Investigation of the Plausibility of 5-Alpha-Reductase Inhibitor Syndrome.
An abstract from this was automatically posted in the clinical studies section of solvepfs.com.
I’ve accessed the full text via: sci-hub.ac
Sadly and I’m afraid expectedly being dermatologists, the authors find little validity for pfs and all but one has or has had connections with Merck.
Here it is for anyone interested:
Review Article
Skin Appendage Disord 2016;2:120–129
DOI: 10.1159/000450617
Received: August 18, 2016
Accepted: September 5, 2016
Published online: September 23, 2016
Investigation of the Plausibility of
5-Alpha-Reductase Inhibitor Syndrome
Raymond Fertig a
Jerry Shapiro b Wilma Bergfeld c, d Antonella Tosti a
a Department of Dermatology and Cutaneous Surgery, University of Miami, Miller School of Medicine, Miami, Fla. ,
b The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, N.Y. , and
Departments of c Dermatology and d Pathology, Dermatopathology Fellowship, Cleveland Clinic, Cleveland, Ohio , USA
Key Words
Dutasteride · Finasteride · Side effects · Psychiatric adverse
effects · Physical adverse effects · Permanent sexual
dysfunction · Psyche
Abstract
Postfinasteride syndrome (PFS) is a term recently coined to
characterize a constellation of reported undesirable side effects
described in postmarketing reports and small uncontrolled
studies that developed during or after stopping finasteride
treatment, and persisted after drug discontinuation.
Symptoms included decreased libido, erectile dysfunction,
sexual anhedonia, decreased sperm count, gynecomastia,
skin changes, cognitive impairment, fatigue, anxiety, depression,
and suicidal ideation. The aim of this study is to
review the existing medical literature for evidence-based research
of permanent sexual dysfunction and mood changes
during treatment with 5-alpha-reductase inhibitors including
finasteride and dutasteride. © 2016 S. Karger AG, Basel
Postfinasteride Syndrome
Postfinasteride syndrome (PFS) is a term recently
coined to characterize a constellation of reported undesirable
side effects described in postmarketing reports
and small uncontrolled studies that developed during or
after stopping finasteride treatment, and persisted after
drug discontinuation. Symptoms included decreased libido,
erectile dysfunction, sexual anhedonia, decreased
sperm count, gynecomastia, skin changes, cognitive impairment,
fatigue, anxiety, depression, and suicidal ideation.
The Postfinasteride Syndrome Foundation, which was
created to raise awareness about PFS, recently sent an
email to dermatologists practicing in the United States to
inform them about the syndrome and its inclusion into
the National Institute of Health’s Genetic and Rare Diseases
Information Center (GARD) even though inclusion
in the GARD is not an official recognition of PFS by the
NIH as explained in the website disclaimer. The NIH is
currently founding a study on the epidemiology of adverse
events of 5-alpha-reductase inhibitors (5αRIs) specifically
focused on persistent side effects.
According to information from the website, the Postfinasteride
Syndrome Foundation is also funding research
projects seeking to elucidate the nature of the condition
including hormonal, genetic, and epigenetic causes. The
foundation’s website lists a number of physicians that collaborate
with them including urologists, endocrinologists,
psychiatrists and psychologists, but no dermatologists.
The aim of this study is to review the existing medical literature
for evidence-based research of permanent sexual
dysfunction and mood changes during treatment with
5αRIs including finasteride and dutasteride.
