From th e Department of Biochemistry and Molecular Biology,
University of Miami School of Medicine; and Alopecia Research
and Associated Technologies (ARATEC), Ocala, FL.
Address reprint requests to Marry E. Sawaya, MD, PhD,
Adjunct Professor, Department of Biochemistry and Molecular
Biology, University of Miami School of Medicine and ARATEC,
PO Box 7, Ocala, FL 34478.
Recent approval in the United States of two new
products, Propecia (Merck Co, Rahway, N J) and
Rogaine Extra Strength 5% (Pharmacia & Up John
Co, Kalamazoo, MI), indicated in men to Promote
scalp hair growth, have added a new dimension to
treatment options offered by physicians in treating
androgenetic alopecia (AGA). The search for new
and effective agents to treat many different hair
loss problems has been intensified by the increase
in hair biology research taking place worldwide,
from university-academic institutions to the pharmaceutical
companies. All have a desire to profit
from marketing such drugs that have been termed,
"cosmeceuticals." Millions of men and women of
every race suffer from various forms of alopecia,
the most common being AGA where the target
tissue active androgen, 5 alpha-dihydrotestosterone
i(DHT) aggravates genetically programmed
scalp hair follicles that results in Short, fine, miniaturized
hairs. Currently available to treat alopecia
are drugs indicated for other disease processes
because no other agents are accessable; some
have severe side-effects and many are minimally
effective. These prescription drugs were not originally
indicated for alopecia and have not been
adequately tested in controlled clinical trials to
assess for efficacy, safety, and toxicity. These
agents continue to be used clinically to treat
patients with various forms of alopecia. As a result,
a variety of new agents are emerging in the patient
application process to gain protection and approval
specifically for various forms of alopecia.
This report reviews the most recently approved
products, some of the more promising compounds
in clinical trial development, as well as those in the
over the counter (OTC) "natural" treatments category. T HERE ARE VARIOUS forms of alopecia, the
most common being androgenetic alopecia
(AGA), which affects millions of men and women.
The severity of hair loss in women is usually
much less than in men. 1 Hair loss for both men
and women may begin as early as the teen years,
but can even start in later decades of life. In men
with AGA, one of the earliest findings is an
increase in the percentage of hairs in a telogen
phase of the hair cycle, so that initial hair loss
may appear indistinguishable from a telogen
effluvium. Similar to that in men, AGA in women
can be psychologically devastating to accept,
giving less overall body-image satisfaction and
making it difficult to cope and retain integrity of
personality functioning. 2 AGA has been reported
to be an autosomal dominant trait with partial or
variable penetrance 3 for both men and women.
BIOCHEMICAL ADVANCES FOR MEN
AND WOMEN WITH AGA
Although for many years it had been assumed
that the hormonal basis for AGA in women was
the same as for men, no studies have confirmed
this. Recent word has shown that on the scalp
there are local differences in the amounts of
steroid metabolizing enzymes that convert weak
androgens to more potent androgens (Fig 1). This
is important because the skin is an endocrine
target tissue for androgen hormone action, similar
to ovary, testes, and the adrenal gland. Studies
have shown that persons using anabolic-androgenic
steroids show hypertrophy of sebaceous
glands, with systemic hirsutism, and AGA. 4 In
Figure 1, the hormone pathway describes the
potential of weak and abundant precursor hormones
such as DHEA (dehydroepiandrosterone)
to be metabolized to more potent androgens such
as testosterone (T) and dihydrotestosterone
(DHT). The enzymes have been localized in
sebaceous glands and hair follicles of scalp skin. 1,5
Therefore, the skin has the potential to mediate androgen action without relying on elevated systemic
levels or production of T or DHT. 4,6,7
An important enzyme in the Figure 1 pathway
is 5 alpha-rednctase (5aR), which mediates reduction
of T to DHT, via the reduced pyridine
cofactor, nicotinamide adenine dinucleotide phosphate
(NADPH). There are two forms of 5aR, type
I, which is thought to be primarily in the skin,
especially sebaceous glands, as well as the kidney
and liver; type II isoenzyme is predominant in
gonadal tissues, ie, prostate, seminal vesicles, and
others, but in recent years, it was also found in
hair follicles on the scalp where miniaturization
takes place. This finding explains how finasteride
has hair growth-promoting properties, indicating
efficacy for these specific androgen inhibitors
against the type I or II isoenzyme form for
treating these androgen related skin conditions. 8,9
Overall, the importance of 5aR and the two
specific isoenzyme forms are apparent because
the tissue distribution in the body differs, as well
as biochemical characteristics of the enzymes.
The isolation of these two 5al~ forms raises
interesting questions concerning regulation and
their specific roles in androgen physiology because
new compounds will be designed to target
one specific enzyme or both enzyme forms,
depending on the condition being treated.
Another important enzyme that has come to
recent attention is the cytochrome P-450 aromatase
enzyme (Fig 1). Because it,is known that
androgen metabolism occurs within the hair
follicle structure, finding aromatase to be specifically
located in outer root sheath of hair follicles
adds to the importance of studying the entire hair
follicle and not just the dermal papilla ceils. 1,5
Aromatase has been shown to convert androgens
such as T, and androstenedione to the estrogens,
estradiol and estrone, respectively. It was also
found that in women, there may be two- to
five-fold greater levels of aromatase in female
scalp versus male, perhaps explaining why women
may have a sparing of the frontal hairline in AGA
and may have a less severe pattern of hair loss
than men. 1 It is uncertain if the estrogens formed
from aromatase are playing a role in suppressing
the severity of hair loss, or whether aromatase is
primarily reducing the overall load of androgens
formed locally in the hair follicle.
The next very important step to understanding
androgen action in skin is the binding of the
target tissue active androgens, T and DHT, to the
androgen receptor (Fig 2). The androgen receptor
(AR) has been purified and located in specific
skin structures, such as hair follicles and sebaceous
glands, l~ Although the mechanism described
in Figure 2 depicts T binding to the AR,
we are now realizing that very complex enzyme
mechanisms such as phosphorylation and sulfhydryl
reduction of this receptor are important in
forming an activated hormone-AR complex that
has the ability to bind to specific hormone response
elements at gene sites in the nucleus to stimulate or alter cellular processes mediating
hair growth.~2q5
CLINICAL OBSERVATIONS OF AGA
In genetically predisposed men, the balding
process is triggered by exposure to androgens at
puberty. In women, the relationship between
systemic elevated androgen levels and alopecia is
difficult to determine, because approximately
30% to 40% of women who exPerience AGA have
a systemic endocrine problem, leaving the condition
in a majority of women to be called idiopathic.
We are now finding that many patients
who were once called ~ have qualitative
differences in the N-terminal domain of the
androgen receptor where the number of polyglutatmine
repeats can render androgen sensitivity.
