Mens Health Lecture Flashcards
Leydig cells
- Adjacent to tubules, androgen secretion
- LH targets Leydig cells stimulating testosterone secretion
- Testosterone moves into tubule lumen
Sertoli cells
- Form part of the tubules, tight junctions between cells (blood testis barrier)
- Role in development of spermatocytes
- FSH targets sertoli cells and spermatogonia directly
- If damaged due to an autoimmune attack -infertility can result
Testosterone Targets
- Developing gametes
- Muscle
- Primary & Secondary sexual characters
- The brain
function of testis with seminiferous tubules
sperm production
function of collecting ducts
transport and storage
function of epididymis
transport, maturation and ejaculation
function of sperm duct (vas deferns)
transport and ejaculation
function of seminal vesicles
secrete thick liquid to transport sperm
function of prostate gland
secretes thin alkaline solution to neutralise urine and female system
function of cowpers gland
secretions may lubricate, flush out urine or form a gelatinous plug
function of urethra
passage for urine and sperm
function of penis
copulation
Haemodynamics of Erection and Detumescence
In flaccid penis, smooth muscle of arteriolar and arterial walls tonically contracted allowing a small amount of blood flow for homeostatic purposes (pressure = 35 mmHg)
- Upon stimulation, smooth muscles of cavernous arteries relax, causing dilation. Corporal tissues become engorged with blood
- Engorgement causes corporal tissue to swell, erecting the penis (fullerection phase - pressure = 90-100 mmHg)
- Engorged corporal tissue compresses penile veins and venules behind tunica albuginea, preventing outflow of blood leading to
a) increased cavernosal pressure
b) increased pressure in corpus spongiosum
c) maintained erection (rigiderection phase - pressure
»100 mmHg)
How does sexual stimulation lead to erection?
- Central neural activation
- Perceptual/cognitive – is the stimulus attractive/arousing
- Emotional/motivational – Is this an appropriate time to be aroused?
- Physiological – switch on the machinery (autonomic outflow)
Nerves innervating the penis
• Sympathetic, parasympathetic, somatic and sensory innervation
• Activation of penile mechanoreceptors can initiate
erection via a spinal reflex (e.g. in spinal-cord injury) but this is not usually sustained
• Balance between contractant and relaxant transmitters
Causes of Male Erectile Dysfunction – 1 – Failure to initiate
• Psychogenic
– Often exaggerated inhibitory responses
» Psychotherapy can be helpful
– Excessive sympathetic outflow also inhibitory
» May explain role of stress as a risk-factor for ED
• Neurogenic
– Nerve damage in brain, spinal cord or nerves innervating penis
» Pathologic processes in brain (e.g. Parkinson’s Disease)
» Spinal cord injury
» Iatrogenic damage (e.g. in radical prostate surgery)
» Idiopathic (nerve damage of unknown cause)
Causes of Male Erectile Dysfunction – 2 - Failure to Fill & Store
• Arteriogenic causes
– Atherosclerotic processes reduce arterial flow and perfusion pressure in cavernous sinusoids
– Insufficient penile engorgement to reach full-erection phase, and therefore to initiate rigid-erection phase
– Risk factors for atherosclerosis (e.g. hypertension, hyperlipidemia, smoking, diabetes) are risk factors for ED
– Mechanisms
» Reduced elasticity of vessel walls in sinusoids
» Increased vasoconstriction
» Impaired endothelial NO
• Venogenic
– Failure of adequate venous occlusion following cavernosal engorgement prevents transition to rigid-erection phase, and reduces maintenance of erection
Treatment of Male Erectile Dysfunction 1 – Prostaglandin E1
• Alprostadil - Intracavernosal injection (Caverject/Viridal) or urethral suppository (Muse) (LOCAL APPLICATION)
– Only available on NHS prescription under special circumstances
• PK – low systemic exposure due to local administration
– Intraurethral drug absorbed into corpus spongiosum and thence to CC
• ADR – Priapism, deformation of penis;
– Counselling - condom should be used if partner pregnant (suppository only) – Why?
