UPDATE ON PHARMACOLOGIC THERAPY

Appropriate use of pharmacologic therapy to treat AGA requires an understanding of the mechanism of hair loss. The primary pathology is progressive miniaturization of the hair follicles, leading to short, fine, nonpigmented hairs.¹ Androgens, specifically dihydrotestosterone (DHT), converted from testosterone by the enzyme 5-reductase, cause miniaturization in men. There is considerable controversy as to whether DHT also is the principal driver of this process in women with AGA. The milder course of AGA in women may result from differences in the female scalp compared to the male scalp with respect to 5a-reductase and other enzymes and receptors involved in androgen metabolism.² However, a case report of a young woman with hypopituitarism and the absence of circulating androgens who developed female pattern AGA raises a central question as to whether female AGA is androgen-dependent.³

There are 2 ways to reverse or inhibit the androgen-mediated miniaturization of AGA either by adding a positive substance to directly stimulate growth or by removing a negative substance (eg. androgens) to indirectly stimulate growth. Topical minoxidil solution is an example of the former, and the androgen modulator finasteride is an example of the latter (see Figure I).

Figure I: Progressive follicular miniaturization in AGA


The mechanism of action of topical minoxidil has been extensively studied but is as yet unknown. Although originally used systemically to treat hypertension, vasodilatation does not appear to be the mechanism for hair growth stimulation¹ Minoxidil is sulfated in the hair follicles, and minoxidil sulfate opens potassium channels.⁴ Minoxidil also upregulates vascular endothelial growth factor (VEGF) and prostaglandin endoperoxide synthase-I.^5,6 This finding does not necessarily imply that minoxidil stimulates blood vessel growth, but rather that minoxidil-induced VEGF may also function as a growth factor for follicular cells.⁷ How activation of prostaglandin endoperoxide synthase-1 leads to hair growth is not clearly understood, but several reports (see below) of hair growth with a prostaglandin F2a analogue suggest that prostaglandins may in some way be involved in hair growth.^8.9

Minoxidil topical solution is quite safe. Systemic exposure is low: the serum level after application of the 5% solution is about one-twentieth of the minimum hemodynamically active level achieved with oral doses.¹ The most common side effect is irritant contact dermatitis, with a variable incidence that averages about 5%. There is a higher incidence among those using the 5% solution rather than the 2% solution.^1,10 The propylene glycol vehicle is the most common cause of the scalp irritation,¹ and this vehicle is also frequently implicated in the more unusual cases of allergic contact dermatitis.¹¹ Another side effect, seen mainly in women, is facial hypertrichosis. This effect lessens or even disappears after a year of continued use of minoxidil.¹ It also goes away I to 6 months after the drug is discontinued.¹

Figure 2: Hair weight over 120 weeks¹²


Studies have shown that minoxidil topical solution increases hair weight. In one study, men were randomized to either 5% or 2% topical minoxidil solution vehicle or no treatment over 96 weeks, with hair count and weight measured at 6-week intervals for a total of 120 weeks (see Figure 2).¹² Results showed an increase in hair weight for those treated with minoxidil and continued loss of hair weight for those on vehicle or no treatment. After all treatment was stopped at 96 weeks, those who were on minoxidil lost hair weight to the extent they would have been expected to if not treated initially. It is important to note that there is no greater hair loss when treatment is stopped than there would have been with no treatment at all. Use of the 5% solution was about 50% more effective than use of the 2% solution. Data from this study demonstrate that there is a "saturation effect" with minoxidil and that further increase in solution strength would be unlikely to result in dramatic increases in hair weight.

