Hair Growth Disorders

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Common baldness, also known as male-pattern baldness, affects approximately 50% of men by age 50 (72), although it can start as early as the teen years. Till the late 1980s, common baldness was viewed as a merely cosmetic condition that has no health implications; with the introduction of hair growth agents, the condition was medicalized and redefined as androgenetic alopecia. Androge-netic alopecia affects women as well, but in a different pattern that is usually referred to as female-pattern baldness, diffuse hair loss, or diffuse androgen-dependent alopecia. An estimated 30% of Caucasian women, and 15-20% of all women, develop the condition before age 50 (73, 74). Whereas hair loss, like other lifestyle conditions, is not a direct threat to a person's well-being, it can be a distressing and psychologically disturbing condition because of lower satisfaction with one's body image (75, 76). In one of the clinical studies on minoxidil, the majority of participants thought that personal presentation of self was of equal to or greater importance than their job performance (77). Obviously, the condition has a more severe psychological impact on female subjects, which was confirmed in two separate studies (78, 79).

Excessive hair growth in cosmetically undesirable areas is another hair growth disorder of little clinical importance but great lifestyle impact. The condition, which is medically known as idiopathic hirsutism, is defined as increased hair growth in the androgen sensitive areas of women with regular ovulatory menstrual cycle and normal serum androgen levels (80, 81). Hirsutism is a common condition that can have a severe psychological effect on young women and negatively affect their quality of life. The argument that preserving or restoring physical appearance can have profound psychological benefits provides the basis for medicalizing cosmetic disorders such as hair loss, hirsutism, or aging skin wrinkling and discoloration.

5.1 Clinical Use

5.1.1 Current Drugs. Table 9.6 lists the current therapies for hair growth disorders. The effects of the two hair growth agents (minoxidil and finasteride) have not been directly compared in clinical trials, and no clinical studies have been performed on the combination of the two drugs either, but a study in an animal model for male pattern hair loss suggests that the combination of 0.5 mg/day oral finasteride and 2% topical minoxidil has an additive effect on hair growth (82,83). Ef-lornithine is the only drug currently approved for the reduction of unwanted facial hair in women. In addition to approved therapies, hormonal treatments are still commonly used both for female pattern androgenetic alopecia and hirsutism. Estrogens (ethinylestradiol or oral contraceptives) and antiandrogens (cyproterone acetate, spironolactone, and flu-tamide) are used either alone or in combinations for either condition (73, 81). Finasteride was found to be effective for the treatment of idiopathic hirsutism at a dose of 5 mglday, although it is not approved for the indication. This section will mainly focus on the two approved hair growth agents.

5.1.2 Adverse Effects. The side effects of topical minoxidil are mainly local, caused by skin irritation and contact dermatitis. Systemic side effects are uncommon because of limited percutaneous absorption, but diffuse hypertrichosis of the face and limbs has been reported with the 5% solution and was attributed to systemic absorption of the drug (84). Although topical minoxidil does not change blood pressure in healthy subjects, it increases heart rate by 3-5 beats/min and slightly increases the left ventricular end-diastolic volume, cardiac output, and left ventricular mass (85). These effects are not considered clinically significant, and the potential for cardiovascular side effects is very low.

The clinical dose of finasteride is well tolerated. The main side effects reported in phase III clinical studies were sexual function disorders including decreased libido, ejaculation disorders, and erectile dysfunction. All these sexual disorders were mild-to-moderate and were reversed on discontinuation of the drug, and in some patients, they resolved even with continued therapy (86). A 5-mgdose in hirsute women was well tolerated with no significant side effects, although the risk of developing abnormalities in the external genitalia of male fetus, if the drug is taken or a crushed tablet is handled by a pregnant woman, causes a great limitation to its use in women at child-bearing age.

Topical eflornithine has a very good safety profile. The only side effects observed in the clinical trials at a higher frequency than placebo were related to skin irritation and included stinging or burning skin and rash at the site of application.

5.1.3 Pharmacokinetics. Minoxidil is poorly absorbed through skin, and systemic accumulation after topical application is unlikely (87). After topical application, minoxidil appears in the systemic circulation at clinically insignificant levels. The total amount recovered in urine is less than 4% of the applied dose. Applying the drug to the entire scalp is equivalent to a systemic dose of 2.4-5.4 mg/day (88). A total of 4145% of the applied dose remains on the scalp or is lost on the pillowcase. Dermal metabolism of minoxidil is negligible (89). Systemic minoxidil elimination, after topical administration, is zero order, which indicates that it is controlled by zero order percutaneous absorption. The main route of elimination after oral absorption is hepatic metabolism. The primary metabolite is a glucuronic acid conjugate at the N-oxide position of the pyrimidine ring. Twenty percent cf the orally administered drug is excreted unchanged in urine, and 95% of the total dose is recovered in urine within 48 h.

Finasteride is rapidly absorbed after oral administration, with peak plasma concentration reached in 1-2 h. The oral bioavailability is about 80% and is not dose-dependent. Food has no effect on the bioavailability of finasteride. Moderate accumulation occurs with multiple dosing, and steady state is reached within 3 days. Finasteride has a large voluine of distribution (76 L) as a result of wide tissue distribution. Approximately 90% of the circulating drug is bound to plasma proteins. Fin-asteride undergoes extensive hepatic metabolism. Finasteride metabolism occurs in the liver through an oxidative pathway by cytochrome P450 3A4 enzymes. The two major metabolites are ft>-hydroxyfinasteride and a monocarboxylic acid derivative. Their in vitro activity is less than 20% of that of finasteride, but their invivo activity has not been studied. Virtually no unchanged drug is excreted in urine; 56.8% of the metabolized drug is excreted in bile and 39.1% in urine. The mean elimination half-life after multiple oral dosing is 4.8 h, and the mean clearance after intravenous infusion is 9.9 L/h. The mean serum halflife is about 6 h in middle-aged men and slightly longer in the elderly, but dosage adjustment is not necessary (86, 90). The biological half-life of finasteride is longer than its serum half-life. After discontinuation of the drug, dihydrotestosterone (DHT) takes at least 2 weeks to return to baseline levels.

Eflornithine absorption after percutaneous administration is minimal (<1% of the applied dose). Commonly used hair removal methods such as shaving, plucking, or tweezing, when performed within 2 h before application, did not increase the percutaneous absorption. Steady state is reached after 4 days of twice daily application. Eflornithine is excreted unchanged in urine, and no metabolism has been observed. The apparent steady-state half-life is approximately 8 h.

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