ANDROGENETIC ALOPECIA

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ANDROGENETIC ALOPECIA New Approved and Unapproved Treatments

Marty E. Sawaya, MD, PhD, and Jerry Shapiro, MD, FRCPC

There are various forms of alopecia, the most common being androgenetic alopecia (AGA), which affects millions of men and women. Hair loss for both men and women may begin as early as adolescence but can start even in later decades of life. Hair loss severity in women is usually much less than in men?8 In men with AGA, one of the earli- est findings is an increase in the percentage of hairs in a telogen phase of the hair cycle, so that initial hair loss may appear indistin- guishable from a telogen effluvium. As in men, AGA in women can be psychologically devastating to accept, leading to overall less body-image satisfaction and making it difficult to cope and retain integrity of personality f~nctioning.~ Androgenetic alopecia has been reported to be a polygenic autosomal trait that is believed to involve several genesI8 for both men and women.

BIOCHEMICAL MECHANISMS IN MALE AND FEMALE AGA

Although for many years it had been as- sumed that the hormonal basis for AGA in women was the same as that for men, no studies confirmed this. Recent has shown that on the scalp there are local differences in the amounts of steroid metabolizing

enzymes that convert weak androgens to more potent androgens. This is important because the skin is an endocrine target tissue for androgen hormone action, similar to the ovaries, testes, and adrenal gland. Studies have shown that persons using anabolic, androgenic steroids demonstrate hypertrophy of the sebaceous glands, with systemic hirsutism and AGA.41 It is known that weak and abun- dant precursor hormones such as dehydro- epiandrosterone can metabolize to more potent androgens such as testosterone (T) and 5a-dihydrotestosterone (DHT). The enzymes have been localized in the sebaceous glands and hair follicles of scalp 38 Therefore, the skin has the potential to mediate androgen action without relying on elevated systemic levels of T or DHT.34, 40

An important enzyme called 5a-reductase (5aR) mediates the reduction of T to DHT via the reduced cofactors (e.g., NADPH). There are two forms of 5aR: (1) Type I, which is thought to reside primarily in skin, especially the sebaceous glands, as well as in the kidney and liver; and (2) Type 11, an isoenzyme form that predominates in gonadal tissues (prostate, seminal vesicles, and so forth). In recent years, however, Type I1 was also found in hair follicles on the scalp, where miniaturization takes place. This finding explained how finasteride, a 5aR inhibitor, had hair growth

From the Division of Clinical Research, ARATEC (Alopecia Research Association Technologies); Department of Bio- chemistry and Molecular Biology, University of Miami School of Medicine, Ocala, Florida (MES); and the Division of Pediatric Dermatology, University of British Columbia, Vancouver, British Columbia, Canada US)

DEFWATOLOGIC CLINICS

VOLUME 18 NUMBER 1 *JANUARY 2000 47

48 SAWAYA & SHAPIRO

promoting properties, indicating efficacy for specific androgen inhibitors against A-Type I or Type I1 isoenzyme forms in treating androgen-related skin conditions.z, l6

Overall, the importance of 5aR and the two specific isoenyzme forms is apparent because tissue distribution in the body differs, as do the biochemical characteristics of the enzymes. The isolation of the two 5aR forms raises interesting questions concerning their regulation and specific roles in androgen physiology, because new inhibitor compounds will be designed to target one or both enzyme forms, depending on the condition being treated.

Another important enzyme that has come to recent attention is the cytochrome P450 aromatase enzyme. Because it is known that androgen metabolism occurs within the hair follicle structure, finding aromatase to be specifically located in outer root sheath of hair follicles adds to the importance of studying the entire hair follicle and not just the dermal papilla ~ells.3~. 38 Aromatase has been shown to convert androgens such as T and androstenedione to the estrogens estradiol and es- trone, respectively. In addition, there may be two- to fivefold greater levels of aromatase in the female versus the male scalp, perhaps explaining why the frontal hairline may be spared in women with AGA, and why women may have a less severe pattern of hair loss than men.38 It is uncertain if the estrogens formed from aromatase are playing a role in suppressing hair loss severity, or whether aromatase is primarily reducing the overall load of androgens formed locally in the hair follicle. At this time, the role of estrogens in hair growth is still uncertain.

The next important step in understanding androgen action in skin is the binding of the target tissue active androgens, T and DHT, to the androgen receptor (AR). The AR has been purified and located in specific skin structures, such as the hair follicle and sebaceous gland.33,35 This receptor is important for form- ing an activated hormone-AR complex, which has the ability to bind to specific hormone response elements at gene sites in the nucleus to stimulate or alter cellular processes mediating hair growth.I3, 25, 31, 36

In genetically predisposed men the balding process is triggered by exposure to androgens at puberty. In women, the relationship between systemic elevated androgen levels and alopecia is difficult to determine, because approximately 30% to 40% of women who expe-

rience AGA have a systemic endocrine problem, leaving the condition to be called idiopathic in most women. We are now finding that many conditions once called idiopathic have qualitative differences in the N-terminal domain of the androgen receptor, where the number of polyglutamine re eats can render

tative and qualitative factors targeting the AR must be recognized prior to considering treatment options in that not all patients may respond to the conventional or latest treatments based on 5a- or other non-receptor mediated mechanisms.

Based on these direct mechanisms regarding cellular DHT metabolism via quantitative and qualitative aspects of the 5aR isoenzymes and AR in AGA, it is important to also keep in mind that some therapies may target the cofactors that mediate these reactions, such as reduced NADPH, which is necessary in mediating 5a-reduction of T to DHT. There- fore, these "secondary" mechanisms must be considered because novel therapeutics may target them as well. An example of such an agent is zinc, as is discussed in a subsequent section.

Previous publicationsz9 provide an over- view of novel compounds undergoing patent protection and approval for alopecia, and at the time of this writing these agents are not available for public use. As of 1999, there are no Food and Drug Administration (FDA)- approved treatments specifically for alopecia areata (AA). Treatment approaches for AA using unapproved or off-label drugs have been reviewed in other publication^.^^^ 43

This article examines some of the available new approved and unapproved agents commonly used to treat AGA, with implications for effluvium (hair shedding) as well. These agents are discussed in the following order:

androgen ~ensitivity.'~, 30, 39 T R erefore, quanti-

1. 2. 3.

4.

5. 6.