Figure 3: Before-and-after photographs of study subjects treated with 5% minoxidil whose hair growth was rated as minimal (left) or moderate (right)¹³


It is important to educate patients about what to expect with minoxidil treatment. It may take up to 4 months to begin to see an effect, and, if the drug is stopped, hair loss will resume. In addition, patients may have a temporary increased shedding of hair about 3 to 5 weeks after the start of treatment. This is thought to be due to the initial growth surge in miniaturized hairs and the conversion of resting telogen follicles to anagen follicles.¹ The hair shed would have been shed as part of the natural cycle. Since this hair loss occurs over a short period of time, it can alarm patients. Because of its observed effects on the physiology of hair growth, minoxidil is ideally used for a year before assessing efficacy (see Figure 3)'"

The FDA-approved androgen modulator finasteride is a competitive inhibitor of type 2 5a-reductase. Finasteride lowers the level of DHT both in serum and in the scalp by over 60%.¹ Since type I 5a-reductase is not inhibited, serum levels of DHT in patients on finasteride are about 30% of normal. Although 5a-reductase in the hair follicles can produce DHT, much of the DHT that gets to the follicle is from the systemic circulation. In one study, topical 0.05% finasteride lowered serum levels of DHT by 40% but did not lead to hair regrowth.¹⁵ For these reasons, one can conclude that inhibitors of 5a-reductase must be used systemically. Many unproven over-the-counter products promoted as topical DHT-lowering agents are also unlikely to be effective. Theoretically, an androgen receptor antagonist could work topically. Several over-the-counter products claim to work by blocking the androgen receptor but have unproven efficacy.¹⁶

Finasteride is a very safe drug. The only adverse effects of any consequence reported in both the 1-year study and the 5-year study were decreased libido and increased erectile dysfunction. In the 1-year study, the difference in the incidence of these 2 side effects in treated and placebo groups was 0.5 and 0.6 percentage points, respectively.¹⁷ In the 5-year study, 0.3% of men on finasteride complained of libido decrease or erectile dysfunction increase compared to none in the placebo arm.¹⁸

From the patient's perspective, the most meaningful cosmetic outcome is the global photographic assessment. The 5-year study showed that 9 out of 10 men treated with finasteride either had gained or at least had not lost hair.¹⁸ After 5 years of treatment 48% had gained hair (see Figure 4). The peak increase in scalp coverage as judged by global photographic assessment was seen at 2 years.¹⁸

Figure 4: Global photographic assessment - 5-year finasteride study¹⁸


Looking at the hair count data in the longer study, there is a peak in the number of new terminal hairs at 1 year, with a continued increase from baseline over 5 years. Because the men in the placebo arm of the study had continued loss, the difference in hair count between the 2 groups increased each year (see Figure 5)

As with minoxidil, it is important to counsel patients starting finasteride about appropriate expectations and the need for continued therapy. Patients need to know that reversing miniaturization is a slow process and that they should continue taking finasteride for at least a year before making a decision about efficacy.¹⁴

Figure 5: Hair count data – 5-year finasteride study¹⁸

In summary, there are 2 FDA-approved treatments for AGA: minoxidil topical solution and finasteride, with minoxidil being the only approved agent for women. Treatment of male AGA with a combination of minoxidil topical solution and oral finasteride may be advantageous.¹⁴ Many of the roundtable participants have used combination therapy (see Figure 6)
However, combination therapy is not FDA-approved. It has been studied in animals and in a single published trial in humans (see "The Role of Pharmacologic Treatments as Adjuncts to HTS:").

Figure 6: Patient treated with combination of finasteride and minoxidil topical solution; photographs show efficacy at 10-month follow-up (Photo, courtesy of Ken Washenik, MD, PhD)


There are several agents that are FDA-approved for other indications and may someday be beneficial for treating AGA. One of these in latanoprost, available as an eye drop for the treatment of glaucoma.

