The Potentials of Dehydroepiandrosterone (DHEA) in Skin ageing process.

 

Anshita Gupta1, Swarnlata Saraf1, Chanchal Deep Kaur2*, Shailendra Saraf1

1University Institute of Pharmacy, Pt.Ravishankar Shukla University,Raipur,C.G

2Shri Rawatpura Sarkar Institute of Pharmacy, Kumhari,Dist-Durg,C.G, India

*Corresponding Author E-mail: dr.chanchaldeep@gmail.com; research_iop@rediffmail.com

 

 

ABSTRACT

Ageing and hormones are inter-related terms playing crucial role in human’s life. Dehydroepiandrosterone, commonly known DHEA, is among those hormones which directly interfere with the ageing process and its effects is remarkably visible. The role of DHEA in fighting against the signs of aging have been tested for a long time. Recent researches in the field of hormones and steroids has provided the researcher with new insights to investigate the potentials of DHEA and its sulfate esters in the field of skin aging complications. DHEA, which is an adrenal cortex hormone act as mediator in various biochemical pathways, essentially required for maintaining the homeostasis of the body. The present aim of this review is to focus on the role of DHEA and its sulfate esters in skin aging process and in its related disorders. The review also highlights different delivery systems available for targeting this drug to the desired site of action for better therapeutic activity.

 

KEYWORDS: DHEA, Testosterone ,Estrogen ,Targeted drug delivery.

 


INTRODUCTION:

Dehydroepiandrosterone, also known as DHEA and its sulphate esters [DHEA-S] are the major androgens secreted by adrenal glands during the course of puberty. These hormones are converted into testosterone and estrogens in systemic circulation. Dehydroepiandrosterone ester has longer half life but it is an inactive prohormone which is further needs to synthesized [1][2]. The role of DHEA is like an indirect precursor of the sex hormone, Since it is abundantly produced by the body in man and women both in adulthood the level decreases with age however its concentration is found higher in women rather than in men. The deficiency of DHEA in body results in rapid ageing process [3][4].The DHEA is required by the body to initiate the release of various hormones that keeps the body young. The term buffer hormone is used for the DHEA and its sulfate ester  which emphasis about the chemical nature of the compound [5][6].

 

Chemistry of DHEA and DHEA-S

Dehydroepiandrosterone is produced by the adrenal gland and remains in the systemic circulation of the body. It is an endogenous type of hormone which is steroidal in nature. It actively participates in the synthesis of various hormones and key player in the biosynthesis of sex hormones [7][8]. The term “neurosteroid hormone” perfectly describes the role of DHEA in human body.

 

Dehydroepiandrosterone (DHEA) which is chemically known as 3β-hydroxyandrost-5-en-17-one or 5-androsten-3β-ol-17-one,(Figure: 1)has multiple binding sites at different cellular levels and exert specific action of its own [9][10]. Chemically, dehydroepiandrosterone is deprived of hydrogen atom in the epiandrosterone skeleton. There are a number of isomers of DHEA, some of them are 1-dehydroepiandrosterone and 4-dehydroepiandrosterone.

 

                (A)                                              (B)

Figure: 1 (A) Structure of Dehydroepiandrosterone (DHEA)  [Adaptated and modified from ]

(B)  Dehydroepiandrosterone  sulfate(DHEA-S)

Dehydroepiandrosterone sulfate

The another active form of DHEA is the Dehydroepiandrosterone sulfate (DHEAS) whose reaction is mediated by enzyme steroid sulfotransferase (SULT2A1) as catalyst [11][12][13]. Since it is more stable than DHEA and remain available in the blood more significantly than DHEA hence can be easily measured for any pathological interventions. Dehydroepiandrosterone sulfate (DHEAS) act as a reservoir for the conversion of DHEAS to DHEA [14].

 

Production  And Biosynthesis of DHEA

Cholesterol is the precursor compound for the initiation of biosynthesis of Dehydroepiandrosterone (DHEA) by the activity of cytochrome P450scc and P450c17, enzymes. Pregnenolone and 17α-hydroxypregnenolone  is the intermediate product formed during the course of synthesis. Earlier, it was thought that DHEA forms the pool from where different hormones are produced, but later on it was fond that, the DHEA has its own action and exert potential pharmacological effects when act alone [15][16]. The structure of DHEA is similar to that of many of the steroid hormones that’s why when there is a need the conversion of DHEA to specific hormones takes place.(Figure:2)

 

 

 

The role of DHEA and its sulfate ester commands over various physiological functions of the body like-

·      Regulation of the hormonal balance inside the body (consisting of production, biosynthesis and circulation of these hormones).

