TRT and LUTS Mick Jagger, 70 years PRISM IV Sept 2014
Combination of LUTS and LOH In ageing male : -LUTS increases -LOH increases So: the combination is a common clinical scenario
TRT and LUTS Startingpoint / first thought: Treatment of LUTS prevails treatment of LOH
TRT and LUTS Guidelines: TRT relative contra-indicated if IPSS 21 points (no data!) - Wang, ISA, ISSAM, ASA etc, 2012 - Buvat, 2010 - Dohle, EAU, 2012
TRT and LUTS; what do we know? Gradual increase of prostate volume, concomitant with progressive decline of T Hypogonadism affects 20% of elderly men with LUTS In men with Metabolic Syndrome : LUTS earlier in life Although there is no consistent relationship between TT and ft and LUTS/BPH: in eugonadal middle-aged men(lee, 2014) May be : T is the common link between : Advancing age LUTS MetS Francomano, Urology 83 (1), 2014 Rohrmann, Urology 69, 2007 Litman,BJU Int. 100,2007
TRT and LUTS; what is in the literature? Mild LUTS improve with TRT, Yassin, World J Urol, 2013. Mild LUTS was stable after 5y of TRT, Francomano, Urology, 2014, 83,1 -signifant lower incidence of prostatitis: T prevents prostatitis? Severe LUTS and TRT: no data!
TRT and LUTS Hypothesis: - Testosteron may act on the structures of the lower urinary tract: Some prove: Androgenreceptors on urethra and bladder epithelial cells are detected T maintains reflex activity of the pelvic autonomic nervous system Chavalmane, J Sex Med 8 2010,
TRT and LUTS Two Questions: -Is TRT bad for LUTS? -Is LUTS-therapy bad for LOH?
TRT and LUTS Is TRT bad for LUTS? - is TRT bad for bladder as the cause of LUTS? Probably not! - is TRT bad for BPH as the cause of LUTS? We don t know! no data
TRT and LUTS First recommendation: -No TRT in severe LUTS, but no data available -Just treat severe LUTS first
TRT and LUTS Two Questions: -Is TRT bad for LUTS? -Is LUTS-therapy bad for LOH?
TRT and LUTS Is LUTS-therapy bad for LOH: bad for sexual functions, bad for TRT? LUTS-Treatments: -alfa-blockers -5alfa-reductase-inhibitors -anti-cholinergic drugs in urge-patients -TURP and other operations
TRT and LUTS BPH-treatments: -alfablockers: alfuzosine dry orgasm; ED tamsulosine dry orgasm; ED silodine dry orgasm; ED -PDE-5-I tadalafil improves erections and LUTS/BPH!! -PDE-5-I plus alfablockers improves LUTS and ED -5ARI s: finasteride dutasteride -TURP: 10% improvement / 10% worsening of ED Leliefeld, BJU Int 2002, 89, 208-13 Gacci, Eur Urol 2011;60:809-25 Huilei Yan, J Sex Med 2014;11:1539-45
CanTRT-patients with LUTS benefit from Dutasteride? Could be conflicting because: Effects of Dutasteride : Effects of TRT: -90% decrease of DHT in serum and prostate -prostate volume decreases ± 30 % -PSA decreases ±50 % after 3-6 months -Sexual side effects : ± 30 % -Testosterone increases -DHT increases Rittmaster, 2008, Roehrborn, 2011 Andriole, 2004 Toren, 2013
Question: Is Dutasteride therapy still effective in TRT-patiënts with LUTS? or: What is the influence of Dutasteride on : -PSA -prostate volume -sexual symptoms in patients that are on stable TRT
Randomised placebo-controlled study in patients stable on TRT TRT + dutasteride (n=11) TRT plus placebo(n=11) PSA change: 23,2% decrease no change Prostate volume: 6,65% decrease no change Sexual side effects: a trend (MSHQ) no change Kacker, R et al, Andrologia 2014; 20, 1-5
CanTRT-patients with LUTS benefit from Dutasteride? Possible Conclusions with caution : -PSA decreases less: 23,2%% versus 50% -Prostate volume decreases less: 6,65% versus 30% -Sexual side effects: a trend to still appear despite TRT DHT important for sexual function Kacker R, et al, Andrologia, 2014; 20, 1-5
CanTRT-patients with LUTS benefit from Dutasteride? In simple language might be stated: Dutasteride in TRT-patients brings : -less decrease of PSA More large volume studies are necessary -less prostate volume reduction -still sexual side effects - LUTS not examined: no data