Latanoprost is a prostaglandin F2a analogue and was reported to cause hypertrichosis of the eyelashes in 77% of patients after once-daily use for a mean of 4 months.⁸ In a small study of 8 stump-tailed macaque monkeys – an animal model for baldness – latanoprost was found to lead to minimal scalp hair regrowth when used daily for 5 months at the concentration used in the commercial eye drop preparation (50 Ug/mL).⁹ However, when used at a higher concentration, 500 Ug/mL, applied daily for 3 months, moderate-to-marked regrowth was seen.⁹

Another FDA-approved agent that may be useful in the treatment of AGA is dutasteride.⁶ Dutasteride is approved for use in the treatment of benign prostatic hyperplasia and is an inhibitor of both type 1 and type 2 5a-reductase.²⁰ Development of the drug for an AGA indication has been stopped, but a Phase II study showed that 0.5 mg dutasteride was about 30% more effective than 5 mg finasteride, as measured by change in hair count from baseline at 24 weeks.²¹ The dual-enzyme inhibition decreases DHT by 90% to 93%.²⁰ The side effect profile is similar to that of finasteride, with a small number of men complaining of decreased libido or increased erectile dysfunction.²⁰ Dutasteride has a very long half-life – 5 weeks at steady state²⁰ – which could be a disadvantage should one want to stop the drug because of side effects.

There are also a number of non-FDA-approved treatments currently available that supposedly improve circulation and nutrition in the scalp.^4,16 These therapies are sold over the counter or via the Internet as treatment for AGA, but do not have efficacy proven by scientific study. One website, www.regrowth.com, lists over 75 different treatments. One such agent is saw palmetto berry extract. The saw palmetto (Serenoa repens, also known as Sabol serrulata) is a dwarf palm tree indigenous to the southeastern US, and was first used by Native Americans in Florida in the 1700s to treat various urological disorders.²² Many herbal products sold to treat AGA contain saw palmetto berry extract and make the claim of affecting DHT levels.¹⁶ The extract has been shown to be beneficial in the treatment of benign prostatic hyperplasia (BPH),²² but several studies have shown it has no effect on DHT levels.^23,24 Rather than being an androgen modulator, the mechanism of action in BPH may be via a-adrenergic blockade.²⁵ There are no scientific studies showing effectiveness of saw palmetto berry extract in treating AGA.

Pharmacologic therapy can be used by hair replacement surgeons to optimize the results of surgery.

The Role of Pharmacologic Treatments as Adjuncts to HTS Dow B, Stough, MD

This section addresses clinical studies of pharmacologic therapy in hair transplant patients as well as patients with AGA in general. This review includes studies using single agents as well as trials involving combination therapy. Consensus recommendations will also be made regarding use of pharmacologic adjuncts to hair transplant surgery (HTS).

The medical treatment of male and female AGA is directed to the affected thinning area of the scalp. In contrast, transplant surgeons treat both the donor site and the recipient site.¹ Donor dominance is one of the early principles of modem HTS.² A theoretical approach to using adjunctive medical therapy for the donor area can be derived from this principle. While the beneficial effect of oral 5a-reductase blockers at the donor occipital area is debatable,³ this area can be responsive to treatments with an alternative mechanism of action. Hair-growth-promoting agents such as minoxidil may work for this area of the scalp by reversing follicular miniaturization, inducing telogen-to-anagen-phase conversion, and prolonging anagen phase duration.⁴ Hair follicles in the original recipient area and adjacent scalp would still be responsive to androgen modulators as well as to growth promoters. While the experimental evidence for an additive or synergistic effect of combination therapy is limited,⁶ the donor dominance principle provides a rationale for combined treatment in hair transplant patients. Thus, some hair transplant surgeons employ both topical treatment for the donor and recipient scalp as well as concurrent oral therapy.^1*

Use of adjunctive therapy is widespread In a 2001 roundtable of hair transplant surgeons, more than 70% of the participants stated that they sometimes recommend the combination of minoxidil and finasteride for their transplant patients.¹ The 2003 round-table participants agreed that there is even greater use today of combination therapy in HTS. In addition, the current roundtable participants collectively have noted that some hair transplant surgeons are prescribing dutasteride for their patients (while acknowledging that use of this newer medication has not received FDA approval for the treatment of AGA).