Materials and Methods
A MEDLINE search (PubMed 1950–2016) was performed to
identify the cases described in the literature. The following MEDLINE
search terms were used: ‘finasteride side effects’, ‘finasteride
side * ’, ‘finasteride sexual’, ‘finasteride side effects alopecia’, ‘finasteride
gynecomastia’, ‘finasteride male breast cancer’, ‘finasteride
cognitive effects’, ‘finasteride anxiety’, ‘finasteride depression’, ‘finasteride
suicidal ideation’, ‘finasteride syndrome’, ‘post-finasteride
syndrome’, ‘dutasteride side effects’, ‘dutasteride side * ’,
‘dutasteride sexual’, ‘dutasteride side effects alopecia’, ‘dutasteride
gynecomastia’, ‘dutasteride male breast cancer’, ‘dutasteride cognitive
effects’, ‘dutasteride anxiety’, ‘dutasteride depression’, and
‘dutasteride suicidal ideation’. We included case reports, case series,
review articles, and clinical trials which specifically mentioned
side effects of finasteride and dutasteride use. After the initial
search was performed, we reviewed the bibliographies of all manuscripts
to discover any cases not uncovered in our initial MEDLINE
search. We also reviewed the information obtained online
including the content on the Post - Finasteride Syndrome Foundation
website (pfsfoundation.org).
Level of evidence of the studies was graded from high to very
low according with the American College of Physicians outcome
study grading system. This system rates quality of studies in accordance
with the underlying methodology in four categories:
1 High, including randomized trials or double-upgraded observational
studies.
2 Moderate, including downgraded randomized trials or upgraded
observational studies.
3 Low, including double-downgraded randomized trials or observational
studies.
4 Very low, including triple-downgraded randomized trials or
downgraded observational studies or case series/case reports.
Studies can be downgraded in presence of factors that may decrease
the quality level of a body of evidence. These include:
1 Limitations in the design and implementation of available
studies suggesting high likelihood of bias.
2 Indirectness of evidence (indirect population, intervention,
control, outcomes).
3 Unexplained heterogeneity or inconsistency of results (including
problems with subgroup analysis).
4 Imprecision of results (wide confidence intervals).
5 High probability of publication bias.
Results
Sexual Adverse Effects
Sexual side effects in men who have been taking finasteride
(1 and 5 mg) and dutasteride (0.5 mg) are well documented
and include decreased libido, erectile dysfunction,
and ejaculatory dysfunction [1–11] ( table 1 ).
Persistent Sexual Side Effects
Persistent sexual side effects were discussed in 1 highquality
randomized trial and 2 low-quality uncontrolled
studies ( table 1 ). The Proscar Long-Term Efficacy and
Safety Study (PLESS), a 4-year, double-blind, placebocontrolled
study of 3,040 men with BPH evaluated the
efficacy of finasteride (5 mg/day) as well as the incidence
of sexual adverse events [4] . Subjects completed a questionnaire
at screening pertaining to their history of sexual
dysfunction. At screening, 46% of patients in each
treatment group reported some history of sexual dysfunction,
with a higher rate expected given the older age
of the study population (aged 45–78 years). During year
1 of the study, 15% of total finasteride subjects (n = 1,524)
and 7% of total placebo subjects (n = 1,516) experienced
sexual adverse events, including decreased libido, erectile
dysfunction, and decreased ejaculate volume [4] . During
years 2–4, the incidence of new sexual adverse events
(decreased libido, erectile dysfunction, or ejaculation
disorders) was the same in each group (7% in each group)
[4, 8] . The drug-related sexual adverse event profile for
subjects who took finasteride was similar for subjects
with or without a history of sexual dysfunction at baseline.
A total of 4% of finasteride and 2% of placebo subjects
discontinued the study due to sexual adverse events.
A surprising finding in this study was that in these subjects
who withdrew from the study due to sexual adverse
events, 50% of finasteride users experienced continual
sexual side effects after discontinuing finasteride, while
59% of placebo subjects noted continual sexual side effects.
Thus, in this study persistent sexual side effects
were reported more in placebo subjects than in patients
treated with finasteride.
Persistent sexual side effects following finasteride use
were also reported in 2 uncontrolled studies. Irwig and
Kolukula [12] interviewed 71 men with male pattern hair
loss (MPHL) (aged 21–46 years) who reported new-onset
sexual side effects that persisted for more than 3
months after discontinuation of finasteride. The mean
duration of finasteride use was 28 months and the mean
duration of persistent sexual side effects was 40 months
at the standardized interview date. Patients were recruit
ed from the authors’ clinical practice and the website
propeciahelp.com. The Arizona Sexual Experience
Scale (ASEX) was used during subject interviews to assess
sexual dysfunction and was designed to measure 5
core elements of sexual function: libido, sexual arousal,
erectile function, ability to reach orgasm, and satisfaction
of orgasm [12, 13] . Scores range from 5 to 30, with sexual
dysfunction present if the total ASEX score is ≥ 19.