7.

Approved FDA products Off-label prescription products Over-the-counter (OTC) products with antiandrogen mechanisms Over-the-counter herbal agents and nutritional agents Products in FDA clinical trial testing Patented products in research and development Medical devices

FDA-APPROVED PRODUCTS

Finasteride

Finasteride (Propecia; Merck and Company, Rahway, NJ) is sold as a 1-mg tablet. The

ANDROGENETIC ALOPECIA 49

FDA approved finasteride’s use in men with AGA in December 1997. Finasteride is a 4- azasteroid derivative of the 3-0x0-5a- steroids synthesized as a 5aR Type I1 inhibitor. The mechanism of action for finasteride inhibiting 5aR is not a simple competitive inhibitory pattern. Rather, it is a unique one in that it uses the reduced cofactor NADPH at the enzyme’s active site, but with a reduction of the carbon 1-2 double-bond position of the steroid nucleus rather than the carbon 4-5 double-bond position, which is normally reduced in T.

Phase I1 dosing studies for finasteride, performed at 0.4 to 100 mg daily for 11 to 14 days, revealed serum DHT levels lowered by 63% to 78Y0.l. 43 A double-blind, randomized, placebo-controlled study was performed to determine the effect of low doses of finasteride on hair growth in otherwise healthy men with AGA. The doses ranged from 0.01 mg/ day to 5 mg/day. As determined by the efficiency criteria of hair counts, patient self-assessment, investigator assessment, and evalu- ation of clinical photography, the 0.01 mg/ day dose was subtherapeutic whereas the 1 mg/day dose was superior to the 0.2 mg/ day dose but had similar efficacy to that of the 5 mg dose. Therefore, 1 mg/day finasteride was chosen as the appropriate therapeutic dosage in subsequent clinical studies on its effect on male-pattern hair loss.

The clinical efficacy of finasteride has been assessed in three double-blind studies.43 In two 12-month, double-blind, placebo-controlled randomized multicenter studies, 1553 men between 18 and 41 years of age with AGA were given either oral finasteride 1 mg/ day or placebo; 1215 of these men continued in a further 12-month double-blind extension study. The efficacy of finasteride treatment was evaluated by scalp hair counts, patient self-assessment using a validated question- naire, investigator assessment using a standardized 7-point rating scale of hair growth from baseline, and an independent expert re- view of photographs taken every 6 months. All evaluations found that finasteride treatment resulted in improvement (P < 0.001 versus placebo, all comparisons). Finasteride produced progressive increases in hair counts at 6,12, and 24 months whereas placebo treatment resulted in significant hair loss. By 12 months, 58% of the placebo patients had lost hair compared with baseline, compared with only 14% of patients on finasteride. Patients self-assessed finasteride as superior to placebo, and at 12 months investigators rated

65% of finasteride-treated patients as improved compared with 37% of placebo- treated patients; at 24 months the correspond- ing figures were 80% versus 47%. Similarly, at 12 months the expert panel considered 48% of finasteride-treated patients improved versus only 7% of those on placebo.

In these trials particular note was taken of any adverse events associated with finasteride treatment. In the first year, 4.2% of men on finasteride and 2.2% of men on placebo reported side effects related to sexual dysfunction, which resolved both after discontin- uation and spontaneously in many men who chose to remain on drug treatment. No other significant adverse effects related to finasteride treatment were observed.

Finasteride is by no means a miracle cure. Approximately 20% to 30% of men do not respond, and treatment must be continued indefinitely to maintain the benefit. In addition, finasteride has not been approved for use in women with AGA because of possible effects on the reproductive system of the developing male fetus. Nevertheless, these three studies gave convincing evidence that 1 mg finasteride taken daily represents a realistic oral therapy for AGA in men.

Minoxidil

Minoxidil (Rogaine, Upjohn Co., Kalama- zoo, MI) was approved by the FDA in 1988 as a 2% topical solution for men with AGA. This was the first FDA-approved product for hair growth in AGA. In 1991, the FDA also approved 2% minoxidil for women with AGA. In November 1997, the FDA approved 5% minoxidil (Rogaine Extra Strength, Up- john Co., Kalamazoo, MI) for use “in men only” with AGA, as an OTC product. Further discussion about minoxidil in men and women is provided in a subsequent section of this article.

“OFF LABEL” PRESCRIPTION PRODUCTS TO TREAT HAIR LOSS

Spironolactone and Aldactone

Spironolactone is an aldosterone antagonist that acts as a weak antiandrogen in blocking the AR, but also inhibits androgen biosynthe- sis. Spironolactone may convert to other active metabolites via the progesterone 17-hy- droxylase enzyme, which reversibly inhibits

50 SAWAYA & SHAPIRO

adrenal and ovarian cytochrome P450, which acts to decrease T and DHT. The progestational 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 (GJGW).~~, 49

Spironolactone is a steroid with a basic steroid nucleus of four rings, resembling the min- eralcorticoids but with an esterified lactone ring. The bioavailability from oral administration exceeds 90% but varies depending on the tablet manufacturer. Spironolactone is 98% protein bound and the primary metabolite, canrenone, is at least 90% protein bound. Ca- nrenone is the active aldosterone antagonist, and it is the primary metabolite contributing to the diuretic activities of spironolactone.

Food increases spironolactone absorption. Spironolactone is rapidly metabolized by the liver. Canrenone can be interconverted enzy- matically to its hydrolytic product, canren- oate. No unmetabolized drug appears in the urine. Metabolites of spironolactone are excreted in urine and bile.47

In some women with hirsutism the drug decreases the growth rate and mean diameter of facial hair." Side effects include metrorrha- gia, so spironolactone is commonly given with an oral contraceptive pill (OCP).15 In efficacy studies spironolactone is less effective in improving hirsutism scores than flutamide;s however, it was shown to be more effective than finasteride.I2

In a dosage range of 25 to 200 mg, a linear relationship between a single dose of spironolactone and plasma levels of canrenone occurs by 96 hours. The half-life is approximately 19.2 k 6.57 hours for canrenone, and for spironolactone it is 12.5 k 3.39 hours. Again, binding to plasma proteins is extensive and virtually no unmetabolized drug appears in the urine.3 The most serious side effect of spironolactone is hyperkalemia, which can also occur when spironolactone is given with a thiazide to patients with severe renal insufficiency. Other side effects include gynecomastia and minor gastrointestinal symptoms. Spironolactone is primarily indicated for hypertension and refractory edema.