J Sex Med 2012;9:2927-32 Sex Med Rev 2014;2: 24-35
Time to learn more about Finasteride and Dutasteride
Finasteride : 5 alfa reductase-2-inhibitor : reduces DHT -Male pattern hair loss: 1977 1mg -a sign of virility, due to high T/DHT -high DHT means baldness -high 5α-reductase-2-activity in skin of head -BPH: 1992 5 mg
Baldness: sign of virility
Persistent sexual side effects of 1mg in Propecia In 2008: Swedish Medical Products Agency: persistent ED after discontinuation In 2009: Agency in UK : difficulty having erection after discontinuation In 2011: Traisch JSM 8:872-84: Persistent ED, low libido and depression:1 case In 2011: Irwig, JSM 8:1747-53: Persistent sexual side effects: series of 71 men In 2012: Irwig, JSM 9:2927-32: Persistent sexual side effects: Permanent? - Inclusion: men with SD for 3 months despite cessation of finasteride 89 % still had sexual disfunction at mean FU of 14 months (n=54)
Rates of withdrawal because of sexual side effects of 5 mg in BPH Lowe,McConnel, Urology, 2003;61:791-6 1,3% Prospectstudy, CMAJ, 1996,155:1251-9 long duration PlessStudy, Urology, 2003:61:579-84 4% Whether the sexual side effects ever resolved, has not been published!!
Finasteride : background Three isoforms of 5α-reductase: -Type I: in brain, liver, muscle, skin and little in the prostate -Type II: in epididymis, hair follicles, liver, prostate and seminal vesicles -Type III: in brain, heart, lung, pancreas, colon, stomach, liver, muscle, prostate and testicles Attention: Type III at higher levels than I and II ; potent inhibition by Finasteride and Dutasteride! Yamana, Horm.Mol Biol Clin Invest 2010;2:293-9
Finasteride : background Is a synthetic steroid that acts as an alternative substrate for the 5α-reductase enzymes Is lipophilic: can cross the blood-brain barrier Inhibition of formation of not only DHT but also of: -allopregnanolone (ALLO), a progesterone metabolite -androsterone -epiandrosterone -THDOC -and many other steroids Duskova, Prague Med Rep 2009; 110:222-30
Finasteride and Neurosteroids Neurosteroids: - steroids that are synthesized in the brain - or metabolized in the brain from steroids from gonads or adrenal glands - play a role in neurogenesis, neuroprotection, synaptic formation, plasticity of the brain and myelination Finasteride: - can alter the concentrations of neurosteroids like ALLO and THDOC - decreases neurogenesis and proliferation of neural precursor cells in mice Römer Pharmacopsychiatry 2010;43:174-8 Irwig Sex Med Rev 2014; 2: 24-35
Finasteride : background The 5α-reductase Type 2 that binds to finasteride have significant genetic variation with probably different affinities for finasteride In other words: finasteride can act different in different individuals Andersson, Proc Natl Acad Sci USA 1990;87:3640-4
Incomplete Recovery of Erectile Function in Rat after Discontinuation of Dual 5 Alpha Reductase Inhibitor Therapy In vivo erectile response in rats after pelvic nerve stimulation Controls 8 weeks dutasteride 6 weeks dutasteride and 2 weeks wash out The Journal of Sexual Medicine, CV Öztekin.e.a. Volume 9, Issue 7, pages 1773-1781, 8 MAY 2012 DOI: 10.1111/j.1743-6109.2012.02759.x http://onlinelibrary.wiley.com/doi/10.1111/j.1743-6109.2012.02759.x/full#f1
Incomplete Recovery of Erectile Function in Rat after Discontinuation of Dual 5 Alpha Reductase Inhibitor Therapy In vitro bath responses of CC smooth muscle Controls 8 weeks dutasteride 6 weeks dutasteride and 2 weeks wash out The Journal of Sexual Medicine, CV Öztekin e.a. Volume 9, Issue 7, pages 1773-1781, 8 MAY 2012 DOI: 10.1111/j.1743-6109.2012.02759.x http://onlinelibrary.wiley.com/doi/10.1111/j.1743-6109.2012.02759.x/full#f4