ASEX scores increased from 7.4 ± 2.3 before finasteride
use to 21.6 ± 3.4 after finasteride use at the time of interview
[12] . The prevalence of sexual dysfunction was 94%
for low libido, 92% for erectile dysfunction, 92% for decreased
arousal, and 69% for problems with orgasm [12] .
The majority of patients experienced sexual adverse
events while on finasteride, but some subjects reported
onset after discontinuing therapy. In a subsequent study
by Irwig [14] , 54 subjects from the prior study with persistent
sexual side effects associated with finasteride were
reassessed after a mean of 14 months following the last
interview. A total of 89% of these subjects had ASEX
scores of sexual dysfunction, raising the possibility of
permanent effects connected with finasteride in a small
subset of patients.
Possible Placebo Effect
A significant placebo effect has been detected in patients
who were informed of potential sexual side effects
before taking finasteride [15] . In a blinded control study,
107 subjects with a clinical diagnosis of BPH were randomized
to receive finasteride (5 mg/day) for 1 year with
1 group receiving counseling (n = 55) on the drug sexual
side effects and the other group not receiving such counseling
(n = 52). The phrase used to inform counseled patients
was this drug ‘may cause erectile dysfunction, decreased
libido, problems of ejaculation but these are uncommon’.
Those patients informed of the potential
sexual side effects of the drug reported a significant higher
proportion of sexual side effects (43.6%) as compared
to those who were not informed (15.3%). The incidence
of erectile dysfunction, decreased libido, and ejaculation
disorders was 9.6, 7.7, and 5.7% for patients not informed,
and 30.9, 23.6, and 16.3% for informed patients [15] .
Psychiatric Adverse Effects
The physiological basis of mood disorders caused by
5αRIs has been associated with the dysregulation of
neurosteroids and androgen deficiency [16, 17] . Neurosteroids,
along with their derivatives, are steroids active
in the brain and include allopregnanolone, dihydrodeoxycorticosterone,
dehydroepiandrosterone, and pregnenolone
[18] . It has been postulated that neurosteroids
have anxiolytic, antidepressant, and memory enhancement
properties and play a role in neuroprotection [19,
20] . As 5αRIs inhibit the enzyme 5-alpha-reductase required
to synthesize these neurosteroids, the resulting decrease
in the neurosteroid biosynthesis could contribute
to psychiatric adverse events. Reduction in allopregnanolone
is associated with depressive symptoms and unipolar
major depression in men [16, 17, 21] . Although finasteride
and dutasteride were shown to inhibit allopregnanolone
in animal models, there is no information in humans
[22, 23] . Other possible mechanisms involve reduction in
levels of DHT. A study by Barrett-Connor et al. [24]
showed that BDI survey scores for measuring depression
were inversely associated with bioavailable DHT levels
and genetic predisposition. Two polymorphisms (CAG)
rs4045402 and (GGN) rs3138869 in the gene encoding for
the androgen receptor have been hypothesized to play a
role in finasteride sensitivity [25] .
Psychiatric side effects have not been documented in
high-quality randomized trials. Psychiatric side effects
were reported in 2 moderate-quality studies [26, 27] , 4 lowquality
studies [27–30] , and 1 very low-quality study [31] .
These included depression, anxiety, and suicidal ideation.
