The Journal of International Medical Research 1992; 20: 445 - 453
A Comparative Study of a New Food Supplement, ViviScal®, with Fish Extract for the Treatment of Hereditary Androgenic Alopecia in Young Males
A. Lassus and E. Eskelinen
Department for Dermatological Research, ARS-Medicina, Helsinki, Finland
A controlled, randomized, double-blind, parallel-group study compared the effects of Viviscal® (a new food supplement incorporating special marine extracts and a silica compound) with those of a fish extract in the treatment of young males with hereditary androgenic alopecia. The pretreatment histological diagnosis was alopecia with a mild to moderate perifollicular inflammation zone. The study consisted of 20 subjects who received two tablets of Viviscal® once daily and 20 who received two tablets of fish extract once daily for 6 months. The mean patient age and mean duration and severity of baldness compared well between the two groups. Most patients had been treated with long-term topical 2% minoxidil for 1 year or more prior to the study. At baseline and after 6 months' treatment, a biopsy was taken for histological examination. A non-vellus hair count was performed at baseline and after 2, 4 and 6 months. In the fish extract treatment group three patients withdrew from the study before the fourth month due to lack of therapeutic effect. After 6 months' treatment, patients receiving Viviscal® showed a mean increase in non-vellus hair of 38% compared with a 2% increase in the fish extract treatment group (P‘0.0001). In the Viviscal® group, 19 (95%) subjects showed both clinical and histological cure, whereas none treated with fish extract showed any clinical or histological difference after 6 months' treatment (P ‘0.0001). In both groups, a minimal decrease in the erythemal index was observed. In conclusion, Viviscal® appears to be the first highly active treatment for androgenic alopecia in young males.
INTRODUCTION
Basic amino acids, fats and vitamins are essential for the growth of healthy hair. Undernourishment slows the growth rate of hair and extreme starvation may render people totally bald. In some animals, such as rats and mice, all hair appears to be in the same state of activity and all cyclic changes are synchronized(1), whereas in humans the cycle of each follicle occurs independently from that of the adjacent ones, thus exhibiting a mosaic pattern. Hair cycles are divided into three stages: anagen, a growing or active phase; catagen, a regressive stage; and telogen, a resting stage(2-4). The relative duration of these phases varies with the individual's age, nutritional status and hormonal influences.
Hair growth is regulated by several factors(2-4) and the roles of innervation and vascularization have not been fully elucidated. Sex hormones play an important role in the growth, distribution and pigmentation of human hair. The varying effects of circulating androgens and the different types of human hair in various locations have led to the hypothesis that there are differences in the metabolism of hormones in follicular tissue. The conversion of testosterone to the more active dihydrotestosterone (DHT) in certain target cells depends upon the presence of the enzyme 5alpha -reductase(5,6). The DHT combines with a cytosol receptor to form a complex that enters the nucleus and joins with chromatin to initiate protein synthesis. The metabolism of androgens can be impaired either by decreased conversion of testosterone to DHT or by an inability of cells to accumulate DHT because of the absence of the cytosol receptor protein. The primary catabolic product of androgen metabolism in both growing and resting hair follicles is androstenedione(7) . The conversion of testosterone to androstenedione via 17beta hydroxysteroid dehydrogenase present in the cell occurs at 10 times the rate of the 5alpha- reductase system that yields DHT. The effects of androgens on sexual hair growth and scalp hair loss could be mediated through changes in intracellular concentrations of cyclic adenosine monophosphate.
In terms of structure, there are three types of hair: vellus; terminal; and intermediate. Vellus hairs are short, fine, soft, usually non-pigmented and unmedullated, whereas terminal hairs are large, heavily pigmented and medullated, and intermediate hairs occur on the scalp and demonstrate a morphology between those of terminal and vellus hairs, i.e. they are medullated and contain a moderate amount of pigment. The balding process involves conversion of the follicles such that they produce vellus hairs rather than terminal hairs(8). 
Of the 100 000 - 150 000 scalp hairs on a human adult, 90% are in the growing or anagen phase, which lasts for 4 - 8 years. The remaining 10% are in the resting or telogen phase, which lasts for about 100 days. About 50 - 100 clubbed hairs are shed each day and this occurs regardless of sex, although there is considerable variability between individuals. 
Throughout history men have concocted various potions from animal, vegetable and mineral substances in an attempt to improve hair growth and at the present time hair transplants and scalp reductions are used to minimize visible alopecia. A hair transplant involves removal of hair from the back of the head and transplantation to the bald area. The large follicles removed from the back of the head remain normal in size after transplantation and continue to produce long, large hairs in the new area. Scalp reduction involves excision of the bald area and drawing together the remaining skin. This procedure can be combined with the management of skin flaps, whereby parts of the hairy scalp are surgically moved to the bald area. The results of such surgical procedures, however, are not always cosmetically acceptable.
The alternative approach is the use of pharmaceutical preparations. Minoxidil, a piperidinopyrimidine derivative, is a potent peripheral vasodilator. Recent trials using topical minoxidil have shown that it has a stimulatory effect on hair regrowth in some individuals with either androgenic alopecia or alopecia areata(9-12). Several reports have recently demonstrated that certain proteins derived from marine fish have a stimulatory effect on hair growth in females(13-15). It was, therefore, of interest to develop a new compound containing a special mixture of an extract of marine origin with a silica compound and compare it with a fish extract that contains the same type of proteins. The study was carried out in a double-blind fashion for 6 months in young healthy males with androgenic alopecia. 
PATIENTS AND METHODS
Patients
A total of 40 males with androgenic alopecia classified on the Hamilton scale(16) as III - V took part in the study. The patients were divided randomly into two groups, 20 in each (Table 1), and one group received two tablets of Viviscal® for 6 months and the other group two tablets of fish extract for the same period of time. The two groups compared well with regard to demography (Table 1) and clinical baldness, and all were aged between 20 and 30 years. The duration of hair loss suffered by the volunteers varied between 2 and 9 years, and most of them had received prior treatments, most commonly 2% minoxidil solution. All subjects were in good health and gave oral informed consent before the start of the study.

