5-ARIs can be used in the treatment of
hirsutism in women.[1] The usefulness of 5-ARIs for the potential treatment of
acne is uncertain.[4] 5-ARIs are sometimes used as antiandrogens in
feminizing hormone therapy for
transgender women to help reduce body hair growth and scalp hair loss.[2]
They have also been explored in the treatment and prevention of
prostate cancer. While the 5-ARI
finasteride reduces the cancer risk by about a third, it also increases the fraction of aggressive forms of prostate cancer. Overall, there does not seem to be a survival benefit for prostate cancer patients under finasteride.[5]
Available forms
Finasteride (brand names Proscar, Propecia) inhibits the function of two of the isoenzymes (types 2 and 3) of 5α-reductase.[6][7] It decreases circulating DHT levels by up to about 70%.[8]Dutasteride (brand name Avodart) inhibits all three 5α-reductase isoenzymes and can decrease DHT levels by 95%.[9][10] It can also reduce DHT levels in the prostate by 97 to 99% in men with prostate cancer.[11][12]Epristeride (brand names Aipuliete, Chuanliu) is marketed in
China for the treatment of benign prostatic hyperplasia.[13][14][15] However, it can only decrease circulating DHT levels by about 25 to 54%.[16]Alfatradiol (brand names Ell-Cranell Alpha, Pantostin) is a topical 5-ARI used to treat pattern hair loss in
Europe.[17][18] An extract of Serenoa repens, also known as
saw palmetto extract, is a 5-ARI[citation needed] that is sold as an
over-the-counterdietary supplement. It is also used under the brand name Permixon[citation needed] in Europe as a pharmaceutical drug for the treatment of benign prostatic hyperplasia[citation needed].
5-ARIs are generally
well tolerated in both men and women and produce few
side effects.[19][20] However, they have been found to have some risks in studies with men, including slightly increased risks of decreased
libido,
erectile dysfunction,
ejaculatory dysfunction,
infertility,
breast tenderness,
gynecomastia,
depression,
anxiety,
self-harm, and
dementia.[20][21][22] In addition, although 5-ARIs decrease the overall risk of developing
prostate cancer, they have been found to increase the risk of developing certain rare but high-grade forms of prostate cancer.[19] As a result, the FDA has notified healthcare professionals that the Warnings and Precautions section of the labels for the 5-ARI class of drugs has been revised to include new safety information about the increased risk of being diagnosed with these rare but more serious forms of prostate cancer.[23] Finasteride has also been associated with
intraoperative floppy iris syndrome and
cataract formation.[24][25] Depressive symptoms and suicidality have been reported.[26]
Sexual dysfunction
Sexual dysfunction, including
erectile dysfunction,
loss of libido, and
reduced ejaculate, may occur in 3.4 to 15.8% of men treated with finasteride or dutasteride.[19][27] This is linked to lower
quality of life and can cause stress in relationships.[28] There is also an association with lowered sexual desire.[29] It has been reported that in a subset of men, these adverse sexual side effects may persist even after discontinuation of finasteride or dutasteride.[29]
A 2017
population-based,
matched-
cohort study of 93,197 men aged 66 years and older with BPH found that finasteride and dutasteride were associated with a significantly increased risk of depression (
HRTooltip Hazard ratio, 1.94; 95%
CITooltip Confidence interval, 1.73–2.16) and
self-harm (HR, 1.88; 95% CI, 1.34–2.64) during the first 18 months of treatment, but were not associated with an increased risk of
suicide (HR, 0.88; 95% CI, 0.53–1.45).[31][32][33][21] After the initial 18 months of therapy, the risk of self-harm was no longer heightened, whereas the elevation in risk of depression lessened but remained marginally increased (HR, 1.22; 95% CI, 1.08–1.37).[31][32][21] The absolute increase in the rate of depression was 247 per 100,000 patient-years and of self-harm was 17 per 100,000 patient-years.[21][34] As such, on the basis of these findings, it has been stated that cases of depression in patients that are attributable to 5-ARIs will be encountered on occasion, while cases of self-harm attributable to 5-ARIs will be encountered very rarely.[34] There were no differences in the rates of depression, self-harm, and suicide between finasteride and dutasteride, suggesting that the specific 5-ARI used does not influence the risks.[33][21][34] The absolute risks of self-harm and depression with 5-ARIs remain low (0.14% and 2.0%, respectively).[35]
Pharmacology
The pharmacology of 5α-reductase inhibition is complex, but involves the binding of
NADPH to the enzyme followed by the substrate. Specific substrates include
testosterone,
progesterone,
androstenedione,
epitestosterone,
cortisol,
aldosterone, and
deoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic.[4] 5α-Reductase reduces the steroid Δ4,5 double bond in testosterone to its more active form DHT. Thus, inhibition results in decreased amounts of DHT. Because of this, slight elevations in testosterone and estradiol levels occur.[36] The 5α-reductase reaction is a rate-limiting step in the testosterone reduction and involves the binding of
NADPH to the enzyme followed by the substrate.[4][37]
In BPH, DHT acts as a potent cellular androgen and promotes
prostate growth; therefore, it inhibits and alleviates symptoms of BPH. In alopecia, male and female-pattern baldness is an effect of androgenic receptor activation, so reducing levels of DHT also reduces hair loss.
History
Finasteride was the first 5-ARI to be introduced for medical use.[43] It was marketed for the treatment of BPH in 1992 and was subsequently approved for the treatment of pattern hair loss in 1997.[43] Epristeride was the second 5-ARI to be introduced and was marketed for the treatment of BPH in
China in 2000.[14] Dutasteride was approved for the treatment of BPH in 2001 and was subsequently approved for pattern hair loss in
South Korea in 2009 and in
Japan in 2015.[44][45] The
patent protection on finasteride and dutasteride has expired and both drugs are available as
generic medications.[46][47]
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