It is difficult to study the use of adjunctive medical therapy in hair transplant patients, as there are many uncontrolled factors to consider. There are several older studies of the use of topical minoxidil solution in transplant patients, only one of which was a controlled trial, and there is also a small recent study during which the patients served as controls for themselves.^7,8,9,10 And there are no published studies of finasteride in hair transplant patients. Despite their age and the paucity of evidence, the older studies provide some insight.

In 1987. Kassimir reported the results of a study of 12 men treated with 3% topical minoxidil following transplantation. Two of the patients had no shedding and another 2 had hair regrowth less than 4 weeks after the usual postsurgical telogen effluvium.⁸ Bouhanna published a study in 1989 of 16 men treated with a 2% topical minoxidil solution before and after transplant. Hair continued to grow in 71 % of grafts by 30 days, and hair loss at 3 months was less than 50% in 84% of the grafts.⁷ In a placebo-controlled trial,⁹ 12 men were randomized to 2% topical minoxidil solution or placebo applied to the donor scalp for 6 weeks prior to surgery and to the recipient area for 17 weeks after surgery. At 17 weeks, there was significantly less grafted hair lost in those treated with minoxidil compared to controls (22% and 52%, respectively; P=0.001).

More recently, Sandoval followed 8 patients undergoing hair transplantation who applied 5% minoxidil topical solution to only a single side of their scalp in the recipient area, starting 4 days after surgery. By photographic analysis it appeared that both hair density and hair length were superior on the treated side. In addition, there was faster hair regrowth on the treated side, as measured by hair counts at 6 months. Longer follow-up - at least 18 months posttransplant - would be necessary to evaluate final hair count differences between the treated side and the untreated side.¹⁰

One can conclude from these studies that the expected posttransplant telogen effluvium may be minimized by the use of topical minoxidil solution. In addition, it appears that treatment of both the donor area and the recipient area may be necessary to achieve this result.¹ Most hair transplant surgeons do not routinely treat the donor area. This approach may be of interest in the future.

Recently published studies support the rationale for the use of both minoxidil and finasteride as medical adjuncts in HTS. Olsen and colleagues and Lucky and colleagues reported the results of their studies of 2% and 5% minoxidil topical solution versus placebo in men and women, respectively.^11,12 In both double-blind studies, minoxidil or placebo was applied twice daily for 48 weeks. The primary end-point was the mean change in nonvellus hair count, with computer-assisted counts performed at base-line and at weeks 8, 16, 32, and 48, Global photographic review also was done.

In the study in men, 5% topical minoxidil was superior to the 2% solution, leading to 45% more hair growth, earlier hair growth, and a superior global photographic review at week 48 (see Figure I)¹¹ As with prior studies, there was dose-dependent scalp irritation, about which patients need to be informed. In their conclusion, Olsen and colleagues cited older studies showing that hair diameter is also increased with use of topical minoxidil.^13,14 These results suggest that it may be beneficial to start medical therapy months prior to transplant surgery.¹

Figure I: Minoxidil in men - change in hair count over 48 weeks¹¹


The study of minoxidil in women seemed to show that the 5% topical solution was no more effective than the 2% solution However, there was a treatment-by-investigator effect whereby one site had markedly different results because of 2 patients with "inordinate" hair loss at 48 weeks.¹² Reanalyzing the results after excluding these patients, there was a significantly greater increase in nonvellus hair counts in the 5% group compared to the 2% group, as well as significantly better patient assessment of benefit. For women undergoing transplantation, there is particular concern with minimizing posttransplant telogen effluvium, as well as with preserving the existing hair.¹⁵ Therefore, the results of this recent study support the rationale for use of minoxidil 5% solution in women undergoing hair transplant (recognizing that such use is off-label).

There are several recent studies of the general use of finasteride for AGA, one of which - as-year multinational study - was discussed in a prior section of the monograph.¹⁶ The hair count data in that study were obtained by serial photography of a circle of clipped hair 1 inch in diameter (about the size of a quarter). The difference in hair count in the 1-inch circle between those treated with finasteride and those treated with placebo at 5 years was 277 hairs (see Figure 2)" For hair transplant surgeons who think in terms of follicular units per square centimeter, this difference is equivalent to 24 follicular units per square centimeter, using the average 2.3 hairs per follicular unit. Progressive loss of hair can degrade surgical results over time, so the preservation of hair with adjunctive therapy can playa role in sustaining the cosmetic benefits of surgery.

