5α-Reductase inhibitor

5α-Reductase inhibitors (5-ARIs), also known as dihydrotestosterone (DHT) blockers.

A class of medications with antiandrogenic effects which are used primarily in the treatment of enlarged prostate and scalp hair loss. 

They are also sometimes used to treat excess hair growth in women and as a component of hormone therapy for transgender women.

These agents inhibit the enzyme 5α-reductase, which is involved in the metabolic transformations of a variety of endogenous steroids. 

5-ARIs are most known for preventing conversion of testosterone, the major androgen sex hormone, to the more potent androgen dihydrotestosterone (DHT), in certain androgen-associated disorders.

5-ARIs are clinically used in the treatment of conditions that are exacerbated by DHT:

Mild-to-moderate benign prostatic hyperplasia and lower urinary tract symptoms

Pattern hair loss in both men and women

5-ARIs can be used in the treatment of hirsutism in women.

Their use for the treatment of acne is uncertain.

5-ARIs are used as antiandrogens in feminizing hormone therapy for transgender women to help reduce body hair growth and scalp hair loss.

The 5-ARI finasteride reduces the cancer risk by about a third.

5-ARIs May increase the fraction of aggressive forms of prostate cancer. 

In a systemic review and meta-analysis that included 138,477 users of 5-ARI and 3,105,098 non-users, no statistical significance association between 5-ARI use and prostate cancer mortality was found (Baboudjian M).

Finasteride inhibits the function of two of the isoenzymes (types 2 and 3) of 5α-reductase.

It decreases circulating DHT levels by up to about 70%.

Dutasteride  inhibits all three 5α-reductase isoenzymes and can decrease DHT levels by 95%. 

It can also reduce DHT levels in the prostate by 97 to 99% in men with prostate cancer.

5-ARIs are generally well tolerated in both men and women and produce few side effects.

5-ARIs have some risks:  increased risks of decreased libido, erectile dysfunction, ejaculatory dysfunction, infertility, breast tenderness, gynecomastia, depression, anxiety, self-harm, and dementia.

5-ARIs decrease the overall risk of developing prostate cancer.

Have been found to increase the risk of developing high-grade forms of prostate cancer.

Finasteride has also been associated with intraoperative floppy iris syndrome and cataract formation, depressive symptoms and suicidality have been reported.

Sexual dysfunction, including erectile dysfunction, loss of libido, and reduced ejaculate, may occur in 3.4 to 15.8% of men treated with these agents, lowering  quality of life and can cause stress in relationships.

The lowered sexual desire, and adverse sexual side effects may persist even after discontinuation of 5-alpha reductase agents.

5-ARIs have a small risk of breast changes in men including breast tenderness and gynecomastia.

 The risk of gynecomastia is about 1.3%.

Finasteride and dutasteride are  associated with a significantly increased risk of depression and self-harm during the first 18 months of treatment, but were not associated with an increased risk of suicide.

The absolute risks of self-harm and depression with 5-ARIs remain low, 0.14% and 2.0%, respectively.

5α-reductase inhibition is complex, involving  the binding of NADPH to the enzyme followed by the substrate. 

Specific substrates include testosterone, progesterone, androstenedione, epitestosterone, cortisol, aldosterone, and deoxycorticosterone. 

5α-Reductase reduces the steroid Δ4,5 double bond in testosterone to its more active form DHT. 

Thus, 5α-Reductase inhibition results in decreased amounts of DHT, and

slight elevations in testosterone and estradiol levels occur.

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.

5α-reductase isoforms I and II reduce progesterone to 5α-dihydroprogesterone (5α-DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). 

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: reducing levels of DHT also reduces hair loss.

5-ARIs have been studied in combination with the nonsteroidal antiandrogen bicalutamide for the treatment of prostate cancer.

In a Swedish study of 349,152 men there was no association between 5– ARI and increase prostate cancer mortality of men without a previous diagnosis of prostate cancer.

In addition a time dependent association with  decreased risk of prostate cancer mortality with longer 5-ARI treatment.

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