An unused, superior treatment
for androgenic alopecia
Jordan Owen Pharm D. Candidate 2020
This Photo by Unknown author is licensed under CC BY-NC-ND.
After this seminar the audience should be
able to
Understand the biology and pathophysiology of androgenic alopecia (AGA)
Recognize the impact of AGA on the individual patient.
Describe the pharmacologic roles of 5-alpha reductase inhibitors in the treatment of AGA
Evaluate dutasteride’s place in therapy relative to finasteride
What is androgenic alopecia?
• AKA Male pattern baldness (can also be female pattern)
• A specific pattern of hair loss due to the effects of androgens in
the body.
• The pattern is a result of androgen sensitive follicles. (Genetically
predisposed)
• The culprit androgen is Dihydrogentestosterone (DHT)
• This region spans from the crown to the top of the head and
reaches as far as the temples
Who is affected by AGA?
• AGA accounts for 95% of hair loss in men.
• Looking at America (151.8 million males in 2018)
• 25% of men are likely to suffer from MPB before the age of 21
• 66% of men will experience some degree of noticeable hair loss by age 35
• 85% of men have noticeable hair loss by age 50
American Hair Loss Association, Paul McAndrews. American Hair Loss Association - Men's Hair Loss /
Introduction
Details of AGA
• Male pattern baldness is
graded on the Hamilton-
Norwood Scale (NW
scale)
(2009) Int J Trichology. 1 (2): 120–2.
What comes with hair loss?
• People with hair loss have an increased occurrence of psychiatric disorders
• Anxiety
• Depression
• Paranoia
• Resources
• $$$
• Time
Int J Dermatol 1994; 33: 849–50.
How does AGA work?
• AGA is specific to the scalp, therefore hairs on the side and back of the head are
unable to be effected by this process.
• It is theorized that Dihydrogentestosterone (DHT) is the offending agent. DHT is a
derivative of testosterone that is converted by the enzyme 5-alpha reductase.
• We are aware (according to JAMA dermatology) that the difference in concentration
of DHT in the scalp of an AGA patient against an individual without hair loss is not
statistically significant. Ruling out that there is an ideal DHT or free testosterone
concentration in all males that is "Hair protective."
JAMA Dermatol. 2017;153(9):935-937
• DHT then binds to receptors within the scalp and by some unknown reason
causes atrophy of the hair follicle
• As the DHT initiates the unknown process that shrinks the hair follicle, this
results in the follicle receiving less delivery of blood flow. This dual effect causes
the rapid decline of hair density by essentially “starving” the hair of nutrients.
JAMA Dermatol. 2017;153(9):935-937
Idea behind treatment
Idea behind treatment
Idea behind treatment
5 alpha reductase has three isoenzymes of Steroid 5α-
reductase, SRD5A1, SRD5A2, and SRD5A3. The
concentration of these enzymes vary depending on
their location.
• SRD5A1
• SRD5A2
J Clin Invest. 1993 Aug; 92(2): 903–910
Steroid 5 Alpha Reductase I
• 5α-R1 is expressed in more locations, including
the liver, skin, scalp and prostate
J Clin Invest. 1993 Aug; 92(2): 903–910
Steroid 5 Alpha Reductase II
• 5α-R2 is expressed in prostate, seminal vesicles,
epididymis, liver, and to a lesser extent the scalp
and skin
J Clin Invest. 1993 Aug; 92(2): 903–910
5AR-I vs 5AR-II in physiologic expression
• After birth hepatic expression of both 5α-R1 and 2 is
immediate but disappears in the skin and scalp at month
18
• By puberty, only 5α-R1 is re-expressed in the skin and
scalp
J Clin Invest. 1993 Aug; 92(2): 903–910
Pharmacology
• Finasteride
• Specifically, selective of types II and III isoforms.
• Can decrease circulating DHT by roughly 65-70% with 1mg daily.
• Finasteride does not completely suppress DHT production because it
lacks inhibitory effects on 5AR type I with more than 100-fold less
potency for type I compared to type II.
• Remember the locations of 5ARI and 5ARII?
