Week 7 - Male Reproductive System Flashcards
ED (erectile dysfunction)
a medical condition that prevents a man from achieving an erection or
maintaining one throughout sexual intercourse
- Reduced sexual desire
- Difficulty (or complete inability) producing or maintaining an erection
- Poor erection quality sufficient to hinder penetration
- Loss of erection during intercourse or prior to completion
- Lack of sexual satisfaction or enjoyment arising from erection difficulties
Statistics:
Chances of ED with age
1 in 5 Australian men >40 years have some form of ED (increases to >50% over 70 years)
1 in 10 Australian men >40 years have the inability to achieve an erection
Penile anatomy
…
Erection physiology
Normal flaccid state
Sympathetic nervous system keeps smooth muscle in the corpus cavernosa and blood vessels (arterioles) contracted
Maintains unhindered bidirectional blood flow – prevents blood retention
Erect state
Sexual stimulation – release of
neurotransmitters from the cavernous nerve terminals
Smooth muscle relaxes
Allows more blood in and clamps down on veins (so blood can’t escape)
Erection results
Erection biochem
It all starts with the brain (if its
not interested, forget the rest)
Stimuli (afferent nerve inputs):
* Visual
* Smell
* Imaginary
* Touch
Spinal cord (parasympathetic nonadrenergic/noncholinergic
[NANC] nerves)
stimulation: (erection)
1) NANC nerve –> Ca+2 influx –> production of nitric oxide (NO)
2) Cholinergic nerve –> release of Ach –> activation of muscarinic receptor on endothelial cell –> NO release
Inhibition:
Adrenergic nerve –> release of NA –> muscle contraction (detumescence)
NO Pathway
1) NO activates guanylate cyclase which converts GTP to cGMP
2) cGMP activates protein kinase G
3) Phosphorylates certain proteins:
a. Opens K + channels & closes Ca+2 channels & sequesters Ca+2 back into SR
b. Reduced intracellular Ca+2
c. Smooth muscle relaxation
Prostaglandin Pathway
1) PGE1 binds to its receptor (G protein coupled receptor) on CC smooth muscle cells
2) Activated adenylate cyclase
3) Converts ATP to cAMP
4) cAMP activates protein kinase A
5) Phosphorylates certain proteins to cause
a. Opens K + channels & closes Ca+2 channels & sequesters Ca+2 back into SR
b. Reduced intracellular Ca+2
c. Smooth muscle relaxation
Alprostadil
increase PGE1
Efficiency is ~ 70-90% (10 min to effect)
* More likely to work than other ED drugs
* Injectable- into the corpus cavernosa!
* Requires several ‘training sessions’ in how to perform the injections by the GP
Side effects?
* Pain (PGE1)
* Painful erection (priapism) lasting
>8h
* Redness/lump
* Rash/Itching
* Trouble urinating
* Feeling faint
* Permanent damage to penis/fibrosis
Papaverine
Less commonly used
* Mechanism of action not completely known, but
proposed to inhibit phosphodiesterase 5
(covered on next slides).
* Causes vasodilation
* Only used if alprostadil use is contraindicated
* Does not induce localised pain
Phentolamine
Mechanism of action is via vasodilation as a
result of potent competitive antagonism of α1
adrenoceptors
* Generally used along with papaverine and/or
alprostadil (Trimix, also available as a gel)
* Trimix has to be formulated by a pharmacist and
used within 1-6 months (>90% effective).
* Dose is 50 to 200 ul depending on severity of
problem (increase dose in 25 ul increments)
* Prescribed when single dose therapy has failed
Phentolamine mechanism of action
Stimulation:
1) NANC nerve –> Ca+2 influx –> production of nitric oxide (NO)
2) Cholinergic nerve –> release of Ach –> activation of muscarinic receptor on endothelial cell –> NO release
Inhibition:
1) Adrenergic nerve –> release of NA –> muscle contraction (detumescence)
Phosphodiesterase 5 (PDE5) inhibitors
- Need to take the pills 1-2h before intercourse (time to reach tmax)
- ~70% effective in healthy patients
- Inhibits hydrolysis of cGMP –> longer residence of cGMP –> increase cGMP activity –> prolonged smooth muscle relaxation
- Still need stimulation coming from the NANC nerves
- The ‘fils’ are eventually metabolised/inactivated by liver P450 3A4
What conditions could prevent ED drugs from working?
