Finasteride

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Finasteride
Finasteride.svg
Finasteride-3D-balls.png
Systematic (IUPAC) name
N-(1,1-dimethylethyl)-3-oxo-
(5α,17β)-4-azaandrost-1-ene-17-carboxamide
Clinical data
Trade names Propecia, Proscar
AHFS/Drugs.com monograph
MedlinePlus a698016
Pregnancy cat. X (will cause birth defects in a fetus)
Legal status POM (UK) -only (US)
Routes Oral
Pharmacokinetic data
Bioavailability 63%
Metabolism Hepatic
Half-life Elderly: 8 hours
Adults: 6 hours
Excretion Feces (57%) and urine (39%) as metabolites
Identifiers
CAS number 98319-26-7 YesY
ATC code G04CB01 D11AX10
PubChem CID 57363
DrugBank DB01216
ChemSpider 51714 YesY
UNII 57GNO57U7G YesY
KEGG D00321 YesY
ChEBI CHEBI:5062 YesY
ChEMBL CHEMBL710 YesY
Chemical data
Formula C23H36N2O2 
Mol. mass 372.549 g/mol
 YesY (what is this?)  (verify)

Finasteride (MK-906, Proscar and Propecia by Merck, among other generic names) is a synthetic drug for the treatment of benign prostatic hyperplasia (BPH) and male pattern baldness (MPB). It is a type II 5α-reductase inhibitor. 5α-reductase is an enzyme that converts testosterone to dihydrotestosterone (DHT).

Medical uses

Benign prostatic hyperplasia

Physicians use finasteride for the treatment of benign prostatic hyperplasia (BPH), informally known as an enlarged prostate. The FDA-approved dose is 5 mg once a day. Six months or more of treatment with finasteride may be required to determine the therapeutic results of treatment. If the drug is discontinued, any therapeutic benefits reverse within about 6–8 months. Finasteride may improve the symptoms associated with BPH such as difficulty urinating, getting up during the night to urinate, hesitation at the start of urination, and decreased urinary flow.[1]

Male pattern baldness

As measured by hair counts, in a five-year study of men with mild to moderate hair loss, two out of three of the men who took 1 mg of finasteride daily regrew some hair. In contrast, all of the men in the study who were not taking finasteride lost hair. In the same study, based on photographs that were reviewed by an independent panel of dermatologists, 48% of those treated with finasteride experienced visible regrowth of hair, and a further 42% had no further loss. Average hair count in the treatment group remained above baseline, and showed an increasing difference from hair count in the placebo group, for all five years of the study. Finasteride is effective only for as long as it is taken; the hair gained or maintained is lost within 6–12 months of ceasing therapy.[2] In clinical studies, finasteride, like minoxidil, was shown to work on both the crown area and the hairline,[3] but is most successful in the crown area.

A recent 10-year study of 118 men treated with 1 mg/day finasteride for androgenic alopecia found that 86% of men continued to benefit from treatment over the entire course of 10 years—showing increased or stable rates of hair growth—and only 14% experiencing any further hair loss. Interestingly, it was found that subjects who showed the most hair growth in their first year of treatment were more likely to have better hair growth after 5 years, with nearly 69% of these patients experiencing continued growth; however, many of those who experienced no growth in their first year of treatment were found to improve later on. It was also found that subjects who were older than 30 years of age tended to have better hair growth in the long run, presumably due to having experienced more hair loss by that point in their lives in comparison.

Side effects were seen in only 5.9% of patients, and no patients reported depression or gynecomastia. The authors concluded that the effectiveness of finasteride in treating androgenic alopecia does not reduce over time, even in older patients (including those over 40 years of age), and that it is well-tolerated.[4][5] This study specifically looked at users who continued using the medication. A recent case control evaluated male pattern baldness patients with psychiatric sequellae after discontinuation of finasteride, and reported depressive symptomatology and suicidal ideation for those who also experienced sexual side effects during use of the drug.[6]

Some users, in an effort to save money, buy Proscar (finasteride 5 mg) instead of Propecia, and split the Proscar pills into several parts to approximate the Propecia dosage.[7] The pills are coated to prevent contact with the active ingredient during handling, and the dust or crumbs from broken Proscar tablets should be kept away from pregnant women or women who may become pregnant.[8]

Off-label uses

Finasteride is sometimes used in hormone replacement therapy for male-to-female transsexuals in combination with a form of estrogen due to its antiandrogen properties.[9][10] However, little clinical research of finasteride use for this purpose has been conducted and evidence of efficacy is limited. Indeed, finasteride is a substantially weaker antiandrogen in comparison to conventional antiandrogens like spironolactone and cyproterone acetate. Finasteride has also been found to mitigate the effects of withdrawal after chronic alcohol use.[11]

