- 5 α Reductase Inhibitors
5 α reductase is an enzyme encountered in specific organs in humans such as the hair follicles, prostate,
testicles, seminal vesicles, brain, liver, and gastrointestinal tract (Motofei et al., 2017; Yamana, Labrie, &
Luu-The, 2010). Finasteride is a selective 5 α reductase inhibitor (type II) and dutasteride is a dual type I
and II 5 α reductase inhibitor (Yim, Nole, & Tosti, 2014). By inhibiting the 5 α reductase enzyme,
finasteride and dutasteride prevent the conversion of testosterone to dihydrotestosterone,
deoxycorticosterone to dihydrodeoxycorticosterone, and progesterone to dihydroprogesterone (Caruso
et al., 2015; Motofei et al., 2017). Sexual side effects including erectile dysfunction, ejaculatory
dysfunction, and decreased libido in males who have been taking finasteride (1 and 5 mg) and
dutasteride (0.5 mg) are well known and documented in randomized clinical trials (R. Fertig, Shapiro,
Bergfeld, & Tosti, 2017).
In the last few years the literature has reported irreversible side effects in males treated with 5 α
reductase inhibitors (Ali, Heran, & Etminan, 2015; A. K. Gupta, Sharma, & Shukla, 2016; Motofei et al.,
2017). These side effects persisting after the discontinuation of the drug i.e. post –finasteride syndrome
(PFS) included sexual dysfunction, gynecomastia, mental impairment involving suicidal ideations,
depression, anhedonia, and lack of mental concentration (Chiriaco, Cauci, Mazzon, & Trombetta, 2016;
R. Fertig et al., 2017; Motofei et al., 2017). Other adverse effects include secondary infertility, insomnia,
and chronic fatigue (Salvarci & Istanbulluoglu, 2013; Tu & Zini, 2011). These effects are summarized in
Table 3.
9.1. Sexual Adverse Events
Tosti and her colleagues conducted a multi-center study that evaluated variations in sexual and erectile
function in patients taking finasteride (1 mg) for male pattern hair loss through a self-administered
abridged 5-item version of the International Index of Erectile Function (IIEF-5) questionnaire. The IIEF-5
questionnaire is composed of 5 elements which include erectile function, orgasmic function, sexual
desire, intercourse satisfaction, and overall sexual satisfaction. A total of 186 subjects with male pattern
hair loss and an age range of 19-43 years completed the questionnaire at baseline and at 4 to 6 months
after beginning finasteride therapy. The score on each of the 5 domains of the IIEF-5 did not show any
significant changes after 4-6 months of treatment compared to baseline (Tosti et al., 2004).
Tosti et al. reviewed the literature for evidence-based research of permanent sexual dysfunction and
mood swing during treatment with 5-alpha-reductase inhibitors including finasteride and dutasteride.
This review revealed that persistent sexual side effects after 5αRI were only reported in low-quality
studies with a strong bias selection. Psychiatric adverse effects were only documented in moderate or
low-quality studies including studies conducted on subjects with existing sexual side effects, which may
impact a patient’s mood. The authors emphasize the need for prospective clinical trials to investigate
the true incidence and frequency of PFS (R. Fertig et al., 2017).
The Proscar Long-Term Efficacy and Safety Study (PLESS), a 4-year, double-blind, placebo-controlled
study of 3,040 males with benign prostatic hyperplasia evaluated the efficacy and safety profile of
finasteride (5 mg daily). During the first year of the study, 15% of the total finasteride subjects (n =
1,524) and 7% of the total placebo subjects (n = 1,516) experienced sexual adverse events including
decreased libido, erectile dysfunction, and decreased ejaculatory volume. During years 2-4, the
incidence of new sexual side effects (decreased libido, erectile dysfunction, or ejaculation disorders) was
the same in each group (7% in each group). Surprisingly, 50% of subjects who withdrew from the PLESS
study due to sexual side effects noted continued sexual side effects, whereas 59% of placebo subjects
experienced continual sexual side effects. Therefore, persistent sexual adverse events were documented
more in patients receiving placebo treatment than in subjects treated with finasteride (Wessells et al.,
2003).
