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The Finasteride El finasteride.
Saludos colegas, DERMAGIC de nuevo con ustedes, el tema de hoy EL FINASTERIDE
(PROSCAR, PROPECIA).
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AB: Dihydrotestosterone (DHT), the 5 alpha-reduced metabolite of testosterone,
is theactivemolecule triggering androgen action, and 5 alpha-reductase (5
alpha-R), the enzyme converting testosterone to DHT, is a key step in this
mechanism. Skin, like prostate, is a DHT- dependent tissue. Our laboratory
demonstrated, many years ago, that 5 alpha-R in external genitalia was not
regulated by androgens, whereas it was androgen dependent in public skin. As two
genes, 5 alpha-R types 1 and 2, encoding for 5 alpha-R enzymes have been
recently cloned, we undertook the present study to determine whether the two
enzymes we had postulated on the basis of regulation studies were coincident
with the cloned isoforms. The expression of the two isoforms was studied in
genital and pubic skin fibroblasts from normal men, normal women, and hirsute
patients. Messenger ribonucleic acid analysis, using Northern blot and RT-PCR
techniques, indicated that both 5 alpha-R1 and -2 messenger ribonucleic acids
are expressed in genital skin as well as in public skin fibroblasts. In
contrast, studies using specific inhibitors of 5 alpha-R1 (LY306089) and 5
alpha-R2 (finasteride) showed that 5 alpha-R2 is predominant in pubic skin of
normal men, normal women, and hirsute patients. These data raise the question of
the possible use of specific 5 alpha-R1 inhibitors in the treatment of
idiopathic hirsutism.
Castro-Magana M; Angulo M; Fuentes B; Canas A; Sarrantonio M; Arguello R;
Vitollo PDepartment of Pediatrics, Winthrop-University Hospital, Mineola, New York
11501, USA.
Finasteride treatment resulted in an improvement in the male pattern baldness and prostatic shrinkage that was
associated with an increase in serum testosterone levels (17.2 +/- 2.5 vs. 26.3 +/- 1.7
nmol/L) and a decrease in dihydrotestosterone (DHT) levels (1.45 +/- 0.41 vs. 0.38 +/-
0.10 nmol/L), causing a marked increase in that testosterone/DHT ratio. A
significant increase in the serum levels of androstenedione (3.67 +/- 0.49 vs. 7.05 +/-
0.70 nmol/L) and estradiol (132 +/- 44 vs. 187 +/- 26 pmol/L) was also noted,
whereas androstanediol glucoronide (33.3 +/- 6.4 vs. 10.7 +/- 4.5 pmol) and PSA (1.6 +/-
0.6 vs. 0.4 +/- 0.1 ng/ml) were significantly decreased. No changes in basal or stimulated levels of gonadotropin were observed.
There was a significant
increase in the testosterone response to hCG during finasteride therapy (delta: 16.7 vs.
35.5 nmol/L) that could be explained, at least in part, by the reduction of
testosterone metabolism resulting from the blockage induced by finasteride. The decrease in
the
These individuals are specifically deficient in the type 2 isozyme,
whereas the normal type 1 isozyme activity has been found. The purpose of this
study
was to determine 1) the suitability of the rhesus monkey for testing the safety
of 5
alpha R inhibitors when administered during pregnancy and 2) the potential risk
of
administering a known type 2 5 alpha R inhibitor, finasteride, during the
critical
period of internal and external genital differentiation in rhesus monkeys. In
vitro
studies were also performed on selected rhesus monkey tissues to determine the
distribution of the 5 alpha R isozymes. Gravid monkeys were treated once daily
from
gestational days (GD) 20 to 100. Sonographic monitoring was performed during
the
course of gestation to monitor viability, growth, and organ system development.
Detailed fetal evaluations for developmental abnormalities were performed at
term (GD
152 +/- 2). A group of 13 pregnant monkeys ("positive control") were given a
high
oral dose (2 mg/kg/day) of finasteride to demonstrate that inhibiting type 2 5
alpha
R results in specific external genital abnormalities in male fetuses.
Thirty-two
pregnant monkeys were administered an intravenous (i.v.) formulation of
finasteride
at doses of 8, 80, or 800 ng/day. The highest i.v. dose selected was at least
60-750
times the semen levels of finasteride in man given orally 5 or 1 mg/day,
respectively.