16-I8 Therefore, quantitative and qualitative
factors targeting the androgen receptor must be
recognized before considering treatment options
because not all patients may respond to conventional
treatments based on 5aR, or other nonreceptot-
mediated mechanisms.
Based on these direct mechanisms regarding
cellular DHT metabolism via quantitative and
qualitative aspects to the 5aR isoenzymes and AR
in AGA, it is important to also keep in mind that
some therapies may even target cofactors that
mediate these reactions, such as reduced NADPH,
which is necessary in mediating 5aR of testosterone
to DHT. Therefore, these "secondary" mechanisms
must be considered because novel therapeutics
may target this direction as well (see Zinc).
Previous publications 19 provide a more detailed
overview of novel agents for alopecia; however,
this review will cover some of the more pertinent
agents approaching the marketplace for clinical
application.
5aR Inhibitors
In this category there are the structural steroid
competitive inhibitors that chemically resemble
the substrate, T and bind to the active site of the
enzyme so that DHT is not formed.
Table 1 describes 5aR inhibitors along with
their structures, trade names (chemical names),
and indication(s).
In Propecia (finasteride; Merck Co, Rahway,_
NJ) has recently been approved by the Food and
Drug Administration (FDA) in the US for men
with AGA. Propecia is a specific 5aR type II
enzyme inhibitor and does not bind to the AR;
therefore, it is not called an antiandrogen, but an
androgen inhibitor. The pharmokinetics of finasteride show that
after a 1 mg dose, serum concentration of DHT
decreases by 65% in 24 hours. Serum concentrations
of testosterone and estradiol increase about
15%, but remain within normal limits. Prostate
concentrations of testosterone increase about sixfold.
20 Finasteride is well absorbed in the gastrointestinal
tract, metabolized in the liver, and excreted
in urine and feces, with a half-life of 5 to 6
hours. Small nanogram levels of the drug are
detectable in human semen; this is not thought,
however, to have any consequence in women who
are exposed by sexual contact.
Three double-blind multicenter trials were conducted
in men ages 18 to 41 yeardand the results
of these trials have been presented as ab,
stracts. 21-22 In combined results from two of the
trials, 1,553 men with mild to moderate male
AGA of the vertex took finasteride 1 mg/day or
placebo orally for 1 year. After 3 months of
treatment, the men who took finasteride were
more satisfied with the appearance of their hair.
At the end of 1 year, in a circle on the vertex scalp,
a 1 inch diameter-mean baseline hair count was
876; patients who took the drug had an average of
107 more hairs than those who took the placebo.
Hair counts were maintained for up to 24 months
in the men who continued to take the drug. 22 A
third study of 326 men with mild to moderate
frontal hair loss found that after 1 year, finasteridetreated
men had statistically significantly higher
hair counts on the frontal scalp. Approximately
50% of treated men and 30% of those who took
placebo thought the appearance of their hair had
improved. Hair regrowth was not reported in
older men taking 5 mg finasteride (Proscar;
Merck Co, Rahway, NJ), perhaps because it was
not indicated in those trials to make observations
on the scalp.
Adverse events described with 5 mg finasteride
(Proscar) in a small perent of older men were loss
of libido, erection, ejaculatory dysfunction, hypersensitivity
reactions, gynecomastia, and severe
myopathy. 2~ Finasteride causes a 30% to 50%
decrease in prostate specific antigen (PSA) in
clinical trials with 1 mg tablets in men 18 to 41
years old. A decreased libido, erectile dysfunction,
or a decreased volume of ejaculate have been reported in less than 2% of patients, which in
reality is between 0.5% to 1% when compared
with placebo. Finasteride had teratogenic effects
in'animals on high doses, causing genitourinary
abnormalities in male offspring. The concentration of
the drug in semen of men who took 1 mg/day was
much lower than the concentration associated with
teratogenic effects in monkeys. The Merck manufacturers
warn that women who are or may be
pregnant should not have exposure to finasteride
orally or handle crushed or broken tablets.
Thirty tablets of Propecia 1 mg/day cost the
pharmacist less than $47, according to wholesale
price (AWP) listings, whereas 30 tablets of Proscar
5 mg/day cost less than $64.
GI198745 (GlaxoWellcome, Research Triangle
Park, NC) investigational compound is currently
in clinical trial studies around the US for men
with AGA. Structurally, as shown in Table 1, it is
similar to the parent structure of finasteride,
maintaining the 4-aza structure of the steroid
nucleus; however, on the 21-carbon position is a
tri-fluorophenyl group that renders the molecule
to be electronegative and perhaps gives greater
affinity for both the type I and II isoenzyme forms
of 5aR. 23 Therefore, this drug is similar to finasteride,
in that both competitively inhibit .SaR;
however, finasteride is specific for inhibiting type
II, whereas GI198745 inhibits both isoenzymes.
This compound is known to inhibit >90% serum
DHT levels in 24 hours after oral administration,
and because of this greater ability to inhibit DHT,
it may be more effective in promoting hair growth
on the scalp of men, as well as treating acne, with
clinical trials results still pending.
WO9704002 is a new compound undergoing
patent review for Pharmacia & Upjohn Co
(Kalamazoo, MI).19 It has great structural similarity
to the above two compounds, with activity
against 5aR inhibition similar to GI198745. This
compound is not available, an&it is not known if
there are plans for clinical trial development at
this time, but has been indicated for AGA and
other dermatologic hormone-related conditions.
Vascular/Angiogenic-Related
Compounds
Regaine/Rogaine (minoxidil; Pharmacia & Up-
John Co, Kalamazoo, MI) 2% has been used
worldwide for over 10 years, and is now over the
counter (OTC) in the US. Most recently, Extra
Strength 5% Rogaine (Pharmacia & UpJohn Co)
has hit the OTC shelves in the US, with approval
on November 1997. Pharmacia & Upjohn has
sole rights to being the only manufacturer for the
next 3 years for this new version of minoxidil,
which is indicated only for men.
Despite lack of understanding of the distinct
mechanism of action, in women it has been
shown to increase the nonvellus hairs when using
it for 32 weeks or more. 2~ One potential drawback
to minoxidil therapy is that spontaneous reversal
to the pretreatment state can be expected 1 to 3
months after.cessation of therapy, indicating minoxidil
has a direct effect on the hair follicle,
sensitizing it and making it dependent on the
drug for future growth. In the US, various generic
brands are now available OTC, which have
brought down the price of minoxidil therapy
from $50/bottle when it was Rogaine, a prescription
product, to now approximately $10 to $15
dollars per generic bottle, which lasts about 1
month. Rogaine Extra Strength costs the pharmacist
approximately $28.32 for 60 mL, who can
raise the price to the consumer; therefore, good
advice to patients would be to to shop around
before buying the product, at least in the US.
The mechanism of action although still unclear,
seems to open potassium channels and
increases proliferation and differentiation of epithelial
cells in the hair shaft. 2~
Serum concentrations after topical application of 2% minoxidil, used twice a day, (about 5% of
those with oral minoxidil), and of the 5% solution
(about 10% of those with the oral drug), have
been reported in some patients using 2% solution.
