1 | HISTORY
In 1992 the U.S. FDA approved Proscar (finasteride 5 mg daily) for the
treatment of benign prostatic hyperplasia (BPH). A 4-year placebocontrolled
study of 3,040 men suffering from BPH (the Proscar Long
Term Efficacy and Safety Study [PLESS]) was conducted (US FDA,
2011). About 1,524 subjects were administered Proscar and 1,516
subjects were administered a placebo. During the first year, decreased
libido was reported in 6.4% of subjects in the Proscar group versus
3.4% observed in the placebo group. Erectile dysfunction was
reported in 8.1% of subjects in the Proscar group versus 3.7% in the
placebo group. However, in the second year of the study there was
no significant difference in the rate of sexual adverse events between
the Proscar and placebo groups. Decreased libido was reported in
2.6% of subjects in the Proscar group versus 2.6% in the placebo
group (p = 1.00). Erectile dysfunction was reported in 5.1% if subjects
in the Proscar group versus 5.1% in the placebo group (p = 1.00)
(US FDA, 2011).
As early as 1942, James Hamilton observed that low testosterone
due to castration prevented the development of AGA in males
(Hamilton, 1942). Additional evidence for hormonal involvement in
the development of AGA came from a group suffering from congenital
5-alpha reductase deficiency. In this group, males failed to develop
AGA (Imperato-McGinley, Guerrero, Gautier, & Peterson, 1974). Subsequently,
scientists at Merck, Inc. developed a lower dosage oral
finasteride for the treatment of AGA. In 1997, the U.S. FDA approved
Propecia (finasteride 1 mg daily) for the treatment of AGA.
In three 12 months clinical studies, 945 subjects were administered
Propecia and 934 subjects were administered a placebo. During
the first year, decreased libido was reported in 1.8% of subjects in the
Propecia group versus 1.3% in the placebo group. Erectile dysfunction
was reported in 1.3% of subjects in the Propecia group versus 0.7% in
the placebo group. In the fifth year of treatment the rate of adverse
events decreased to less than 0.3% in all groups (US FDA, 2011).
Additionally, men that discontinued therapy had no further sexual
adverse events. A recent study by Gupta et al. examined finasteride
adverse events from 2004–2015 using the Food and Drug Administration
Adverse Event Reporting System (FAERS) database. Similarly,
they concluded that occurrence sexual adverse events from finasteride
are rare (Gupta, Carviel, MacLeod, & Shear, 2017).
In 2011 the U.S. FDA conducted a post marketing evaluation of
reported cases of persistent sexual dysfunction after finasteride discontinuation.
About 2,527 cases of Propecia related adverse events
were identified from December 19, 1997 to April 14, 2011. Of the
2,527 cases, the U.S. FDA identified 59 reported cases of sexual dysfunction
that lasted three or more months after finasteride discontinuation.
In 20 of these cases (34%) sexual dysfunction persisted for 1–2
years and in 7 of the cases (12%) sexual dysfunction persisted for
three or more years (US FDA, 2011). It was noted that in some of the
cases subjects had low testosterone values. Subsequently, the FDA
has required Merck to revise the Propecia label to disclose the post
marketing sexual adverse events. Shortly after Merck revised its label,
thousands (or perhaps hundreds of thousands) of websites claim that
Propecia and finasteride cause erectile dysfunction and loss of libido.
In addition, dozens of lawsuits and support group websites were
formed. As of the writing of this chapter, a Google search (www.
google.com) yielded the following number of results (Table 1).
2 | CLINICAL PRACTICE
2.1 | Aging in males
Lower testosterone is associated with erectile dysfunction, decreased
libido, and depression (Wu, 2010). It is widely recognized that males
experience a gradual decline in testosterone concentration starting as
early as their third decade (Dimopoulou et al., 2016); however, erectile
dysfunction can afflict men of all ages. In a study of 27,839 men from
eight countries, Rosen et al. (2004) observed a prevalence of erectile
dysfunction of 11% in men between the ages of 30 and 39, and 8% in
men between the ages of 20 and 29. Different methodologies are
often used to diagnose erectile dysfunction (Nguyen, Gabrielson, &
Hellstrom, 2017) and these varied methodologies can produce different
prevalence rates. Nevertheless, it is evident that the rate of sexual
adverse events in patients treated with finasteride is consistent with
the prevalence of erectile dysfunction in the general population. Additionally,
the age of onset for hormonal changes that manifest as sexual
dysfunction often coincide with the age of onset for the development
of AGA. As such, subjects experiencing AGA may be more likely to
experience sexual dysfunction; hence, it may be difficult to attribute
the development of sexual dysfunction to finasteride use alone.
2.2 | Other drugs
It is important to note that several widely used drugs elicit sexual dysfunction.
Selective serotonin reuptake inhibitors (SSRIs) and serotonin
norepinephrine reuptake inhibitors (SNRIs) are well known for their
sexual side effects. In his review, Rothschild (2000) concluded that
antidepressants may cause sexual adverse events in up to 40% of
patients. Higgins, Nash, and Lynch (2010) literature review concludes
that incidence of sexual adverse events among SSRIs users is greater
than 50%. In contrast, the long-term rate of sexual adverse events
among patients using finasteride is less than 1%.
All drugs carry a risk of adverse events. As clinicians, when prescribing drugs, we strike a balance between the risk of developing adverse events and the benefit of the treatment. While some drugs such as finasteride are effective in the treatment of the underlying disease, the controversy surrounding the risk of adverse events clouds patient’s willingness to use the drug. This is a dilemma frequently faced by pediatricians when attempting to immunize children. Pediatricians attempt to overcome the resistance to immunization by educating parents with evidence from controlled studies. While physicians should avoid controversial topics, finasteride is unfortunately the only U.S. FDA approved drug with significant efficacy in arresting the progress of AGA. The other common alternative, minoxidil, has relatively low efficacy; less than 40% of patients regrow hair following 16 weeks of daily application of 5% minoxidil (Olsen et al., 2007). Prior to prescribing finasteride, physicians should adequately educate patients and thoroughly assess their current sexual and psychological well-being. To that end we have developed the following short workup questionnaire:
• Do you experience any symptoms of sexual or erectile dysfunction?
• Do you experience nocturnal erection three or more times per week?
• How often do you have sex?
• Are you using any anti-depressants?
• Do you suffer from hypertension?
• Do you suffer from diabetes?
• Do you have a history of depression?
Together these questions help assess the risk a patient has or is likely to develop sexual dysfunction. Patients that are not suffering from sexual dysfunction or are less likely to develop sexual dysfunction, are good candidates for finasteride. In patients that are candidates for finasteride, it would be appropriate to explain the evidence from the controlled studies presented on the finasteride FDA label. It is ultimately up to the patient to decide if the relatively low risk of sexual dysfunction outweighs the benefit of finasteride in the treatment of AGA, but the evidence speaks for itself.
Goren Andy1 | McCoy John1 | Situm Mirna2 | Dhurat Rachita3 | Krychman Michael1 | Kovacevic Maja2 | Sharma Aseem3 | Bolanca Zeljana2
1Applied Biology, Inc., Irvine, California
2Department of Dermatology and
Venereology, University Hospital Center
Sestre Milosrdnice, Zagreb, Croatia
3Department of Dermatology, LTM Medical
College & Hospital Sion, Mumbai, India
Maja Kovacevic, MD, Department of
Dermatology and Venereology, University
Hospital Center Sestre Milosrdnice,
Vinogradska cesta 29, Zagreb, Croatia.