Expert Opin Pharmacother. 2004 Apr;
5(4):933–40
Pharmacology
• Dutasteride
• Inhibits all 3 isoforms of 5AR and can decrease serum DHT up to 98% in the
blood. It blocks isoenzyme 1 with twice the affinity of isoenzyme II. It is a
competitive irreversible inhibitor.
• Both drugs work by competitively, and irreversibly inhibiting 5-alpha reductase and
prevent the conversion of testosterone to DHT.
• Hormone changes? 2018 study found that the change in levels of testosterone while
on these medications (5 alpha reductase inhibitors) was statistically insignificant.
Sexual Medicine Reviews Volume 7, Issue 1, January 2019, Pages 95-114
U.S. vs European
Guidelines for the treatment of androgenic alopecia
This Photo by Unknown author is licensed under CC BY-SA.
The U.S. has no guidelines and only 2 FDA approved drugs for
treatment of male pattern hair loss as of 2017
J Am Acad Dermatol. 2017
Jul;77(1):136-141 This Photo by Unknown author is licensed under CC BY-SA.
Guideline For
the Treatment
Of
Androgenetic
Alopecia in
Women and in
Men
- Blumeyer - 2011 –
Journal of the
German Society and
Dermatology
Hypothesis
Dutasteride is superior to finasteride in the
treatment of androgenic alopecia based on
pharmacologic action.
Clinical Question
Is dutasteride superior to finasteride in the *treatment
of androgenic alopecia?
*Treatment: returning hair density and thickness to as close to pre-AGA as possible and
with little-to-no quality of life impairing side effects.
"A randomized, active- and placebo-controlled
study of the efficacy and safety of different doses
of dutasteride versus placebo and finasteride in the
treatment of male subjects with androgenetic
alopecia"
Gubelin Harcha, Walter, et al. Journal of the American Academy
of Dermatology, U.S. National Library of Medicine, Mar. 2014
Objective: The authors of the study aimed to compare both
the efficacy and the safety of dutasteride to finasteride and
placebo in men with androgenetic alopecia.
Background: DHT is the main androgen causative
of androgentic alopecia, a psychologically and physically
harmful condition warranting medical treatment.
Design of Study
• Randomized • 29-week study conducted at 39
• Double blinded, centers in 9 countries (Argentina,
Chile, Japan, Mexico, Philippines, Peru,
double dummy Russian Federation, Taiwan, and
• Placebo controlled Thailand)
• Parallell assigned • Up to 3 week screening period
• Interventional • 24 weeks of treatment
• Phase III Clincial trial • 2 week followup
Methodology
• Men Aged 20-50 years having androgenic alopecia
• Randomized in 1 of 5 study arms (all medications on once daily basis for 24
weeks)
• Dutasteride 0.02mg
• Dutasteride 0.1mg
• Dutasteride 0.5mg
• Finasteride 1mg
• Placebo
Inclusion Criteria
• 20-50 years
• Male
• NW Type III-vertex,
IV, or V
Exclusion Criteria
• Scarring of the scalp
• Use of dutasteride in previous 18 months
• Use of finasteride within previous 12 months
• Hair transplantation or hair weaving within 6 months
• Use of Minoxidil within previous 6 months
• Use of drugs with anti-androgenetic/androgenetic properties within previous 6 months
• Use of Drugs that cause hypertrichosis or hypotrichosis within previous 6 months
• Light or laser treatment of scalp within previous 3 months
• Cosmetic products aimed at improving or correcting signs of hair loss within previous 2 weeks
Study Endpoints
Primary Secondary
• Hair count in a 2.54cm • Hair count in 1.13cm diameter on scalp
diameter on scalp • Width measurement of bald area
• Photographic assessments by
investigators and panel
• Change in NW stage
• Health Outcomes
Assessments
• Primary efficacy end point: change from baseline in hair count within a 2.54cm
diameter using macrophotographic technique.
• Secondary panel consisted of 3 dermatologists using global
photographic assessment.
