Mens Health Lecture

Question 1

Leydig cells

Answer 1

• Adjacent to tubules, androgen secretion
• LH targets Leydig cells stimulating testosterone secretion
• Testosterone moves into tubule lumen

Question 2

Sertoli cells

Answer 2

• 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

Question 3

Testosterone Targets

Answer 3

• Developing gametes
• Muscle
• Primary & Secondary sexual characters
• The brain

Question 4

function of testis with seminiferous tubules

Answer 4

sperm production

Question 5

function of collecting ducts

Answer 5

transport and storage

Question 6

function of epididymis

Answer 6

transport, maturation and ejaculation

Question 7

function of sperm duct (vas deferns)

Answer 7

transport and ejaculation

Question 8

function of seminal vesicles

Answer 8

secrete thick liquid to transport sperm

Question 9

function of prostate gland

Answer 9

secretes thin alkaline solution to neutralise urine and female system

Question 10

function of cowpers gland

Answer 10

secretions may lubricate, flush out urine or form a gelatinous plug

Question 11

function of urethra

Answer 11

passage for urine and sperm

Question 12

function of penis

Answer 12

copulation

Question 13

Haemodynamics of Erection and Detumescence

Answer 13

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)

1. Upon stimulation, smooth muscles of cavernous arteries relax, causing dilation. Corporal tissues become engorged with blood
2. Engorgement causes corporal tissue to swell, erecting the penis (fullerection phase - pressure = 90-100 mmHg)
3. 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)

Question 14

How does sexual stimulation lead to erection?

Answer 14

• 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

Question 15

Causes of Male Erectile Dysfunction – 1 – Failure to initiate

Answer 15

• 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)

Question 16

Causes of Male Erectile Dysfunction – 2 - Failure to Fill & Store

Answer 16

• 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

Question 17

Treatment of Male Erectile Dysfunction 1 – Prostaglandin E1

Answer 17

• 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

Question 18

Treatment of Male Erectile Dysfunction 2 – Phosphodiesterase 5 inhibitors

Answer 18

• 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.

Question 19

Erectile Dysfunction Summary

Answer 19

• 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)

Question 20

BPH and LUTS – not one and the same

Answer 20

• 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

Question 21

Goals of Therapy for BPH

Answer 21

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

Question 22

a1-adrenergic blockers

Answer 22

• 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)

Question 23

5 a-reductase inhibitors

Answer 23

• 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).

Question 24

Treatment of BPH

Answer 24

5a-Reductase Inhibitors: Arrest Disease Progression

Alpha Blockers: Relieve Symptoms Rapidly

Combination Therapy: Arrest Disease Progression and Rapidly Relieve Symptoms