Men’s Health Pharmacology

What is a diagram showing anatomy of the male reproduction system?

What are Leydig cells?

Adjacent to tubules

What are Leydig cells responsible for?

Androgen secretion, LH also targets cells and stimulates testosterone secretion

Where does testosterone go after secreted from Leydig cells?

Moves into tubule lumen 

What are Sertoli cells?

Form part of the tubules, tight junctions between cells in blood testis barrier

What is the role of Sertoli cells?

Developing spermatocytes, FSH targets Sertoli cells and spermatogonia

What can happen if the blood testis barrier is damaged?

Autoimmune attack can occur directed at the sperm, infertility can be the result 

What is a diagram showing Leydig cells and Sertoli cells?

What are the main testosterone targets?

• Developing gametes

• Muscle

• Primary and secondary sexual characters

• The brain

What is a diagram showing the pituitary testis axis?

• Hypothalamus releases GnRH

• Acts on gonadotrophs in anterior pituitary 

• Negative feedback initiates from Sertoli cells where they release inhibin - inhibits FSH secretion by AP

• Testosterone inhibits GnRH secretion by hypothalamus and decreases pituitary sensitivity to GnRH

What does FSH produce when acting on Sertoli cells?

Inhibin and ABP (androgen binding protein)

Why are ABPs needed?

Allows androgens to bind as they are not soluble enough to cross membranes

What can testosterone be converted to?

DHT 

Why is DHT preferred over testosterone?

10x higher efficacy than testosterone

What is a diagram showing anatomy of the male reproduction system highlighting ED and BPH?

How do the haemodynamics of an erection work?

• Flaccid penis - smooth muscle is contracted of arteriolar and arterial walls an allows a small amount of blood flow

• When stimulated - smooth muscles of cavernous arteries relax and causes dilation - corporal tissues become engorged with blood 

• Engorgement causes corporal tissues to swell and erects the penis - pressure 90-100mmHg 

• Engorged corporal tissue compressses veins and venules and prevents blood outflow 

What is the result of the engorged corporal tissue from an erection on pressure?

Increased cavemosal pressure, increased pressure in corpus spongiosum and maintains erection

How does stimulation lead to erection in central neural activation?

Perceptual/cognitive = stimulus arousing, emotional/motivation - appropriate time for arousal? Physiological leafdds to switch on machinery/autonomic outflow

What nerves innervate the penis?

Sympathetic, parasympathetic - somatic and sensory innervation

How do receptors activate the penis from stimulation?

Penile mechanoreceptors activated, initiates erection via a spinal reflex but not usually sustained and instead balanced between contractant and relaxant transmitters

How does smooth muscle contraction work before an erection?

• norepinephrine acts on the smooth muscle cell

• Adenyl cyclase is activated which decreases cAMP level

• Phospholipase C increases IP3 and increases calcium release which leads to myosin chain phosphorylation and smooth muscle contraction

How does smooth muscle relaxation work to cause an erection?

• Acetylcholine decreases sympathetic activation

• AcH works on eNOS, which sends nitric oxide to the cell

• This activates guanyl cyclase which works to decrease Calcium

• Prostaglandin e1, at the same time, acts on adenylyl cyclase to increase cAMP

What can the causes of male erectile dysfunction be?

• Psychogenic - exaggerated inhibitory responses or excessive sympathetic outflow

• Neurogenic - nerve damage in brain, spinal cord or nerves innervating penis e.g., spinal cord injury, Parkinson’s, iatrogenic damage

• Arteriogenic causes

• Venogenic changes

What subcategory of ED are psychogenic and neurogenic?

Failure to initiate

What subcategory of ED causes are arteriogenic and venogenic?

Failure to fill and store

What are the 2 classes for reasons for ED?

• Failure to initiate 

• Failure to fill and store 

What are the risk factors for ED and also atherosclerosis?

Hypertension, hyperlipidemia, smoking, diabetes are all risk factors for atherosclerosis and ED

What are arteriogenic causes of ED?

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

What is the mechanism for how arteriogenic causes cause ED?

Reduced elasticity of vessel walls in sinusoids, increased vasoconstriction, impaired endothelial NO

What are venogenic causes for ED?

Failure of adequate venous occlusion following cavernosal engorgement - prevents transition to rigid-erection phase and reduces maintenance of erection

What hormone targets Leydig cells?

LH

What hormone targets Sertoli cells?

FSH

Where do PDE5 inhibitors work?