Figure 2: Hair count in circles of 1-inch diameter, placebo and finasteride¹⁶

In a study by Stough and colleagues involving identical twin males with AGA, 9 pairs of twins were assigned to either placebo or finasteride for 1 year in a double-blinded fashion. In each twin pair, one individual received placebo and the other finasteride, with outcomes measured by hair counts and global photographic assessment. At 1 year, 100% of the finasteride group had retained hair. whereas 44% of the placebo group had lost hair, based on hair count data. A positive effect of the drug was clearly defined by these data.¹⁷

In the 5-year finasteride study, those patients who were given placebo for a year and then began finasteride did not achieve the same hair counts as those who were on finasteride from the beginning.¹⁶ This supports the rationale for early treatment of patients undergoing hair transplant. However, many of the roundtable participants have observed that individuals with far-advanced alopecia, ie, Norwood VII, receive little benefit from medical therapy alone.

None of the placebo-treated men in the 5-year finasteride study had an increase in hair count, and the difference in hair counts between the treated men and the men receiving placebo increased year by year.¹⁶ These data can be used by hair transplant surgeons to dispel the notion that hair loss reaches some point and stops. Hair loss in AGA is truly progressive - it could even be described as "relentless" - and requires continued medical therapy.¹⁵

The rationale for using combination therapy in AGA (that is, finasteride and topical minoxidil) is based on an animal study of balding stump-tailed macaque monkeys, as well as on a recent human trial from India.^6,18 (Note: combination use of the 2 agents has not received FDA approval.)

Diani and colleagues studied minoxidil and finasteride, alone and in combination, in the stump-tailed macaque - an excellent animal model for the study of AGA.¹⁸ The stump-tailed macaque has a balding pattern similar to that of humans and is responsive to minoxidil. In this study, 21 adult monkeys were randomized to 1 of 4 groups for 20 weeks: topical vehicle alone (6), topical 2% minoxidil (5), oral finasteride (0.5 mg daily) and vehicle (5), and oral finasteride and topical 2% minoxidil (5). The outcome measure was the weight of hair shaved from a 1-inch square in the middle of the balding area. The change in hair weight was greatest in the group treated with finasteride and topical minoxidil (see Figure 3).¹⁸ These findings led the investigators to conclude that combined use of oral finasteride and topical minoxidil has an additive or synergistic effect on hair growth.

Figure 3: Combination therapy in the balding stump-tailed macaque¹⁸


Khandpur and colleagues reported results from a 1-year study of 100 men randomized to 1 of 4 treatments: oral finasteride, oral finasteride plus 2% topical minoxidil solution, oral finasteride plus ketoconazole shampoo, and 2% topical minoxidil alone.⁶ The outcomes measured were subjective assessment by both patients and physicians, using 7-point and 5-point scoring systems, respectively, as well as global photographic assessment.

The best results in terms of patient and physician assessment were seen with both of the combination therapies, with no significant difference between the assessments of patients and those of physicians. Finasteride, either alone or in combination with minoxidil or ketoconazole, worked significantly better than 2% minoxidil solution by itself. Posttreatment photos showed improvement in all 4 groups, comparable to the findings based on patient and physician assessment.⁶

The conclusion drawn from this study was that there is a synergistic effect when agents with different mechanisms of action are combined.⁶ The rationale for use of ketoconazole is based on its antifungal action against yeast species thought to contribute to an inflammatory reaction adjacent to hair follicles, which is proposed as an additional mechanism for
AGA.¹⁹ In addition, there is evidence that ketoconazole has a direct anti-inflammatory effect.²⁰ Although the use of ketoconazole shampoo for this indication is not FDA-approved, these findings suggest that ketoconazole may be beneficial for patients with AGA who cannot use minoxidil topical solution because of scalp irritation or contact dermatitis. Further studies of combination therapy using outcome measures that are more objective, such as hair count, hair weight, and hair shaft diameter, are needed.⁶

Timing for use of adjunctive medical therapy with hair transplant surgery was recommended on the basis of group consensus. Medical treatment should be started at the time of initial consultation, regardless of when the transplant surgery was planned.