Minoxidil is metabolized in the liver and excreted
in the urine.
As far as effectiveness, four unpublished 32 to
48 week studies presented to the FDA compared
the effects of placebo, 2% minoxidil, and 5%
minoxidil by counting the net gain in hairs in 1
cm 2 areas of the scalp. As described, 2~ two studies
in women did not find statistically significant
differences between 2% and 5% minoxidil. A
32-week study in men found that the mean
increase from baseline in hairs/cm 2 was 5 with
placebo, 30 with 2% minoxidil, and 39 with 5%
minoxidil. A 48-week study in men found a mean
increase in hairs/cm 2 of 3.9 with placebo, 12.7 with 2% m.inoxidil, and 18.5 with 5% minoxidil.
Previous studies have shown that when the drug
is stopped, all of the newly regrown hair falls
out. 2~ I~espite these reports, the new advertisements
claim 45% more effective hair growth than
regular strength 2%, with regrowth occurring as
early as 2 months, with five times more hair
regrowth overall than placebo and with no major
safety concerns. Most physicians and lay people
who have been using minoxidil for many years
are not concerned about safety aspects because
most feel it to be a very safe product. Concerns are
more focused on the effectiveness of the product
in promoting and maintaining hair growth. The
5% Extra Strength brings a new glimmer of hope
by showing improved hair growth for individuals
that may not have seen results with 2% minoxidil.
Adverse effects noted with oral minoxidil include
tachycardia, angina pectoris, and fluid retention.
When taken orally during pregnancy, minoxidil
has been associated with hypertrichosis of the
fetus and congenital anomalies. One double-blind
study in 35 balding men found that topical use of
2% minoxidil caused small but statistically significant
increases in left ventricular end-diastolic
volume, cardiac output, and left ventricular mass. 2~
Infrequently, dizziness and tachycardia have been
reported with 2% solution, and patients are advised
to reduce frequency of application, which
helps to eliminate these side effects. Local irritation,
itching, dryness, and erythema may occur
with use of topical minoxidil, most likely caused
by the vehicle formulation of alcohol and propylene
glycol.
The conclusion on minoxidil 5% and 2% solutions
are that they can produce a modest increase
in hair growth on scalps of young men with mild
to moderate hair loss, with continuous application
for years to maintain the effect. Questions as
to the use of 5% Extra Strength in women are
being posed, with some cliniciang already giving
this to young women with early hair loss, even
though it is only indicated by the manufacturer,
Pharmacia & Upjohn Co, for use in men.
Combinations. Many patients may be asking
their physicians now and in the future about
using both topical Extra Strength 5% Rogaine
along with oral Propecia 1 rag/day, which many
believe may be beneficial working together synergistically;
however, further human clinical trials
are needed to verify this because the only previous
study was performed in the macaque monkey
model, which did show benefit when used together.
25
Although other vasodilatory/angiogenic related
compounds are progressing through the development
pipeline, 19 it is difficult to ascertain their
effectiveness at this time until human clinical
trials are performed. Many compounds that mimic
minoxidil in vasodilatory properties fail to show
the same results, hence there may still be a unique
mode of action about this compound that is yet to
be fully uncovered. Unpublished investigations
have suggested-minoxidil to have oxidativereductive
potential to facilitate cofactor reactions
necessary in side chain steps for hair follicle
growth, as well as other suggestions of stimulating
some of the keratin genes of hair matrix cells
for synthesis of hair shaft keratins, producing
thin, fine, indeterminate hairs often seen with
continued use of minoxidil.
Other New Compounds in Development
lamin (prezatide copper). Iamin (Procyte
Co, Seattle, WA) is a new drug that was just
FDA approved in 1996, which is one of the
superoxide dismutases (copper binding peptide).
It was FDA approved as an antiinflammatory
wound healing geL-Procyte, the company that
makes Iamin, is working on getting approval for
one of its other superoxide dismutases, Tricomin,
for use in hair loss treatment. Iamin hit the
shelves in early July 1996, with results thus far
indicating that it may help some people with hair
loss. Some people have reported hair growth
related to Iamin, with most reporting a "strengthening
of existing hair. ''26
ProCyte have also announced release of another
product, GrafCyte, which is basically Iamin
in a few different forms. It has been approved by
the FDA for use after transplants to prevent newly
transplanted hairs from going into a resting
phase. They propose that more hairs will grow
immediately..after transplants and results may be
seen sooner than the typical 6 to 8 months. The
product will be released in moist press applications
to be applied for an hour, 4 times per day for
4 days after a hair transplam:: A mis~ spray and
shampoo have also been announced, with hopes
that it will be used by those suffering from hair loss in general; however the moist presses will
only be available to the transplant surgeons. 26
Polysorbate 80. Polysorbate 80, an OTC
product, has been around since the early 1980s as
it was first used in the Helsinki Formula sold on
television until the FDA banned such advertisements.
There were claims that it grew hair in
some people, but it was not effective in most
individuals who used it. perhaps those who did
see a hair growth response were noting hair that
was growing through successive miniaturization
cycles, which often happens in double-blind studies
where placebos have up to 30% improvement.
26
Folligen (copper chloride). Folligen is a
new treatment similar to Iamin Gel, but in cream
form contains not only a copper complex, but
Saw Palmetto (see later) for use as an androgen
inhibitor of 5aR. Again, another product that has
not been thoroughly tested for positive results in
double-blind clinical trials. 26
Saw Palmetto (serenoa repens). Serenoa
repens berries grow naturally, with the extract
claiming to be an androgen inhibitor of 5aR to
inhibit DHT production, mainly claimed for use
in prostate problems. There have not been extensive
studies performed, but implications in promoting
hair growth on the scalp have been
indicated. Side effects noted have been breast
growth in men, which may indicate that it does
not act on DHT alone. To be effective, the extract
of the berries must be taken, not the berries
themselves. Another active ingredient, pygeum
africanum compound, is added to this extract and
is thought to influence testosterone metabolism,
although it is not clear on how at this point. The
product comes in capsule form (60 capsules for
$11.80) with two to four capsules as the recommended
dose per day in divided doses between
meals. 26
Amino acids. Arginine/I2-arginine and/or
cysteine/L-cysteine have been proposed as play-
!ng a strong role in hair growth and offered in
nutrition health food stores to "make nails stronger
and help hair follicle to make more hair."