PDE5

Where does alprostadil work?

Prostaglandin PGE1

How is alprostadil administered?

Intracarvenosal injection or urethral suppository - local application to minimise side effects

What are the ADRs of alprostadil?

Priapism (prolonged erection), penis deformation

What counselling should be provided for alprostadil?

Condoms should only be used when taking this drug if the partner is pregnant if using the suppository formulation

What are the side effects of alprostadil?

Hypotension, anticoagulant effects, penile and other localised pain

What are the interactions of alprostadil?

Can potentially enhance hypotensive effects with antihypertensive drugs

What are some examples of phosphodiesterase 5 inhibitors?

Sildenafil, vardenafil and tadalafil

How do PDE5 inhibitors work?

Maintains high levels of cGMP and decreases calcium ion levels

What is the PK of PDE5 inhibitors?

Metabolised by Cyp3A4 - tadalafil has a longer half life, once daily rather than PRN

What are the CI of PDE5 inhibitors?

Patients taking nitrates or history of non-arteritic anterior ischaemic optic neuropathy or those where vasodilation is inadvisable

What are the cautions for PDE5 inhibitors?

CVS disease, those taking alpha-blockers and antiarrhythmics

What are the interactions for PDE5 inhibitors?

Potent CYP3A4 inhibitors, can cause 5x+ increase in AUC and can cause large increase in exposure e.g., grapefruit

What are the 2 approaches to dealing with ED?

Pharmacological - pathways that are penis specific e.g., NO-cGMP pathway or pharmaceutical - means to limit exposure of other organs e.g., PGE1

What is the aetiology of BPH?

Increases as age increases

What does pharmacotherapy for BPH focus on?

Stopping disease progression and symptom relief

What is BPH?

Benign prostatic hyperplasia

What is the pathophysiology of the bladder/prostate in BPH?

Growth of prostate/bladder thicken, hypertrophied detrusor muscle, urethra opening is thinner

What is the histology of BPH?

Stromoglandular hyperplasia

What can BPH be associated with?

Presence of lower urinary tract symptoms (LUTS), anatomical - enlargement of gland (BPE), pathophysiologic compression or urethra and compromises urinary flow (BOO) - but all separate conditions also

What is BOO?

Bladder outlet obstruction - urethra compression and urinary flow compromised

Are BPH and LUTS the same?

No - both can occur simultaneously

What is BPE?

Benign prostatic enlargement - subset of BPH

How is BPH treatment success measured?

Less symptoms, less bother and increased QOL, decrease prostate size/growth stopped, increase in peak flow rate/relieve obstruction, prevent long term outcomes, acceptable adverse events profile

How do a1 adrenergic blockers work?

Relax smooth muscle in the prostate producing an increase in urinary flow rate - no effect on prostate size

What are some examples of a1 adrenergic blockers?

Tamsulosin, alfuzosin, doxazosin, indoramin, pazosin, terazosin

What is the PK of a1 adrenergic blockers?

Well absorbed after oral admin and work quickly

What are the CI of a1 adrenergic blockers?

Pts with history of postural hypotension and micturition syncope

What are the cautions of a1 adrenergic blockers?

Drowsiness, hypotension and syncope/fainting

How do 5a reductase inhibitors work?

Prevent conversion of circulating testosterone to more potent DHT

What are examples of 5a-reductase inhibitors?

Finasteride and dutasteride

What is the onset of benefits from 5a reductase inhibitors?

Slow - months to reduce prostate size and symptom relief

What are the safety warnings around handling 5a reductase inhibitors?

Women of childbearing potential should avoid handling, men taking should use condoms if partner is likely to become pregnant due to potential birth defects

What are some side effects of 5a reductase inhibitors?

Reduced libido, impotence and breast tenderness

What typical therapy is used for BPH?

Combination therapy of 5a reductase inhibitors to stop disease progression and alpha blockers to relieve symptoms rapidly

What type of disease is prostate cancer?

Androgen dependant disease in initial phase

How does an GnRH antagonist work?

Competes for receptor binding with endogenous GnRH and shuts whole pathway down

How do GnRH agonists work?

Initial increase in gondatropin secretion, followed 2-3 weeks later by marked inhibition due to desensitised GnRH receptor - suppresses LH and FSH

What are examples of available GnRH agonists?

Leuprolide, goserelin, triptorelin

What are examples of GnRH antagonists?

Abarelix, degarelix