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 has been used to treat hirsutism, acne, and AA as well as hidradenitis suppurativa. Common doses range between 50 and 200 mg/ day, with 100 mg/ day being the most preferred.2s The problem is that many patients get discouraged during treatment because it works so slowly, and it is thought that it may be somewhat effective in preventing hair loss in AGA in women at doses of 200 mg/day, but does not offer the benefit of hair

Doses such as this do induce menorrhagia, or menstrual dysfunction. This problem may correct itself after 2 to 3 months of therapy, and if it does not, decreasing the dose to 50 to 75 mg/day may help in reducing side effects. OCPs are commonly added to assist in treating menstrual dysfunction. Patients less than 35 years of age are usually given OCP, although older women may be treated with conjugated estrogens alone.

Laboratory monitoring every 3 to 4 months is recommended to assist in following androgen suppression if a condition of androgen excess is found. Complete suppression usually takes 4 to 12 months of therapy. Thera- peutic benefit also may plateau after 1 year and it may be necessary to add other ad- junctive therapies. The recommended laboratory monitoring includes the following: CBC, chemistry profile to determine electrolytes, DHEA-sulfate, testosterone, androstenedione, and cortisol levels. Blood pressure and weight should also be monitored.

In Europe topical 5% spironolactone lotion and cream have been used to treat acne Grade 11, which have efficacy similar to that of topical antibiotic therapy.

Contraindications for spironolactone are as follows: renal insufficiency, anuria, chronic renal impairment, hyperkalemia, pregnancy, and abnormal uterine bleeding.

The carcinogenicity of spironolactone has been long debated. The FDA warns in the package insert that tumors have been found in chronic toxicity studies of rats, in which 25 to 250 times the usual human dose (body weight basis) was administered. These doses resulted in benign adenomas of the thyroid, testes, malignant mammary tumors, and pro- liferative changes in liver. Because of these and other changes reported in the rat, it has been recommended that spironolactone not been given to women with genetic predispo- sition to breast cancer.


Spironolactone and metabolites may cross the placental barrier, and rat studies have indicated feminization of the male rat fetus. When lactating women have taken spironolactone, the presence of canrenone was de- tected in breast milk.

Drug interactions with spironolactone may occur when taking salicylates, which have been known to decrease the diuretic effect. Angiotensin converting enzyme inhibitors, such as captopril and enalapril, decrease aldosterone production, which may result in elevated serum potassium levels. Use of spironolactone and potassium supplements may lead to hyperkalemia. Other interactions have included digitalis glycosides, which may increase digitalis absorption, leading to increased blood levels; therefore, reducing maintenance and monitoring dosing requirements may be necessary. Spironolactone may also interfere with radioimmunoassay measurement of digoxin, which can give falsely elevated serum digoxin values.

Flutamide

Flutamide is a nonsteroidal antiandrogen that is devoid of other hormonal activity. It most likely acts after converting to 2-hydro- xyflutamide, which is a potent competitive inhibitor of DHT binding to the AR.23, 32, 47 In mature rat studies it was shown to cause regression of androgen target tissues such as the prostate and seminal vesicles by blocking the inhibitory feedback of T on LH production, which results in a profound increase in their plasma concentration^.^^ Similar effects were noted in adult men treated with 750 mg/ day f l~ ta rn ide .~~ The predominant pitu- itary effect appears to be enhancement of the frequency of pulses of LH secretion.47 The drug may be effective in vitro as an antiandrogen; in vivo, however, the rise in plasma T levels may limit its antiandrogenic effects.

Flutamide is useful in inhibiting the action of adrenal androgens in castrated men or those receiving GnRH blockage (i.e., leuprol- ide), or in situations in which LH production is not under predominant control by androgen, such as in women. Flutamide is indicated for prostatic cancer, and has been used in conjunction with OCP for treating hirsutism; if it crosses the placenta, however, it would be expected to produce male pseudo- hermaphroditism, similar to cyproterone acetate. A noted side effect to oral administration

is hepatotoxicity, including progressive liver failure, which limits its usefulness?, 48 Further studies are needed to evaluate its efficacy as a topical agent in treating AGA and hirsutism.

Progesterone

Progesterone is a compound that has high structural similarity to T, and therefore can use the same enzymes (5aR), and bind to the AR, acting both as an antiandrogen and androgen inhibitor. Some progestins have in- herent estrogenic as well as androgenic ef- f e c t ~ . ~ ~ Although progesterone binds to its own intracellular transcription receptor, it has affinity to the AR (after 5a reduction produc- ing 5a-pregnane-3,20-dione, similar to DHT), which renders it able to act as an androgen or antiandrogen.

Progesterone is secreted by the ovary mainly from the corpus luteum during the second half of the menstrual cycle, which leads to the development of a secretory endo- metrium. Progesterone is vital for the dura- tion of normal gestation of pregnancy as well as developing mammary glands; it also has a known thermogenic effect during the luteal phase of the menstrual cycle.

Progesterone can be given intramuscularly or orally and in both routes it is readily ab- sorbed, but at a rate that may be too rapid for optimal therapeutic efficiency. Inactivation takes place largely in the liver. Many progestins are derivatized to glucuronide or sulfated for excretion in the urine. A small amount can be stored in body fat. Many analogs of progesterone are less susceptible to hepatic metabolism and may be more effective in last- ing longer therapeutically than progesterone. Approximately 50% to 60% of administered radioactive progesterone appears in the urine and about 10% in feces.

Most therapeutic indications for progesterone are for ovarian disorders and contracep- tion. Off-label uses have indicated variable effectiveness as a topical agent for treating AGA at 2% concentration^?^, 24 Overall, topical progesterone has not been found to be of great value in treating AGA in the authors’ experien~e.~~, 24

Cyproterone Acetate

Cyproterone acetate, a well-known antiandrogen, is not available in the United States.