These amino acids can be taken alone or together
in oral liquid form with doses recommended at
500 to 1000 mg a few times a week. 26
Biotin and folic acid., These too have been
around for a long time with claims to help hair
grow. Nutritionally speaking, biotin and folic acid
are required for hair growth and are usually
supplied in a normal diet; therefore, unless there
is a deficiency in these because of poor nutrition
or wasting diseases, increased doses may not help
hair grow. In fact, excess megadoses of these may
cause hair loss, so if an adequate balanced diet is
being maintained, a general vitamin supplement
should do as well in providing nutritional needs
for hair growth requirements. 26
Zinc, A lot has been claimed about zinc for
use in various diseases, including topical use for
acne, another androgen related problem. 27 Specific
forms of zinc, ie, zinc acetate, zinc sulfate,
and others, have various properties that promote
wound healing, help treat acne, and promote hair
growth. The last few years spouted a new formulation
of zinc in a skin cap to treat scalp psoriasis,
and scaley, erythematous conditions of the skin,
with findings that the main ingredient was actually
clobetasol, a corticosteroid that was found'to
be the active ingredient that caused the great
improvement when used for various conditions.
In any case, it is cautioned that zinc may be an
important factor topically or for oral use depending
on the formulation of the zinc. Zinc sulfate
was found to be an inhibitor of DHT production,
not that it inhibits 5aR, but that it limits reduced
cofactor, NADPH,-which is necessary for the 5aR
of testosterone to form DHT. 26
A criticism to many of these herbal or OTC
remedies is that they are not governed by strict
FDA criteria, and that the purity, consistency, and
concentration of these agents can vary from batch
to batch, whether they are in liquid, pill, or
topical formulation.
In conclusion, there are various new novel
treatments for use in alopecia. Some of these have
gone through rigorous double-blind clinical trial
testing with FDA approval as to their proven
claims, whereas others have yet to do so. Although
many new products described here may
be approaching the marketplace, it is wise to
guide patients and advise them of how these
agents work and if they have been adequately
tested before spending their money and raising
their hopes. Realistic expectations should continue
to be the main guideline when offering any
treatment for alopecia.
REFERENCES
1. Sawaya ME, Price VH: Different levels of 5a-reductase
type F and II, aromatase, and androgen receptor in hair
follicles o'}"women and men with androgenetic alopecia. J
Invest Dermatol 109:296-300, 1997 "
2. Cash T: The psychological effects of androgenetic alopecia
in men. J Am Acad Dermatoi 26:926-931, 1992
3. Smith MA, Wells RS: Male-type alopecia, alopecia areata,
and normal hair in women. Arch Dermato189:95-98, 1964
4. Scott MJ, Scott AM: Effects of anabolic-androgenic
steroids on the pilosebaceous unit. Cutis 50:113-116, 1992
5. Sawaya ME, Penneys NS: Immunohistochemical distribution
of aromatase and 3B-hydroxysteroid dehydrogenase in
human hair follicle and sebaceous gland. J Cutan Pathol
19:309-314, 1991
6. Schweikert HU, Wilson JD: Regulation of human hair
growth by steroid hormones: II. Androstenedione metabolism
in isolated hairs. J Clin Endocrinol Metab 39:1012-1019, 1974
7. Sawaya ME, Honig LS, Garland LD: 3B-hydroxysteroid
dehydrogenase activity in sebaceous glands of scalp of malepattern
baldness. J Invest Dermato191:101-105, 1988
8. Anderson S, Bishop RW, Russell DW: Expression cloning
and regulation of steroid 5a-reductase, an enzyme essential for
male sexual differentiation. J Biol Chem 264:16249-i6252,
1989
9. Itami S, Kurata S, Sonoda T, et al: Characterization of
5a-reductase in cultured human dermal papilla cells from
beard and occipital hair. J Invest Dermato196:57-59, 1991
10. Sawaya ME: Purification of androgen receptors in
human sebocytes and hair. J Invest Dermato198:92-96, i992
11. Sawaya ME, Lewis LA, Hsia SL: Presence of a converting
factor for androgen receptor proteins in isolated human
hair follicles and sebaceous glands. FASEB J 2:4765-4767,
1989
12. Grody W, Schrader W, O'Malley B: Activation, transformation,
and subunit structure of steroid hormone receptors.
Endocr Rev 3:141-152, 1982
13. Peleg S, Schraader WT, O'Malley B: Sulfhydryl group
content of chicken progesterone receptor. Effect of oxidation
on DNA binding activity. Biochemistry 27:358-362, 1988
14. Sawaya ME: Androgen receptor regulation in human
hair follicles and sebaceous glands, in Matias J (ed): Androgens
and Antiandrogens. Proc Terra Symposia 1:i01-105,
1992
15. Sawaya ME, Mendez AJ, Hsia SL: Translocation of
androgen receptor protein complex into nuclei of hair follicles
and sebaceou s glands from human scalp. ] Invest Dermatol
90:605-606, 1988
16. Sawaya ME: Androgen receptor gene polymorphisms
effecting human hair follicle growth in hirsutism and androgenetic
alopecia. J Invest Dermatol 106:563, 1996 (abstr)
17. Hardy DO, Scher HI, Bogenreider T, et al: Androgen
receptor CAG repeat lengths in prostate cancer: Correlation
with age of onset. J Clin Endocrinol Metab 81:4400-4405,
1996
18. Sawaya ME, Shalita AR: Androgen receptor polymorphisms
(CAG repeat lengths) in androgenetic alopecia, hirsutism,
and acne. J CutanMed Surg 1998 (in press)
19. Sawaya ME: Alopecia---The search for novel agents
continues. Exp Opin Ther Patents 7:859-872, 1997
20. Abramowicz M: Propecia and rogaine extra strength for
alopecia. The Medical Letter 40:25-27, 1998
21. Kaufman K: Clinical studies on effects of oral finasteride,
a type 2 5a-reductase inhibitor on scalp hair in men with
male pattern baldness. Proceedings from the First Tricontinental
Meeting of Hair Research Societies, Brussels, Belgium,
October 16-19, 1995
22. Kaufman K: Updates of clinical phase III trial data and
results. Presented at the American Academy Dermatology
Meeting, San Francisco, CA, March 12-15, 1997; the World
Congress Meeting, Australia, June 8-10, 1997
23. Bramson HN, Hermann D, Batchelor KW, et al: The
unique preclinical characteristics of GG745, a potent dual
inhibitor of 5AR. J Pharmacol Exp Ther 1997
24. Kidwai BJ, George M: Hair loss and minoxidil withdrawal.
Lancet 340:609-610, 1992
25. Diani AR, Mulholland MJ, Shull KL, et al: Hair growth
effects of oral administration of finasteride, a steroid 5-alpha
reductase inhibitor, alone and in combination with topical
minoxidil in the balding stumptail macaque. J Clin Endocrino1
Metab 74:345-350, 1992
26. Pure Encapsulations. Sudbury, MA, 1998
26a. Hair Regrowth: The Less Research Treatments. www.regrowthhttp://.
com
27. Stamatiadis D, Bulteau-Portois MC, Mowszowicz I:
Inhibition of 5a-reductase activity in human skin by Zinc and
azelaic acid. BrJ Dermatol 119:627-632, 1988
University of Miami School of Medicine; and Alopecia Research
and Associated Technologies (ARATEC), Ocala, FL.
