Abstract

1. Introduction

Androgenic alopecia (AGA), also known as male pattern baldness, is the most common type of progressive hair loss. According to published data, up to 30% of men with Caucasian origin are going to get AGA by the age of 30 years, up to 50% by 50 years, and 80% by 70 years [1].

It is well known that AGA is found in genetically predisposed people, as shown in our [2] and other studies [3,4,5]. An important role in the emergence and development of this disease is also traditionally attributed to hormonal changes, mainly to an increased levels of male sex hormones [6], changing the transcription profiles in the hair follicle cells. In addition, multiple metabolic, trace element, and vitamin changes that disturb the nutrition of the hair follicle and lead to hair loss have also been discussed [7,8,9,10].

A comparison of the role of genetic and non-genetic factors shows that patients with a low level of genetic risk of AGA developing have a higher number of significant non-genetic factors, including an increased level of dihydrotestosterone, 17-OH-progesterone, and insulin, as well as deficiencies in Mg, Cu, Zn, and Se, as well as vitamins D, E, and folic acid, compared to patients with a high level of genetic risk [10]. The obtained result indicates the variability of pathogenetic pathways leading to pathological hair loss. The currently proposed methods for treatment of alopecia are based on the use of surgical techniques [11,12], which are required in the late stages of this condition, as well as a variety of conservative therapeutic approaches aimed at correcting hormonal and nutrient changes in patients with early stages of AGA [13,14,15]. The positive experience of topical minoxidil therapy, a piperidino–pyrimidine derivative (2,4-diamino-6-piperidino–pyrimidine-3-oxide) [16] that is an ATP-sensitive potassium channel agonist (K(ATP)) channels), is known [17]. Partial restoration of hair growth is indicated after the systematic use of trace elements [18,19], vitamins [20], and their combinations [15,21,22]. At the same time, the substantial price and labor costs for such treatment are not always justified, which determines the relevance of the search for early informative predictors of the effectiveness of conservative therapy.

The aim of this study was to analyze the effectiveness of conservative treatment in patients with early stages of AGA, and to compare outcomes with the initially identified genetic and non-genetic factors with the previously proven value in the occurrence and development of AGA. The obtained results should determine the list of informative predictors of a positive or negative response to such therapy.

2. Materials and Methods

3. Results

4. Discussion

The results of the study showed a significant role of zinc as a possible indicator of the effectiveness of conservative AGA therapy in males. Zinc is a structural component of more than 1000 zinc-associated transcription factors, including DNA-binding zinc finger proteins, and is required in more than 300 zinc-containing metalloenzymes [27].

It has long been suggested that Zn plays an important role in hair loss [7]. A number of studies have shown reduced serum Zn in individuals with AGA [28,29]. Rahman and Akhter showed that lower serum levels of zinc (75.41 ± 9.47 vs 99.97 ± 7.72 µg/dl in the controls) and copper (74.55 ± 9.65 vs 100.23 ± 10.95 µg/dl in the controls) may be associated with alopecia regardless of gender, and an assessment of serum Zn and Cu concentrations may be useful for the correct treatment of alopecia [30].

Chronic telogen effluvium (TE) was also associated with low levels of serum zinc [31]. On the other hand, Ozturk et al.’s study did not show a reduced serum Zn content in men with AGA, but revealed a significant decrease in hair Zn [32]. It should be noted that the exact relationship between Zn and AGA has not yet been identified, but a number of cases show that hair loss can be successfully treated with zinc supplements [18]. Progression of AGA can be effectively reduced by regular intake of L-Carnitine and zinc with dietary supplements, and topically as part of a lotion [15]. At the same time, the concentration dependence of zinc on the proliferation of the dermal papilla cells of a human follicle and the expression of regulatory proteins of the cell cycle have also been demonstrated. Tsai et al. reported that zinc chloride at a dose of 200–500 nmol significantly increases the proliferation of human follicle dermal papilla cells and the expression of cell cycle regulatory proteins [33]. However, the production of proteins associated with the cell cycle has decreased when the cells were treated with 1000 nmol zinc chloride. An increase in the apoptotic Bax protein and caspase-3 activation were observed. The results of this study suggest that zinc is involved in the regulation of proliferation or death of human dermal papilla cells in the follicle, but in a narrow dose range [33]. The fact that Zn plasma levels in the positive effect and absence of effect groups were equal upon completion of conservative treatment most likely indicates the prognostic significance of the initial Zn plasma level in relation to the effectiveness of conservative therapy, but not a decisive role in realizing the positive effect of treatment.