The group also recommended stopping minoxidil topical solution up to 3 days prior to surgery. Several of the surgeons preferred, however, to stop 2 weeks prior to surgery because of the theoretical risk of increased bleeding due to the vasodilatory effect of minoxidil. In light of this concern, it is worth noting that there are no published studies of an increased bleeding risk by any mechanism with use of minoxidil. Early studies of cutaneous blood flow by laser Doppler following topical minoxidil application gave varying results, with no effect lasting
longer than an hour.^21,22 The group speculated that patients with an inflammatory condition affecting the scalp – either secondary to minoxidil use or primary (due to seborrhea, for example) – should stop minoxidil earlier, as this patient group may be more likely to have increased intraoperative bleeding. It was agreed that the reason for stopping topical minoxidil as close to surgery as possible was that doing so reduces the risk of shedding due to the cessation of therapy. Finasteride therapy can be continued without interruption.

Following surgery, the group consensus was that minoxidil therapy should be restarted within 3 to 14 days. This delay in restarting minoxidil will prevent the exposure of the recipient area to the propylene glycol vehicle of topical minoxidil during the healing process and will prevent excess manipulation. In addition, some members of the group noted the theoretical increased risk for allergic contact dermatitis with minoxidil exposure at an open wound, as well as the potential for increased systemic absorption.

The consensus was also to use 5% topical minoxidil solution in women undergoing hair transplantation, although it is recognized that such use is currently off-label.

Based on the consensus of the group as well as on a 2001 roundtable consensus meeting,¹ the benefits of using adjunctive medical therapy with hair transplant surgery include the following:

• The recipient site will show increased numbers of hairs in the anagen phase, promotion of hair growth, and increased hair density.
• There will be a decreased risk for posttransplant telogen effluvium.
• Treatment of the donor site prior to surgery can convert telogen follicles to anagen follicles so that hairs will be easier to see, thereby increasing the number of units available for transplant.

The patients for whom adjunctive therapy may be particularly helpful include women, younger males with a strong family history of AGA and diffuse thinning, and those receiving transplants in the whorl area (vertex) of the posterior scalp.¹ In addition, it was the consensus of the group that patients with high vellus hair counts in the recipient area prior to transplant generally receive more benefit from medical therapy, as they may be more likely to regrow hair by reversal of miniaturization in that area.⁵

The progressive nature of AGA is a major obstacle to maintaining a natural-appearing hair transplant. The consensus of the roundtable participants was that adjunctive therapy leads to hair of larger diameter, more hair weight, and increased pigment, all giving the appearance of more hair volume. Surgery and medical therapy should not be considered mutually exclusive, as the benefits of medical therapy can enhance long-term results. Adjunctive therapy can often lead to good results after just 1 or 2 transplant sessions, potentially avoiding multiple sessions, which is beneficial to long-term results since hair loss due to AGA progresses if left untreated.