• Investigator assessment included Investigator Photographic
Assessment Questionnaire (IPAQ)
• Questionnaires that assessed patient satisfaction with hair growth on a graded
scale at 12 and 24 weeks
Assessments
• Sexual Problems
• 3 question problem assessment scale of Sexual Function Inventory at
6, 12, and 24 weeks
• Adverse events monitoring
• Vital signs
• Clinical laboratory tests
• Breast examinations
• Prostate specific antigen levels
Statistical Analyses
• 20% post randomization dropout rate estimation
• n=900 * 0.2 = 720 (~715 completers)
• 715/5 arms = 143 patients/arm
• Needed for 90% power to test non-inferiority of a single dutasteride dose versus
finasteride at the 1-sided significance level with a 35-hair noninferiority margin.
• 715 completers also provided more than 99% power at the 2-sided 0.0167
significance level to detect a 100-hair superiority margin of dutasteride over
placebo and finasteride.
Statistical Analyses
1. Dutasteride vs placebo > superiority test
This Photo by Unknown author is licensed under CC BY-SA.
This Photo by Unknown author is licensed under CC BY.
Statistical Analyses
1. Dutasteride vs placebo > superiority test
2. Dutasteride vs Finasteride > noninferiority test
This Photo by Unknown author is licensed under CC BY-SA.
Statistical Analyses
1. Dutasteride vs placebo > superiority test
This Photo by Unknown author is licensed under CC BY-SA.
2. Dutasteride vs Finasteride > noninferiority test
3. Dutasteride vs Finasteride > superiority test
Statistical Analyses
• Intent to treat population: All randomized, used for efficacy, safety, and
health outcome analyses.
• Per protocol population: confirm noninferiority analysis results
for primary endpoint.
• General linear analysis model: Primary and secondary endpoints of
growth/restoration along with all scoring
scales/assessments/questionnaires
• Fisher exact test: AE's, drug related AE's, and AE's leading to withdraw
Results
• Intent to treat population: 917 patients
• Completed study: 761
• 90% of subjects were compliant with study treatment
• Assessed by pill count
• 75% to 125% of assigned study drug was taken
Organization of
study groups
Primary Endpoint:
Hair Count
Secondary
Endpoint: Hair
Width at 24
weeks
(units in
micrometers)
47
% { ~35
% {
39
% { 29
% {
And just to drive a point home...
Summarization of Results
• Non inferiority was achieved by Dutasteride 0.5mg and 0.1mg compared
to Finasteride 1mg (CI 99.165%).
• Noninferiority demonstrated if the lower end of the CI was greater than -35 hairs
and results were 6.1-60 at week 24.
• Superiority (positive difference of 100 hairs) was only achieved
by Dutasteride 0.5mg at weeks 12 and 24 (P = .003) in overall hair count
and in overall thickness.
Authors Conclusion
In this study, dutasteride 0.5 mg was statistically superior to finasteride 1 mg and
placebo, whereas finasteride was superior to placebo, at increasing hair count and width
after 24 weeks of treatment in men with androgenetic alopecia.
Consistent with previously reported data, dutasteride and finasteride were relatively well
tolerated with similar tolerability data reported here for both active treatments.
Because of short treatment duration in this study, long-term data may be required to
establish the full effects of dutasteride versus finasteride on hair growth and restoration.
Seminarian Assessment of Study
Strengths Weaknessess
• Large study size for hairloss • Narrow hair loss profile
• Methodology to challenge current • IPAQ assessed investigator
accepted treatment "satisfaction" and NW scale changes.
• Assessement for side effects • Nonvellus hair definition.
• 30mm but also "thick and noticible"
• Measurement systems to track hair
growth/count • Duration
"Superiority of dutasteride over finasteride in hair regrowth and
reversal of miniaturization in men with androgenetic alopecia: A
randomized controlled open-label, evaluator-blinded study"
Shanshanwal, Sujit J S, and Rachita S Dhurat. Indian Journal of Dermatology,
Venereology and Leprology, U.S. National Library of Medicine, 2017, Jan-
Feb;83(1):47-54
Objective: To compare the efficacy, safety and tolerability of
dutasteride and finasteride in men with androgenetic alopecia.
Background: Due to the locations and proportions of 5 alpha reductase
enzymes, it is theorized dutasteride will be more effective than finasteride
in the treatment of AGA
Design of Study
• Randomized control • 24 week study at the Medical
• Open label College and Hospital in Sion,
Mumbai from January 2013 to
• Parallel May 2014
• Prospective
• Superiority study
Methodology
• Ninety patients who fulfilled the inclusion and exclusion criteria were recruited
after taking informed consent and randomized to receive either 0.5 mg dutasteride
or 1 mg finasteride daily for a period of 24 weeks.