Address reprint requests to Marry E. Sawaya, MD, PhD,
Adjunct Professor, Department of Biochemistry and Molecular
Biology, University of Miami School of Medicine and ARATEC,
PO Box 7, Ocala, FL 34478.
Recent approval in the United States of two new
products, Propecia (Merck Co, Rahway, N J) and
Rogaine Extra Strength 5% (Pharmacia & Up John
Co, Kalamazoo, MI), indicated in men to Promote
scalp hair growth, have added a new dimension to
treatment options offered by physicians in treating
androgenetic alopecia (AGA). The search for new
and effective agents to treat many different hair
loss problems has been intensified by the increase
in hair biology research taking place worldwide,
from university-academic institutions to the pharmaceutical
companies. All have a desire to profit
from marketing such drugs that have been termed,
"cosmeceuticals." Millions of men and women of
every race suffer from various forms of alopecia,
the most common being AGA where the target
tissue active androgen, 5 alpha-dihydrotestosterone
i(DHT) aggravates genetically programmed
scalp hair follicles that results in Short, fine, miniaturized
hairs. Currently available to treat alopecia
are drugs indicated for other disease processes
because no other agents are accessable; some
have severe side-effects and many are minimally
effective. These prescription drugs were not originally
indicated for alopecia and have not been
adequately tested in controlled clinical trials to
assess for efficacy, safety, and toxicity. These
agents continue to be used clinically to treat
patients with various forms of alopecia. As a result,
a variety of new agents are emerging in the patient
application process to gain protection and approval
specifically for various forms of alopecia.
This report reviews the most recently approved
products, some of the more promising compounds
in clinical trial development, as well as those in the
over the counter (OTC) "natural" treatments category. T HERE ARE VARIOUS forms of alopecia, the
most common being androgenetic alopecia
(AGA), which affects millions of men and women.
The severity of hair loss in women is usually
much less than in men. 1 Hair loss for both men
and women may begin as early as the teen years,
but can even start in later decades of life. In men
with AGA, one of the earliest findings is an
increase in the percentage of hairs in a telogen
phase of the hair cycle, so that initial hair loss
may appear indistinguishable from a telogen
effluvium. Similar to that in men, AGA in women
can be psychologically devastating to accept,
giving less overall body-image satisfaction and
making it difficult to cope and retain integrity of
personality functioning. 2 AGA has been reported
to be an autosomal dominant trait with partial or
variable penetrance 3 for both men and women.
BIOCHEMICAL ADVANCES FOR MEN
AND WOMEN WITH AGA
Although for many years it had been assumed
that the hormonal basis for AGA in women was
the same as for men, no studies have confirmed
this. Recent word has shown that on the scalp
there are local differences in the amounts of
steroid metabolizing enzymes that convert weak
androgens to more potent androgens (Fig 1). This
is important because the skin is an endocrine
target tissue for androgen hormone action, similar
to ovary, testes, and the adrenal gland. Studies
have shown that persons using anabolic-androgenic
steroids show hypertrophy of sebaceous
glands, with systemic hirsutism, and AGA. 4 In
Figure 1, the hormone pathway describes the
potential of weak and abundant precursor hormones
such as DHEA (dehydroepiandrosterone)
to be metabolized to more potent androgens such
as testosterone (T) and dihydrotestosterone
(DHT). The enzymes have been localized in
sebaceous glands and hair follicles of scalp skin. 1,5
Therefore, the skin has the potential to mediate androgen action without relying on elevated systemic
levels or production of T or DHT. 4,6,7
An important enzyme in the Figure 1 pathway
is 5 alpha-rednctase (5aR), which mediates reduction
of T to DHT, via the reduced pyridine
cofactor, nicotinamide adenine dinucleotide phosphate
(NADPH). There are two forms of 5aR, type
I, which is thought to be primarily in the skin,
especially sebaceous glands, as well as the kidney
and liver; type II isoenzyme is predominant in
gonadal tissues, ie, prostate, seminal vesicles, and
others, but in recent years, it was also found in
hair follicles on the scalp where miniaturization
takes place. This finding explains how finasteride
has hair growth-promoting properties, indicating
efficacy for these specific androgen inhibitors
against the type I or II isoenzyme form for
treating these androgen related skin conditions. 8,9
Overall, the importance of 5aR and the two
specific isoenzyme forms are apparent because
the tissue distribution in the body differs, as well
as biochemical characteristics of the enzymes.
The isolation of these two 5al~ forms raises
interesting questions concerning regulation and
their specific roles in androgen physiology because
new compounds will be designed to target
one specific enzyme or both enzyme forms,
depending on the condition being treated.
Another important enzyme that has come to
recent attention is the cytochrome P-450 aromatase
enzyme (Fig 1). Because it,is known that
androgen metabolism occurs within the hair
follicle structure, finding aromatase to be specifically
located in outer root sheath of hair follicles
adds to the importance of studying the entire hair
follicle and not just the dermal papilla ceils. 1,5
Aromatase has been shown to convert androgens
such as T, and androstenedione to the estrogens,
estradiol and estrone, respectively. It was also
found that in women, there may be two- to
five-fold greater levels of aromatase in female
scalp versus male, perhaps explaining why women
may have a sparing of the frontal hairline in AGA
and may have a less severe pattern of hair loss
than men. 1 It is uncertain if the estrogens formed
from aromatase are playing a role in suppressing
the severity of hair loss, or whether aromatase is
primarily reducing the overall load of androgens
formed locally in the hair follicle.
The next very important step to understanding
androgen action in skin is the binding of the
target tissue active androgens, T and DHT, to the
androgen receptor (Fig 2). The androgen receptor
(AR) has been purified and located in specific
skin structures, such as hair follicles and sebaceous
glands, l~ Although the mechanism described
in Figure 2 depicts T binding to the AR,
we are now realizing that very complex enzyme
mechanisms such as phosphorylation and sulfhydryl
reduction of this receptor are important in
forming an activated hormone-AR complex that
has the ability to bind to specific hormone response
elements at gene sites in the nucleus to stimulate or alter cellular processes mediating
hair growth.~2q5
CLINICAL OBSERVATIONS OF AGA
In genetically predisposed men, the balding
process is triggered by exposure to androgens at
puberty. In women, the relationship between
systemic elevated androgen levels and alopecia is
difficult to determine, because approximately
30% to 40% of women who exPerience AGA have
a systemic endocrine problem, leaving the condition
in a majority of women to be called idiopathic.
We are now finding that many patients
who were once called ~ have qualitative
differences in the N-terminal domain of the
androgen receptor where the number of polyglutatmine
repeats can render androgen sensitivity.