Depression and Anxiety
Altomare and Capella [31] reported a series of 19 patients
that developed a moderate to severe depressive syn
drome when treated with finasteride (1 mg/day) for androgenetic
alopecia (AGA). All these patients fit the diagnosis
of ‘substance-induced mood disorder’ as defined by
the DSM-IV-TR criteria [31] . In this retrospective case
series, 14 of the patients were male and 5 were female with
a mean age of 28 years, all of whom had a negative history
of psychiatric disorders prior to starting treatment
with finasteride. Depression in these subjects developed
at approximately 9–19 weeks, with an average time of onset
of 14 weeks after commencing treatment with finasteride.
Depression developed despite the fact that the majority
of the patients were satisfied with the impact that
finasteride had in stabilizing hair loss. The reported adverse
symptoms that are consistent with depression included
impairment of sociofamilial relations, eating behavior
changes (anorexia), and sleep behavior changes
including insomnia or hypersomnia. In addition to depression,
6 of the patients developed concomitant anxiety
while taking finasteride. Such depression resolved completely
after discontinuing finasteride therapy, with resolution
of depressive symptoms ranging from 3 days to 3
weeks. Two patients who were rechallenged with finasteride
after discontinuing therapy due to depressive symptoms
quickly relapsed within 2 weeks and experienced a
recurrence of the depressive symptoms.
A prospective study conducted by Rahimi-Ardabili et
al . [28] investigated whether mood disorders developed
in 128 male patients who were treated for androgenetic
alopecia with finasteride (1 mg/day). This study had no
controls. The average age was 25.8 years for the study subjects.
Patients who had a history of diagnosed mood disorder
were excluded from the study. In addition, patients
who used any medications prior to 10 days of study commencement
were excluded, as were patients who had a
positive history of medication use, with the exception of
acetaminophen, antacids, or cold medicine. Information
on depressed mood and anxiety was elicited using two
self-administered questionnaires: the Beck Depression
Inventory (BDI) and Hospital Anxiety and Depression
Scale (HADS). Subjects completed the BDI and HADS
questionnaires at study onset and then again 2 months
following daily finasteride treatment.
The BDI is a survey of 21 questions, with each question
having a range of 0 to 3 points for a maximum score of
63. Higher total scores indicate more severe depressive
symptoms. A score from 0–9 suggests a normal score with
absence of depression, while a score of 10–15 indicates a
minimal depressive state, with 16–31 (mild depression),
32–47 (moderate depression), and >47 (severe depression).
The mean BDI score of the study subjects was 12.11
at study onset with a standard deviation of ±7.50. After 2
months of finasteride therapy, the mean BDI score was
12.80 with a standard deviation of ±7.64. The increase in
BDI score was minimal, yet statistically significant (p <
0.001). While the BDI survey measures depression, the
HADS survey measures both depression (HADS-D) and
anxiety (HADS-A). The HADS consists of 7 questions,
with a point range of 0 to 3 per question. There are 7 questions
corresponding to depression and 7 questions that
measure anxiety. The depression and anxiety scores are
divided into 4 score categories: normal (0–7), mild (8–
10), moderate (11–15), and severe (16–21). The mean ±
standard deviation of the HADS-D score before treatment
was 4.04 ± 2.51 and 4.61 ± 3.19 after treatment. This
slight increase in the HADS-D was found to be statistically
significant (p = 0.005). However, there was no significant
change in the anxiety scores before and after finasteride
treatment. The mean HADS-A score increased
slightly from 6.24 to 6.60, but this was deemed not to be
statistically significant. The results of this study showed
that there was a statistically significant increase in the BDI
and HADS survey scores that measure depression in subjects
taking daily finasteride treatment, although such increase
was minimal. Notably, transient libido loss occurred
in 9.4% of subjects, yet no significant difference in
BDI and HADS scores was found between the group that
reported libido loss and the group that did not experience
such side effects.
Suicidal Ideation
Ali et al. [27] performed a retrospective pharmacovigilance
disproportionality analysis to detect disproportional
reporting of suicidal ideation events in finasteride
users compared to suicidal ideation events reported in
users of other drugs. For this statistical study, the authors
searched the United States Food and Drug Administration
Adverse Event Reporting System (FAERS) database
for finasteride-related adverse event reports for men aged
18–45 years that were submitted to the FAERS between
1998 and 2013. A total of 4,910 finasteride-related adverse
reports were found for this time period, of which 39 reports
(0.79%) were filed for suicidal ideation. A disproportional
reporting of suicidal ideation was found with
finasteride use compared to other drugs within the FAERS
database (empirical Bayes geometric mean 1.72) [27] .