Persistent sexual adverse events following finasteride use were also reported in 2 uncontrolled studies.
Irwig and Kolukula interviewed 71 males with androgenetic alopecia (aged 21-46 years) who reported
new-onset sexual adverse events that continued for more than 3 months after cessation of finasteride.
The mean duration of finasteride use was 28 months and the mean duration of persistent sexual
adverse events was 40 months (Irwig & Kolukula, 2011; McGahuey et al., 2000). Sexual dysfunction
increased after treatment with finasteride. The incidence of sexual dysfunction was as follows: low
libido, 94%, decreased arousal, 92%, erectile dysfunction, 92%, and problems with orgasm, 69%. The
majority of subjects noted sexual side effects during treatment with finasteride, although some patients
reported onset after discontinuing treatment (Irwig & Kolukula, 2011). In another study by Irwig, 54
patients from the prior study with persistent sexual adverse events associated with finasteride were
reevaluated after a mean of 14 months following the last interview. A total of 89% of these subjects had
scores of sexual dysfunction, raising the possibility of the long-lasting sexual side effects associated with
finasteride (Irwig, 2012b).
Giatti et al. discussed whether the persistent sexual dysfunction observed in post finasteride syndrome
(PFS) could be determined by neuroactive steroids (Giatti, Diviccaro, Panzica, & Melcangi, 2018). Plasma
and CSF levels of various neuroactive steroids were examined in three different trials assessing three
(Melcangi et al., 2013), seven (Caruso et al., 2015), and fourteen (Melcangi et al., 2017) PFS patients.
Data indicated that finasteride has widespread consequences on the level of these molecules in CSF and
plasma (Caruso et al., 2015; Melcangi et al., 2013; Melcangi et al., 2017). This suggests that PFS patients
are not a homogenous pathological group. Interestingly, the upregulation of steroid receptors occurred
in the prostates of patients taking finasteride for BPH (Hsieh, Chen, Yu, & Chang, 2011) as well as in the
prepuce of AGA patients who have PFS (Di Loreto et al., 2014).
9.2. Potential Placebo Effects
A significant placebo effect has been noticed in subjects who were educated of possible sexual adverse
events before starting finasteride (Mondaini et al., 2007). In a blinded, controlled study, 107 patients
with benign prostatic hyperplasia were randomized to receive finasteride 5 mg daily for 1 year, with one
group being informed (n = 55) about the sexual side effects of the treatment and the other group not
receiving such education (n = 52). Those subjects that were aware of the possible sexual adverse events
of the drug described a significantly higher percentage of sexual dysfunction (43.6%) in comparison 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% respectively for subjects who were not educated about
the sexual side effects. On the other hand, the reported incidence of erectile dysfunction, decreased
libido, and ejaculation disorders was 30.9%, 23.6%, and 16.3% respectively for subjects that were
informed about the sexual adverse effects (Mondaini et al., 2007).
9.3. Gynecomastia and Male Breast Cancer
Gynecomastia has been reported with finasteride (1 and 5 mg) and dutasteride (0.5 mg), while male
breast cancer has been noticed with finasteride (5 mg). Finasteride and dutasteride inhibit
dihydrotestosterone synthesis, which may alter the estrogen to androgen ratio by shifting the
metabolism of testosterone to estradiol, hence increasing the risk of gynecomastia and male breast
cancer (Ganzer, Jacobs, & Iqbal, 2015; S. C. Lee & Ellis, 2004; Traish, Hassani, Guay, Zitzmann, & Hansen,
2011). The increase in estrogen level is linked with an increased risk of breast cancer in males (Sasco,
Lowenfels, & Pasker-de Jong, 1993).