• Sample size calculated based on the mean and standard deviation of the two
groups were used from the study by Olsen et al.
• Calculated size: 31.17/group. Therefore sample size of 45 to account for dropout.
• Study arms: Finasteride 1mg/day and Dutasteride 0.5mg/day
J Am Acad Dermatol. 2006 Dec;55(6):1014-23
Inclusion Criteria
• Age 18-40 Males
• NW pattern III-V, IV, or V (excluding IV or V
anterior)
• Non NW patterned androgenic alopecia
involving vertex classified as F1, F2, F3
• "Female pattern hairloss"
• Patients using within the past 6 months:
• Minoxidil
• Anti-androgenic medications
• Drugs causing hypertrichosis (phenytoin,
Exclusion acetazolamide, cyclosporine, daizoxide,
psoralens, penicillamine, streptomycin,
Criteria cortisone)
• Drugs causing hypotrichosis (anti-
coagulants, retinoids, lithium and beta
blockers)
• Known systemic illnesses, tobacco users,
history of breast/prostate cancer
Study Endpoints
Primary Secondary
• Hair counts • Subjective evaluation
• Strands • Global Panel
• Thick vs thin hairs • Adverse effect profile
Assessments
• Global photography assessments
• Performed by blinded and non-blinded dermatologists using standardized
photographs of the vertex scalp taken by placing the head on a stereotactic
positioning device.
• Reviewed photographs taken at 12 and 24 weeks using a 7-point scale
• (Greatly increased (+3), moderately increased (+2), slightly increased (+1), unchanged
(0), slightly decreased (−1), moderately decreased (−2) and greatly decreased (−3).
Assessments
• Phototrichogram
• Growth of new hair and reversal of miniaturization was estimated by total
and thin hair counts performed on vertex bald spot with hair clipped to
1mm
• Tattoos were diagonally placed for reproducibility of target area to measure
number of hairs per cm2
• Used to measure changes in thick and thin hair count
Photo trigonometry? Photo tricuspid valve? Photo trichomonas?
Phototrichogram
[Link]
[Link]
Assessment
Subjective Evaluation Hair growth 3-point rating Overall satisfaction on scale
scale (increased, no change, of 0 (no change) to 5
Size of vertex balding area
decreased) (marked improvement)
Hair loss on top of scalp
Bitemporal recession
Amount of hair shedding
Hair quality
Overall satisfaction with hair
growth
Assessment
• Safety
• Performed through enquiry, physical exam, and laboratory
evaluation
• Hemogram and liver functions tests at baseline, 3 months, and
completion of treatment
• Sexual function questionnaire specifically asked about
occurrence of:
• Decreased libido
• Erectile dysfunction
• Ejaculation disorders
• Data were analyzed using Statistical Package
for the Social Sciences (SPSS) version 18
software by IBM Corporation
• Chi-square test with continuity and Fischer's
exact tests were used for evaluation of
investigator assessment of global photographs
Statistical and subjective parameters, and also all forms of
adverse effects.
Analyses • Cohen's kappa (κ) was used to measure the
degree of inter-investigator agreement.
• Mann–Whitney U-test was used to evaluate the
hair count parameter
• P<0.05 was considered statistically significant
Results
• Demographics
• Differences in baseline characteristics between Finasteride group and Dutasteride group were not
statistically significant.
• Grades of AGA were equally distributed in both groups (P=0.261)
• Mean ages of groups
• Dutasteride: 27.6 years
• Finasteride: 28.1 years
• NW grades (P>0.1)
• IV= 30.6% of patients
• V = 26.4% of patients
Result
s
• 72 patients completed
the study
• 4 patients withdrew
consent
• 3 patients withdrew
due to sexual side
effects
• Dropout rate
comparable between
groups (P=0.793)
Study Endpoint Data
Dutasteride patient
Pre treatment Post treatment
Results
Reversal of Miniaturization
• Thin hair count decreased significantly (n/cm 2 =Thin hair at
baseline-24week thin hair count). Changes in values:
• -7.37/cm 2 in dutasteride group
• -1.27/cm 2 in finasteride group
Pre treatment
overlain a
negative of
post
treatment.