The majority of patients who reported suicidal ideation
also reported persistent sexual dysfunction, with 34 of the
39 patients with suicidal ideation reporting persistent
sexual dysfunction. The authors speculated that possible
sexual dysfunction experienced by finasteride users could
have contributed to the suicidal ideation. Of note, the authors
found 577 reports of sexual dysfunction connected
to finasteride use and concluded that finasteride was associated
with significantly more than expected reporting
of sexual dysfunction in young men compared with reporting
of these events with all other drugs within FAERS
(empirical Bayes geometric mean 28.0) [27] .
Persistent psychiatric effects were reported in 2 studies
including a low-quality [29] and a moderate-quality study
[26] . Both of these studies selected participants through
the Internet or patient groups, and 1 study received financial
support from the PFS Foundation.
Persistent Depression and Suicidal Ideation
A study conducted by Irwing [29] investigated the
prevalence of depressive symptoms and suicidal thoughts
in 61 former users of finasteride 1 mg who developed
chronic sexual side effects after discontinuing finasteride
therapy. Patients were recruited from propeciahelp.com,
a website for finasteride users with persistent
side effects, the author’s clinical practice, and physician
referrals. The prevalence of depressive symptoms
and suicidal thoughts was determined by the BDI-II, a
self-administered questionnaire. Similar to the original
BDI survey, the BDI-II contains 21 questions, albeit with
differing standardized cutoffs. With the BDI-II scale, a
score of 14–19 indicates mild depression, 20–28 indicates
moderate depression, and 29 and over indicates severe
depression. Survey results from the 61 patients with selfreported
prolonged sexual side effects following finasteride
use were compared to survey results from a control
group recruited from the local community. The control
group consisted of 29 men diagnosed with MPHL with no
history of finasteride use, sexual dysfunction, or psychiatric
disorders.
The mean BDI-II score was 23.7 in the former finasteride
user group compared to 5.9 in the control group.
Rates of depressive symptoms were significantly higher in
the finasteride arm with 75% (46/61) of former finasteride
users reporting depression (BDI-II score ≥ 14) compared
to 10% (3/29) of controls (p < 0.0001) [29] . Moderate
or severe depressive symptoms, as determined by a
BDI-II score ≥ 20, were present in 64% (39/61) of the finasteride
group. None of the controls exhibited moderate
or severe depressive symptoms according to the BDI-II.
In addition, suicidal thoughts were present in 44% of former
finasteride users and in 3% of controls (p < 0.0001).
A subsequent study by Ganzer et al. [30] sought to
characterize the symptoms following finasteride therapy
for MPHL that persisted once treatment was abated. Spe
cifically, the study aim was to investigate the extent to
which generally healthy men with a recent history of taking
finasteride for MPHL experienced persistent psychological,
physical, and cognitive adverse effects ( ≥ 3
months) after discontinuing finasteride. An online questionnaire
was constructed that targeted each of these domains.
Patients for the study were recruited from a link
to the questionnaire posted to the website propeciahelp.com
and the author’s clinical practice. In total, 131
patients were recruited with a mean age of 24 years. Patients
who had a positive history of sexual dysfunction or
psychological conditions prior to starting finasteride
therapy were excluded. Of note, most patients were
asymptomatic during treatment and experienced symptoms
after stopping finasteride therapy.