Thompson et al. and Ganzer at al. reported the development of gynecomastia following finasteride use
in a clinical trial with a dosage of (5 mg daily) over 7 years and in a survey, respectively (Ganzer et al.,
2015; Thompson, Tangen, Goodman, Lucia, & Klein, 2009). Kaplan et al. conducted a retrospective 5-
year study to compare the safety and efficacy of finasteride and dutasteride therapy in patients with
benign prostatic hyperplasia. The results showed gynecomastia incidence is significantly higher in
subjects taking dutasteride (3.5%) as compared with the finasteride group (1.2%)(Kaplan, Chung, Lee,
Scofield, & Te, 2012).
There are inconsistent data regarding the incidence of male breast cancer associated with finasteride.
McConnell et al. conducted a double-blind, randomized, placebo-controlled trial that studied 3,040 men
with moderate-to-severe urinary symptoms and enlarged prostate glands who were treated daily with 5
mg of finasteride or placebo for four years (McConnell et al., 1998). At conclusion, no cases of male
breast cancer were reported in the finasteride-treated group (Shenoy & Prabhakar, 2010). Moreover, in
the Prostate Cancer Prevention Trial (PCPT), Thompson et al. randomly assigned 18,882 males aged 55
or older to treatment with finasteride (5 mg per day) or placebo for seven years (Thompson et al., 2003).
One case of breast cancer was reported in the finasteride group and one subject in the placebo group
developed breast cancer (Shenoy & Prabhakar, 2010).
In contrast, the Medical Therapy of Prostatic Symptoms (MTOPS) study was a double-blind, placebocontrolled
trial with a mean follow up of 4.5 years. It involved 3047 male patients with benign prostatic
hyperplasia randomly assigned to 1 of 4 therapeutic arms as follows: finasteride 5 mg per day (n = 768),
doxazosin 8 mg (n = 756), finasteride 5 mg and doxazosin 8 mg daily (n = 786), and placebo (n = 737).
Four patients developed breast cancer (3 patients receiving finasteride and one patient receiving the
combination therapy finasteride and doxazosin). Consequently, the rate of male breast cancer in this
study for subjects taking finasteride either alone or with doxazosin was 4 in 1,554 (McConnell et al.,
2003). However, the incidence of male breast cancer is 1 in 100,000 in the general population (Shenoy &
Prabhakar, 2010).
Duijnhoven et al. conducted a case control study to investigate the association between the use of 5αRIs
(finasteride and dutasteride) for the treatment of lower urinary tract symptoms caused by benign
prostatic hyperplasia and the risk for male breast cancer. Three hundred nighty eight cases were
identified and matched to 3,930 controls. The authors found no evidence of an association between
short- or long-term treatment with 5αRIs and the risk for breast cancer in older men (Duijnhoven et al.,
2014). In addition, Bird et al. found no statistically significant association between 5αRI and male breast
cancer (Bird, Brophy, Hartzema, Delaney, & Etminan, 2013).
9.4. Depression and Anxiety
Steroid hormones, including androgens, undergo extensive metabolism in the brain. Several enzymes
including 5 alpha-reductase, 3 alpha-hydroxysteroid dehydrogenase (3alpha-HSD) and 17 betahydroxysteroid
dehydrogenase (17beta-HSD) intervene in brain androgen and steroid metabolism
(Martini & Melcangi, 1991; Stoffel-Wagner, 2001). Animal studies have shown that finasteride could
alter 5 alpha-reductase activity in some areas of the brain, leading to behavioral and mood changes
(Lephart, Ladle, Jacobson, & Rhees, 1996). Additionally, the literature demonstrates that finasteride may
induce depression and anxiety in humans.
Many cases of drug-induced depression have been reported, especially amongst patients who are more
susceptible for the disease.
