DUTASTERIDE
Dihydrotestosterone (DHT), a steroid hormone produced from testosterone by the enzyme 5-reductase is the primary active metabolite of testosterone (1). In male fetal development and puberty, it is essential for normal masculinization of the external genitalia and normal development of the prostate gland. In later life, DHT is associated with the development of benign prostatic hyperplasia (BPH) and androgenic alopecia. Users of testosterone based anabolic steroids are often at risk of developing disorders associated with excess DHT. These include BPH, scalp hair loss, hirsuitism (excess body hair, a particular problem for females) and acne.
The enzyme 5-reductase is present throughout the body in two forms, type 1 and type 2 (2) Type 1 has been reported to be located predominantly in the skin, both in hair follicles and sebaceous glands, as well as in the liver, prostate, and kidney (3,4,5). Type 2 is found in the male genitalia and the prostate (6,7,8 ); recent research has also identified type 1 mRNA and enzyme activity in the prostate (9,10,11).
The role of DHT in male fetal development was recognized when a deficiency of the type 2 5-reductase isoenzyme was described in association with a clinical syndrome characterized by male pseudohermaphroditism (12,13). These individuals are born with impaired masculinization of the external genitalia and a rudimentary prostate. In later life, they do not develop BPH or prostate cancer (14,15). This lack of development of BPH led to the development of an inhibitor of 5-reductase to treat this common condition (16) The first available 5-reductase inhibitor (finasteride) is selective for the type 2 isoenzyme (17). Its clinical utility in reducing enlarged prostates, relieving symptoms associated with BPH, and reducing the risk of associated complications has been documented in several clinical trials (18,19). More recently, 5-reductase inhibition has been proven effective in treating androgenetic alopecia (20). Finasteride suppresses serum DHT by about 70% (21)..
However, as a selective type 2 isozyme inhibitor, finasteride has proved only moderately effective in treating BPH and more potent compounds are clearly needed. Dutasteride (GI-198745) is a dual inhibitor of 5alpha-reductase types 1 and 2 isozymes which appears to be suitable for use alone or in combination with alpha1-adrenoceptor antagonists for the treatment of BPH and associated symptoms.
Dutasteride is a 6-azasteroid, which inhibits both type 1 and type 2 5-reductase isoenzymes. Its structure is depicted below:
Several studies, conducted both by Glaxo, the developer of the drug, as well as independent studies, have demonstrated the efficacy and safety of dutasteride.
In a randomized, double-blind, parallel group 4-week study sponsored by Glaxo, the developer of dutasteride, dutasteride (40 mg loading dose then 0.1, 0.5, 2.5 and 2.5 mg/day) was shown to more potently suppress dihydrotestosterone (DHT) as compared to finasteride (5 mg/d) in 53 subjects with benign prostatic hyperplasia. DHT was dose-dependently suppressed in dutasteride-treated subjects with a maximum suppression of 95% occurring with the 5 mg dose; 0.5 mg, the lowest maximally effective dose, decreased DHT levels by 90% at 4 weeks and by 94% at 24 weeks, while finasteride only suppressed levels by 67 and 76%, respectively. Although testosterone levels increased (9-27%)with DHT suppression with both agents, levels were considered normal. Similar incidence of adverse effects was observed for placebo and both treatment groups although decreased libido was observed in subjects given 5 mg finasteride or dutasteride.
In an open-label, crossover study presented to the American Urology Association by Glaxo, 38 healthy male subjects were given the alpha-blocker tamsulosin (0.4 mg/day) or terazosin (titrated up to 10 mg/day) for 14 days, followed by 7-day washout and subsequent treatment with dutasteride (0.5 mg/day following a 40-mg loading dose) for 21 days, followed finally by a 14-day treatment with the combination of dutasteride plus tamoxifen or terazosin. The results showed no significant drug interactions as regards pharmacokinetics. In addition, the incidence of adverse events of headache, dizziness, musculoskeletal pain, orthostasis, nausea and emesis was lower when dutasteride was coadministered with tamoxifen (18% vs. 29%) or terazosin (35% vs. 67%) compared to either drug alone.
As an example of an independent study, Clark et al reported that in their study a total of 399 patients with BPH were randomized to receive once-daily dosing for 24 wk of dutasteride (0.01, 0.05, 0.5, 2.5, or 5.0 mg), 5 mg finasteride, or placebo. The mean percent decrease in DHT was 98.4 ± 1.2% with 5.0 mg dutasteride and 94.7 ± 3.3% with 0.5 mg dutasteride, significantly lower (P < 0.001) and with less variability than the 70.8 ± 18.3% suppression observed with 5 mg finasteride. Mean testosterone levels increased but remained in the normal range for all treatment groups. Dutasteride appeared to be well tolerated with an adverse event profile similar to placebo (22).