52 SAWAYA & SHAPIRO

In the search for more potent progestins that had antiandrogenic activity, some steroids with a 1,2-a-methylene substitution were found, such as cyproterone. Known to be a potent antiandrogen, cyproterone also pos- sesses progestational activity and suppresses the secretion of gonadotropin^.^, 23 The primary action of cyproterone is competing with DHT for the AR binding site;48 when given to pregnant animals, cyproterone acetate blocks the actions of androgen in the male fetus and induces a form of pseud~hermaphroditism.~~

Administering 100 mg/ day of cyproterone acetate to normal young men causes a 50% decrease in plasma concentrations of LH and FSH and a 75% decrease in plasma T, which result from the inhibition of T production as well as interference with androgen a ~ t i o n . ~ Although not available in the United States, cyproterone acetate is available in most Euro- pean countries for treating prostatic cancer and benign prostatic hypertrophy, as well as inhibiting libido in persons with deviations of sexual behavior. Off-label uses have included AGA, hirsutism, and virilizing syndromes.U, 24, 32 It is available in Europe and Canada for female acne as an OCP (2 mg cyproterone in combination with ethinyl estradiol; Diane-35, Shering AG, Germany). In women with AGA, 50 to 100 mg/day on the fifth to fourteenth day of the menstrual cycle can be used in combination with an OCP. There are side effects of menstrual irregularities, weight gain, breast tenderness, loss of libido, depression, and nausea. Women are warned of potential feminization of the male fetus if they become pregnant while taking cyproterone acetate.

Cimetidine

Cimetidine, the first H, blocker introduced for general clinical use, was well accepted as a treatment for duodenal ulcers and other gastric hypersecretory conditions. Cimetidine also has the unusual properties of working as an antiandrogen by binding to AR, hence the noted side effects of loss of libido, impotence, and gynecomastia (stimulated prolactin). Ci- metidine also binds to the cytochrome P450 enzyme systems and diminishes the activity of hepatic microsomal mixed function oxi- dases. Off-label uses of cimetidine have included treatment for AGA, hirsutism, and even multiple papilloma verrucous lesions (warts) in patients; however, no clinical trials have ever been performed to prove efficacy.

The preferred dosage range is 800 to 1600 mg/day, or commonly given as 300 mg by mouth five times a day.39

OTC PRODUCTS THAT MAKE “ANTIANDROGEN” CLAIMS

In this category there are three different types of mechanistic agents that claim to inhibit the action or ”trap” the hormone DHT; inhibit one or both of the 5aR isoenzymes; or block the AR, to which DHT must bind to elicit a molecular response. These companies often confuse which compound their drug interacts with (the enzyme 5aR, the hormone 5a-DHT, or the AR), as the nomenclature can be confusing. At times advertisements use 501 reductase to mean the hormone, DHT, rather than the 5aR enzymes. The companies often use these terms interchangeably; therefore the products usually mention DHT in some manner, by blocking it once it is already made, or blocking its synthesis, or blocking it, binding it, and trapping it to make it unavailable for cellular use. The companies are very clever with their advertisements and it sometimes takes an expert to see the discrepencies in their product advertisements.

Serenoa Repens, Saw Palmetto, and Permixon

These agents are very commonly known by patients and clinicians as they are widely available in most nutritional and food stores. Serenoa repens berries grow naturally, with companies claiming that the extract inhibits DHT production, mainly for use in prostate problems. Extensive studies have not been done, but because of the stated implications of affecting DHT, men are anxious to try this OTC rememdy to see if it promotes hair growth.

Studies that have been performed6 have compared Permixon with finasteride in the treatment of 1098 men with benign prostatic hypertrophy (BPH). Permixon improved BPH symptoms but had no effect on androgen- dependent parameters such as DHT levels or 5aR, indicating that its effects must be caused by other as yet undetermined pathways that do not involve DHT or 5aR directly. Another s t u d y in 32 young men (20 to 30 years of age) in a 1-week open trial looked at the effects of finasteride versus Permixon with


regard to serum androgen levels, finding that no effect on DHT levels were found in the Permixon-treated group, similar to the placebo group, whereas in the finasteride group DHT was reduced by 65%.

Side effects noted in the use of S. repens in either commercial form of Permixon or Saw Palmetto have been breast growth in men, indicating that it does not act on DHT alone, but by other unrevealed mechanisms. To be effective the extract of the berries must be taken, not the berries themselves. Another active ingredient, a Pygeum ufiicunum compound, is added to this extract and is thought to influence T metabolism, although the mechanism is not yet clear. The product comes in capsule form (60 capsules cost approximately $11.80) with two to six capsules as the recommended dose per day in divided doses between meals.

Kevis Hair Rejuvenation Program

Kevis (www.kevisnet.com) is another OTC agent available to men and women with hair loss problems ranging from AGA to effluvia that claims to bind and block the 5a-DHT receptor, which is the AR. It claims to be safe and effective for men and women of all ages and cost efficient, as well as preventing hair loss and making hair healthier. Kevis claims to ”have an anti-falling out effect,” that is, less hair shedding.

Although the claims seem broad the active ingredients are composed of mucopolysac- charides and glycoproteins associated with substances that favor their bioavailability. Kevis claims to contain hyaluronic acid, glycoproteins, and amino acids that have hydrat- ing and antiinflammatory action, thiogly- coran (a mucopolysaccharide acid), thurtyl nicotinate, a cutaneous vasodilator, and so- dium pantothenate and biotin. Studies claim that this treatment helps women with post- partum effluvia as well as acne, wrinkles, li- podystrophies, dermosclerosis, AGA, and hypertrichosis.

Again, these claims are confusing because the literature states that Kevis “blocks DHT” and ”blocks the androgen receptor” by creat- ing a cell wall barrier to keep DHT out of the follicle. These claims confound attempts to understand their scientific basis.

Some European studies on Kevis have been performed. One study cites localization of ”5a-DHT” in hair follicle by use of mono-

clonal antibodies, and again it is not clear whether it is assessing the enzyme 5aR (or which isoenzyme), the hormone DHT, or the AR. The study’s findings stated that ”what- ever” was localized was found in the dermal papilla. The dermal papilla is always mentioned as where most androgen-related factors are found, because much of the older literature mentions this as the major site of control for hair follicle growth. Recent investi- gative research in the last few years cites other important areas of the hair follicle involved in regulation of growth, such as the follicular stem cells in the ”buldge” as well as the fact that many androgen-related factors, such as 5aR and AR, are also expressed in the outer root sheath of hair follicles, not just the dermal ~apilla.3~. 38

Clinical testing of Kevis in a double-blind placebo-controlled study indicates that in the Kevis-treated group, after 90 days of treatment, telogen hairs decrease by 16% versus 6% in the placebo group. What is important is the anagen-to-telogen ratio, and no mention of anagen hairs is given. The 10% differ- ence found in telogen hairs is of no signifi- cance because this can be caused by error or hair cycling, and the study does not mention if the hairs that cycled out of telogen were stimulated back to anagen, as no anagen counts are given. Also, it is unknown what the study‘s ”three comb stroke” test is, as this is not a standardized measurement used in clinical trials in the United States or Canada.

