Testosterone and 5-Testosterone and 5-Alpha Reductase Alpha Reductase

InhibitorsInhibitorsStephen Chromi, PharmDStephen Chromi, PharmD

PGY-1 Pharmacy Practice PGY-1 Pharmacy Practice ResidentResident

St. Joseph’s/Candler Health St. Joseph’s/Candler Health SystemSystem

TESTOSTERONETESTOSTERONE

Testosterone EnanthateTestosterone Enanthate

Testim 1% GelTestim 1% Gel

Other Testosterone Other Testosterone ProductsProducts

Cream: Cream: First-Testosterone MC, 2%First-Testosterone MC, 2%

Implant, SubQ: Implant, SubQ: Testopel, 75mgTestopel, 75mg

Injection, Oil, as Cypionate:Injection, Oil, as Cypionate: Depo-Testosterone, 100mg/ml, 200mg/mlDepo-Testosterone, 100mg/ml, 200mg/ml

Mucoadhesive, Buccal:Mucoadhesive, Buccal: Striant, 30mgStriant, 30mg

Other Testosterone Other Testosterone ProductsProducts

Ointment:Ointment: First-Testosterone, 2%First-Testosterone, 2%

Patch, transdermal:Patch, transdermal: Androderm, 2.5mg/24hr, 5mg/24hrAndroderm, 2.5mg/24hr, 5mg/24hr

Powder for compounding, USP and Powder for compounding, USP and PropionatePropionate

Solution, topical:Solution, topical: Axiron, 30mg/actuationAxiron, 30mg/actuation

Androgel 1%, 1.62%Androgel 1%, 1.62%

DihydrotestosteroneDihydrotestosterone Dihydrotestosterone or DHT is a potent Dihydrotestosterone or DHT is a potent

metabolite of testosterone. It is known metabolite of testosterone. It is known to be involved in BPH and hair loss. It to be involved in BPH and hair loss. It also has potent anabolic effects, like also has potent anabolic effects, like testosterone itself.testosterone itself.

The role of DHT in post-embryonic life The role of DHT in post-embryonic life remains poorly understood.remains poorly understood.

At least 2 isoenzymes of steroid 5 alpha-At least 2 isoenzymes of steroid 5 alpha-reductase convert testosterone into reductase convert testosterone into DHT, although alternative pathways DHT, although alternative pathways exist.exist.

5-Alpha-Reductase5-Alpha-Reductase

The isoenzymes of 5-Alpha-The isoenzymes of 5-Alpha-Reductase are concentrated in Reductase are concentrated in certain tissues, particularly the certain tissues, particularly the prostate and skin.prostate and skin.

There is a question as to whether There is a question as to whether DHT is the only form of testosterone DHT is the only form of testosterone that acts on those tissues or if the that acts on those tissues or if the presence of DHT simply magnifies presence of DHT simply magnifies the effects of testosterone.the effects of testosterone.

AvodartAvodart

Avodart Avodart (Dutasteride) (Dutasteride) comes in 0.5mg comes in 0.5mg soft capsules.soft capsules.

Unlike Unlike Finasteride, it Finasteride, it inhibits both 5-inhibits both 5-alpha-reductase alpha-reductase isoforms 1 and 2isoforms 1 and 2

DutasterideDutasteride

Dutasteride efficacyDutasteride efficacy

In a 4 year study involving over 2000 In a 4 year study involving over 2000 patients, Dutasteride (compared to patients, Dutasteride (compared to placebo) was found to decrease placebo) was found to decrease prostate volume by 20.7% and prostate volume by 20.7% and increase peak urinary flow by increase peak urinary flow by 1.8ml/sec.1.8ml/sec.

5-Alpha-Reductase 5-Alpha-Reductase InhibitorsInhibitors

Side effects:Side effects: Mostly sexual side effectsMostly sexual side effects ImpotenceImpotence Decreased ejaculate volumeDecreased ejaculate volume Decreased libidoDecreased libido GynecomastiaGynecomastia

Article ReviewArticle Review

““Effect of Testosterone Effect of Testosterone Supplementation With and Without a Supplementation With and Without a Dual 5-Alpha Reductase Inhibitor on Dual 5-Alpha Reductase Inhibitor on Fat-Free Mass in Men With Suppressed Fat-Free Mass in Men With Suppressed Testosterone Production: A Testosterone Production: A Randomized Controlled Trial”Randomized Controlled Trial”

Published in JAMA; March 7, 2012Published in JAMA; March 7, 2012 Bhasin S, Travison TG, Storer TW et alBhasin S, Travison TG, Storer TW et al

Study PurposeStudy Purpose

To determine if testosterone To determine if testosterone supplementation is still effective for supplementation is still effective for anabolic purposes when a dual 5-anabolic purposes when a dual 5-alpha-reductase inhibitor is also alpha-reductase inhibitor is also used.used.

