Phytotherapy
Issues:
- Same plant sold by different companies can have different biological or clinical effects – one brand cannot be extrapolated to others
- Pharmacokinetic properties can vary widely with significant heterogeneity between products
- Some possible in vitro effects are hard to replicate or confirm in vivo
- Many products combine multiple plant extracts or compounds in one medication
Suggested mechanism:
- Anti-inflammatory effects via inhibition of cyclooxygenases and lipoxygenases which prevents prostaglandins and leukotrienes
- Also in vitro suggestion of inhibition of 5AR, DHT binding to nuclear androgen receptor and inhibition of oestrogen receptors in prostatic tissue
Saw palmetto (Serenoa repens)
- Heterogeneity in different extraction methods can cause different results – suggestion that hexane extracted product seems to be best with highest biologic availability
- 2009 Cochrane review concluded no benefit cf. placebo overall
- Benefit for nocturia with 0.6 – 0.7 less nocturnal voids
- AUA guideline suggests 2 RCTs (STEP 2006, CAMUS 2011) showed no benefit over placebo
- 2016 meta-analysis of hexane extracted S.repens showed may be more effective than placebo for nocturia (-0.3 voids) and increasing Qmax
- Trial of saw palmetto in combination with silodosin showed more benefit than silodosin taken alone
- Quite safe with minimal adverse effects – occasionally GI upset if taken on empty stomach
EAU recommendation
Offer hexane extracted Serenoa repens to men with LUTS who want to avoid any potential sexual side effects – inform the benefit may be modest
Alpha blockers
Mechanism of action
Inhibit endogenously released noradrenaline binding to alpha receptors (specifically alpha-1 and alpha-1a), preventing smooth muscle contraction at bladder neck and prostate and therefore reducing tone
Efficacy
Expected improvement in IPSS 5 – 8 points (cf. placebo 2 – 4 points) or by 30 – 40 %.
Increase Qmax by 20 – 25 %.
Full effects take a few weeks, but often effect is noticed quickly. Effect is maintained for at least four years, but do not reduce progression to AUR or reduce prostate size.
No significant difference in efficacy between drugs.
Improve success at TOV for those in retention.
Side effects
Dizziness
Postural hypotension
Asthenia (weakness, lack of energy)
Ejaculatory dysfunction (highest with selective blockers – tamsulosin, silodosin)
?Higher ejaculatory dysfunction in patients with more efficacy
Probably actually anejaculation cf. retrograde ejaculation (AUA guideline)
Intraoperative floppy iris syndrome
Prazosin – non selective alpha blocker, short half life requiring BD dosing, RCTs in late 80s and early 90s showed improvement in flow rates cf. placebo. Higher rates of orthostatic/postural hypotension.
5 alpha reductase inhibitors
Mechanism of action
Inhibition of the enzyme 5α-reductase which converts testosterone to the more potent form DHT.
Type 1 5a-R is found in skin and liver, type 2 5a-R mainly in prostate.
Finasteride inhibits type 2 only, dutasteride inhibits both.
Serum DHT reduced by 70 – 90 % (more for dutasteride) and prostatic DHT levels reduced by 85 – 90 % inducing apoptosis of prostatic epithelial cells and reduction in volume.
Efficacy
Requires 6 months of continued use for true effect to allow prostate volume reduction.
After 2 – 4 years; IPSS improves by 15 – 30 % (3 – 4 points), prostate volume reduces by 25 %, Qmax improves by 1.5 – 2.0 mL/sec
5-alpha reductase inhibitors reduce progression to AUR to surgery:
50 – 60 % relative risk reduction for both AUR/surgery (2 – 5 % absolute RR)
Efficacy is mostly studied in those with volume > 30 – 40 cc.
50 % reduction in serum with sustained use (most pronounced atrophy in glandular epithelial prostate).
Evidence for reduction in blood loss prior to TURP is conflicting – some support.
Side effects
Reduced libido
Erectile dysfunction
Ejaculatory dysfunction / reduced ejaculatory volume
Breast tenderness or gynaecomastia (1 – 2 %)
Potential increased risk of depression
5 alpha reductase inhibitors and prostate cancer – 23 – 25 % risk reduction of overall diagnosis of prostate cancer in PCPT and REDUCE trials, but small increased risk in diagnosis of high risk prostate cancer (absolute numbers very small, no different in prostate cancer specific mortality).
Combination therapy – alpha blocker with 5αRI
Well studied combination with 2 large RCTs with long term follow up:
MTOPS (Medical Therapy of Prostate Symptoms)
3000 men
Doxazosin vs finasteride vs combination vs placebo
Main outcome was progression – +4 IPSS, AUR, recurrent UTIs, renal insufficiency
At 4 years: 5 % progression in combination, 10 % in single agents, 17 % in placebo
AUR and progression to surgery lower only with finasteride and combination
Strongest effect for patients with PSA > 4.0 and PV > 40 cc
CombAT (Combination of Avodart and Tamsulosin)
4800 men, PV > 30 cc or PSA > 1.5
Dutasteride vs tamsulosin vs duodart
65 % relative risk reduction for AUR and progression to surgery in combination cf. tamsulosin alone
Greater effect seen in PV > 40 cc
Total adverse effect rates were higher for combination groups, but withdrawal rates and specific symptom rates were comparable.
Overall, long term (4 year) data confirms combination therapy gives greater improvement in LUTS, Qmax and prevention of progression compared to monotherapy (at the expense of increased rate of side effects).
Discontinuation of the alpha blocker after 6 months doesn’t seem to be detrimental to long term outcomes.
Best suited to men with prostate over > 40 cc for best results.
OAB medications
Can be used safely in men with storage symptoms and overactivity. Most of the initial studies are in women or in men without BOO.
Risk of potentiating urinary retention although most studies show the incidence of this is low – one study in men with mild to moderate BOO taking tolterodine showing increased PVR (49 mL vs 16 mL) but no difference in rates of AUR (3 %).
Use in caution in men with PVR > 150 mL.
Combination of anti-muscarinics with alpha blocker showed symptom improvement in men cf. monotherapy or placebo and low rates of retention.
NEPTUNE – solifenacin/tamsulosin combination efficacious reducing IPSS by 9, 1 % AUR
Combination of b3-agonists and alpha blockers also widely used with no significant safety concerns noted.
PDE5 inhibitors
Mechanism of action
cGMP facilitates smooth muscle relaxation. cGMP is degraded by the enzyme phosphodiesterase 5. Therefore, PDE5 inhibitors prevent the breakdown of cGMP and increase smooth muscle relaxation in prostate, detrusor and urethra.
Long term treatment with PDE5i may have other mechanisms including:
- Increasing perfusion and oxygenation to lower urinary tract
- Reduction in chronic inflammation
- Alteration in reflex pathways in spinal cord and neurotransmission relating to lower tract
Efficacy
Reduces IPSS – but only by 1.9 points in meta-analysis
Little effect on Qmax
Significant improvement in IIEF and can be used in patients with concomitant ED (or in those without ED).
Most information limited to 1 year follow up, and 5 mg daily tadalafil.
Good data for combination with low dose PDE5i and alpha blockers or 5ARIs lacking – not recommended by AUA guidelines but some evidence high dose tadalafil (20 mg) in combination with alpha blockers can give marginal improvement.
Side effects
Headache 10 – 20 %
Flushing
Indigestion / dyspepsia
Nasal congestion
Visual changes around 2 % including blue vision with sildenafil
Back pain and myalgia (6 % with tadalafil)