Adverse effects

In a four year controlled clinical study, 3040 patients with symptomatic benign prostatic hyperplasia were treated with 5 mg per day finasteride or placebo. Discontinuation rates due to adverse reactions related to sexual function were 3.7% in the finasteride arm and 2.1% in the placebo arm. Sexual effects were the most common type of adverse reaction.[12]

In 12 month duration double-blind clinical trials including more than 3000 patients, adverse effects included decreased libido (5% in the finasteride group and 3% in the placebo group), erectile dysfunction (8% finasteride, 3% placebo), and ejaculation disorder (2% finasteride, 0.6% placebo).[13]

Prostate cancer

The FDA has added a warning to 5α-reductase inhibitors concerning an increased risk of high-grade prostate cancer.[14] While the effect of finasteride on the risk of developing prostate cancer has not been established, evidence suggests it may temporarily reduce the growth and prevalence of benign prostate tumors, but could also mask the early detection of prostate cancer. The primary concern is patients who develop prostate cancer while taking finasteride for benign prostatic hyperplasia, which in turn could delay diagnosis and early treatment of the prostate cancer, thereby potentially increasing the risk of these patients developing high-grade prostate cancer.[15]

The 2005 Prostate Cancer Prevention Trial (PCPT) showed at a dosage of 5 mg per day, as is commonly prescribed for BPH, participants taking finasteride were 25% less likely to have developed prostate cancer at the end of the trial compared to those taking a placebo.[16] It appeared (incorrectly) that finasteride increased the specificity and selectivity of prostate cancer detection, thus creating an apparently increased rate of high Gleason grade tumor. A 2008 update of this study found that finasteride reduces the incidence of prostate cancer by 30%. In the original study, the smaller prostate caused by finasteride facilitated detection of cancer nests and aggressive-looking cells. Most of the men in the study who had both low and high-grade prostate cancer chose to be treated, and many had their prostates removed. A pathologist then carefully examined each of those 500 prostates and compared the kinds of cancers found at surgery to those initially diagnosed at biopsy. This study concluded that finasteride did not increase the risk of high-grade prostate cancer.[17][18]

Sexual side effects

There are case reports of persistent diminished libido or erectile dysfunction, even after stopping the drug.[19] In December 2008, the Swedish Medical Products agency concluded a safety investigation of finasteride and advised that finasteride may cause irreversible sexual dysfunction. The Agency's updated safety information lists difficulty in obtaining an erection that persists indefinitely, even after the discontinuation of finasteride, as a possible side effect of the drug.[20] The UK's Medical and Healthcare Products Regulatory Agency (MHRA) cites reports of erectile dysfunction that persists once use of finasteride has stopped.[citation needed][21] In April 2011 Merck revised the United States' warning in consumer and medical leaflets to include erectile dysfunction that may persist after stopping finasteride.[22] In April 2012, the warning label was further strengthened to include reports of persistent libido disorders, ejaculation disorders, orgasm disorders, and decreased libido. According to FDA, these warnings were added as precaution after reviewing 678 case reports of post-treatment sexual dysfunction received over an 18 year period. The Agency further stated that "despite the fact that clear causal links between finasteride (Propecia and Proscar) and sexual adverse events have NOT been established, the cases suggest a broader range of adverse effects than previously reported in patients taking these drugs.".[23][24][25]

Anxiety and depression

Mood disorders were not observed as an important adverse effect in the phase 3 trials leading to regulatory approval of finasteride for the treatment of benign prostatic hyperplasia.[13] Nonetheless, regulatory authorities have listed mood disorders as among the possible adverse effects of finasteride,[26] and a variety of small studies have suggested a possible connection.[27]

In a small study examining the use of finasteride to treat hirsutism in women, fewer patients in the finasteride-treated group reported depression relative to the control group.[28]

Another study with a larger sample size of 128 men, though no women, also at a dose of 1 mg per day, found that finasteride increased both BDI and HADS depression scores significantly.[29] The authors concluded that finasteride should be prescribed cautiously to patients at a high risk of depression.