Results
• Global photography assessment
• Dutasteride group: showed higher marked improvement in both
blinded and non-blinded evaluations (P<0.001)
• Kappa coefficient for scores by the 2 dermatologists for assessment of
hair growth
• Dutasteride: 0.742
• Finasteride: 0.789
Great
improvement
Great
improvement
Moderate
improvement
Slight
improvement
Slight
improvement
Safety Assessment
• Reported adverse events post-randomization were mild to moderate
• Dutasteride group n = 8
• Finasteride group n = 7
Sexual Side effect Dutasteride Finasteride
Erectile Dysfunction 3 1
Loss of libido 4 3
No statistical significance between groups in regards AE, drug related AE, AE leading to
withdrawal and specifically sexual AE
Authors Conclusion
• Dutasteride 0.5mg was found to be more effective than finasteride 1mg in men aged
18-40 years with androgenetic alopecia as assessed by hair counts, subject self
assessment, and blinded and non-blinded evaluation of global photographs.
• The change in hair counts in the dutasteride group in our study was comparable with
previously published data.
• The incidence of sexual side effects in this study in the dutasteride group (15.6%) was
similar to that reported in a previous study Jung et al. (17.1%)
• Limitations to the study include the short duration (6 months), small sample size and
being an open label study.
Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, et al
• Strengths of the study:
• Use of Trichogram for accurate hair
measurements (growth and thickness)
Review of • Concise use of definitions and
Study incorporation of picture-definition
associations
• Incorporation of previous study data
• Weaknesses of the study:
• I agree with all weaknesses listed by
author
• Size, duration, open-label
Review of • Panel only included two dermatologists,
low variance and generalizability
Study • Hair assessment is not formulistic enough
• Sexual side effect assessment was
leading
• Low ethnic variation
Summary of Seminar
• Androgenic Alopecia is driven by DHT
• Finasteride is currently the only 5-AR inhibitor in US approved for hair
loss.
• Dutasteride inhibits more 5-AR than finasteride. Especially 5-alpha
reductase 1 , which is mostly present in the scalp.
• Both studies found a degree of superiority in dutasteride compared to
finasteride, therefore disproving the null hypothesis.
Seminarians Conclusion
• Recognizing the strengths and weaknesses of the studies, Dutasteride 0.5mg is
superior to Finasteride 1mg in the treatment of androgenic alopecia.
• Applicability to Norwood types
• Thickening of existing hair follicles
• Improvement of growth of dormant follicles
• Low prevalence of adverse effect profile
• While superiority is represented I believe a stepwise approach should be used in the treatment of
AGA since it is fundamentally impacted hormones at a greater level and we still don’t know
enough about it.
Final Recommendations
• Dutasteride deserves a place in therapy for the treatment of Androgenic
Alopecia
• America needs to establish a system of guidelines or at least a
comprehensive evaluation of treatment options
• Hair loss is economically viable, psychologically taxing, and physiologically
nebulous… but there are options.
An unused, superior treatment
for androgenic alopecia
Jordan Owen Pharm D. Candidate 2020
This Photo by Unknown author is licensed under CC BY-NC-ND.
References
• Olsen EA, Hordinsky M, Whiting D, Stough D, Hobbs S, Ellis ML, et al. The importance of dual 5alpha-reductase inhibition in the treatment of
male pattern hair loss: Results of a randomized placebo-controlled study of dutasteride versus finasteride. J Am Acad Dermatol 2006;55:1014-
23.