Secondary goals were to also look at Secondary goals were to also look at the effectiveness of the 5-alpha-the effectiveness of the 5-alpha-reductase inhibitor when reductase inhibitor when testosterone is supplementedtestosterone is supplemented

Trial DesignTrial Design

Healthy men age 18-50 yearsHealthy men age 18-50 years 8 treatment groups, 20 weeks total:8 treatment groups, 20 weeks total:

all patient received testosterone, all patient received testosterone, either…either… 50mg, 125mg, 300mg, or 600mg/wk50mg, 125mg, 300mg, or 600mg/wk

Placebo vs. Dutasteride Placebo vs. Dutasteride 2.5mg/day2.5mg/day

OutcomesOutcomes

Primary outcome:Primary outcome: Change in fat-free mass from baseline Change in fat-free mass from baseline

measured by dual-energy x-ray absorptiometrymeasured by dual-energy x-ray absorptiometry Secondary outcomes:Secondary outcomes:

Fat mass, Leg-press and Chest-press strength, Fat mass, Leg-press and Chest-press strength, sexual function, sebum production, and sexual function, sebum production, and prostate volumesprostate volumes

All outcomes measured at baseline and after All outcomes measured at baseline and after 20 weeks20 weeks

ResultsResults

Of the 3792 men screened, 102 Of the 3792 men screened, 102 patients completed the 20-week trialpatients completed the 20-week trial

Participants displayed similar Participants displayed similar baseline characteristicsbaseline characteristics

Total and free testosterone levels Total and free testosterone levels increased with testosterone dose in increased with testosterone dose in all groups and did not differ all groups and did not differ significantly between groups.significantly between groups.

ResultsResults

Fat-free mass: Increased with Fat-free mass: Increased with increasing testosterone doses but increasing testosterone doses but did not differ between groups.did not differ between groups.

Muscle strength: Increased with Muscle strength: Increased with increasing testosterone doses but increasing testosterone doses but did not differ between groups.did not differ between groups.

Sexual function: Did not differ Sexual function: Did not differ significantly among or between any significantly among or between any groups.groups.

ResultsResults

Prostate volumes and PSA levels: Prostate volumes and PSA levels: Did not differ significantly among or Did not differ significantly among or between any groupsbetween any groups

Sebum production and acne: Sebum Sebum production and acne: Sebum production on the forehead was production on the forehead was related to testosterone dose and did related to testosterone dose and did not differ between the placebo and not differ between the placebo and dutasteride groups. The acne scores dutasteride groups. The acne scores did not differ between groups.did not differ between groups.

DiscussionDiscussion

The placebo vs dutasteride groups did The placebo vs dutasteride groups did not differ significantly in any way.not differ significantly in any way.

It seems obvious that the anabolic It seems obvious that the anabolic effects of testosterone on muscle can effects of testosterone on muscle can still be accomplished while on a 5-still be accomplished while on a 5-alpha-reductase inhibitor.alpha-reductase inhibitor.

Unfortunately, the study ended up Unfortunately, the study ended up being very small, which calls into being very small, which calls into question the legitimacy of the results.question the legitimacy of the results.

DHT’s role better DHT’s role better understood?understood?

It may be theorized that some effects of It may be theorized that some effects of testosterone do not require the testosterone do not require the conversion to DHT, such as muscle and conversion to DHT, such as muscle and bone anabolism. The effects of DHT may bone anabolism. The effects of DHT may be more related to the tissues of the be more related to the tissues of the prostate and skin (hair).prostate and skin (hair).

It may be that DHT is the primary It may be that DHT is the primary hormone in these areas, or that it hormone in these areas, or that it amplifies testosterones effects on these amplifies testosterones effects on these tissues. tissues.

Future ResearchFuture Research

I think a larger study of testosterone I think a larger study of testosterone therapy with 5-alpha-reductase therapy with 5-alpha-reductase therapy is warranted.therapy is warranted.

We need to know if testosterone We need to know if testosterone therapy mitigates the effectiveness of therapy mitigates the effectiveness of 5-alpha-reductase inhibitors in BPH 5-alpha-reductase inhibitors in BPH and hair loss.and hair loss.

I think we should also use the I think we should also use the practical dose of Avodart, 0.5mg daily.practical dose of Avodart, 0.5mg daily.

QUESTIONS?QUESTIONS?