From: ARCHIVES OF DERMATOLOGY, Vol. 131, December 1995
Improvement in Androgenetic Alopecia (Stage V)
Using Topical Minoxidil in a Retinoid Vehicle
and Oral Finasteride.
SECTION EDITOR: JUNE K. ROBINSON, MD; ASSISTANT SECTION EDITORS: JEROME M. GARDEN, MD, AMY S. PALLER, MD
MAJ Douglas S. Walsh, MC, USA; CPT Cary L. Dunn, MC, USA;
COL William D. James,MC,USA; Walter Reed Medical Center, Washington DC
The Cutting Edge: Challenges in Medical and Surgical Therapeutics
REPORT OF A CASE----A 32-year old healthy white man with androgenetic alopecia (AGA) (Hamilton-Norwood Stage V) of 10 years' duration presented for therapy. The patient desired to pursue medical treatment only.
THERAPEUTIC CHALLENGE----To optimize the opportunity for hair regrowth in a patient with advanced, extensive AGA using non-surgical intervention.
Figure 1. Pretreatment photographs reveal extensive frontoparietal
(left) and vertex (right) balding consistent with Hamilton-Norwood
stage V androgenetic alopecia.
THE SOLUTION----Following informed consent, the patient agreed to a 6- to 12-month trial of topical minoxidil in an optimized retinoid vehicle applied twice per day and 5 mg of finasteride taken orally each day. The topical solution was prepared as follows:
Minoxidil tablets were dissolved in distilled water, polyethylene glycol, and absolute ethanol (volume ratio, 20:30:50, respectively) to a final minoxidil concentration of 3.75% (grams per deciliter). Following filtration, the 3.75% minoxidil solution was combined with 0.05% tretinoin (4:1 vol/vol) for final concentrations of 3% minoxidil and 0.01% tretinoin. The preparation was stored at room temperature and protected from light.
Each application consisted of 1 ml of solution (0.03 g of minoxidil) applied to the bald scalp with gentle fingertip massage. The patient was compliant, and no side effects were observed.
Figure 1. Left, Five months following initiation of treatment with topical minoxidil
and tretinoin and oral finasteride reveals a marked increase in terminal hair density
over the parietal and vertex areas, respectively. Mild improvement is noted in the
extreme frontal area. Right, Seven months following initiation of treatment with
topical minoxidil and tretinoin and oral finasteride reveals a marked increase in
terminal hair density over the area of the vertex.
Increased terminal hair growth on the scalp was initially observed after only 3 months of therapy, especially over the area of the crown and vertex. Following 5 months of therapy, marked improvement was noted over the parietal region. Striking terminal hair growth continued in the region of the crown and vertex. After 8 months of therapy, some growth in the extreme frontal area was noted, while the crown, vertex, and parietal areas continued to increase the terminal hair density.
The patient chose to discontinue oral finasteride therapy after 8 months because his cosmetic objective had been met. The patient has continued the topical therapy with minoxidil and tretinoin for approximately 4 months with continued gradual improvement. No thinning or shedding has been observed.
After a total of 12 months of therapy, the patient's AGA has improved from stage V, pretreatment to stage III.
THE COMMENTARY----Topical minoxidil is the ONLY therapy approved for AGA by the US Food and Drug Administration.(1) Recent studies using combinations of minoxidil and the oral 5a-reductase inhibitor finasteride in the stumptailed macaque (an animal model of AGA) have proven more effective in preventing the onset and progression of alopecia than either agent used alone. (1,2) Human trials using combinations of finasteride and minoxidil to alter AGA are currently underway. (1,3)
The pathogenesis of AGA involves increased scalp follicle susceptibility to androgens. (1) Scalp follicles in AGA contain increased levels and activity of 5a-reductase, the enzyme that converts testosterone to dihydrotestosterone (DHT). (1) DHT shortens the hair cycle and miniaturizes scalp follicles. (1) Other sites of body hair are testosterone independent and, thus, do not exhibit AGA patterns.
5a-reductase in the prostate increase levels of DHT and clinically manifests as benign prostatic hypertrophy.(3) Recently, oral finasteride was found to decrease the level of DHT in bald scalps to the level found in hairy scalps, suggesting a potential use in the therapy of AGA. (3)
Two isoenzymes of 5a-reductase occur in humans: type 1 is predominantly found in the skin of the scalp, and type 2 is primarily found in the prostate. Finasteride effectively inhibits type 2 5a-reductase with little activity against type 1 5a-reductase.(3) A daily dose of 5 mg lowers serum DHT levels by 65% to 80% and prostatic DHT by 85%.(3) Because of its selective inhibition of the type 2 isoenzyme, the observed decrease in scalp DHT is puzzling. The scalp is highly vascularized and may be influenced by decreased levels of circulating DHT.