Studies with 5-reductase have highlighted differences between the two major androgens: testosterone and DHT. Whereas testosterone is largely responsible for muscle development, libido, and potency, DHT is essential for prostate growth and its effects on hair follicles can lead to androgenetic alopecia. Whereas DHT can act as a potent androgen, DHT does not appear to be essential in the adult male. Skeletal muscle has little 5-reductase activity, so testosterone is thought to be the major androgen in this tissue, although circulating DHT may contribute a minor effect in normal men. Treatment with finasteride for 4 yr has not shown an adverse effect on bone mineral density associated with decreased DHT levels (23). The short-term safety data in the present study appear to support the tolerability of reduced DHT levels because no unexpected adverse events were reported in conjunction with the almost complete suppression of DHT. Although mean serum testosterone levels rose in association with DHT suppression, testosterone concentrations did not exceed the normal range.
Thus far we have focused on the beneficial effects of dutasteride on the prostate. We mentioned that type I 5 alpha reductase (AR) is found primarily in the skin and scalp, while the type II enzyme is more localized to the prostate. Since DHT has been implicated in both male pattern baldness and acne in both sexes, we would expect dutasteride to be superior to finasteride in treating these conditions. In one in vitro study (24), Dutasteride completely abolished DHT formation in the skin and scalp. The authors concluded that “Dutasteride may be useful in acne and androgenetic alopecia.”
Although independent research on the efficacy of dutasteride for hair restoration are lacking,
GlaxoSmithKline completed Phase II trials for FDA approval of Avolve (dutasteride) for treating hair loss. After six month of treatment, the hair counts measured in a 1 inch diameter circle increased by an average 96 hairs with 0.5mg Avolve daily, compared to an average 72 hairs with 5mg Propecia (Finasteride) daily. So these initial trials show that Avolve (dutasteride) is around 30% more effective than Propecia in promoting hair regrowth.
Will dutasteride help hair re-growth for all men?
As with Propecia, Avolve increases the number of scalp hairs, helping to fill-in thin areas of the scalp. Although results will vary, generally men will not re-grow all of the hair they have lost. Male pattern hair loss occurs gradually over time, but Avolve can significantly reduce or delay hair loss.
If you are able to obtain Dutasteride in its raw form, you might even be able to compound your own Dutasteride topical solution. It was reported in Avodart's prescribing information that the medication is absorbed through the skin as well. Dutasteride in its raw form is a white-yellowish powder. It is insoluble in water but can easily be dissolved in ethanol (44mg/mL), methanol (64 mg/mL) and polyethylene glycol 400 (3mg/mL). Although 0.5 mg is the standard dosage for treatment of BPH, many users of dutasteride report 0.25 mg to be just as effective as the higher dose for treating hair loss.
Little research has been carried out on the use of dutasteride for acne treatment. However, Since most experts agree that DHT is involved in acne development and dutasteride blocks the type 1 apha reductase found in skin, one might expect dutasteride to help prevent and treat acne. There are numerous anecdotal accounts of this happening. Interestingly, dutasteride’s competitor finasteride can actually cause acne. This is due to the increase in testosterone associated with finasteride use (as with dutasteride as well). However, since finasteride fails to prevent the conversion of T to DHT in the skin (unlike dutasteride), the higher T levels corrrespond to increased DHT production in the skin.
In summary, then, there is considerable evidence that dutasteride is an effective treatment for BPH. Company sponsored research clearly suggests that dutasteride is superior to finasteride for hair restoration. Regarding acne, we are forced to rely on the extremely positive feedback from dutasteride users. Interestingly, many women take progestin containing oral contraeptives to control acne. One very popular OC is Ortho Tri-Cyclen. Norgestimate is the progestin used in this compound, and norgestimate has been shown to act as a type I 5AR inhibitor.
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22) Clark RV, Hermann DJ, Cunningham GR, Wilson TH, Morrill BB, Hobbs S Marked suppression of dihydrotestosterone in men with benign prostatic hyperplasia by dutasteride, a dual 5alpha-reductase inhibitor. J Clin Endocrinol Metab. 2004 May;89(5):2179-84.
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24) Munster U, Hammer S, Blume-Peytavi U, Schafer-Korting M Testosterone metabolism in human skin cells in vitro and its interaction with estradiol and dutasteride Skin Pharmacol Appl Skin Physiol. 2003 Nov-Dec;16(6):356-66.
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Increasing the likelyhood of gyno.