·      Maintenance of Immunological status of body.

·      Glucose Metabolism

·      Lipid Metabolism

·      Regulation of the Central Nervous system activity

·      Maintenance of Vascular system of the body

DHEA,always tend to be a key player, in indirect building for hormones [17][18][19]. Various researches in the field of ageing and pathology has suggest that the DHEA is not only an anabolic steroid but its synthesis is always subjected to various biochemical pathways, depending upon the body need, in healthy adults for the production of various essential hormones.

 

At the time of birth, DHEA levels start relatively low and gradually increase until puberty, when levels increase markedly, reaching a peak around 20 to 24 years of age. From there, serum and tissue DHEA levels decline at a rate of 2 to 3% per year, with a steep decline occurring around middle age. [20] By age 75, humans exhibit very less amount of DHEA i.e only 10 to 20% of young adult DHEA levels.

 

 


Figure2: Physiological role of DHEA and  its sulfate esters.

 

Role of Dehydroepiandrosterone and its Sulphate in Skin ageing Process:

Aging is a fundamental process of gaining maturity [21]. The process of aging is highly complicated and involves a series of biochemical and genetic changes. The course of aging is accomplished by various changes occurring at the cellular and molecular level which are governed by multiple factors like stress, diseases, environmental factors etc. The sign of aging is characteristically displayed on the surface of the skin. The first few signs are fine lines, wrinkles, dryness, black spots, dull appearance, etc. All these are influenced by the metabolic and hormonal changes which leads to aging progressively [22][23]. Aging can be further classified as intrinsic aging which is also known as endogenous aging [24]. The other type is exogenous aging [25][26].

 

The deficiency of DHEA in later age of life causes decrease in the rate of procollagen synthesis which further causes acceleration of MMP-1 activity. A progressive decrease of DHEA leads to retardation of TIMP-1 activity. It also degrade the collagen by increasing the production of stromelysin-1 [27][28][45]. The unavailability of DHEA leads to the development of signs of skin aging. The reduction of  DHEA  level is one of the major reason of lack of elasticity in the skin [29][30]. The treatment followed with hormone replacement therapy can be an option for enhancing  collagen production rate, higher hydration and elasticity rate ,good vascularity, higher lipid content, etc for restoring and maintaining the property of skin(Figure.3) [31] [32][33]. There are various topical preparations containing DHEA which are present in the market giving relief from the skin problems occurring at a higher stage [34][35]. (Table 1:Showing marketed topical DHEA preparations).

 

DHEA, other than its steroidal effects exhibits a series of activities on skin. It is an antioxidant and has skin protective effect. It accelerates wound healing also. DHEA has also proved to be remarkable in the case of chemical induced DNA damage [36]. Various clinical trials on DHEA has proved its  usage significant in various elderly women [37].

 

Current status of drug delivery systems of DHEA:

Several clinical trials of DHEA have been conducted, investigating the use of this steroid in the treatment of conditions ranging from chronic inflammatory disease to psychiatric disorders. Possible replacement therapy with DHEA in adrenal insufficiency and in old age has also been investigated. Presently the delivery system available for DHEA have enhanced its therapeutic benefits [39][40] . But the drug delivery of DHEA faces certain problems regarding the solubility and permeation ability of the compound, in case of transdermal. In order to combat these problems various researches have been now focused to develop such vehicles which can facilitate the delivery of DHEA inside the skin [39].

 

Vassilia-Ismini Alexaki et.al in 2009, demonstrated the role of DHEA against apoptosis in keratinocytes, using human HaCaT cells. They showed that the DHEA utilizes specific G protein-coupled signaling to inhibit apoptosis. The result revealed that the treatment of epidermal apoptosis can be  done through DHEA conjugates [40].

 

Calvo E  et.al in 2008 through their findings postulated the possible role of DHEA as antiaging agent through the activation of collagen biosynthesis and stimulating the extracellular matrix components as well as altering the keratinocyte metabolism also [38].

 

Mi Hee Shin, et.al in 2005 demonstrated that the topical formulation of DHEA consisting of  DHEA (5%) in ethanol:olive oil (1:2)can increase Procollagen synthesis and inhibit collagen degradation by decreasing matrix metalloproteinases (MMP)-1 synthesis [45] and enhancing tissue inhibitor of matrix metalloprotease (TIMP-1) production in cultured dermal fibroblasts [41]. These results potentiate the use of DHEA as antiaging and anticancer agent.