Importantly, the cost of Kevis should be of concern. When patients call the Kevis cus- tomer service line, they are given information on the hair rejuvenation program, which can cost between $650 and $975 per year. A 12- month supply includes 216 vials (each vial contains two tablespoons of Kevis lotion to be applied topically to the scalp) and 8 bottles of shampoo. The $650.00 value is a nonrefundable package and patients cannot get their money back. For $900.00 patients can get the same 12-month supply but with a money-back guarantee. There is also the Extra Strength Kevis, which is a 25% stronger formulation that sells for $715 (nonrefundable plan) or $975 (refundable plan).

Overall, it is uncertain if there are any side effects with Kevis, but one study revealed an increase in pityriasis scaling and an increase in pr~rit is .*~ The main concern is ”cost to efficacy,” as no rigidly standardized double- blind studies have shown true increases in hair counts in studies for 12-month periods.

54 SAWAYA & SHAPIRO

Some of the previously mentioned studies were conducted for only 36 to 90 days, which is not an adequate amount of time to assess hair growth in the hair cycle, as a reversal in hair growth to a full anagen stage may take multiple hair cycles (4 to 7 years).

Zinc

Much has been claimed regarding the use of zinc to treat various diseases, including topical use for acne, another androgen-related problem.@ Specific forms of zinc, such as zinc acetate and zinc sulfate, have various properties in promoting wound healing, clearing acne, and promoting hair growth. In the last few years a new formulation of zinc in a “Skin Cap” (Cheminova, SA, Spain) has been used to treat scalp psoriasis, and scaly, ery- thematous conditions of the skin; it has been found, however, that the main ingredient is actually clobetasol, a corticosteroid that was the active ingredient responsible for the great improvements noted. In any case, it is cau- tioned that zinc may be an important factor when treating diseases topically or orally depending on the formulation. Zinc sulfate was found to inhibit DHT production, not in that it inhibits 5aR, but because it limits NADPH, which is necessary for the 5a reduction of T to DHT.

OTHEROTCHERBALAGENTS

Fabao 101 D and Formula 101

Fabao lOlD (Pan State Health Products) is an ”oldie” and it is believed that it is a remar- keting of Formula 101, which came from China years ago. This herbal concoction claims to come from medicinal plants containing Sophera jlavescens, Radix astragali, cap- sicum, Seu radis notopterygi i , safflower oil, Cortex dictamni radicis, Rhizhoma gastroidia gin- seng, notoginseng, heshouwu, and peach ker- nel oil. The reading insert material states that the molecular structures of these active compounds are very delicate and that they are only active in their native molecular structure, which is kept intact during the company’s manufacturing process, such that other companies cannot duplicate the product because of the technologies involved. Product brochures show patients who appear to have AA totalis patterns who have supposedly

benefited from the treatment. Again, there are no published double-blinded, placebo-controlled trials to document the effectiveness of this agent.

lamin (Prezatids Copper)

Iamin (Procyte Company, Redmond, WA) is a new drug, approved by the FDA in 1996, that is one of the superoxide dismutases (copper-binding peptides). It was FDA approved as an antiinflammatory wound-healing gel. Procyte, which makes Iamin, states that there are many copper peptide derivatives that can be used on the skin. Another formulation of one of its other superoxide dismutases, Tri- comin, is promoted for use in hair loss treatment and is available as an OTC product. Iamin hit the shelves in early July 1996, with results showing that it may help some people with hair loss. Some have reported hair growth related to Iamin, with most reporting a “strengthening of existing hair.” The company’s efforts in formulating Tricomin are geared toward providing a specific product line for hair loss.

The makers of Iamin have also released another product, GrafCyte, which is basically Iamin in a few different forms. It has been approved by the FDA for use after transplants to prevent newly transplanted hairs from go- ing into a resting phase. The company pro- poses that more hairs will grow immediately after transplants and that results may be seen sooner than the typical 6 to 8 months after surgery. The product is available in moist press applications applied for 1 hour, four times per day for 4 days following a hair transplant. A mist spray and shampoo are also available, with hopes that they will be used by those suffering from hair loss in general; however, the moist presses are available only to physicians or hair transplant sur- geons. Results with use of GrafCyte have been very positive and successful for use as a wound-healing agent.

Polysorbate 80

Polysorbate 80 is an OTC product that has been around since the early 1980s, when it was first used in the Helsinki Formula (Bio- generation Laboratories, Inc.) sold on televi- sion until the FDA banned such advertisements. There were claims that it grew hair in


some people, but it was not effective in most individuals who used it. Perhaps those who did see a hair growth response were noting hair that was growing through successive miniaturization cycles, which often happens in double-blind studies in which placebo- treated subjects have up to 30% improvement.

Folligen (Copper Chloride)

Folligen (www.regrowth.com) is a new treatment similar to Iamin, but in a cream form that contains a copper complex and Saw Palmetto for use as an androgen inhibitor of 5aR. Folligen is another product that has not been thoroughly tested for positive results in double-blind clinical trials.

Amino Acids

Arginine and L-arginine or cysteine and L-cysteine have been proposed as playing a strong role in hair growth and are offered in nutrition health food stores to ”make nails stronger and help hair follicles to make more hair.” These amino acids can be taken alone or together in oral liquid form with doses recommended at 500 to 1000 mg a few times a week. For patients receiving an adequate dietary intake, these supplements may not be of benefit.