TABLE 1:
Demographic details of patients with hereditary androgenic alopecia treated daily with two tablets of ViviScal® or fish extract
TREATMENT GROUP 	

Characteristics 	
Viviscal® 	
Fish extract 	

No. of subjects 	
20 	
20 	

Mean (±SD) age (years) 	
25.1±2.9 	
25.0±2.7 	

Mean duration of baldness (years) 	
3.2±1.5 	
3.4±1.0 	

Mean weight (kg) 	
74.4±6.5 	
73.7±7.6 	

Mean height (cm) 	
181.5±3.0 	
182.8±4.3 	

Hamilton scale type 	

II 	
15 	
16 	

IV 	
3 	
4 	

V 	
2 	
0 	

EARLIER TREATMENTS 	

2% minoxidil solution for 6-18 months 	
16 	
17 	

Psolaren and ultraviolet therapy >6 months 	
3 	
2 	

5% tretinoin solution 	
2 	
1 	

Hair transplants 	
1 	
0 	

Study design
Clinical visits were scheduled bimonthly for 6 months and non-vellus hair counts were performed at baseline and at each clinical visit, with an individual template used for each patient. A template with a 2.5-cm diameter hole was centred over the posterior vertex and non-vellus hairs within the hole were counted with the aid of magnification and bright illumination. 
A punch biopsy specimen (5 mm) was obtained from the centre of the bald scalp both at baseline and after 6 months. The punch biopsy was subsequently used to locate the target area for hair counts. 
At the start of the study and at each subsequent visit, an erythemal index meter (Diastron Ltd, UK) was used to measure the erythemal index(17) at the centre of the bald area. In addition, patients were questioned about their observations regarding hair loss. 
STATISTICAL ANALYSIS
Statistical methods were applied to continuous as well as categorical data collected during the study. Categorical variables were analysed with a standard X2-test for homogeneity and Fisher's exact test was also used. Results were declared statistically significant if the corresponding P-value was less than 0.05 and marginally significant if the P-value was greater than or equal to 0.05, but less than or equal to 0.10. 
RESULTS
Of the 40 patients randomized, 37 were evaluable after 6 months: 20 in the Viviscal® treatment group and 17 in the fish extract group. All three patients in the fish extract group who withdraw from further treatment before the 4-month assessment of progress did so because of lack of efficacy or increased hair loss. 
In the Viviscal® treatment group all patients reported that there was no hair loss after 2 months' treatment, whereas in the fish extract group hair loss continued during the entire treatment period. 
There was significantly more regrowth of non-vellus hair throughout the treatment period in the Viviscal®-treated patients compared with those treated with fish extract (Table 2). Comparison of baseline bald area and after 6 months' treatment showed a marked improvement. The mean number of new non-vellus hairs was 472 (mean increase 38.1%) in the Viviscal® treatment group and 26 (mean increase 2.1%) in the fish extract group; this difference was highly statistically significant (P‘0.0001). Patients' estimates of new hair growth were similar to those of the investigators. A non-significant decrease of the erythemal index was observed in both groups. 