to the top

REFERENCES

Update On Pharmacologic Therapy
1. Price VH. Treatment of hair loss. N Engl J Med 1999;341:964-973.
2. Price VH, Roberts JL, Hordinsky M, et al. Lack of efficacy of finasteride in postmenopausal women with androgenetic alopecia. J Am Acad Dermatol 2000;43:768-776
3. Orme S, Cullen DR, Messenger AG. Diffuse fema!e hair loss: are androgens necessary? Br J Dermatol 1999;141:521-523.
4. Meidan VM, Touitou E. Treatments for androgenetic alopecia and alopecia areata: current options and future prospects. Drugs 2001;61:53-69.
5. Lachgar S, Charveron M. Gall Y, Bonafe JL. Minoxidil upregulates the expression of vascular endothelial growth factor in human hair dermal papilla cells. Br J Dermatol 1998;138:407-411.
6. Michelet JF, Commo S, Billoni N, Mahe YF, Bernard BA. Activation of cytoprotective prostaglandin synthase-1 by minoxidil as a possible explanation for its hair growth-stimulating effect. J Invest Dermatol 1997;108:205.209.
7. Philpott MP, Sanders DA, Kealey T. Whole hair follicle culture. Dermatol Clin 1996;14:595-607.
8. Demitsu T, Manabe M, Harima N, et aI. Hypertrichosis induced by latanoprost. J Am Acad Dermatol 2001;44:721-723.
9. Uno H, Zimbric ML, Albert DM, Stjernschantz J. Effect of latanoprost on hair growth in the bald scalp of the stump-tailed macacque: a pilot study. Acta Derm VenereoI 2002;82:7-12.
10. Lucky AW, Piacquadio DJ, Ditre CM, et al. A randomized. placebo-controlled trial of 5% and 2% topicaI minoxidil solutions in the treatment of androgenetic alopecia in females. J Am Acad Dermatol. In press.
11. Friedman ES, Friedman PM, Cohen DE, Washenik K. Allergic contact dermatitis to Optical minoxidil solution: etiology and treatment. J Am Acad Dermatol 2002;46:309-312.
12. Price VH, Menefee E, Strauss PC. Changes in hair weight and hair count in men with androgenetic alopecia, after application of 5% and 2% topical minoxidil, placebo, or no treatment. J Am Acad Dermatol 1999;41:717-721.
13. Olsen EA, Dunlap FE, Funicella T,et al. A randomized clinical trial of 5% topical minoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetic alopecia in men. J Am Acad Dermatol 2002;47:377-385.
14. Shapiro J, Prlce VH. Hair regrowth. Therapeutic agents. Dermatol Clin 1998;16:341-356
15. Sinclair R. Male pattern androgenetic alopecia. BMJ 1998;317:865-869.
16, Sawaya ME, Shapiro J. Androgenetic alopecia. New approved and unapproved treatments. Dermatol Clin 2000;18:47-61.
17. Kaufman KD, Olsen EA, Whiting D, et al. Finasteride in the treatment of men with androgenetic alopecia. Finasteride Male Pattern Hair Loss Study Group. J Am Acad Dermatol 1998;39:578-589
18. Finasteride Male Pattern Hair Loss Study Group. Long-term (5-year) multinational experience with finasteride 1 mg in the treatment of men with androgenetic alopecia. Eur J Dermatol 2002;12:32-37.
19. Xalatan Pl. Pharmacia.
20. Avodart product insert. GlaxoSmithKline.
21. Palmer J. Sustaining growth and maintaining product potential. Slide presentation at GlaxoSmithKline Inaugural lnvestor Meeting, February 22, 2001. London, England.
22. WiltTJ, Ishani A, Stark G, et aI. Saw palmetto extracts for treatment of benign prostatic hyperplasia: a systematic review. JAMA 1998;280:1604-1609.
23. Carraro JC, Raynaud JP, Koch G, et aI. Comparison of phytotherapy (Permixon) with finasteride in the treatment of benign prostate hyperplasia: A randomized international study of 1098 patients. Prostate 1996;29:231-240.
24. Strauch G, Perles P, Vergult G, et al. Comparison of finasteride (Proscar) and Serenoa repens (permixon) in the inhibition of 5-alpha reductase in healthy male volunteers. Eur Urol 1994;26:247-252.
25. Goepel M, Hecker U, Krege S, Rubben H, Michel MC. Saw palmetto extracts potently and non-competitively inhibit human alpha 1-adrenoceptors in vitro. Prostate 1999;38:208-215.