Biotin and Folk Acid

These compounds have been around for a long time with claims to help hair grow. Nutritionally speaking, biotin and folic acid are required for hair growth and are usually supplied in a normal diet; unless there is a deficiency in these because of poor nutrition, wasting diseases, and so forth, increased doses may not help hair grow. In fact, excess doses of these may cause hair loss, so if an adequate balanced diet is being maintained, a general vitamin supplement should do as well in providing nutritional needs for hair growth requirements.

text. One internet product is the ”Smart Hair Care Program” (Edmonton, Alberta, Canada). This is just one of the hundreds of products available, but they all follow a similar structure in making claims to grow hair if one uses the entire program, which involves revitalizer, shampoo, and conditioner, and powder gelatin. Sometimes it can be confusing as to whether one should eat these things or apply them topically, especially things like the “powder gelatin.” In any case, this particular program claims that aZZ the products must be used as directed.

The revitalizer is the ”expensive part” in that it is the one controlling the hair loss, and will promote new healthy hair. The product states that it will be most effective on existing hairs, and that as long as there are little fuzzy hairs, the revitalizer will stimulate growth again.

A 1.5-mL dose is suggested per treatment, which patients apply nightly. It must be left on the scalp for 6 hours, followed by the shampoo and conditioner; after this is com- pleted, the patient then uses the powder gelatin orally as a dietary supplement, taken with juice or other liquid to ”help the small developing hairs to grow as thick, healthier hairs.”

The approximate cost of such a program is as follows: revitalizer (1-month supply) $90 to $180; shampoo, $10 per month; conditioner, $10 per month; and powder gelatin, $14 per month. This can total between $124 and $214 per month, more expensive than using an ”approved” product that has been proven to grow hair.

Nioxin System The Nioxin System (www.cherises.com)

consists of the following multi-step system: (1) Bionutrient cleanser (one for men and another separate one for women) and conditioner as ”scalp therapy”; (2) Bionutrient treatments; and (3) Nioxin-recharging complex vitamins.

In this system the Bionutrient cleanser is used to clean the ”cosmetic buildup of chlo- rine and minerals from normal to oily hair,” and to cleanse the scalp of hydrophobic lipids moduced bv the bodv that can interfere with healthy hai; growthwhen left on the scalp. ”Only the Nioxin cleansers will dissolve this lipid buildup, and with daily use, keep it at ’safe’ levels.” The scalp therapy conditioner is stated ”not to block pores or hair follicles, thereby improving oxygen and nutrient up- take.” Topically applied after washing the

Shampoo or Revitalizer Systems

Smart Hair Care Program

In this category there are too many products to be mentioned within the limits of this

56 SAWAYA & SHAPIRO

hair with the Bionutrient cleanser, it is stated that the Scalp therapy conditioner consists of vitamins, proteins, amino acids, and exotic herbs to restore a healthy scalp moisture bal- ance, which also helps with scalp tightness, dryness, flaking, and itching, although no cited studies are given.

Other OTC products make similar un- proven claims that lipids block the pores so that hair follicles cannot grow. Another Ni- oxin topical regimen is NX3, which is used after the cleanser but before the Bionutrient cleanser system. In this step it states that high levels of DHT are the primary causes of hair thinning, which is brought about by the effects of ultraviolet light (sunlight) on the scalp. A phototoxic chemical reaction in skin from sun exposure forms free radicals that have a deadly effect on all cells, especially the hair follicle cells, in regeneration and regrowth. This topical lotion is used around the receding hair lines and thinning areas of the scalp. The Nioxin-recharging complex vitamins are provided as an oral vitamin supplement containing phyto-estronic and phyto- testronic supplements with a unique profile of vitamins, minerals, herbs, and amino acids. Also listed in the vitamin ingredients are other previously mentioned herbal agents, such as serenoa repens, pygeum africanum, something called proteusterone complex (Dis- corea multispecies complex), and smilex med- ica.

The cost of the complete regimen is as follows: a 45-day kit is $59.99, plus shipping and handling, which includes a bottle of Bio- nutrient cleanser, Bionutrient treatment, and scalp therapy with a special bonus of bionu- trients and scalp recharging complex treatment, NX3. The Nioxin recharging complex vitamins cost $24.99 for 60 caplets. Again, these advertised hair care systems can cost as much if not more than approved medications on a monthly basis.

Piliel

It was announced in December 1997 that clinical testing on Piliel (Life Medical Sciences Inc., Princeton, NJ) was being terminated due to lack of efficacy. Prior to this testing had been performed in Europe, where it was reported that the product was able to stimulate hair growth and reduce hair loss. There were 140 participants in the clinical testing, which took place early in 1997. Later the company

indicated that the product was not likely to generate satisfactory results for AGA, and consequently all testing was terminated.

ViviScal

ViviScal (www.viviscal.com) another food supplement, incorporates special marine ex- tracts and a silica compound. A study was describedI9 in a double-blind randomized manner in 20 men with AGA, of whom 10 were treated with two tablets daily of fish extract and the other 10 were treated with two tablets of ViviScal for 6 months. After 6 months, patients receiving ViviScal showed a mean increase in nonvellus hairs of 38%, compared with 2% increase in the fish extract group. In the ViviScal group, 19 of 20 men showed a clinical and histologic "cure" compared with none of the fish extract treated group. When mention of "cure" is given, one should always be cautious about the product's effectiveness. Standard FDA-approved endpoints are needed to test this product.

Aminexil

Aminexil (L'Oreal, Paris, France) is a 2,4- diamino-pyrimidineoxide (DPO). In a recent studyz0 351 patients were treated with Ami- nexil or placebo in six successive single-blinded trials that lasted 3 to 6 months. Patients applied to their scalps 6 mL of water-alcohol solution that contained 1.5% DPO (90 g DPO) daily. Phototrichograms were used to determine hair growth. Results described the Aminexil-treated group as having a decrease in percent of telogen hairs and increase in percent of anagen hairs compared with placebo. The mode of action of this agent is to inhibit collagen formation around the hair follicle and maintain the hair tract for follicle survival; therefore it is described as an antifibrotic agent. The primary claim for this OTC agent is to prevent further hair loss. Again, this product has not gone through FDA approval testing requirements.

Thym US ki n

ThymuSkin (Manheim, Germany) is de- rived from calf thymus extract. Thymosin, the peptide molecules from thymus extract used in Thymuskin, is thought to be immunomo-


dulating, inhibiting the ”aging” processes. It is available as a shampoo and revitalizer lotion in Europe and Canada. There are publi- cations in the German literature discussing its use in AGA and AA, but more testing by FDA-approved standards is needed.

