Spironolactone is an aldosterone antagonist employed in clinical practice as a potassium-sparing diuretic and to treat high blood pressure. Potassium-sparing diuretics are commonly used to help reduce the amount of water in the body by acting on the kidneys to increase the flow of urine. This in turn also helps to lower blood pressure. Unlike some other diuretics, these medicines do not cause the body to lose potassium, an important electrolyte required by the human body.
Spironolactone therapy may reduce shedding of hair in those individuals without hyperandrogenism and may promote some hair growth in those with hyperandrogenism (an excessive production of male hormones). In some women with hirsutism the drug decreases the growth rate and mean diameter of facial hair.
Spironolactone is a steroid with a basic steroid nucleus of four rings. Spironolactone is 98% protein bound and the primary metabolite, canrenone, is at least 90% protein bound. Canrenone is the active antagonist of the hormone aldosterone, and it is the primary metabolite contributing to the diuretic action of spironolactone.
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Absorption and metabolism of spironolactone
Spironolactone is rapidly absorbed, with maximum plasma levels being reached in 30 to 60 minutes. Food increases spironolactone absorption. The percentage of drug that is detected in the systemic circulation after its oral administration exceeds 90%, depending on the tablet manufacturer.
Spironolactone is rapidly metabolized by the liver. Canrenone can be inter-converted enzymatically to its hydrolytic product, canrenoate. No un-metabolized drug is passed out via the urine. The major metabolites are canrenone and potassium canrenoate and are excreted through urine and bile.
Mechanism of spironolactone action in treatment of androgenetic alopecia
Spironolactone is a potent antiandrogen. The term antiandrogen, as defined by Dorfman, implies prevention of expression of androgen activity at target sites and does not include other mechanisms of decreasing androgen action, such as a decrease in production of androgens, interference with androgen metabolism, or change in androgen plasma protein binding.
However, the action of Spironolactone is directed at both decreasing production and blocking the effect of androgens at the cellular level. It is evident that Spironolactone decreases testosterone production in the adrenal gland by depleting microsomal cytochrome P450 and by affecting the cytochrome P450-dependent enzymes 17a-hydroxylase and desmolase. The destruction of microsomal cytochrome P450 by spironolactone may be limited to those tissues in which microsomal 17a-hydroxylase activity is high. The binding of spironolactone to 17- hydroxylase-cytochrome P450 may convert spironolactone to a metabolite that destroys the heme portion (molecule containing iron) of cytochrome P450, thereby decreasing steroid 17-hydroxylation.
Spironolactone is also a competitive inhibitor of DHT-receptor binding and interferes with the translocation of this complex into the nucleus. Spironolactone, a strong competitor for the androgen receptor, is a potent agonist, whereas canrenone, a weak competitor, is a potent antagonist. The true antagonists of endogenous or exogenous androgens are the weak agonists, which rely only on a continuous supply of the compound to achieve full inhibition. The antiandrogen effect of spironolactone may be produced by the parent compound on the adrenal gland and the metabolite on the receptor site.
The protestation activity of spironolactone is variable but influences the ratio of luteinizing hormone (LH) to follicle-stimulating hormone (FSH) by decreasing the response of LH to gonadotropin-releasing hormone (GnRH), thereby decreasing androgen production.
Dosage of spironolactone
Spironolactone as a drug is available only in 25-mg or 50-mg tablets. The dosage of spironolactone used in clinical practice varies from 50 to 300 mg per day and can be given as a single dose or in divided doses. The minimum threshold for effective treatment of pattern hair loss however has been found to be 100 mg daily, similar to that seen in hirsutism. At doses of 100mg per day, minimal changes in circulating androgens are observed. With a higher dose of 300mg or more per day, plasma testosterone decreases significantly, but this elevated dose has almost no clinical advantages and only serves to increase the side effects.
Clinical reports of use of spironolactone in patterned hair loss
There are very few documented reports in the literature regarding the use of spironolactone in pattern hair loss. Small open trials have shown some clinical effect in androgenetic alopecia, but re-growth takes a long time to develop.
All studies so far have been performed in women only.
- In one study, 12 women with “androgen-dependent alopecia“, were observed for 12 months. 6 were on spironolactone therapy of 75 to 100 mg per day and 6 were untreated controls. Both groups showed a mean decrease in target area nonvellus hairs, but the decrease in the control group was statistically significant. Enhanced non-vellus growth was noted in two patients who had their spironolactone dose doubled after 12 months from the 75 or 100 g per day used during the first year.
- In a second study, there was an improvement in six of seven female patients with androgenic alopecia treated with 200 mg spironolactone daily.
Side effects of spironolactone
One of the potential side effects of spironolactone in both men and women is acute intoxication of potassium, a condition called hyperkalemia. Decreased libido, impotence, and worse still, gynecomastia (excessive development of the male breasts) can occur in men treated with spironolactone, thus confining the systemic use to women. In women, breast tenderness, irregular menses, and mood swings are not uncommon side effects. Women of childbearing age who are treated with spironolactone should use effective contraception, preferably a concomitant oral contraceptive pill. If pregnancy occurs while they are on spironolactone, there is a possible risk of feminization of the male fetus.
No dermatologic indications for spironolactone have been approved by the FDA. It is only approved as a diuretic, for the treatment of primary hyperaldosteronism, idiopathic hyperaldosteronism, edematous conditions of congestive heart failure, cirrhosis with ascites, nephrotic syndrome, essential hypertension, or hypokalemia. Spironolactone is perceived to be somewhat effective in preventing hair loss in androgenetic alopecia in women at doses of 200 mg per day, but hair re-growth is limited. Laboratory monitoring every 3 to 4 months is recommended to assist in following androgen suppression if a condition of androgen excess is found.