A study comparing depression in impotent men with a history of exposure to finasteride found that they experienced greater depression and suicidal ideation relative to non-impotent men without a history of finasteride exposure. The authors did not comment on the relative extent to which sexual dysfunction and prior finasteride treatment might have contributed to the depression.[30]

Male breast cancer

In December 2009, the Medicines and Healthcare products Regulatory Agency in the UK announced new drug safety advice on finasteride and the potential risk of male breast cancer. The agency concluded that, although overall incidence of male breast cancer in clinical trials for finasteride 5 mg was not significantly increased, a higher risk of male breast cancer with finasteride use cannot be excluded. A warning on this risk will be included in the product information.[31] Merck revised the United States' warning in consumer and medical leaflets to include the risk of male breast cancer.[22]

Teratogenicity

Finasteride is in the FDA pregnancy category X. This means that it is known to cause birth defects in a fetus. Women who are or who may become pregnant must not handle crushed or broken finasteride tablets, because the medication could be absorbed through the skin. Finasteride is known to cause birth defects in a developing male baby. Exposure to whole tablets should be avoided whenever possible, however exposure to whole tablets is not expected to be harmful as long as the tablets are not swallowed. It is not known whether finasteride passes into breast milk, and thus should not be taken by breastfeeding women. Finasteride may pass into the semen of men, but Merck states that a pregnant woman's contact with the semen of a man taking finasteride is not an issue for concern. Finasteride is known to affect blood donations, and potential donors are typically restricted for at least a month after their most recent dose.[32]

Interference with doping assays

Many sports organizations have banned finasteride because it can be used to mask steroid abuse.[33] Since 2005, finasteride has been on the World Anti-Doping Agency's list of banned substances. However, it was removed from the list in 2009.[34] Notable athletes who used finasteride for hair loss and were banned from international competition include skeleton racer Zach Lund, bobsledder Sebastien Gattuso, footballer Romário and ice hockey goaltender José Théodore.[35]

Mechanism of action

Testosterone in males is produced primarily in the testicles, but also in the adrenal glands. The majority of testosterone in the body is bound to sex hormone-binding globulin (SHBG), a protein produced in the liver that transports testosterone through the bloodstream, prevents its metabolism, and prolongs its half-life. Once it becomes unbound from SHBG, free testosterone can enter cells throughout the body. In certain tissues, notably the scalp, skin, and prostate, testosterone is converted into 5α-dihydrotestosterone (DHT) by the enzyme 5α-reductase. DHT is a more powerful androgen than testosterone (as it has approximately 3-10 times the potency at the androgen receptor, the site of action of the androgen hormones), so 5α-reductase can be thought to amplify the androgenic effect of testosterone in the tissues in which it's found.

Finasteride, a 4-azasteroid and analogue of testosterone, works by acting as a potent and specific, competitive inhibitor of one of the two subtypes of 5α-reductase, specifically the type II isoenzyme.[36] In other words, it binds to the enzyme and prevents endogenous substrates such as testosterone from being metabolized. 5α-reductase type I and type II are responsible for approximately one-third and two-thirds of systemic DHT production, respectively.[37]

Other 5a-reductase substrates include progesterone, androstenedione, epi-testosterone, cortisol, aldosterone, and deoxycorticosterone. The entire physiologic effect of their reduction is unknown, but likely related to their excretion or is itself physiologic. Beyond being a catalyst in the rate-limiting step in testosterone reduction, 5alpha-reductase enzyme isoforms I and II reduce progesterone to dihydroprogesterone (DHP) and deoxycorticosterone to dihydrodeoxycorticosterone (DHDOC). In vitro and animal models suggest subsequent 3alpha-reduction of DHT, DHP and DHDOC lead to steroid metabolites with effect on cerebral function by enhancing gamma-aminobutyric acid GABAergic inhibition. These neuroactive steroid derivatives enhance GABA at GABA(A) receptors and have anticonvulsant, antidepressant and anxiolytic effects, and also alter sexual and alcohol related behavior.[38] 5α-dihydrocortisol is present in the aqueous humor of the eye, is synthesized in the lens, and might help make the aqueous humor itself.[39] Allopregnanolone and THDOC are neurosteroids, with the latter having effects on the susceptibility of animals to seizures. 5α-dihydroaldosterone is a potent antidiuretic agent, although different from aldosterone. Its formation in the kidney is enhanced by restriction of dietary salt, suggesting it may help retain sodium as follows:[40]

Substrate + NADPH + H+ → 5α-substrate + NADP+

5α-DHP is a major hormone in circulation of normal cycling and pregnant women.[41]

By inhibiting 5a-reductase, finasteride prevents conversion of testosterone to DHT by the type II isoenzyme, resulting in a decrease in serum DHT levels by about 65–70% and in prostate DHT levels by up to 85–90%,[42] where expression of the type II isoenzyme dominates. Unlike dual inhibitors of both isoenzymes of 5α-reductase which can reduce DHT levels in the entire body by more than 99%, finasteride does not completely suppress DHT production because it lacks significant inhibitory effects on the 5α-reductase type I isoenzyme, with 100-fold less affinity for I as compared to II.[37] In addition to blocking the type II isoenzyme, finasteride competitively inhibits the 5β-reductase type II isoenzyme,[43] though this is not believed to affect androgen metabolism.