The histological examination at baseline showed typical alopecia in all 40 patients, with mild to moderate perifollicular inflammation. After 6 months, alopecia could no longer be diagnosed in 19 of the 20 patients in the Viviscal®-treated group. The remaining patient in the Viviscal® treatment group (a 29-year old male) still had typical alopecia and moderate perifollicular inflammation and showed no increase in non-vellus hair. He had had androgenic alopecia for 9 years and, during that time, had been topically treated with 2% minoxidil for 18 months, with 20% tretinoin solution for 8 months and, additionally, had undergone two hair transplants, both of which failed. 
All 17 patients in the fish extract treatment group who completed the 6 months' course still had histologically verified alopecia with persistent perifollicular inflammation. 
No adverse reactions were observed by the investigators or were reported by the patients in either group. 
TABLE 2:
Non-vellus hair counts in men with hereditary androgenic alopecia before, during and after 6 months of daily treatment with two tablets of ViviScal® or fish extract

ViviScal® 	

Fish extract 	

Time (months) 	
No. of patients 	
Non-vellus hair counts 	
No. of patients 	
Non-vellus hair counts 	

0 	
20 	
1238±73.8 	
20 	
1233±74.6 	

2 	
20 	
1318±42.2 	
20 	
1230±45.2 	

4 	
20 	
1419±95.2 	
1 	
1257±75.4 	

6 	
20 	
1710±18.9 	
17 	
1259±80.6 	

Total increase in
hair counts 	
	
472 (38.1%) 	
	
26 (2.1%) 	

DISCUSSION
In the present study, Viviscal® proved to be highly effective in the treatment of androgenic alopecia of short duration in young males, with 19 of the 20 patients being completely cured as shown by non-vellus hair count and histological examination. The only treatment failure occurred in a subject who had the longest duration of alopecia in this group. This subject had severe psychological problems associated with his condition and had attempted suicide. He had earlier tried a variety of treatments including topical minoxidil and tretinoin as well as hair transplants, but without success. This patient may not be suitable for treatment with such preparations as Viviscal®, and possibly no treatment would be effective for this subject.
The mechanism by which Viviscal® works has not been elucidated, although in the present study the treatment has been shown to be highly effective. Previous studies have indicated that oral treatment with Vivida®, a fish protein extract, resulted in improved hair growth in women being treated for photo-aged skin(13-15). The silica compound component of Viviscal® may also be important and it is probable that several nutritional factors have a synergistic effect and improve the efficacy of the compound.
There was a decrease, although not significant, in the erythemal index indicating that the mechanism of Viviscal® may not depend on vasodilatation, which has been speculated to be an important factor regarding the mechanism of action of topical minoxidil.
In conclusion, Viviscal® seems to be effective in the treatment of androgenic alopecia in young males. The present study also suggests that the cartilaginous fish extract, which affects the condition and growth of hair in females, does not affect androgenic hair loss in young males. A further two studies in older males with a longer period of androgenic hair loss are in progress.
REFERENCES
1) Takashima I, Kawagishi I: Comparative study of hair growth in mammals, with special references to hair grouping and hair cycle; and hair growth rate in the juvenile stump-tailed macaque. In: Biology and Disease of the Hair (Toda K, et al, eds). Baltimore: University Park Press, 1976; pp 457 - 471.