Maidenhair

Maidenhair (Adian turn capillus-veneris) is an herbal agent that comes from southern Eu- rope from the frond of the Maidenhair fern, which is gathered in June and dried. The plant compound is mainly known as an ex- pectorant, but in the Middle Ages it was taken for various illnesses of the respiratory tract, in the form of pectoral teas, and as a syrup for severe coughs. This plant compound has also been used to treat a lack of hair growth and to promote hair color. The active compounds in this are flavonoids, pro- anthocyanidins, and hydroxycinnamic acid ester. No health hazards or side effects are known, and efficacy has not been proven.26 The compound is taken orally as a tea pre- pared from ground or powder, with doses of 1.5 g or 1 cup of liquid per dose.

Arnica

M . arnica (arnica montana), is an herbal agent that comes from the 6- to 8-cm terminal composite flower found in leaf axils of the upper pair of leaves, with the aromatic flower head described as having a “scratchy” taste. The plant mainly grows in Europe, Scandina- via, and Russia. This agent is applied topically and used for various ailments, including fevers, colds, inflammatory conditions of skin, rheumatism, cough, bronchitis, and AA or hair loss due to psychological causes or stress. The active ingredients are as follows: sesquiterpene lactones, thymol esters and free fatty acids, polyenes, hydroxycumarine, and helenaline derivatives. The herb powder is externally applied with 1 part to 10 parts ethanol, or is used as an ointment. Side effects noted are topical sensitization leading to al- lergic contact dermatitis, blister formation, and ulceration, especially when applied at high

Horsetail

Horsetail (equisetum arvense) is an herbal agent in which the medicinal parts are taken

from the dried green sterile shoots of the plant, which grows throughout all of Europe and Asia. The active compounds are thought to be flavonoids, caffeic acid ester, silicic acid, styrolpyrone glucoside, and pyridine alka- loids. The effect of the agent is a mild diuretic for urinary tract infections but it is also used for wound healing with other cutaneous applications for brittle fingernails and hair loss, although none of these claims have been proven.2b The compound is taken orally as a tea with a recommended dose of 6 g daily. Contraindications for taking this agent include congestive heart failure and abnormal kidney function.

Black Bryony

Black bryony is an herbal agent made from the root of Tami communis, which is native to Europe. The roots usually are gathered at the end of the vegetation period, with the bark peeled off and roots cut into slices or pieces. Direct contact with the root is known to cause skin irritation. Active compounds found in this root herbal agent include histamine-oxa- late, mucilage, volatile oil, and steroid sapo- nins. The effects of this agent are to stimulate external nerve ends, similar to histamine increase in blood circulation in the skin, so it is indicated for rheumatoid disorders, torn muscles, and a tonic for hair loss to improve blood circulation to the scalp.26 The agent is provided in a lotion form and applied topically. Side effects are described as contact irritation with formation of wheals, inflamma- tion, and pustules.

A commentary to some of these herbal, nutritional, OTC remedies is that when or if they have been tested, many studies, if not all, were done in foreign countries that do not follow consistent testing parameters (i.e., standardized photography and hair count measures) now routinely done in the United States. If their claims are only ”herbal or nutritional’’ then they do not have to follow the strict guidelines as a ”medicinal” or ”drug” classified agent, which means they are not governed by strict FDA criteria. Also, there are a lot of questions as to the purity, consis- tency and concentration of these nutritional and herbal OTC agents, which can vary from batch to batch, whether they are in liquid, oral pill, or topical formulations.

58 SAWAYA & SHAPIRO

NEW AGENTS UNDERGOING FDA CLINICAL TRIAL TESTING

Other 5mR Agents

There are several investigational compounds up for consideration by pharmaceuti- cal companies and planned for FDA-regulated clinical trial studies. These agents are in the research and development phases, with some being published and reported in a fash- ion similar to that of finasteride. Clinical trials results are pending but some of these are as follows.

FK- 143

FK-143 (Fujisawa Healthcare, Deerfield, IL) is a nonsteroidal compound that inhibits both 5aR Types I and I1 cloned human and rat enzymes. This is a noncompetitive inhibitor with kinetic constants of approximately 20 nM for both isoenzymes, and is described as decreasing DHT to 65% after a single dose, with a slow recovery in DHT levels found at 168 hours.

Turosteride

Turosteride 1-(4-methy1-3-0~0-4-aza-5a-an- drostane-l7~-carbony1)-1,3 diisopropylurea, is similar to finasteride and is a Type I1 5aR inhibitor. In rat and human prostate, it inhibits Type I1 5aR with ICso values of 55 and 53 nM, respectively, and in rats causes a 40% reduction in serum DHT levels without affecting T levels.'O It is currently in Phase I trials in humans.

GI198745

GI198745 (Glaxo-Wellcome, RTP, North Carolina) is an investigational compound currently in FDA-regulated clinical trial studies around the United States for men with AGA. This compound is similar in structure to finasteride (Merck, Rahway, NJ), maintaining the 4-aza structure of the steroid nucleus, but is a "dual" inhibitor of both 5aR en~ymes ,~ whereas finasteride is a specific Type I1 inhibitor, Clinical trial results are still pending.

Extra Strength Rogaine 5% for Women

Regaine or Rogaine (minoxidil) 2% has been used worldwide for over 10 years, and is

now OTC in the United States. Most recently, Extra Strength 5% Rogaine has hit the US OTC shelves but approval is only given to men with hair loss, not women. Pharmacia- Upjohn has sole rights to being the only manufacturer for the next few years for this new version of minoxidil.

Despite lack of understanding of the dis- tinct mechanism of action, it has been shown to increase the nonvellus hairs in women using it for 32 weeks or more.' One potential drawback to minoxidil therapy is that sponta- neous reversal to the pretreatment state can be expected 1 to 3 months after cessation of therapy, indicating that minoxidil has a direct effect on the hair follicle, sensitizing it and making it dependent on the drug for future growth. In the United States various generic brands are now available OTC, which have brought down the price of minoxidil therapy from $50 per bottle when it was Rogaine, a prescription product, to now approximately $10 to $15 per generic bottle, which lasts about 1 month. Rogaine Extra Strength costs the pharmacist approximately $28.32 for 60 mL, which can raise the price to the con- sumer; thus good advice to patients would be to shop around before buying the product, at least in the United States.

The mechanism of action, although still un- clear, seems to open potassium channels and increase proliferation and differentiation of epithelial cells in the hair shaft.'