Altomare and Capella reported 19 patients (14 males and 5 females with a mean age of 28 years) who
developed a mood disturbance (moderate to severe depression) during treatment with finasteride 1 mg
daily for androgenetic alopecia. The reported adverse symptoms consistent with depression included
impairment of sociofamilial relations, eating behavior changes (anorexia), and sleep behavior changes
including insomnia or hypersomnia. Depression was associated to marked anxiety in 6 patients,
developing after 9-19 weeks of treatment with finasteride, and promptly resolving after discontinuation
of therapy (Altomare & Capella, 2002). Rahimi-Ardabili et al. investigated 128 males (with a mean age of
25 years) diagnosed with androgenetic alopecia and receiving 1 mg of finasteride daily. Data on
depressed mood and anxiety was obtained by Beck Depression Inventory (BDI), and Hospital Anxiety and
Depression Scale (HADS). After two months finasteride therapy ultimately significantly increased both
BDI and HADS depression scores, indicating that finasteride treatment may increase depression and
anxiety (Rahimi-Ardabili, Pourandarjani, Habibollahi, & Mualeki, 2006).
Melcangi et al. found major depressive disorder and altered levels of neuroactive steroids in males who
reported persistent sexual and mental adverse events after the use of 1-1.25 mg daily of finasteride for
AGA. Furthermore, erectile dysfunction and abnormal somatosensory evoked potentials of the pudendal
nerve were reported (Melcangi et al., 2017).
A retrospective pharmacovigilance disproportionality analysis was performed by Ali and his colleagues
to detect signals of sexual dysfunction and suicidal ideation with low-dose finasteride use (1 mg daily) in
young men, aged 18 to 45-years-old with androgenetic alopecia. Out of 4910 reports, 577 men showed
persistent sexual dysfunction and 39 suicidal ideation adverse event reports were identified; 34 out of
the 39 males with suicidal ideation also experienced sexual dysfunction. The majority of these adverse
effects were serious, contributing to the patient’s death, hospitalization, or disability. A disproportional
reporting of suicidal ideation was found with finasteride use compared to other drugs (Ali et al., 2015).
Irwig and colleagues conducted a controlled study to evaluate depressive symptoms and suicidal
thoughts in former finasteride users who developed persistent sexual adverse events despite the
cessation of finasteride. Rates of depressive symptoms were significantly higher in the former
finasteride users 75% (46/61) as compared with controls 10% (3/29). Additionally, suicidal thoughts
were more prevalent in the finasteride group than the control (Irwig, 2012a).
-
Summary
Emerging therapeutic modalities for alopecia include JAK inhibitors, hair transplantation, mesotherapy,
oral minoxidil, platelet-rich plasma, microneedling, and 5 α reductase inhibitors. Although these
treatments have demonstrated efficacy in hair regrowth and treating established disease, their safety
profiles vary widely. Our literature review revealed that upper respiratory infections, elevated AST and
ALT, and headaches are among the most common complications resulting from JAK inhibitors. Further,
oral minoxidil has frequently been documented to result in fluid retention, postural hypotension, and
hypertrichosis. Patients receiving platelet-rich plasma universally experienced pain despite local
anesthesia. No adverse events were reported with microneedling, although the literature describing this
procedure for alopecia was limited to one study.
Folliculitis was the most commonly cited adverse event from hair transplantation, although cases of
alopecia following hair transplantation have been described.
Mesotherapy can cause hair loss at injection sites, as well as subcutaneous necrosis and scalp abscesses.
Finasteride and dutasteride are 5 α reductase inhibitors that have been linked with sexual abnormalities
in men including sexual dysfunctions and gynecomastia, as well as psychological issues in patients
including suicidal ideations, depression, anxiety, anhedonia, and lack of mental concentration.
Novel therapies for alopecia exemplify the dynamic field of medicine and show promise in ameliorating
a condition causing high psychological impact. When considering the new treatments for alopecia,
physicians should weigh the potential benefits and risks of each treatment or combination treatment to
ensure safe and successful outcomes. -
Expert Opinion
Evolving treatments of alopecia include JAK inhibitors, hair transplantation, mesotherapy, oral minoxidil,
platelet-rich plasma, microneedling, and 5 α reductase inhibitors (finasteride and dutasteride). Although
these therapeutic modalities have demonstrated efficacy to halt disease progression, decrease hair loss,
and to some extent inducing hair regrowth, their safety profiles vary widely.