Finasteride and erectile disfunction Already in 1981 shown to be harmful for erections in male rats DHT in castrated rats improves erections So: Dutasteride has detrimental effects on EF in rats, proven by: -decreased erectile response with cavernosal stimulation -strips of smooth muscle :contraction and stimulation -increased collagen deposition in cavernous tissue -26% lower weight of corpora cavernosa than in controls Lit: Irwig 2014 Sex Med Rev 2:24-35
Finasteride and the persistent side effects Erectiele disfunction Low libido and decreased orgasm Depression Decrease in Alcohol consumption in young men and animal models Irwig, MS Sex Med Rev 2014; 2: 24-35 Overview of the literature
Finasteride and depression in former users Depressive symptoms in finasteride group : 75% in control group : 10% Suicidal thoughts in finasteride group : 44% in control group : 3% Irwig J Clin Psychiatry 2012;73:1220-3
Finasteride and decrease in alcohol consumption Decrease of alcoholconsumption in 65% (41 of 63 subjects) Quitting drinking entirely: 18 of 63 subjects because of effects of alcohol on mental function: decreased euphoria Mechanism: modulation by ALLO in male mice and rats Janak 1998, Alcohol Clin Exp Res 22:1106-12
Finasteride and side effects Why so late reported in the literature? -Incidence of persistent side effects is less than 1% -general underreporting of adverse effects of medications -no validated instrument used in RCT of 5α-reductase inhibitors FDA in 2012: persistent sexual side effects on the label of finasteride FDA in 2010: depression on the label of Propecia
Finasteride and side effects Finasteride alters the levels of multiple hormones and neurosteroids Studying the brain of living humans will be difficult Persistent effects : intriguing and bothersome for men who suffer - 89% still sexual disfunction 14 months after stopping Genetics presumably determine the individual s risk for a side effect At now: no test available to predict if the patient will be unlucky!! At now: no pharmacological therapy available other than PDE-5-I TRT did not help Irwig 2012 J Sex Med 9:2927-32
Finasteride and side effects Messages / Summing up: - Literature on long term side effects comes mainly from 1mg finasteride - Literature on long term sexual side effects of finasteride /dutasteride in BPH is lacking - Literature on sexual side effects concerns mainly experiments in rats and mice - FDA warns for persistent sexual side effects and depression since 2010/2012 - It is not possible to estimate the risk of persistent (sexual) side effects anno 2014 - Finasteride can lower many neurosteroids and not only DHT
Finasteride and side effects Prescribers and users should be aware of the potential serious persistent risks of finasteride and dutasteride
Take home messages No TRT in severe LUTS-patients; but no data Treat severe LUTS before starting TRT Many LUTS-treatments can be : bad for LOH-patients Finasteride / Dutasteride can give sexual disfunctions/depressions Finasteride / Dutasteride can give persistent sexual disfunctions! Finasteride / Dutasteride only in patients with prostate volume 40 gram Discuss side effects with your patients
The End
Finasteride and Neurosteroids In the brain: -G-aminobutyric acid (GABA) : major inhibitory neurotransmitter - 2 important neurotransmitters are modulators of the GABA receptor: -ALLO and THDOC -The sensitivity of the GABA receptor can be altered by: -ALLO -chronic steroid administration -age, stress and social isolation Majewska, Science1986,;232:1004-7
Finasteride and Low libido and Decreased Orgasm Difficult to study ; mechanisms less clear; indirect evidence Sexual excitation : neurotransmitter: norepinepfrine and dopamine Inhibition of sexual arousal : serotonine and opioids -5α reductase is present in many of the brain regions linked to sexual desire -reduction of neurosteroids leads to loss of neuroprotection: sexual desire Römer Pharmacopsychiatry 2010; 43 :174-8