The Role of Pharmacologic Tfreatments as Adjuncts to HTS

1. Avram MR, Cole JP, Gandelman M, et al. The potential role of minoxidil in the hair transplantation setting. Dermatol Surg 2002;28:894-900
2. 0rentreich N. Autografts in alopecias and other selected dermatologic conditions. Ann NY Acad Sci 1959;83:463-479.
3. Stough DB, Miner JE. Male pattern alopecia. SurgicaI options. Dermatol CIin 1997;15:609-622.
4. Meidan VM, Touitou E. Treatments for androgenetic alopecia and alopecia areata: current options and future prospects. Drugs 2001;61:53-69
5. Price VH. Treatment of hair loss. N Engl J Med 1999;341:964.973.
6. Khandpur S, Suman M, Reddy BS. Comparative efficacy of various treatment regimens for androgenetic alopecia in men. J Dermatol 2002;29:489-498.
7. Bouhanna P. Topical minoxidil used before and after hair transplantation. J Dermatol Surg Oncol 1989;15:50-53.
8. Kassimir JJ. Use of topical minoxidil as a possible adjunct to hair transplant surgery. A pilot study. J Am Acad Dermatol 1987;16:685-687.
9. Roenigk HH, Berman MD. TopicaI 2% minoxidil with hair transplantation. Face 1993;4:213-216.
10. Sandoval A. Minoxidil 5% following hair transplantation for increased growth. Abstract of presentation at European Society of Hair Restoration Surgery, June 2002. London, England
11. Olsen EA, Dunlap FE, Funicella T. et al. A randomized clinical trial of 5% topical mlnoxidil versus 2% topical minoxidil and placebo in the treatment of androgenetlc alopecia in men. J Am Acad Dermatol 2002;47:377-385.
12. Lucky AW, Piacquadio DJ, Ditre CM. et al. A randomized placebo-controlled trial of 5% and 2% topical minoxidil solutions in the treatment of androgenetic alopecia In females. J Am Acad Dermatol. In press.
13. Headington JT, Novak E. Clinical and histologic studies of male pattern baldness treated with topical minoxidil. Curr Ther Res 1984;36:1098-1106.
14. Abeil E. Histologic response to topically applied minoxidil in male-pattern alopecia. Clin Dermatol 1988;6:191-194.
15. Shapiro J. Hair Loss: Principles of Diognosis and Management of Alopecia. London, England: Martin Dunitz Ltd; 2002
16. The Finasteride Male Pattern Hair Loss Study Group. Long-term (5-year) multinational experience with finasteride 1 mg in the treatment of men with androgenetic alopecia. Eur J Dermatol 2002;12:38-49.
17. Stough DB, Rao NA, Kaufman KD, Mitcheil C. Finasteride improves male pattern hair loss in a randomized study in identical twins. Eur J DermatoI 2002;12:32-37.
18. Diani AR, Mulholland MJ, Shull KL, et al. Hair growth effects of oral administration of finasteride, a steroid 5 alpha-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab 1992;74:345-350.
19. Pierard-Franchimont C, De Doncker P, Cauwenbergh G, Pierard GE. Ketoconazole shampoo: effect of long-term use in androgenic alopecia. Dermatology 1998;196:474-477.
20. Van Cutsem J, Van Gerven F, Cauwenbergh G, Odds F, Janssen PA. The antiinflammatory effects of ketoconazole. A comparative study with hydrocortisone acetate in a model using living and killed staphylococcus aureus on the skin of guinea-pigs. J Am Acad Dermatol 1991;25:257-261.
21. de Boer EM, Bezemer PD, Bruynzeel DP, Nieboer C. Does topical minoxidil increase skin blood flow? A laser Doppler flowmetry study. Acta Derm Venereol 1988;68:271-274.
22. Wester RC, Maibach HI, Guy RH, Novak E. Minoxidil stimulates cutaneous blood flow in human balding scalps: pharmacodynamics measured by laser Doppler velocimetry and photopulse plethysmography. J Invest Dermatol 1984;82:515-517.