1) Diabetes
Endothelial dysfunction
Increased contractile sensitivity
Reduced NO signalling
Diabetic neuropathy
2) Vascular problems (veno-occlusive disorders)
Simply can’t get enough blood vessel dilation
Drug intervention is useless
3) Hypogonadal patients
Reduced testosterone
Testosterone regulates NOS & PDE5
4) Prostate removal
Surgery can damage the penile nerve bundle
No signalling from the brain
Can damage the whole organ
5) Smoking
The flaccid smoker…
- Damages endothelial cells
- Respond by releasing vasoconstrictors
- Hardens blood vessels
- All together reduced penile
blood flow
Smoking cessation can overcome these problems, but only if the patient has not been a life time smoker
The prostate
- Doughnut shaped structure sitting just inferior to the bladder and anterior to the rectum
- Surrounds proximal end of the urethra (usually 20-30 cm3 in size)
- Consists of glandular, connective and smooth muscle tissue.
- Its job is to secrete a milky fluid that contributes to ~ 25% of semen volume
- The secreted fluid also contains citrate (to feed sperm ATP production) and enzymes that liquefy coagulated semen (eg. prostate specific antigen or ‘PSA’)
Benign Prostatic Hyperplasia
- Enlargement of the prostate due to nodular prostatic remodelling of the stroma and endothelium and inflammation
- Remodelling and inflammation begin in the transition zone usually and is characterised by an increase in cell numbers and increase in cell size (advanced)
- Hyperplasia and hypertrophy are stimulated by androgens
- Enlargement leads to the following….
Symptoms:
* Pushes on bladder and rectum and constructs urethra, leading
to:
- Abdominal pain
- Difficulty urinating and slow urine flow
- Incontinence (by pushing on bladder)
- Feeling of urinary ‘urgency’
- Pain can be worse in the cold or when stressed
* Commonly asymptomatic earlier in life and when the condition is mild, but can get very bad later in life.
* Generally asymptomatic when prostate is <30 cm3, but beyond
this it needs to be treated.
- Chronic common disorder in men and occurs in 50% of men aged >50 years old & in 90% of men aged >80.
BPH at the cellular level
Androgen dependent process, caused by high local concentrations of the testosterone metabolite 5α-dihydrotestosterone (or DHT)
* DHT is…..
* produced by the enzyme 5α reductase (5AR)
* Important in promoting prostate development, growth and differentiation
* A very potent androgen, 5x more potent than testosterone
* Binds the testosterone receptor with higher affinity than testosterone and binds longer
* The cause of male patterned balding due to high local 5AR levels in the scalp
* BPH pathogenesis results from chronic inflammatory reactions induced by the growing prostate
stromal cells
BPH treatments
- RETURN NORMAL URINARY FUNCTION!
Approach 1:
* drug treatments to inhibit 5AR ( DHT and reduce prostate size)
Approach 2:
* drug treatments to inhibit prostate smooth muscle contraction and reduce urinary obstruction (α1 adrenergic antagonists)
Final straw:
* surgical removal of prostate
5AR inhibitors (the ‘sterides’)
Finasteride
* Also used for androgenic alopecia
* 6 month treatment for men with >30 cm3 prostate
* Plasma half life ~8h
Dutasteride
* Plasma half life ~ 5 days
* better and more consistent therapy than finasteride
* Ideally the drug of choice
Side effects for both drugs:
* ED, ejaculation problems and reduced libido
* Male breast enlargement
* May increase the chances of male breast cancer, so need to monitor changes in breast tissue
α1 adrenergic antagonists (the ‘sins’)
Aim to reduce the degree of smooth muscle contraction in the prostate –> reduce pressure on the urethra and increase urinary flow (5AR inhibitors are better if they can be tolerated or are not contraindicated)
- Specific for α1, so will not associate with presynaptic α2 receptors in the heart ∴ no tachycardia
Alfuzosin & Tamsulosin
- alpha-1A selective
- less cardiac side effects
- less effective against BPH but also less hypertension
Prazosin & Terazosin
- less receptor selectivity
- more effective in BPH treatment but dose titration is neeed to minimise hypotensive effects