2) Sato Y: The hair cycle and its control mechanism. In: Biology and Disease of the Hair (Toda K, et al, eds). Baltimore: University Park Press, 1976; pp 3 -13.

3) Moretti G, Rampini E, Rebora A: The hair cycle re-evaluated. Int J Dermatol 1976; 15: 277 - 285.

4) Orentreich N, Durr NP: Biology of scalp hair growth. Clin Plast Surg 1982; 9: 197 - 205.

5) Farthing MJ, Mattei AM, Edwards CR, et al: Relationship between plasma testosterone and dihydrosterone concentrations and male facial hair growth. Br J Dermatol 1982; 107: 559 - 564.

6) Schweikert HU, Wilson JD: Regulations of human hair growth by steroid hormones. 1. Testosterone metabolism in isolated hairs. J Clin Endocrinol Metab 1974; 38: 811 - 819.

7) Adachi K: The metabolism and control mechanism of human hair follicles. Curr Probl Dermatol 1973; 5: 37 - 78.

8) Roberts JL: Androgenetic alopecia: treatment results with topical minoxidil. J Am Acad Dermatol 1987; 16: 705 - 710.

9) De Villez RL: Topical minoxidil therapy in hereditary androgenic alopecia. Arch Dermatol 1985; 121: 197 - 202.

10) Olsen EA, Weiner MS, Delong ER, et al: Topical minoxidil in early male pattern baldness. J Am Acad Dermatol 1985; 13: 185 - 192.

11) Weiss VC, West DP, Fu TS, et al: Alopecia areata treated with topical minoxidil. Arch Dermatol 1984; 120: 457 - 463.

12) Katz HI, Hien NT, Prawer SE, et al: Long-term efficacy of topical minoxidil in male pattern baldness. J Am Acad Dermatol 1987; 16: 711 - 718.

13) Lassus A, Jeskanen L, Happonen HP, et al: Imedeen® for the treatment of degenerated skin in females. J Int Med Res 1991; 19: 147 - 152.

14) Eskelinen A, Santalahti J: Special natural cartilage polysaccharides for the treatment of sun-damaged skin in females. J Int Med Res 1992; 20: 99 - 105.

15) Eskelinen A, Santalahti J: Natural cartilage polysaccharides for the treatment of sun-damaged skin in females: a double-blind comparison of Vivida( and Imedeen®. J Int Med Res 1992; 20: 227 - 233.

16) Hamilton JB: Patterned loss of hair in man: types and incidence. Ann NY Acad Sci 1951; 53: 708 - 711.

17) Diffey BL, Oliver RJ, Farr PM: A portable instrument for quantifying erythema induced by ultraviolet radiation. Br J Dermatol 1984; 111: 663 - 672.

A. Lassus and A. Eskelinen
A Comparative Study of a New Food Supplement, ViviScal®, with Fish Extract for the Treatment of Hereditary Androgenic Alopecia in Young Males
The Journal of International Medical Research 1992; 20: 445 - 453
Received for publication 20 August 1992
Accepted 26 August 1992
Copyright 1992 Cambridge Medical Publications
Address for correspondence
Dr A. Lassus
Department of Dermatological Research, ARS-Medicina, Stora Robertsgatan 8 A 1, SF-00120 Helsinki, Finland
Viviscal® is the registered trade name of Vivida Europe BV, Holland.
Key words: Viviscal, Fish Extract, Hereditary Androgenic Alopecia, Young Males