16-I8 Therefore, quantitative and qualitative
factors targeting the androgen receptor must be
recognized before considering treatment options
because not all patients may respond to conventional
treatments based on 5aR, or other nonreceptot-
mediated mechanisms.
Based on these direct mechanisms regarding
cellular DHT metabolism via quantitative and
qualitative aspects to the 5aR isoenzymes and AR
in AGA, it is important to also keep in mind that
some therapies may even target cofactors that
mediate these reactions, such as reduced NADPH,
which is necessary in mediating 5aR of testosterone
to DHT. Therefore, these "secondary" mechanisms
must be considered because novel therapeutics
may target this direction as well (see Zinc).
Previous publications 19 provide a more detailed
overview of novel agents for alopecia; however,
this review will cover some of the more pertinent
agents approaching the marketplace for clinical
application.
5aR Inhibitors
In this category there are the structural steroid
competitive inhibitors that chemically resemble
the substrate, T and bind to the active site of the
enzyme so that DHT is not formed.
Table 1 describes 5aR inhibitors along with
their structures, trade names (chemical names),
and indication(s).
In Propecia (finasteride; Merck Co, Rahway,_
NJ) has recently been approved by the Food and
Drug Administration (FDA) in the US for men
with AGA. Propecia is a specific 5aR type II
enzyme inhibitor and does not bind to the AR;
therefore, it is not called an antiandrogen, but an
androgen inhibitor. The pharmokinetics of finasteride show that
after a 1 mg dose, serum concentration of DHT
decreases by 65% in 24 hours. Serum concentrations
of testosterone and estradiol increase about
15%, but remain within normal limits. Prostate
concentrations of testosterone increase about sixfold.
20 Finasteride is well absorbed in the gastrointestinal
tract, metabolized in the liver, and excreted
in urine and feces, with a half-life of 5 to 6
hours. Small nanogram levels of the drug are
detectable in human semen; this is not thought,
however, to have any consequence in women who
are exposed by sexual contact.
Three double-blind multicenter trials were conducted
in men ages 18 to 41 yeardand the results
of these trials have been presented as ab,
stracts. 21-22 In combined results from two of the
trials, 1,553 men with mild to moderate male
AGA of the vertex took finasteride 1 mg/day or
placebo orally for 1 year. After 3 months of
treatment, the men who took finasteride were
more satisfied with the appearance of their hair.
At the end of 1 year, in a circle on the vertex scalp,
a 1 inch diameter-mean baseline hair count was
876; patients who took the drug had an average of
107 more hairs than those who took the placebo.
Hair counts were maintained for up to 24 months
in the men who continued to take the drug. 22 A
third study of 326 men with mild to moderate
frontal hair loss found that after 1 year, finasteridetreated
men had statistically significantly higher
hair counts on the frontal scalp. Approximately
50% of treated men and 30% of those who took
placebo thought the appearance of their hair had
improved. Hair regrowth was not reported in
older men taking 5 mg finasteride (Proscar;
Merck Co, Rahway, NJ), perhaps because it was
not indicated in those trials to make observations
on the scalp.
Adverse events described with 5 mg finasteride
(Proscar) in a small perent of older men were loss
of libido, erection, ejaculatory dysfunction, hypersensitivity
reactions, gynecomastia, and severe
myopathy. 2~ Finasteride causes a 30% to 50%
decrease in prostate specific antigen (PSA) in
clinical trials with 1 mg tablets in men 18 to 41
years old. A decreased libido, erectile dysfunction,
or a decreased volume of ejaculate have been reported in less than 2% of patients, which in
reality is between 0.5% to 1% when compared
with placebo. Finasteride had teratogenic effects
in'animals on high doses, causing genitourinary
abnormalities in male offspring. The concentration of
the drug in semen of men who took 1 mg/day was
much lower than the concentration associated with
teratogenic effects in monkeys. The Merck manufacturers
warn that women who are or may be
pregnant should not have exposure to finasteride
orally or handle crushed or broken tablets.
Thirty tablets of Propecia 1 mg/day cost the
pharmacist less than $47, according to wholesale
price (AWP) listings, whereas 30 tablets of Proscar
5 mg/day cost less than $64.
GI198745 (GlaxoWellcome, Research Triangle
Park, NC) investigational compound is currently
in clinical trial studies around the US for men
with AGA. Structurally, as shown in Table 1, it is
similar to the parent structure of finasteride,
maintaining the 4-aza structure of the steroid
nucleus; however, on the 21-carbon position is a
tri-fluorophenyl group that renders the molecule
to be electronegative and perhaps gives greater
affinity for both the type I and II isoenzyme forms
of 5aR. 23 Therefore, this drug is similar to finasteride,
in that both competitively inhibit .SaR;
however, finasteride is specific for inhibiting type
II, whereas GI198745 inhibits both isoenzymes.
This compound is known to inhibit >90% serum
DHT levels in 24 hours after oral administration,
and because of this greater ability to inhibit DHT,
it may be more effective in promoting hair growth
on the scalp of men, as well as treating acne, with
clinical trials results still pending.
WO9704002 is a new compound undergoing
patent review for Pharmacia & Upjohn Co
(Kalamazoo, MI).19 It has great structural similarity
to the above two compounds, with activity
against 5aR inhibition similar to GI198745. This
compound is not available, an&it is not known if
there are plans for clinical trial development at
this time, but has been indicated for AGA and
other dermatologic hormone-related conditions.
Vascular/Angiogenic-Related
Compounds
Regaine/Rogaine (minoxidil; Pharmacia & Up-
John Co, Kalamazoo, MI) 2% has been used
worldwide for over 10 years, and is now over the
counter (OTC) in the US. Most recently, Extra
Strength 5% Rogaine (Pharmacia & UpJohn Co)
has hit the OTC shelves in the US, with approval
on November 1997. Pharmacia & Upjohn has
sole rights to being the only manufacturer for the
next 3 years for this new version of minoxidil,
which is indicated only for men.
Despite lack of understanding of the distinct
mechanism of action, in women it has been
shown to increase the nonvellus hairs when using
it for 32 weeks or more. 2~ One potential drawback
to minoxidil therapy is that spontaneous reversal
to the pretreatment state can be expected 1 to 3
months after.cessation of therapy, indicating minoxidil
has a direct effect on the hair follicle,
sensitizing it and making it dependent on the
drug for future growth. In the US, various generic
brands are now available OTC, which have
brought down the price of minoxidil therapy
from $50/bottle when it was Rogaine, a prescription
product, to now approximately $10 to $15
dollars per generic bottle, which lasts about 1
month. Rogaine Extra Strength costs the pharmacist
approximately $28.32 for 60 mL, who can
raise the price to the consumer; therefore, good
advice to patients would be to to shop around
before buying the product, at least in the US.
The mechanism of action although still unclear,
seems to open potassium channels and
increases proliferation and differentiation of epithelial
cells in the hair shaft. 2~
Serum concentrations after topical application of 2% minoxidil, used twice a day, (about 5% of
those with oral minoxidil), and of the 5% solution
(about 10% of those with the oral drug), have
been reported in some patients using 2% solution.