• Side effects include hypotension, anticoagulant effects, penile and other localised pain
• Interactions – potential for enhance hypotensive effects with antihypertensive drugs, although systemic exposure low
• Alprostadil should first be administered under supervision, which gives opportunity to monitor hypotensive side effects
Treatment of Male Erectile Dysfunction 2 – Phosphodiesterase 5 inhibitors
- Sildenafil (Viagra), Vardenafil (Levitra) and Tadalafil (Cialis)
- PK – Major metabolism by Cyp3A4 for all three drugs; Tadalafil has longer half life, and can be taken as once-daily dose rather than “as required”
- Contraindicated for patients taking nitrates or with a history of nonarteritic anterior ischaemic optic neuropathy; or in whom vasodilation is inadvisable; Use with caution in cardiovascular disease and those taking antiarrhythmics and alpha-blockers
- Interactions – potent CYP3A4 inhibitors can cause >5-fold increase in AUC, hence can cause a large increase in the exposure to the PDE5 inhibitor.
Erectile Dysfunction Summary
• Many potential underlying causes of erectile dysfunction
– Caused by problems in different parts of the very specific pathway controlling penile erections
• Specificity comes largely from activation of specific neuronal pathways rather than “neurochemical” specificity
– Limits choice of drug targets
• Specificity achieved by two approaches
– Pharmacological approaches - Identify those pathways which are most specific to penis (i.e. NO-cGMP pathway)
– Pharmaceutical approaches – Identify means to limit exposure of other organs (i.e. short half-life & local administration of PGE1 agonists)
BPH and LUTS – not one and the same
• BPH = Benign Prostatic Hyperplasia
– Histologic: stromoglandular hyperplasia1
• May be associated with
– Clinical: presence of bothersome LUTS2
– Anatomic: enlargement of the gland (BPE = Benign
Prostatic Enlargement)2
– Pathophysiologic: compression of urethra and compromise of urinary flow (BOO = Bladder Outlet Obstruction)2
• LUTS = lower urinary tract symptoms
Goals of Therapy for BPH
BPH Treatment Success measured by:
• ↓ symptoms (Questionnaire-based)
• ↓ bother (bother score) and ↑ QOL (quality of life)
• ↓ prostate size or arrest further growth
• ↑Increase in peak flow rate / Relieve obstruction
• Prevention of long-term outcomes/complications
• Acceptable adverse events profile
a1-adrenergic blockers
• Relax smooth muscle in the prostate producing an increase in urinary flow rate; no effect on prostate size
- Alfuzosin, Doxazosin, Indoramin, Pazosin, Tamsulosin and Terazosin
- PK - well absorbed after oral administration; extensive hepatic metabolism. T1/2: <3hrs - indoramin and prazosin; ~10hrs – alfuzosin, terazosin, and tamsulosin; >20hrs – doxazosin
- Contraindicated in patients with history of postural hypotension and micturition syncope; use with caution in patients receiving antihypertensives
- Side effects include drowsiness, hypotension, and syncope (fainting)
5 a-reductase inhibitors
• Prevent conversion of circulating testosterone to more potent dihydrotestosterone (prostate growth is driven by androgens)
- Dutasteride and Finasteride
- PK - well absorbed after oral administration; extensive hepatic metabolism. T1/2: 5 weeks (Dutasteride); 6 hours (Finasteride)
- Onset of benefits slow – months for reduction in prostate size and symptom relief
- Women of childbearing potential should avoid handling these medicines, and use of a condom is recommended if partner likely to become pregnant (potential birth defects)
- Side effects include reduced libido. Impotence and breast tenderness and enlargement (lack of testosterone).
Treatment of BPH
5a-Reductase Inhibitors: Arrest Disease Progression
Alpha Blockers: Relieve Symptoms Rapidly
Combination Therapy: Arrest Disease Progression and Rapidly Relieve Symptoms