The results of the study expand an understanding of the role of Zn trace elements in AGA, and demonstrate their importance not only for the development of this disease, but also its sensitivity to conservative therapy. Our results show that the Zn concentration can be used as a criterion for predicting the effectiveness of conservative therapy: if the plasma concentration of Zn is ≤10 µmol/L, treatment is most likely to be ineffective; if the concentration of Zn is >10 µmol/L, treatment is likely to be effective. The calculated positive predictive value obtained in this study was 88%, the negative predictive value was 55%, and the integral predictive value was 72.3%, which confirm our recommendations on the use of Zn plasma levels as a predictor of the conservative therapy outcome. Taking this into account, the estimation of plasma Zn levels and their correction to a level above 10 µmol/L before applying conservative AGA therapy is suggested to be included to standard protocols of AGA treatment.

One of the possible mechanisms of the Zn influence on conservative therapy outcome is its participation in the metabolism of a number of trace elements and vitamins [34]. For example, competitive inhibition of iron absorption by zinc has been shown [35]. In another study, dietary Zn deficiency decreased plasma vitamin E levels [36]. Zn supplementation affected trace elements status in healthy rats [37]. In patients with chronic liver diseases, the association of Zn and other trace elements, vitamins, and hormones has been indicated [38]. Thus, the obtained data on the relationship between the initial level of zinc and the dynamics of selenium correspond to the available data on their role in the antioxidant defense system [39]. Selenium is necessary element for implementation of the activity of a number of enzymes, especially glutathionperoxidase, thioredoxinreductase, and iodothyroninedeiodinase. These selenoenzymes provide antioxidant cell defense, modification of redox status, and the conversion of the prohormone thyroxine (3,5,3′,5′-tetraiodothyronine) to the active hormone triiodothyronine [40]. Because many risk factors for hair loss, such as smoking, stress, or exposure to UV radiation, are associated with the damaging effects of reactive oxygen species (ROS) [41,42], an antioxidant defense system compromised by selenium deficiency is likely to exacerbate the effects of these risk factors [15]. This statement is also confirmed by the evidence that the lack of Zn promotes oxidative stress, and consequently, oxidative damage to DNA, proteins, and lipids [43].

Another regulating factor is vitamin E, which in addition to zinc is part of the body’s antioxidant defense system that prevents cells from free radical damage [44,45]. Bunk et al. reported that there is a relationship between zinc level in the diet and the content of α-tocopherol in plasma: a lower level of vitamin E (4.02 ± 1.20 μg/ml) in a zinc-deficient compared with a zinc-adequate diet (9.21 ± 0.70 μg/ml) [36]. Moreover, the combined use of zinc and vitamin E at a dosage of 120 mg/kg Zn plus 200 mg/kg of vitamin E in conditions accompanied by oxidative stress (for example, under the action of toxic silver nanoparticles) did not lead to an increase in glutathionperoxidase (GSH-Px) activity, and even reduced Toll-like receptor 2 (TLR2)-1 mRNA levels [46]. In our study, an initially high level of zinc may have contributed to the effective restoration of vitamin E levels, which may be due to the close relationship of zinc with the lipid metabolism [47] and fat-soluble vitamins.

Of course, the specific molecular mechanisms of the relationship between the initial level of Zn and the effectiveness of conservative AGA therapy require further study. However, taking into account the importance of this trace element in the almost all aspects of cell metabolism, and the revealed correlations between the initial Zn level and the dynamics of some trace elements and vitamins in AGA, multiple mechanisms which are dependent on the individual characteristics of the patients’ metabolism are proposed. A limitation of the present study is the small number study subjects participating. We think it is important to conduct a large-scale study, which may provide more detailed information.

In general, the obtained data demonstrate the following:

1. The algorithm for genetic risk calculation and the artificial neural networks based on SNP A/G data at the rs5919324, rs1998076, rs929626, rs12565727, and rs756853 loci did not show effectiveness in assessing the prognosis of patient sensitivity to conservative therapy;

2. There were no differences in baseline trichogram and biochemical parameters in patients with and without the effect of conservative AGA treatment;

3. Lower zinc levels in patients who showed no effects from AGA treatment;

4. The Zn level may be a relative criterion for predicting the effectiveness of conservative therapy: if the concentration of Zn ≤ 10 µmol/L, treatment is most likely to be ineffective; if the concentration of Zn > 10 µmol/L, treatment is likely to be effective;

5. The positive predictive values, negative predictive values, and the integral indicator of significance of Zn in relation to the ongoing conservative therapy were 88%, 55%, and 72.3%, respectively;

6. An initially higher serum Zn level determines a more pronounced increase in vitamin E level.

Acknowledgments

Abbreviations

Author Contributions

Conceptualization, D.G.D. and I.N.K.; methodology, resources and investigation I.N.K.; formal analysis, software, and visualization, A.M.Z. and E.R.G.; validation, A.A.N. and D.G.D.; data curation, I.N.K. and D.A.V.; writing—original draft preparation, A.A.N. and E.R.G.; writing—review and editing, D.G.D. and D.A.V.; supervision, A.A.K.; project administration, D.A.V. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Conflicts of Interest

The authors declare no conflict of interest.

References