Minoxidil is metabolized in the liver and excreted
in the urine.
As far as effectiveness, four unpublished 32 to
48 week studies presented to the FDA compared
the effects of placebo, 2% minoxidil, and 5%
minoxidil by counting the net gain in hairs in 1
cm 2 areas of the scalp. As described, 2~ two studies
in women did not find statistically significant
differences between 2% and 5% minoxidil. A
32-week study in men found that the mean
increase from baseline in hairs/cm 2 was 5 with
placebo, 30 with 2% minoxidil, and 39 with 5%
minoxidil. A 48-week study in men found a mean
increase in hairs/cm 2 of 3.9 with placebo, 12.7 with 2% m.inoxidil, and 18.5 with 5% minoxidil.
Previous studies have shown that when the drug
is stopped, all of the newly regrown hair falls
out. 2~ I~espite these reports, the new advertisements
claim 45% more effective hair growth than
regular strength 2%, with regrowth occurring as
early as 2 months, with five times more hair
regrowth overall than placebo and with no major
safety concerns. Most physicians and lay people
who have been using minoxidil for many years
are not concerned about safety aspects because
most feel it to be a very safe product. Concerns are
more focused on the effectiveness of the product
in promoting and maintaining hair growth. The
5% Extra Strength brings a new glimmer of hope
by showing improved hair growth for individuals
that may not have seen results with 2% minoxidil.
Adverse effects noted with oral minoxidil include
tachycardia, angina pectoris, and fluid retention.
When taken orally during pregnancy, minoxidil
has been associated with hypertrichosis of the
fetus and congenital anomalies. One double-blind
study in 35 balding men found that topical use of
2% minoxidil caused small but statistically significant
increases in left ventricular end-diastolic
volume, cardiac output, and left ventricular mass. 2~
Infrequently, dizziness and tachycardia have been
reported with 2% solution, and patients are advised
to reduce frequency of application, which
helps to eliminate these side effects. Local irritation,
itching, dryness, and erythema may occur
with use of topical minoxidil, most likely caused
by the vehicle formulation of alcohol and propylene
glycol.
The conclusion on minoxidil 5% and 2% solutions
are that they can produce a modest increase
in hair growth on scalps of young men with mild
to moderate hair loss, with continuous application
for years to maintain the effect. Questions as
to the use of 5% Extra Strength in women are
being posed, with some cliniciang already giving
this to young women with early hair loss, even
though it is only indicated by the manufacturer,
Pharmacia & Upjohn Co, for use in men.
Combinations. Many patients may be asking
their physicians now and in the future about
using both topical Extra Strength 5% Rogaine
along with oral Propecia 1 rag/day, which many
believe may be beneficial working together synergistically;
however, further human clinical trials
are needed to verify this because the only previous
study was performed in the macaque monkey
model, which did show benefit when used together.
25
Although other vasodilatory/angiogenic related
compounds are progressing through the development
pipeline, 19 it is difficult to ascertain their
effectiveness at this time until human clinical
trials are performed. Many compounds that mimic
minoxidil in vasodilatory properties fail to show
the same results, hence there may still be a unique
mode of action about this compound that is yet to
be fully uncovered. Unpublished investigations
have suggested-minoxidil to have oxidativereductive
potential to facilitate cofactor reactions
necessary in side chain steps for hair follicle
growth, as well as other suggestions of stimulating
some of the keratin genes of hair matrix cells
for synthesis of hair shaft keratins, producing
thin, fine, indeterminate hairs often seen with
continued use of minoxidil.
Other New Compounds in Development
lamin (prezatide copper). Iamin (Procyte
Co, Seattle, WA) is a new drug that was just
FDA approved in 1996, which is one of the
superoxide dismutases (copper binding peptide).
It was FDA approved as an antiinflammatory
wound healing geL-Procyte, the company that
makes Iamin, is working on getting approval for
one of its other superoxide dismutases, Tricomin,
for use in hair loss treatment. Iamin hit the
shelves in early July 1996, with results thus far
indicating that it may help some people with hair
loss. Some people have reported hair growth
related to Iamin, with most reporting a "strengthening
of existing hair. ''26
ProCyte have also announced release of another
product, GrafCyte, which is basically Iamin
in a few different forms. It has been approved by
the FDA for use after transplants to prevent newly
transplanted hairs from going into a resting
phase. They propose that more hairs will grow
immediately..after transplants and results may be
seen sooner than the typical 6 to 8 months. The
product will be released in moist press applications
to be applied for an hour, 4 times per day for
4 days after a hair transplam:: A mis~ spray and
shampoo have also been announced, with hopes
that it will be used by those suffering from hair loss in general; however the moist presses will
only be available to the transplant surgeons. 26
Polysorbate 80. Polysorbate 80, an OTC
product, has been around since the early 1980s as
it was first used in the Helsinki Formula sold on
television until the FDA banned such advertisements.
There were claims that it grew hair in
some people, but it was not effective in most
individuals who used it. perhaps those who did
see a hair growth response were noting hair that
was growing through successive miniaturization
cycles, which often happens in double-blind studies
where placebos have up to 30% improvement.
26
Folligen (copper chloride). Folligen is a
new treatment similar to Iamin Gel, but in cream
form contains not only a copper complex, but
Saw Palmetto (see later) for use as an androgen
inhibitor of 5aR. Again, another product that has
not been thoroughly tested for positive results in
double-blind clinical trials. 26
Saw Palmetto (serenoa repens). Serenoa
repens berries grow naturally, with the extract
claiming to be an androgen inhibitor of 5aR to
inhibit DHT production, mainly claimed for use
in prostate problems. There have not been extensive
studies performed, but implications in promoting
hair growth on the scalp have been
indicated. Side effects noted have been breast
growth in men, which may indicate that it does
not act on DHT alone. To be effective, the extract
of the berries must be taken, not the berries
themselves. Another active ingredient, pygeum
africanum compound, is added to this extract and
is thought to influence testosterone metabolism,
although it is not clear on how at this point. The
product comes in capsule form (60 capsules for
$11.80) with two to four capsules as the recommended
dose per day in divided doses between
meals. 26
Amino acids. Arginine/I2-arginine and/or
cysteine/L-cysteine have been proposed as play-
!ng a strong role in hair growth and offered in
nutrition health food stores to "make nails stronger
and help hair follicle to make more hair."