Serum concentrations after topical application of 2% minoxidil used twice a day are generally about 5% of those with oral minoxidil, and with the 5% solution are about 10% of those with the oral drug, as has been reported.17 Minoxidil is metabolized in the liver and excreted in the urine.

As far as effectiveness, four unpublished 32- to 48-week studies presented to the FDA compared the effects of placebo, 2% minoxidil, and 5% minoxidil by counting the net gain in hairs in 1 cm2 areas of the scalp. As described, two studies in women did not find statistically significant differences between 2% and 5% minoxidil. A 32-week study in men found that the mean increase from baseline in hairs/cm2 was 5 with placebo, 30 with 2% minoxidil, and 39 with 5% minoxidil. A 48-week study in men found a mean increase in hairs/cm2 of 3.9 with placebo, 12.7 with 2% minoxidil, and 18.5 with 5% minoxidil. Previous studies have shown that when the drug is stopped, all of the newly regrown hair falls 0 ~ t . l ~ Despite these reports the new


advertisements claim 45% more effective hair growth than regular strength 2%, with regrowth occurring as early as 2 months with overall 5 times more hair regrowth than placebo, with no major safety concerns. Most physicians and lay people who have been using minoxidil for many years are not con- cerned about safety aspects; most believe it to be a very safe product. Concerns are focused more on the ”effectiveness” of the product in promoting and maintaining hair growth. The new 5% Extra Strength formula brings about a new glimmer of hope in showing improved hair growth for individuals who may not have seen results with 2% minoxidil. Cur- rently, Pharmacia & Upjohn predicts that 90% of men will have some noted positive effects with this new 5% Extra Strength version of minoxidil; they currently offer a money-back guarantee to men who use 5% Extra Strength Rogaine, in that if results are not seen within 4 months, they may get their money back.

In the past, adverse effects noted with oral minoxidil included tachycardia, angina pecto- ris, and fluid retention. When taken orally during pregnancy, minoxidil has been associated with hypertrichosis of the fetus and con- genital an0ma1ies.I~ One double-blind study in 35 balding men found that topical use of 2% minoxidil caused small but statistically significant increases in left ventricular end- diastolic volume, cardiac output, and left ventricular mass.l Infrequently dizziness and tachycardia have been reported with 2% solution, with advice given to patients to reduce frequency of application, which helps in elim- inating these side effects. Local irritation, itching, dryness, and erythema may occur with use of topical minoxidil, most likely due to the vehicle formulation of alcohol and propyl- ene glycol.

The conclusion on minoxidil 5% and 2% solutions is that they can produce a modest increase in hair on scalps of young men with mild to moderate hair loss, with continuous application for years to maintain the effect. The 5% Extra Strength form is now being used off-label in women, with some clinicians already giving this to young women with early hair loss, even though it is only indicated by the manufacturer for use in men at this time. Current clinical trials are nearing completion at multiple United States sites where 5% Extra Strength is being tested against 2% and placebo in women, with hopes of FDA approval in late 1999 and OTC availability in 2000.

PRODUCTS PATENTED BUT STILL IN RESEARCH AND DEVELOPMENT

Gene Therapy for Hair Loss and Color

Anticancer Inc (San Diego, CA) and Ap- plied Genetics (New York, NY) are researching a gene therapy for grey hair and hair loss. This work described genetic chang- ing of hair color by applying a cream to the scalp. The cream is in a liposome base, which is vital to the delivery of the gene to the hair follicle cells. The treatment was thought to be very effective, with no known side effects; however, the treatment needed to be applied every 2 weeks or so, and it is thought that large amounts of genetic material are needed to be effective, which would make commercial use very expensive and impractical in today’s OTC market of hair coloring agents. This gene therapy is also being researched for alopecia, although this use may be similar in regard to impractical cost and the need to re-apply the agent at intervals, necessitating continued treatments. Current studies are still researching the ”optimal” liposomes for the treatments to be more effective.

Antisense Technology

Antisense technology (Dyad Pharmaceuti- cal, Baltimore, MD) has been around for quite some time, but with little success in treating human disease. This is mainly because of the stability of antisense chimeras, which consist of nucleotide sequences specific to a target gene site. It was thought that use of antisense chimeras could block or affect specific gene sequences, but the technology has been ham- pered by the lack of specificity, instability of nucleotides, cost, and variability of results. The Dyad antisense molecule is stated to be targeted against the 5aR enzyme (not certain as to Type I, Type 11, or both) and targeted for topical application on the scalp. There are drawbacks in dealing with antisense technology, such as stability of the antisense chimeras, specificity of the chimeras, costs, and variability in penetration when using it as a topical preparation, which is why other companies have abandoned this technology in favor of more specific molecular and gene-related technologies to treat human disease.

60 SAWAYA & SHAPIRO

OTHER DEVICES THAT CLAIM HAIR GROWTH

Tricologic Biowave Helmet. This device claims to grow hair by use of electrical bio- waves for a cost of $510. It is manufactured and produced by BIOFARM Cosmetics, Glebe NSW, Australia.

ElectroTrichoGenesis (ETG). The ETG is a device that resembles a hair dryer that claims to noninvasively stimulate hair follicles to grow by positive influence of an electrostatic field. The ETG is thought to inhibit further hair loss and stimulate or promote actual hair regrowth, with use of 12-minute painless treatment sessions.21, 22 The device has been developed by Current Technologies, Vancou- ver, BC, Canada.

Laser Light Therapy. This laser device uses specific wavelengths for stimulating hair follicles. The device is stated to be approved by the FDA, but for safety only, not for efficacy in growing hair. This device is sold by New Image (Laser Light Hair Therapy).

CONCLUSIONS

There are various new novel treatments for use in alopecia. Only the FDA-approved products have gone through rigorous double- blind clinical trial testing as to their proven claims, whereas others have yet to do so. Again, many products may claim to be ”FDA approved” but may be approved for safety only (it may not hurt one), but not for efficacy in hair growth. Although many products described here are OTC in the marketplace, it is wise to guide patients and advise them of how these agents work and if they have been adequately tested before patients spend their money and raise their hopes. Realistic expec- tations should continue to be the main guide- line when offering any treatment for alopecia. Manufacturers of these products may be eva- sive, and lure patients with their marketing and advertising, which make the physicians’ job a most difficult task in effectively treating their patients.

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