JAK inhibitors appear quite safe in the short-term treatment of AA, however serious side effects have
been reported in patients receiving JAK inhibitors for autoimmune and hematological disorders and data
on long term use are not available yet. Given the fact that treatment interruption is associated with
relapse of AA, data on long term use are really needed. Most common side effects reported in the AA
population include upper respiratory infections, nasopharyngitis, elevated liver enzymes, and
headaches. We believe dermatologists should use caution when prescribing these expensive off label
treatments and really need to explain patients that JAK inhibitors are just a new effective treatment and
not a cure (Iorizzo & Tosti, 2018).
With the development of new oral and possibly of new effective topical JAK inhibitors, we foresee
increased treatment options for severe alopecia areata but also increased risk of serious side effects.
Hence, long term large randomized clinical trials are necessary to evaluate the long-standing safety
profile and efficacy of JAK inhibitors in treating alopecia.
Patients are more and more looking for unexpansive options for hair transplantation and this will
definitely increase possible side effects of this relatively safe procedure. It is very important for patients
looking for a hair transplant to be evaluated by a dermatologist as early scarring alopecia can be
associated with androgenetic alopecia and this can be responsible of unsatisfactory results including
development of lichen planopilaris, following hair transplantation. The main limitation of hair
transplantation surgery is how many hairs can be harvested from the back of the scalp. Research on
stem cloning is ongoing but results are not so satisfactory at this moment.
Patients undergoing platelet-rich plasma with microneedling commonly experienced pain despite local
or regional anesthesia. Although not reported in the literature scalp itching and lymph nodes
enlargement are not uncommon.
Oral minoxidil at low dosages will probably become more popular as patients don’t like topical
treatments. It is very important to screen patients for cardiovascular diseases before prescribing oral
minoxidil as data on safety are still limited.
Although 5 α reductase inhibitors have been recently linked with persistent sexual dysfunction, anxiety,
and depression, in the author’s experience sexual side effects always resolved after drug interruption.
However, dermatologists need to discuss this remote possibility with patients and definitely avoid
prescribing these medications in patients suffering from anxiety and/or depressions.
Innovative therapies for hair loss represent the dynamic arena of medicine and show promise in
ameliorating a disorder causing high psychological impact and improving the quality of life. When
considering a new therapeutic modality for alopecia, physicians have to make a benefit/risk evaluation
based on the intervention’s potential benefits outweighing the potential risks. Once therapy is initiated,
the patient is monitored to evaluate the benefit/risk balance based on how the treatment actually
performs for the individual patient to ensure safe and successful outcomes. Even as physicians become
experienced at identifying individual patients that will more likely benefit from a specific therapeutic
modality, it is still not always possible to predict whether the treatment will have the expected
therapeutic benefit or whether adverse effects will occur.
Recently, few proteins are discovered and found to play a role in pathways involved in hair regrowth and
wound-induced hair follicle neogenesis. Lee et al discovered that the CXXC-type zinc finger protein 5
(CXXC5) is a negative regulator of the Wnt/β-catenin pathway, which has been implicated in hair follicle
development and hair regeneration in adults. CXXC5 was upregulated in miniaturized hair follicles in
human balding scalps (S. H. Lee et al., 2017). The research findings suggest that these proteins are a
potential target for the treatment of hair loss. Researchers continue to strive for alopecia cures by trying
to gain a better understanding of how the hair growth cycle is controlled. Rather than treating the
symptoms of hair loss, scientists aim to target the cause, which, in turn, might result in fewer adverse
events.
Funding
This manuscript was not funded.
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a
financial interest in or financial conflict with the subject matter or materials discussed in the manuscript.
This includes employment, consultancies, honoraria, stock ownership or options, expert testimony,
grants or patents received or pending, or royalties.