea < 10% (Pryor et al., The Lancet, 2006)

38. 5-HT & Ejaculation • How they work ? • Speculation: Rapid absorption → abrupt increase in extracellular 5-HT overwhelms the autoregulation mechanism • Lots of other affinities • α1A adrenoreceptor agonist • D1 receptor agonist • 5-HT2B receptor agonist • Histamine 1 & 2 receptor agonist

39. 5-HT & Ejaculation • Future directions: • 5-HT1A antagonists • Postsynaptic 5-HT2C / 5-HT1B / 5-HT7 agonists

40. Dopamine & Ejaculation • Aphrodisiac effect of L-DOPA in Parkinsonian pts. (1970s) • DA plays important role in sexual behavior from motivation to performance • Nigrostriatal dopaminergic system – motor aspects of copulation • Mesolimbic dopaminergic system – appetitive behavior and motivation • Incerto-thalamic dopaminergic system – erection and ejaculation

41. Dopamine & Ejaculation • 5 subclasses of receptors • D1-like receptors (stimulation of adenylate cyclase) • D1 • D5 • D2-like receptors (inhibition of adenylate cyclase) • D2 • D3 • D4

42. Dopamine & Ejaculation • Increased DA release in the MPOA in rats during copulation with a peak in ejaculation • The trigger or the result ? (Hull et al. 1995)

43. Dopamine & Ejaculation • Systemically delivered • Apomorphine & L-DOPA (Nonselective DA agonists) → proejaculatory (Paglietti et al. 1978) • Haloperidol (central nonselective DA antagonist) → inhibition of copulation and ejaculation (Pfaus et al. 1989) • D2-like receptor agonists (quinelorane, SND-919) → proejaculatory, reduce ejaculatory latency (Giuliani et al. 1996) • D3 receptor selective agonist (7-OH-DPAT) → proejaculatory, reduce ejaculatory latency and No. of intromissions (Ahlenius et al. 1995, Ferrari et al. 1996)

44. Dopamine & Ejaculation • ICV delivered • D2-like receptor agonist (quinelorane) → BS mm contractions (Clément et al. 2005) • Effect reversed with D2-like receptor antagonists (spiperone, raclopride) (Clément et al. 2005)

45. Dopamine & Ejaculation • Microinjection to MPOA • Apomorphine (nonselective DA agonist) • → increased no. of ejaculations (proejaculatory) (Hull et al. 1986, Scaletta et al. 1990) • Low dose → proerectile & procopulatory – blocked by selective D1-like antagonist (Hull et al. 1992) • High dose → proejaculatory – blocked by selective D2-like antagonist (Hull et al. 1992)

46. Dopamine & Ejaculation • Microinjection to PVN • Quinelorane (D2-like receptor agonist) • Low dose → proerectile • High dose → proejaculatory & inhibition of erection • + D1-like receptor antagonist → enhancement of proejaculatory effect (Eaton et al. 1991)

47. Dopamine & Ejaculation Hypothesis: Evolution of dopamine stimulation through copulation Proerectile D1 mediated Proejaculatory D2/3 mediated

48. Microinjection of the preferential dopamine receptor D3 agonist 7-OH-DPAT into the hypothalamic medial preoptic area induced ejaculation in anesthetized rats • Noam D. Kitrey (1,2), Pierre Clément (2), Jacques Bernabé (2), Laurent Alexandre (2), François Giuliano (2)(3) • Department of Urology, Sheba Medical Center, Tel-Hashomer, ISRAEL • Pelvipharm Laboratories, Centre National de la Recherche Scientifique, FRANCE • AP-HP, Neuro-Uro-Andrology, Department of Physical Medicine and Rehabilitation, Raymond Poincaré Hospital, FRANCE

49. תודות האיגוד האורולוגי הישראלי החברה הישראלית להפרעות בתפקוד מיני חברת פייזר - ישראל