By blocking DHT production, finasteride reduces androgen activity in the scalp. In the prostate, inhibition of 5α-reductase reduces prostate volume, which improves benign prostatic hyperplasia (BPH) and reduces risk of prostate cancer. 5α-reductase inhibition also reduces epididymal weight, and decreases motility and normal morphology of spermatozoa in the epididymis.[44]

Cause of mood-related and sexual side effects

DHT, and neuroactive steroids (NAs) such as allopregnanolone (ALLO) and tetrahydrodeoxycorticosterone (THDOC)—potent positive allosteric modulators of the GABAA receptor (the same site of action of euphoriant and anxiolytic drugs like benzodiazepines and alcohol)—are important endogenous neuroregulators that have been shown to possess powerful antidepressant and anxiolytic effects as well as to play a positive role in sexual function.[27][45][46] Their biosynthesis is dependent on both isoforms of 5α-reductase, and accordingly, finasteride has been shown to reduce their formation in the body.[47][48][49] As such, this effect of finasteride is a likely cause of the emotional and sexual side effects associated with the drug.[27][45]

Vehicle

Drug trade names include Propecia and Proscar, the former marketed for male pattern baldness (MPB) and the latter for benign prostatic hyperplasia (BPH), both are products of Merck & Co. There is 1 mg of finasteride in Propecia and 5 mg in Proscar. Merck's patent on finasteride for the treatment of BPH expired on June 19, 2006.[50] Merck was awarded a separate patent for the use of finasteride to treat MPB. This patent is set to expire in November 2013.[51]

Some studies have shown that the dose of finasteride needed to treat male pattern baldness may be smaller than 1 mg.[52] Petitions to the FDA to re-examine the approved dosage in light of the statistical evidence and possible long-term risks,[53] were met with the response that a study had shown increased effect of a 1 mg dose compared to 0.2 mg without added risks; the same study also concluded that doses of 0.01 mg per day were found to be ineffective in treating hair loss.[53]

Finasteride is lipophilic,[54] and development of a liposomal system of finasteride for topical application has been a subject of recent study.[55] Topical formulations show some effect in reversal of androgenic effects on hair follicles,[56] as well as in hirsutism.[57] More recent studies have looked at microemulsions[54] and liquid crystalline nanoparticles for topical finasteride delivery. In the latter, addition of glycerol, propylene glycol, and polyethylene glycol 400, increased finasteride permeation, while addition of oleic acid made it decrease.[58] Topical finasteride in combination with topical minoxidil is more effective than topical minoxidil alone.[59] Small studies of topical finasteride formulations in combination with other drugs have also been found effective.[60] Surfactants have been shown to aid topical absorption.[61] Topical finasteride gel has been shown an effective route of administration.[62]

Chemical synthesis

Propecia (finasteride) 1 mg tablets
Propecia 1 mg & Finpecia 1 mg tablets

Finasteride is synthesized from progesterone:[63][64]

Preparation of finasteride: doi:10.1021/jm00161a028 doi:10.1021/ja00218a062

History

In 1974, Julianne Imperato-McGinley of Cornell Medical College in New York attended a conference on birth defects. She reported on a group of intersex children in the Caribbean who appeared sexually ambiguous at birth, and were initially raised as girls, but then grew external male genitalia and other masculine characteristic post-onset of puberty. Her research group found that these children shared a genetic mutation, causing deficiency of the 5α-reductase enzyme and male hormone dihydrotestosterone (DHT), which was found to have been the etiology behind abnormalities in male sexual development. Upon maturation, these individuals were observed to have smaller prostates which were underdeveloped, and were also observed to lack incidence of male pattern baldness.[65][66][67]

In 1975, copies of Imperato-McGinley's presentation were seen by P. Roy Vagelos, who was then serving as Merck's basic-research chief. He was intrigued by the notion that decreased levels of DHT led to the development of smaller prostates. Dr. Vagelos then sought to create a drug which could mimic the condition found in these children in order to treat older men who were suffering from benign prostatic hyperplasia.[68]

In 1992, finasteride (5 mg) was approved by the U.S. Food and Drug Administration (FDA) for treatment of benign prostatic hyperplasia (BPH), which Merck marketed under the brand name Proscar.

In 1997, Merck was successful in obtaining FDA approval for a second indication of finasteride (1 mg) for treatment of male pattern baldness (MPB), which was marketed under the brand name Propecia.

See also

Epristeride 4-MA Turosteride Lapisteride Izonsteride
Epristeride
4-MA
Turosteride
Lapisteride
Izonsteride


The two isozymes, usually called Type I and Type II, exhibit differences in their biochemical properties, genetics and pharmacology. Both isozymes are now the subject of considerable research and it has been found that Type I is more prevalent in the scalp, and that Type II is more prevalent in the prostate.[69]

References

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