Seventeen vehicle-control pregnant monkeys were also included. Administration of
a
high oral dose (2 mg/kg/day) of finasteride resulted in external genital
abnormalities characterized by hypospadias, preputial adhesions to the glans, a
small
underdeveloped scrotum, a small penis, and a prominent midline raphe in male
fetuses;
however, no developmental abnormalities were seen in female fetuses.
Similarly,
no
abnormalities were observed in either male or female fetuses of mothers given
iv
doses (8, 80, or 800 ng/day) of finasteride during pregnancy. The in utero
sonographic findings in fetuses correlated with the gross findings at term.
These
studies have shown that external genital abnormalities can be produced in male
monkey
fetuses when exposed to a high oral dose (2 mg/kg/day) of finasteride, whereas
no
abnormalities were observed in fetuses exposed to the i.v. formulation of
finasteride.
Detailed in vitro studies demonstrated that the rhesus monkey also has two 5
alpha R
isozymes (types 1 and 2) with a tissue distribution similar to that seen in man
and,
furthermore, that finasteride is a potent, mechanism-based inhibitor with
selectivity
for both human and rhesus type 2 5 alpha R. These studies have demonstrated that
the
monkey is a suitable model for assessing the safety of 5 alpha R inhibitors
administered during pregnancy.
METHODS:
329 patients with prostatism were treated by surgery, administration of
finasteride,
alphablockers or plant extracts, according to the recommendations of the WHO.
Patient evaluation included abdominal US. PSA determination and uroflowmetry.
Patients with urodynamic or other derangements were excluded from the study.
RESULTS: Patients with a worse quality of life and important obstructive
symptoms
underwent surgery. Patients with important obstructive symptoms and no
complications
requiring surgery (infection, urinary retention, etc.) received finasteride,
which
proved to be effective in these patients, although 16.6% required another type
of
treatment and two presented impotence. Patients treated with plant extracts had
moderate prostatism; 17% of these patients required another type of treatment.
Patients treated with alphablockers presented symptoms that were similar to
those
treated with plant extracts, but they had a more important irritative component;
24%
of these patients withdrew from the study due to the side effects or inefficacy
of
their treatment regimen.
CONCLUSIONS: Further studies and a longer follow-up
are
warranted to determine whether these new drugs can replace or effectively delay
(avoiding the appearance of complications) surgery. We believe that the
indications
for each treatment should be established according to the different stages of
prostatism. Moreover, further insight into the pathogenesis of BPH, appropriate
diagnostic methods and patient selection are essential to the development of
new
therapeutical modalities and to achieving enhanced results. (36 References)
AB: OBJECTIVE: To compare the efficacy of finasteride and spironolactone in the
treatment of idiopathic hirsutism.
DESIGN: Prospective, randomized, single-blind
study. SETTING: A tertiary hirsutism clinic. PATIENT(S): Forty women with
idiopathic hirsutism were selected.
INTERVENTION(S): Patients were assigned
randomly to receive either 5 mg of finasteride or 100 mg of spironolactone for 9
months.
MAIN OUTCOME MEASURE(S): Hirsutism scores were measured according to the
Ferriman-Gallwey scoring system, and side effects were monitored for 9 months of
treatment. Blood samples were taken at each visit for assessment of endocrine,
biochemical, and hematologic parameters.
RESULT(S): Hirsutism scores were
decreased significantly in both groups at the end of 9 months. The mean percent
change (+/- SD) in hirsutism scores in the finasteride and spironolactone groups
was as follows: 5.91% +/- 7.18% and 20.60% +/- 12.59% at 3 months, 10.61% +/-
12.18% and 32.57% +/- 15.68% at 6 months, and 15.15% +/- 15.38% and 42.36% +/-
12.31% at 9 months, respectively. There was a significantly better response with
spironolactone treatment at the end of 9 months. Eleven (55%) of 20 patients in
the spironolactone group experienced side effects. However, none of them stopped
treatment because of side effects.
CONCLUSION(S): The present data suggest that
both finasteride and spironolactone are effective in the treatment of idiopathic
hirsutism. However, it appears that the spironolactone group responded
significantly better.
Ab: Finasteride, a 5 alpha-reductase inhibitor, was administered
orally (1 mg/kg.day) for 6 months to six male and five female
stumptail macaques. Vehicle was given to five male and five
female animals over the same period of time. Hair weights in a
defined 1-in.2 area of frontal scalp were measured periodically
every 1-2 months, and serum was collected for measurement of
testosterone and dihydrotestosterone. In addition, scalp biopsies
were taken before and 6 months after treatment to evaluate the
micromorphometry of hair follicles.