• Study1: Gubelin Harcha, Walter, et al. “A Randomized, Active- and Placebo-Controlled Study of the Efficacy and Safety of Different Doses of
Dutasteride versus Placebo and Finasteride in the Treatment of Male Subjects with Androgenetic Alopecia.” Journal of the American Academy of
Dermatology, U.S. National Library of Medicine, Mar. 2014, [Link]
• Study2: Shanshanwal, Sujit J S, and Rachita S Dhurat. “Superiority of Dutasteride over Finasteride in Hair Regrowth and Reversal of
Miniaturization in Men with Androgenetic Alopecia: A Randomized Controlled Open-Label, Evaluator-Blinded Study.” Indian Journal of
Dermatology, Venereology and Leprology, U.S. National Library of Medicine, 2017, [Link]
• Google Image Result for Https://[Link]/Cosmetics/Cosmetics-05-00028/article_deploy/Html/Images/[Link],
[Link]
• “Google Image Result for Https://[Link]/Var/wrbm_gb_food_pharma/Storage/Images/5/7/4/0/3140475-1-Eng-GB/Further-
Understanding-of-Hair-Follicles-Leads-to-Breakthrough-for-L-Oreal-scientist_wrbm_large.Jpg.” L, [Link]
.
• American Hair Loss Association, Paul McAndrews. American Hair Loss Association - Men's Hair Loss / Introduction,
[Link]
• Guarrera M, Cardo P, Arrigo P, Rebora A (2009). "Reliability of hamilton-norwood classification". Int J Trichology. 1 (2): 120–2.
• Koo JY, Shellow WV, Hallman CP, Edwards JE. Alopecia areata and increased prevalence of psychiatric disorders. Int J Dermatol 1994; 33:
849–50.
• Kische, Hanna. “Sex Hormones and Hair Loss.” JAMA Dermatology, American Medical Association, 1 Sept. 2017,
[Link]
• Thigpen, A E, et al. “Tissue Distribution and Ontogeny of Steroid 5 Alpha-Reductase Isozyme Expression.” The Journal of Clinical
Investigation, U.S. National Library of Medicine, J Clin Invest; 92(2): 903–910 Aug. 1993,
[Link]
• Libecco JF, Bergfeld WF (April 2004). "Finasteride in the treatment of alopecia". Expert Opin Pharmacother. 5 (4): 933–40.
• Traish, Abdulmaged M.; Krakowsky, Yonah; Doros, Gheorghe; Morgentaler, Abraham (2018-08-08). "Do 5α-Reductase Inhibitors Raise
Circulating Serum Testosterone Levels? A Comprehensive Review and Meta-Analysis to Explaining Paradoxical Results". Sexual
Medicine Reviews. 7: 95–114.
• Kische, Hanna. “Sex Hormones and Hair Loss.” JAMA Dermatology, American Medical Association, 1 Sept. JAMA
Dermatol. 2017;153(9):935-937 2017, [Link]
• Adil A, Godwin M (July 2017). "The effectiveness of treatments for androgenetic alopecia: A systematic review and meta-analysis". Journal
of the American Academy of Dermatology. 77 (1): 136–141.e5.
• Kanti, V., et al. “Evidence‐Based (S3) Guideline for the Treatment of Androgenetic Alopecia in Women and in Men – Short Version - Kanti -
2018 - Journal of the European Academy of Dermatology and Venereology - Wiley Online Library.” Journal of the European Academy of
Dermatology and Venereology, John Wiley & Sons, Ltd (10.1111), 27 Nov. 2017, [Link]
• Jung JY, Yeon JH, Choi JW, Kwon SH, Kim BJ, Youn SW, et al. Effect of dutasteride 0.5 mg/d in men with androgenetic alopecia recalcitrant to
finasteride. Int J Dermatol 2014;53:1351-7
Assessment Question 1
What Isoenzyme of 5 alpha reductase does Dutasteride inhibit that is not
inhibited by finasteride much?
a) Isoenzyme I
b) Isoenzyme II
c) Isoenzyme III
d) Isoenzyme IV
Assessment Question 2
• Europe does not have a guideline for the level of evidence and efficacy of
approved drugs for hair loss.
a) T
b) F
Assessment Question 3
How does the mechanism of action of Dutasteride reduce the rate of hair
loss?
a) Reduces the amount of testosterone in the scalp
b) Inhibits conversion of androgens
c) Promotes growth supporting hormones
d) Dilates the vessels in the scalp to increase blood flow
Assessment Question 4
Which hormone is the suspected culprit of hair loss regarding Male Pattern
Baldness?
a) Testosterone
b) Dihydrotestosterone
c) DHEA
d) Progesterone