The results from this study showed a high prevalence
of negative psychological effects in former finasteride users
with 74% (96/131) of study subjects reporting elevated
anxiety, 73% (95/131) reporting depressed affect, and
58% (75/131) reporting sleep disturbances [30] . Furthermore,
73% (95/131) of subjects experienced anhedonia
and 55% (72/131) experienced emotional sensitivity once
they discontinued finasteride therapy [30] . In addition,
63% (82/131) of subjects experienced suicidal ideations
and negative thoughts that persisted once treatment was
halted [30] . Adverse cognitive effects in former finasteride
users were also reported in this study. Such cognitive
effects include memory problems (71/131), attention difficulties
(93/131), slowed thought processes (93/131), and
mental cloudiness or brain fog (95/131) [30] .
Persistent Anxiety and Depression
The most recent study by Ganzer and Jacobs [32] investigated
the psychological health of 97 users of finasteride.
The authors explored whether having a preexisting personal
or family history of a psychiatric diagnosis and certain
personality traits influenced anxiety and depression among
finasteride users. Subjects in the study had taken finasteride
for AGA for at least 3 months and stopped taking finasteride
after experiencing negative side effects including anxiety
and depression. Once again, patients were recruited
from a link to the questionnaire posted to the website www.
propeciahelp.com and the author’s clinical practice. Subjects
completed the BDI, the Beck Anxiety Inventory (BAI),
and the Ten-Item Personality Inventory (TIPI). The TIPI
assesses the personality domains: openness, conscientiousness,
extraversion, agreeableness, and neuroticism.
According to the BDI results, 38 subjects scored within
the moderate to severe depression range and 5 subjects
scored within the extreme depression range. In addition,
based on the BAI results, 16 subjects reported moderate
anxiety and 17 scored a potential cause for concern [32] .
A noteworthy finding in this study is that the authors postulated
that subjects would score high on the neuroticism
personality domain according to the TIPI, but found that
this was not the case as subjects were extroverted, agreeable,
emotionally stable, and open to experiences. A total
of 55% (n = 53) of subjects had an established psychiatric
diagnosis prior to initiating finasteride therapy, while
28.8% (n = 27) had a first-degree relative with a mental
health disorder [32] . The authors concluded that pre-existing
mental health disorders among finasteride users
may put this subset of users at an increased risk of developing
emotional disorders caused by finasteride therapy.
The aforementioned studies suffer from a number of
flaws, such as selection bias and recall bias. Selection bias
is particularly a factor in studies where patients were recruited
from the website propeciahelp.com and
sought treatment of reported symptoms after taking finasteride.
These patients may have experienced more severe
symptoms and have been more likely to seek out the
study. Control groups are lacking in all but 1 of the studies
related to mood disorders. Additionally, it is unclear
whether symptoms such as depression were caused by the
drug itself or if side effects experienced by the patient,
such as sexual dysfunction, contributed to the depression.
Due to the inadequacy of these studies, no definitive conclusions
can be reached at this time. However, these study
findings suggest that finasteride may induce psychological
adverse effects in susceptible patients such as depressive
symptoms and anxiety.
Physical Adverse Effects
Gynecomastia and Male Breast Carcinoma
Gynecomastia has been noted with finasteride (1 and 5
mg) and dutasteride (0.5 mg), while male breast cancer has
been noted with finasteride (5 mg). Finasteride and dutasteride
are potent inhibitors of type 2 5-alpha-reductase,
inhibiting the conversion of testosterone to dihydrotestosterone
(DHT) causing a decrease in formation of DHT.
Inhibiting DHT synthesis may alter the estrogen to androgen
ratio by shifting metabolism of testosterone to estradiol,
thus increasing the risk of gynecomastia and male
breast cancer [7, 30, 33] . Relative estrogen excess is associated
with an increased risk of breast cancer in men [34] .
Gynecomastia, an enlargement of breast tissue, is a reported
side effect in males prescribed finasteride therapy.
Results from the Prostate Cancer Prevention Trial
(PCPT), a randomized, double-blind, placebo-controlled
study showed that gynecomastia is among the more com
mon side effects of finasteride therapy along with sexual
dysfunction [35] . Men age 55 years and older were randomly
assigned to treatment with finasteride (5 mg/day)
or placebo for 7 years. At trial conclusion, gynecomastia
was observed in 4.5% (426/9,423) of finasteride subjects
and 2.8% (261/9,457) of placebo subjects [7, 35] . In the
survey conducted by Ganzer et al. [30] that involved subjects
who complained of persistent side effects following
finasteride use, approximately 69% (90/131) of survey respondents
reported gynecomastia.