Results showed that both male
and female serum dihydrotestosterone levels were significantly
reduced (60-70%) by finasteride treatment. Both males and females
showed statistically significant increases in mean hair weight
over the treatment period compared to controls (P = 0.034). In
addition, there was a statistically significant
Ab: Enhanced 5 alpha-reductase activity has been found in the skin of
the majority of women with hirsutism. Finasteride is a specific
competitive inhibitor of 5 alpha-reductase, preferentially
inhibiting the type 2 isoenzyme. Therefore, we randomly assigned
14 hirsute women in a 2:1 ratio to 1 of 2 treatment arms: 1)
finasteride (F) treatment (n = 9; 5 mg, orally, daily), or 2)
spironolactone (S) treatment (n = 5; 100 mg, orally, daily). Each
group was treated for 6 months. Patients were evaluated at
baseline and after 3 and 6 months of treatment. The 2 groups were
similar in age, weight, hip/waist ratio, baseline
Ferriman-Gallwey score (F, 19 +/- 2; S, 19 +/- 2), and baseline
androgen levels.
Finasteride treatment resulted in a significant
increase in testosterone (T; P < 0.01) and the
T/dihydrotestosterone ratio (P < 0.01). Finasteride caused a
significant decrease in 5 alpha-androstane-3 alpha,17 beta-diol
glucuronide (3 alpha-diolG; P < 0.05), the 3 alpha-diolG/T ratio
(P < 0.01), and the 3 alpha-diolG/androstenedione ratio (P <
0.05). All changes were consistent with 5 alpha-reductase
inhibition. In contrast, spironolactone treatment did not result
in significant changes in serum hormone levels.
Both treatments
produced a significant decrease in anagen hair diameters [F,
-14.0 +/- 6.7% (P < 0.05); S, -13.4 +/- 3.8% (P < 0.05)] and
Ferriman-Gallwey scores [F, -2.1 +/- 0.4 (P < 0.05); S, -2.5 +/-
0.7 (P < 0.05)]. In conclusion, despite significantly different
effects on androgen levels, finasteride and spironolactone
treatment resulted in a similar clinical effect on hirsutism.
Both caused significant, but limited, improvement in hirsutism.
Although promising, further studies with finasteride are needed
to verify its effectiveness as a treatment for hirsutism. Such
studies will also provide a better understanding of the relative
contribution of 5 alpha-reductase isoenzymes to hirsutism (Au).
Ab: The authors describe a case of bilateral (with left prevalence)
gynecomastia in a 62-year-old man after finasteride treatment
because of benign prostatic hypertrophy. Finasteride is an
inhibitor of 5 alpha-reductase, the enzyme responsible for
testosterone metabolism to dihydrotestosterone. In this patient,
nonspecific endocrine alterations were found, except for a
significant decrease in dihydrotestosterone levels. In addition,
there were no pathologic conditions affecting other organs or
pharmacologic treatments that could be responsible for
gynecomastia.
Drug withdrawal started a progressive reduction of
the lumps until complete their disappearance. It is possible that
gynecomastia was caused by alterations of estrogen/androgen ratio
because of a finasteride-induced decrease in circulating
dihydrotestosterone levels. In this article, the authors confirm
finasteride antiandrogenic activity and recommend a close
follow-up of long-term treatments with finasteride to find out
other possible side effects (Au).
Ab: OBJECTIVE: To evaluate the effects of long-term administration of
finasteride on hirsutism score, basal gonadotropin, and androgen
secretion in women with idiopathic hirsutism. DESIGN: Randomized
single-blinded study.
PATIENTS: Eighteen patients with
moderate-severe hirsutism were recruited for the study.
INTERVENTIONS: Nine hirsute patients received 7.5 mg/d oral
finasteride for a period of 9 months whereas the other nine were
treated with placebo. Hirsutism score, serum basal gonadotropin,
androgens, estrogen, and sex hormone-binding globulin (SHBG)
levels were evaluated in all patients before treatment and every
3 months during treatment.