Long term therapy with finasteride may progressively inhibit the type 1 isoenzyme, as suggested by in vitro studies showing high dose finasteride inhibition of type 1 isoenzyme.(4) Although type 1 5a-reductase is the dominant enzyme form in the scalp, the fact that AGA does not develop in men with congenital 5a-reductase deficiency (defective type 2 5a-reductase only) suggests a role for type 2 5a-reductase in AGA.(4)
It is not known if inhibition of both 5a-reductase isoenzyme types are necessary to promote hair growth. Finasteride was shown to be nearly as effective in animal models of AGA as N,N-diethyl-4-methyl-3-oxo-4-aza-5a-androstane-17B carboxamide, an inhibitor of both isoenzyme types, suggesting that inhibition of only a single isoenzyme type may be sufficient for preventing AGA.(4) Prolonged exposure to finasteride may be necessary for clinical effectiveness; 6 months of treatment is required for maximal response in benign prostatic hypertrophy, and a similar gradual response pattern may occur in AGA.
Minoxidil is an antihypertensive agent approved as a topical agent for AGA.(1) Although minoxidil dilates peripheral arterioles when taken systemically, the mechanism of stimulating hair growth is not understood. Minoxidil increases cutaneous blood flow when applied topically.(5) However, other topical vasodilators have been unsuccessful in stimulating hair growth. It is likely that minoxidil has a direct effect on hair growth, perhaps by stimulating dermal papillae or follicular hair matrix cells.(5)
Simultaneous administration of topical minoxidil with tretinoin may enhance the response of AGA to minoxidil. (6,) Possible mechanisms include epithelial and vascular proliferation and increased minoxidil absorption through the alteration of the stratum corneum barrier. Both phenomena have been observed experimentally.(6) Indeed, cotreatment with tretinoin resulted in a threefold increase in cutaneous minoxidil absorption compared with a control vehicle without observed side effects.(6)
We were encouraged by the improvement in frontal scalp alopecia in our patient. Most studies using minoxidil alone report response primarily in the area of the vertex.(1) Although this patient underwent follow-up by subjective assessment only, the goal of improving cosmetic appearance was achieved. The efficacy and rate of improvement in this patient may have reflected the 'unopposed' action of minoxidil on hair follicles in the setting of lowered levels of DHT. The response may have also been potentiated by the administration of tretinoin, known to enhance minoxidil absorption, follicle differentiation, and dermal vessel formation.(5-6) Randomized clinical trials will determine if these agents are synergistic in the treatment of AGA.
Finasteride was introduced in 1989 and has demonstrated few adverse effects.(3) Untoward effects occur in fewer than 5% of patients and usually relate to decreased libido and impotence. Up to a 25% reduction in semen volume can be expected in some patients without any changes in sperm counts, motility, or morphologic features.(3) The dose taken for benign prostatic hypertrophy does not effect other hormones, serum lipids, or bone density.(3) Finasteride lowers serum levels of prostate-specific antigen, a laboratory test used to monitor benign prostatic hypertrophy and screen for prostate cancer, since elevated prostate-specific antigen levels occur in both benign prostatic hypertrophy and prostate cancer.
Finasteride may have value in treating acne and hirsutism.(3) Although a 5a-reductase inhibitor should have no adverse hormonal effects in women, ambiguous genitalia might develop in a male fetus exposed to this compound.(3) Finasteride is found in semen, but the levels do not appear to be sufficient to harm a male fetus.(3)
We report a case of extensive AGA in which topical minoxidil and tretinoin and oral finasteride provided an effective combination therapy. This regimen should be considered in those patients with mild to moderate AGA who desire medical therapy following informed consent.
The opinions or assertions contained herein are the private views of the authors and are not to be construed as official or reflecting the views of the Department of the Army or the Department of Defense.
We thank Albert Szkutnik for thoughtful advice and the preparation of the minoxidil-tretinoin solution.
THE REFERENCES---
- Sasson Ms, Shupack JL, Stiller MJ. Status of medical treatment for androgenetic alopecia. 1994;32:701-706.
- Diani AR, Mulholland MJ, Shull KL, et al. Hair growth effects of oral administration of finasteride, a steroid 5a-reductase inhibitor, alone and in combination with topical minoxidil in the balding stumptail macaque. J Clin Endocrinol Metab. 1992;74:345-350.
- Rittmaster RS. Finasteride. N Engl J Med. 1994;330:120-125.
- Dallob AL, Sadick NS, Unger W, et al. The effect of finasteride, a 5a-reductase inhibitor, on scalp skin testosterone and dihydroxytestosterone concentrations in patients with male pattern baldness. J Clin Endocrinol Metab. 1994; 79:703-706
- Headington JT. Hair follicle biology and topical minoxidil: possible mechanism of action. Dermatologica. 1987; 175(suppl 2):19-22.
- Ferry JJ, Forbes KK, Vanderlugt JT, Szpujnar GJ. Influence of tretinoin on the percutaneous absorption of minoxidil from an aqeous topical solution. Clin Pharmacol Ther. 1990;47:439-446.