Gynecomastia has also been experienced by subjects
prescribed dutasteride therapy (0.5 mg) for BPH [36–39] .
Study results obtained by Kaplan et al. [40] comparing
safety and efficacy of BPH patients treated with finasteride
or dutasteride suggest that the incidence of gynecomastia
is greater in dutasteride users than in finasteride users. In
this retrospective 5-year study, the incidence of self-reported
breast tenderness and breast enlargement was significantly
greater in the dutasteride (3.5%) group compared
with the finasteride (1.2%) group (p < 0.01) [40] .
Reports of male breast carcinoma have appeared in patients
who received finasteride. Evidence of the association
of finasteride with male breast cancer comes from the
Medical Therapy of Prostatic Symptoms (MTOPS) study
[41] . The MTOPS, sponsored by the NIH, was a doubleblind,
placebo-controlled trial (mean follow-up, 4.5
years) involving 3,047 men that compared the effects of
placebo, Proscar (finasteride 5 mg/day ), doxazosin (8
mg) and combination therapy (finasteride 5 mg and doxazosin
8 mg) for the treatment of BPH. Subjects were randomly
assigned to 1 of 4 treatment arms: Proscar (n =
768), Proscar and doxazosin (n = 786), doxazosin (n =
756), and placebo (n = 737). Four cases of breast cancer
occurred, with 3 cases reported in the Proscar treatment
group and 1 case reported in the Proscar/doxazosin
group. Therefore, the rate of male breast cancer in this
trial for subjects taking finasteride either alone or with
doxazosin was 4 in 1,554, which is high given that the incidence
of male breast cancer is 1 in 100,000 man years
[33, 42] . This rate is approximately 200 times that observed
in the general population [33] .
In contrast to the MTOPS study results, results from
2 other large trials do not support the association of finasteride
with male breast cancer [3, 11] . In the PLESS,
a double-blind, randomized, placebo-controlled trial,
3,040 men with moderate to severe urinary symptoms
and enlarged prostate glands were treated with finasteride
(5 mg/day) or placebo for 4 years [11] . At study conclusion,
no cases of male breast cancer were reported
in the finasteride-treated subjects. However, 2 cases of
breast cancer were reported in the placebo-treated subjects
[42] . Furthermore, the PCPT randomly assigned
18,882 men 55 years of age or older to treatment with
finasteride (5 mg/day) or placebo for 7 years [3] . One
case of breast cancer was reported in the finasteride arm
and 1 case in the placebo arm [42] . Therefore, according
to results from the PCPT, an increased incidence of
breast cancer in the finasteride group compared to placebo
was not observed.
Other Physical Adverse Effects
In addition to gynecomastia and breast cancer, an aggregate
of other physical adverse effects have been reported
with finasteride use (1 and 5 mg). Three studies have
reported fatigue, lethargy, and listlessness in males who
took finasteride for BPH or MPHL, although the cause of
these symptoms could not be definitively attributable to
finasteride [7, 12, 30] . In addition, skin changes have been
reported, most commonly dry skin [30] . DHT is known
to stimulate sebum production, and as finasteride lowers
DHT, it may also cause sebum production to fall and the
resultant dry skin [43, 44] . Penile shrinkage and sensory
changes, as well as scrotal shrinkage and sensory changes,
have also been reported [30] . Less commonly, Peyronie’s
disease has been reported in finasteride users [30] .