 

Arthur G. Schwartz et.al in 2004 emphasized that the role of DHEA as antioxidant [42]. He strongly stated that DHEA has the potential of inhibiting inflammation, carcinogenicity and hyperplasia too.

 

In a study conducted by Gian Carlo Ceschel et.al in 2005 demonstrated that solubility and permeability of DHEA can be increased by the complexation of the drug with cyclodextrin using hydrophilic and lipophilic vehicles. In their study they used α-cyclodextrin to enhance the solubility of DHEA [43]. They also evaluated the synergic effect of cyclodextrins and microemulsion vehicles on solubility and permeation of DHEA.The result of the study showed that the drug and the vehicle combination increased the solubility and permeation of DHEA notably many folds, which suggest that such combinations can be proved beneficial for topical preparations

 

In a similar study by the same researcher showed that the  formulation containing the complextion α-cyclodextrin enhanced the permeation flux of DHEA. This study also emphasized that gel formulation of DHEA  exhibited better drug permeation in comparison to simple water suspension [44].

Similarly, in a study carried out by Scott A et.al in 2000 aimed in developing a Tri-Calcium Phosphate Lysine (TCPL) drug delivery systems to administer DHEA with diosgenin for sustained action and to evaluate their effect histopathologically using ovariectomized (OVX) adult rats as a model [46]. The study showed that combination of DHEA with diosgenin gave significant results for sustained action.

 

 

Table 1. List of marketed topical DHEA preparations


DHEA Unscented and Paraben-Free topical cream

Topical Cream 

Natural Radiance

Life-Flo DHEA PLUS Cream

Topical Cream 

Life-Flo

Life-Flo 7 Keto DHEA Metabolite

Topical Cream 

Life-Flo

D-35 Complex DHEA Gel

Topical Cream 

Sarati


 

Figure 3: Effect of DHEA on Skin

 

 


 CONCLUSION:

The review presents here a considerational approach in combating skin aging through DHEA. Recent researches have shown that DHEA has the potential to act on different compartments of skin viz, the extraxellular matrix, the dermis and the epidermal-dermal junction. DHEA directly interfere with procollagen synthesis and the proliferation and differentiation of keratinocytes. DHEA is a potent wound healing agent and inhibits inflammation etc. Thus, the DHEA proves itself to be a novel therapeutic target for skin treatment. In the due course of researches also, dehydroepiandrosterone has shown beneficial effects through skin delivery eg. transdermal delivery of dehydroepiandrosterone (DHEA) through cyclodextrin complexation.

 

The administration of dehydroepiandrosterone orally is being available in conventional system of medicine but suffers bioavailability variation because of poor first pass metabolism. Therefore, it is very important to develop novel medicational system for effective and sustained delivery of DHEA. Dehydroepiandrosterone has proven its remarkable ability in reducing skin cancer and frequently employed in combinational therapy in cancer treatments. Our focus lies in elucidating the need of development of novel therapeutic interventions to deliver the dehydroepiandrosterone (DHEA) to the desired site of action both systematically and in controlled manner. Novel drug delivery system can be proved beneficial in eliminating the obstacles being faced in DHEA administration. The delivery of DHEA in the form of nanogel, nanoemulsion, nanomicelles or nanoprticles can not only reduce its dosing frequency but it also can improve its therapeutic benefits. Dehydroepiandrosterone and its sulphate ester has a broad activity spectrum against number of diseases like Alzheimer disease, depression, cardiovascular disease, osteoporosis,skin disorders etc. The development of novel drug delivery system of DHEA will enable them to be utilized as an adjuvant in various pathological conditions. No doubt, dehydroepiandrosterone and its derivative, need to be design and develop into new synthetic analogs for enhancing their potentials in curing various alinments. The DHEA synthetic analogs should be tissue specific as well as receptor specific for proving themselves a better and safer option.

 

ACKNOWLEDGEMENTS:

The authors acknowledge the University Grant Commission-SAP [F. No.3-54/2011(SAP-II)] New Delhi, India, for financial assistance. One of the author extend her gratitude towards the head of the cosmetic lab, University Institute of Pharmacy, Pt., Ravishankar Shukla University, Raipur (C.G.) for providing facilities to carry out research work. Author also wants to thank library of Pt. Ravishankar Shukla University for providing e-resources available through UGC-INFLIBNET.

 

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Received on 30.10.2013                    Accepted on 22.11.2013        

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Res. J. Topical and Cosmetic Sci. 4(2): July –Dec. 2013 page 43-47