These amino acids can be taken alone or together
in oral liquid form with doses recommended at
500 to 1000 mg a few times a week. 26
Biotin and folic acid., These too have been
around for a long time with claims to help hair
grow. Nutritionally speaking, biotin and folic acid
are required for hair growth and are usually
supplied in a normal diet; therefore, unless there
is a deficiency in these because of poor nutrition
or wasting diseases, increased doses may not help
hair grow. In fact, excess megadoses of these may
cause hair loss, so if an adequate balanced diet is
being maintained, a general vitamin supplement
should do as well in providing nutritional needs
for hair growth requirements. 26
Zinc, A lot has been claimed about zinc for
use in various diseases, including topical use for
acne, another androgen related problem. 27 Specific
forms of zinc, ie, zinc acetate, zinc sulfate,
and others, have various properties that promote
wound healing, help treat acne, and promote hair
growth. The last few years spouted a new formulation
of zinc in a skin cap to treat scalp psoriasis,
and scaley, erythematous conditions of the skin,
with findings that the main ingredient was actually
clobetasol, a corticosteroid that was found'to
be the active ingredient that caused the great
improvement when used for various conditions.
In any case, it is cautioned that zinc may be an
important factor topically or for oral use depending
on the formulation of the zinc. Zinc sulfate
was found to be an inhibitor of DHT production,
not that it inhibits 5aR, but that it limits reduced
cofactor, NADPH,-which is necessary for the 5aR
of testosterone to form DHT. 26
A criticism to many of these herbal or OTC
remedies is that they are not governed by strict
FDA criteria, and that the purity, consistency, and
concentration of these agents can vary from batch
to batch, whether they are in liquid, pill, or
topical formulation.
In conclusion, there are various new novel
treatments for use in alopecia. Some of these have
gone through rigorous double-blind clinical trial
testing with FDA approval as to their proven
claims, whereas others have yet to do so. Although
many new products described here may
be approaching the marketplace, it is wise to
guide patients and advise them of how these
agents work and if they have been adequately
tested before spending their money and raising
their hopes. Realistic expectations should continue
to be the main guideline when offering any
treatment for alopecia.
REFERENCES
1. Sawaya ME, Price VH: Different levels of 5a-reductase
type F and II, aromatase, and androgen receptor in hair
follicles o'}"women and men with androgenetic alopecia. J
Invest Dermatol 109:296-300, 1997 "
2. Cash T: The psychological effects of androgenetic alopecia
in men. J Am Acad Dermatoi 26:926-931, 1992
3. Smith MA, Wells RS: Male-type alopecia, alopecia areata,
and normal hair in women. Arch Dermato189:95-98, 1964
4. Scott MJ, Scott AM: Effects of anabolic-androgenic
steroids on the pilosebaceous unit. Cutis 50:113-116, 1992
5. Sawaya ME, Penneys NS: Immunohistochemical distribution
of aromatase and 3B-hydroxysteroid dehydrogenase in
human hair follicle and sebaceous gland. J Cutan Pathol
19:309-314, 1991
6. Schweikert HU, Wilson JD: Regulation of human hair
growth by steroid hormones: II. Androstenedione metabolism
in isolated hairs. J Clin Endocrinol Metab 39:1012-1019, 1974
7. Sawaya ME, Honig LS, Garland LD: 3B-hydroxysteroid
dehydrogenase activity in sebaceous glands of scalp of malepattern
baldness. J Invest Dermato191:101-105, 1988
8. Anderson S, Bishop RW, Russell DW: Expression cloning
and regulation of steroid 5a-reductase, an enzyme essential for
male sexual differentiation. J Biol Chem 264:16249-i6252,
1989
9. Itami S, Kurata S, Sonoda T, et al: Characterization of
5a-reductase in cultured human dermal papilla cells from
beard and occipital hair. J Invest Dermato196:57-59, 1991
10. Sawaya ME: Purification of androgen receptors in
human sebocytes and hair. J Invest Dermato198:92-96, i992
11. Sawaya ME, Lewis LA, Hsia SL: Presence of a converting
factor for androgen receptor proteins in isolated human
hair follicles and sebaceous glands. FASEB J 2:4765-4767,
1989
12. Grody W, Schrader W, O'Malley B: Activation, transformation,
and subunit structure of steroid hormone receptors.
Endocr Rev 3:141-152, 1982
13. Peleg S, Schraader WT, O'Malley B: Sulfhydryl group
content of chicken progesterone receptor. Effect of oxidation
on DNA binding activity. Biochemistry 27:358-362, 1988
14. Sawaya ME: Androgen receptor regulation in human
hair follicles and sebaceous glands, in Matias J (ed): Androgens
and Antiandrogens. Proc Terra Symposia 1:i01-105,
1992
15. Sawaya ME, Mendez AJ, Hsia SL: Translocation of
androgen receptor protein complex into nuclei of hair follicles
and sebaceou s glands from human scalp. ] Invest Dermatol
90:605-606, 1988
16. Sawaya ME: Androgen receptor gene polymorphisms
effecting human hair follicle growth in hirsutism and androgenetic
alopecia. J Invest Dermatol 106:563, 1996 (abstr)
17. Hardy DO, Scher HI, Bogenreider T, et al: Androgen
receptor CAG repeat lengths in prostate cancer: Correlation
with age of onset. J Clin Endocrinol Metab 81:4400-4405,
1996
18. Sawaya ME, Shalita AR: Androgen receptor polymorphisms
(CAG repeat lengths) in androgenetic alopecia, hirsutism,
and acne. J CutanMed Surg 1998 (in press)
19. Sawaya ME: Alopecia---The search for novel agents
continues. Exp Opin Ther Patents 7:859-872, 1997
20. Abramowicz M: Propecia and rogaine extra strength for
alopecia. The Medical Letter 40:25-27, 1998
21. Kaufman K: Clinical studies on effects of oral finasteride,
a type 2 5a-reductase inhibitor on scalp hair in men with
male pattern baldness. Proceedings from the First Tricontinental
Meeting of Hair Research Societies, Brussels, Belgium,
October 16-19, 1995
22. Kaufman K: Updates of clinical phase III trial data and
results. Presented at the American Academy Dermatology
Meeting, San Francisco, CA, March 12-15, 1997; the World
Congress Meeting, Australia, June 8-10, 1997
23. Bramson HN, Hermann D, Batchelor KW, et al: The
unique preclinical characteristics of GG745, a potent dual
inhibitor of 5AR. J Pharmacol Exp Ther 1997
24. Kidwai BJ, George M: Hair loss and minoxidil withdrawal.
Lancet 340:609-610, 1992
25. Diani AR, Mulholland MJ, Shull KL, et al: Hair growth
effects of oral administration of finasteride, a steroid 5-alpha
reductase inhibitor, alone and in combination with topical
minoxidil in the balding stumptail macaque. J Clin Endocrino1
Metab 74:345-350, 1992
26. Pure Encapsulations. Sudbury, MA, 1998
26a. Hair Regrowth: The Less Research Treatments. www.regrowthhttp://.
com
27. Stamatiadis D, Bulteau-Portois MC, Mowszowicz I:
Inhibition of 5a-reductase activity in human skin by Zinc and
azelaic acid. BrJ Dermatol 119:627-632, 1988