Chiriacò et al. [45] employed an observational retrospective
study to assess the type of persistent symptoms
experienced by patients following finasteride therapy for
AGA. Seventy-nine males (aged 18–50 years) were enrolled
who used finasteride for AGA and developed persistent
side effects for at least 6 months following drug
discontinuation. Subjects were enrolled an average of 44
months after finasteride discontinuation. Subjects were
recruited from the author’s clinical practice (n = 17) and
from the website propeciahelp.com (n = 62). The
study subjects completed a series of questionnaires, including
a 100-question ad hoc questionnaire. The most
common somatic and sexual adverse symptoms were loss
of penis sensitivity (87.3%), decreased penile temperature
(78.5%), penile flaccidity/wrinkling (68.4%), loss of scrotum
fullness (68.4%), loss of scrotum sensitivity (62.0%),
reduction in penile dimension (65.8%), and loss of body
muscle tone and mass (51.9%) [45] .
Conclusion
A literature review of adverse side effects associated
with 5αRIs shows that persistent sexual side effects were
only documented in low-quality studies with strong bias
selection as participants were part of an Internet blog. The
only high-quality study documenting persistent sexual
side effects showed that these were more frequent in the
placebo than in the treatment group, implying that the
effects were not necessarily related to the treatment. A
significant placebo/nocebo effect has been documented
among patients informed about possible side effects of
finasteride and this may explain the high prevalence of
reported sexual dysfunction including persistent dysfunction
in subjects participating in Internet groups and
blogs. Psychiatric side effects were only documented in
moderate- or low-quality studies including studies performed
on patients with sexual side effects, which could
influence patient’s mood. Most of these studies recruited
patients through the same Internet patient website.
Is the PFS a reality or not? Up to now, this question has
gone unanswered. The addition of PFS to the NIH’s
GARD database does not officially recognize PFS by the
NIH, but rather serves as a resource to find more information
regarding reported adverse events. Persistent side
effects of finasteride have garnered much media attention.
In fact, legal action has been taken with 742 Propecia
(finasteride) lawsuits filed against the manufacturer
Merck. These cases were consolidated into a multidistrict
class action lawsuit in the Eastern District of New York,
led by US District Judge John Gleeson. The lawsuit is estimated
to go before a United States federal panel in October
2016. The website propeciahelp.com has a link that
offers visitors the possibility to join the lawsuit.
Persistent sexual and psychiatric side effects after
5αRIs are not documented by high-quality studies, and
prospective studies to establish true incidence and frequency
of the problem are really needed. The NIH is cur
rently funding a large epidemiological study, and we hope
that the PFS Foundation will start to involve dermatologists
in their advisory board in order to generate data
from prospective and not retrospective studies. As dermatologist
dealing with hair loss patients, we need to keep
in mind that finasteride 1 mg is an improved medication
and that Propecia (finasteride) labeling includes warnings
of possible sexual dysfunction including persistent
sexual dysfunction (such as difficulty in achieving an
erection after discontinuing the medication), depression,
breast tenderness, breast enlargement, and male breast
cancer.
Disclosure Statement
Dr. Tosti received honoraria as a consultant, advisory board
participant, speaker or book author from the following companies:
Aclaris, Incyte (Consultant and PI), Kythera, P&G, DS Laboratories,
Merck (Consultant and Speaker over 3 years ago), Taylor &
Francis (Author), Springer-Verlag (Author), and National Alopecia
Areata Foundation (Scientific Board Member).
Dr. Shapiro reports the following: Replicel Life Sciences Inc.
(Cofounder and Stockholder), Johnson and Johnson (Consultant),
Aclaris (Consultant), Samumed (Consultant), Incyte (Consultant),
L’Oreal Paris (Consultant), Merck (Consultant and Speaker
over 3 years ago), Bayer (Consultant), Kythera (Consultant), Up to
Date (Author), National Alopecia Areata Foundation (Scientific
Board Member), Cicatricial Alopecia Research Foundation Board
of Directors. All consultancies are present except for Merck.
Dr. Bergfeld reports the following: P&G (Consultant and research),
Bayer Health (Consultant), Samumed, Incyte, Aclaris,
Cassiopea, Allergan, and Merck investigator for finasteride (in the
past, over 20 years ago, no relationship now).
Raymond Fertig has no conflicts of interest to report.