RESULTS: After 6 and 9 months of
treatment, the hirsutism score improved significantly in the
patients receiving finasteride, whereas no significant
modifications were observed in patients treated with placebo. The
side effects observed were headache and depression of modest
entity during the 1st month of treatments, whereas libido did not
change. Serum levels of LH, FSH, androstenedione, unbound T,
DHEAS, E2, 17 alpha-hydroxyprogesterone, and SHBG did not change
during therapy. Hirsute patients treated with finasteride
exhibited a marked decrease of dihydrotestosterone and a
significant increase of T serum levels from the 3rd and 6th
months of treatment, respectively.
CONCLUSION: Finasteride
decreased the hirsutism score of patients affected by idiopathic
hirsutism with few side effects during treatment. No modification
of libido was observed (Au).
Haan J; Hollander JM; van Duinen SG; Saxena PR; Wintzen ARDepartment of Neurology, Leiden University Hospital, The Netherlands.
New research presented this weekend
at an international hair loss workshop in Brussels, Belgium, has determined that
Merck & Co., Inc.'s Propecia(R) (finasteride 1 mg), the once-a-day pill to
treat certain types of men's hair loss, is not an effective treatment for women
with hair loss.
The results of a one-year study in 136 women showed that there was no
significant difference in the change in mean hair count at 12 months between
post-menopausal women treated with Propecia and those given a placebo.
The United States Food and Drug Administration cleared Propecia for
Marketing in December 1997 for men only. In clinical studies over 1,800 men,
18 to 41, with mild to moderate male pattern hair loss on the vertex (at the top
of the head) and anterior mid-scalp area were treated for up to two years.
In These studies, hair count increased during the first year and was maintained in
those men taking Propecia for 24 months. Men in the placebo group continued
to show progressive hair loss.
Although the differences in the factors that cause hair loss in men and women
are not fully understood, Joanne Waldstreicher, M.D., senior director of
clinical
research, Merck Research Laboratories, said women normally have lower
levels of androgens (male sex hormones, such as testosterone and
dihydrotestosterone) than men.
Propecia blocks the conversion of testosterone
to dihydrotestosterone and, by this mechanism, appears to interrupt a key
factor in the development of androgenetic alopecia in men who are genetically
predisposed.
Preliminary efficacy data from this new study are available on 65 women (mean
age 53.2) in the group treated with Propecia and 69 women (mean age 52.6) in
the group given a placebo, or sugar pill. Hair counts were obtained from a one
centimetre square area (approximately 0.155 square inch) in the anterior and
mid-area portion of the scalp at baseline, six months and 12 months. Of the
women in the trial, 73 were on hormone replacement therapy as well.
The use
of hormone replacement therapy did not affect the outcome of the study.
Results of the study showed that:
-- the women treated with Propecia experienced an 8.4 percent decrease in
hair count (150.3 hairs at baseline to 141.0 at 12 months)
-- the women given placebo experienced a 6.5 percent decrease in hair count
(164.8 hairs at baseline to 157.8 at 12 months).
The difference between the treatment and placebo groups was not statistically
significant. In addition, global photographs of the scalp were reviewed by a
blinded panel of dermatologists. Analysis of these photographs revealed no
significant difference in results between the placebo group and the group
treated with Propecia.
"With no demonstrated efficacy and the known risks of Propecia in women
who are or may potentially be pregnant, this study establishes that Propecia
should be used in men only," Dr. Waldstreicher added.
Women who are or may potentially be pregnant must not use Propecia and
should not handle crushed or broken tablets because it may cause abnormalities
of the male baby's sex organs.
Propecia tablets are coated and will prevent
contact with the active ingredient during normal handling, provided the tablets
have not been broken or crushed.
In an earlier analysis of 1,215 men with hair loss in the vertex area of the
scalp
who were followed for up to two years, 83 percent had the same or higher hair
count versus 28 percent of the placebo group.
Most men reported an increase
in the amount of their hair, a decrease in hair loss and improvement in
appearance. There is not sufficient evidence that Propecia works for recession
at the temporal areas. Men may need to take Propecia daily for three months
or more to see visible results.
In clinical studies in men, Propecia was generally well-tolerated and side
effects
were uncommon. A very small number of men reported less desire for sex,
difficulty in achieving an erection and/or a decrease in the amount of semen.
Each of these side effects occurred in less than two percent of men. These side
effects went away in all men who discontinued therapy because of them and
also disappeared in 58 percent of men who chose to continue taking Propecia.
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Produced by Dr. José Lapenta R.
Dermatologist
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