L13 Male Reproduction Flashcards
What enzyme converts testosterone to dihydrotestosterone (DHT)?
5α-reductase
Effects of DHT binding to androgen receptor
External genitalia: differentiation during gestation, maturation during puberty, adulthood prostatic diseases
Hair follicles: increased growth during puberty
Effects of testosterone binding to androgen receptor
Internal genitalia: Wolffian development during gestation
Skeletal muscle: increase mass & strength during puberty
Erythropoiesis
Bone
What enzyme converts testosterone to estradiol?
aromatase
Effects of estradiol binding oestrogen receptor
Bone: epiphyseal closure, increased density
Libido
What guidelines are followed for the treatment of male LUTS?
European Association of Urology
By the age of 80, what percentage of men will suffer from benign prostatic hyperplasia?
~90%
BPH is the most common cause of __.
Bladder outlet obstruction (BOO)
2 distinct mechanisms that cause BOO
- Static - prostate bulk encroaching on urethra (restrictive)
- Dynamic - tension of prostate smooth muscle (increased stromal smooth muscle tone)
What is used to determine the severity of LUTS?
International Prostate Symptom Score (IPSS)
Examples of lower urinary tract symptoms
incomplete emptying, frequency, intermittency, urgency, weak stream, straining, nocturia
Pharmacological treatment of BPH
α1-adrenoceptor antagonists (dynamic component and irritative symptoms)
5α-reductase inhibitors (static component and obstructive symptoms)
Examples of α1-adrenoceptor antagonists
terazosin, doxazosin, tamsulosin, alfuzosin, silodosin
How do α1-adrenoceptor antagonists treat BPH?
- target α1A, α1B and α1D subtypes
- reduce prostatic smooth muscle tone
- relieve bladder outlet tension
- increase urinary flow
Side effects of α1-adrenoceptor antagonists
dizziness, postural hypotension, rhinitis, sexual dysfunction
Examples of 5α-reductase inhibitors
finasteride, dutasteride
How do 5α-reductase inhibitors treat BPH?
- 70-90% reduction in DHT
- 20-30% reduction in prostate size
- ~50% reduction in PSA
- control the static obstructive component of LUTS
- improvement in peak flow rate within 3-6 months
Adverse effects of 5α-reductase inhibitors
reduction in spermatogenesis, decreased libido
What is prostatic artery embolisation?
catheter insertion to cut off blood supply to prostate (microspheres cause calcification and inflammation) - prostate dies in situ and symptomology reversed
Symptoms of overactive bladder
urinary urgency, with or without urinary incontinence, increased frequency and nocturia
During storage phase, __ release is suppressed.
parasympathetic (ACh)
How is overactive bladder and detrusor overactivity treated?
Anti-muscarinic treatment strategy - detrusor M3 receptor antagonists
Examples of anti-muscarinic drugs
oxybutynin, tolterodine, fesoterodine, darifenacin, solifenacin, trospium
How do anti-muscarinics treat OAB?
- reduce spontaneous myocyte activity
- decrease frequency and intensity of detrusor activity
- suppress cholinergic signalling and prolong storage phase (reduced contraction of detrusor)
Side effects of anti-muscarinic treatment
- dry mouth (parotid glands)
- constipation (intestinal smooth muscle)
- headache
- blurred vision (ciliary muscle)
- non-selectivity of antagonists for M3 receptors (also targets other receptor subtypes) - systemic blockade
- blockade of vagal inhibitory input, cardiac arrhythmia
Example of a B3 receptor agonist and how it can treat OAB
Mirabegron
- enhances noradrenaline release - relaxes detrusor
- improves bladder filling
- reduces irritative OAB symptoms of urgency, frequency & nocturia
Side effect of Mirabegron use
increased blood pressure
Pharmacological treatment of erectile dysfunction
α1-adrenoceptor antagonists
phosphodiesterase type 5 inhibitors
How do α1-adrenoceptor antagonists treat ED?
They relax smooth muscle in penile arteries or corpus cavernosum, resulting in increased blood flow, causing erection
Common adverse effect of α1-adrenoceptor blockade to treat ED
retrograde ejaculation, due to relaxation of the bladder neck (reduced smooth muscle tone)
Example of a PDE5 inhibitor and how it can treat ED
Sildenafil (Viagra)
- vascular smooth muscle relaxation - increased blood flow to penis, causing erection
Why take caution when using a combination of PDE5 inhibitors and α1-adrenoceptor antagonists?
can cause significant hypotension
Rationale for endocrine treatment for prostate cancer
deprive cancerous cells of androgens, apoptotic regression
How is testosterone production eliminated in endocrine treatment for prostate cancer?
GnRH agonists and GnRH antagonists
Examples of GnRH agonists used to treat prostate cancer
Goserelin, buserelin, leuprolin, nafarelin
What does high concentration of GnRH agonist result in?
GnRH receptor desensitisation and subsequent testosterone suppression (in 95% of patients)
How are GnRH agonists administered in prostate cancer patients?
subcutaneous administration at 1-3 month intervals
Adverse effects of GnRH agonists?
tumour flare (lasts 1-2 weeks), bone pain due to bone metastases
Example of a GnRH antagonist
Abarelix
Why are GnRH antagonists usually preferred to GnRH agonists?
They avoid the ‘tumour flare’ response as they are associated with a more rapid reduction in testosterone levels (<1 day)
Why are anti-androgens used in prostate cancer endocrine treatment?
intermittent androgen deprivation; inhibition of androgenic-independent tumour cell development - improved quality of life. PSA monitored closely
Example of a steroidal anti-androgen
Cyproterone acetate
- androgenic and progestogenic actions
- suppresses LH release
Adverse effects of cyproterone acetate
Castration syndrome, hepatotoxicity
Examples of non-steroidal anti-androgens
Bicalutamide, flutamide
- androgenic effects
- LH release maintained
Adverse effects of non-steroidal anti-androgens
nausea, diarrhoea, hepatotoxicity
Symptoms associated with Castration syndrome
loss of libido and erectile function, hot flushes, anaemia, obesity, decrease in muscular strength, fatigue, decrease in physical activity, mood changes, depression
How is anaemia associated with Castration syndrome treated?
with recombinant human erythropoietin to help increase levels of RBCs
What is carried out to identify osteoporosis high-risk individuals before initiating treatment?
bone densitometry
How are men with Castration syndrome treated for osteoporosis?
- calcium supplementation
- oestrogen and bisphosphonates
- intermittent androgen deprivation treatment protocol
