Skin in maturity: the endocrine and neuroendocrine pathways
Pascale Quatresooz, Department of Dermatopathology, CHU Sart Tilman, B-4000 Liège, Belgium. Tel.: +32 4 3662429; fax: +32 43662976;
Irrespective of age, most of the skin components are under the physiological control of endocrine and neuroendocrine factors. There is evidence that skin ageing appears complex showing much interindividual variability. Conceptually, ageing is a single biological process that is influenced and modulated by a series of various internal and exogenous factors. Among them, hormones and neuroendocrine signals play key roles in several ways. Ageing of most endocrine glands will in turn alter the skin biology. In addition, the age-related reduction in the intrinsic neuroendocrine activity of the skin will also alter the ageing rate of this organ. At last, various endocrinopathies will boost or conversely decrease the severity of the signs of cutaneous ageing.
Indépendamment de l’âge, la plupart des composants de la peau sont sous le contrôle physiologique de facteurs endocriniens et neuroendocriniens. Il semble évident, que le vieillissement cutané apparaît complexe, révélant une grande variabilité interindividuelle. Conceptuellement, le vieillissement est un processus biologique unique qui est influencé et modulé par une ensemble de divers facteurs internes et externes. Parmi eux, les hormones et les signaux neuroendocriniens jouent des rôles clés de diverses manières. D'une part, le vieillissement de la plupart des glandes endocrines va, par voie de conséquence, altérer la biologie cutanée. D'autre part, la réduction liée à l’âge de l'activité neuroendocrinienne intrinsèque de la peau altère aussi la progression du vieillissement de cet organe. Enfin, diverses endocrinopathies peuvent accélérer ou, en revanche, réduire la sévérité des signes du vieillissement cutané.
Nobody can escape from ageing. However, there are large interindividual differences in the expressions of this multifaceted process. In addition, the different organs of the human body are not affected similarly . For instance, according to many intercurrent factors, the heart, brain, lungs, kidneys, skin and the other organs are affected at different ageing rates in a given subject and among people. To complicate the situation further, there is regional variability of skin ageing over the body. It is indeed quite evident that at any time in adult life the face, scalp, forearms, trunk and other body sites show different manifestations of ageing. Scrutinizing skin ageing at the tissue level (epidermis, dermis, hypodermis, hair follicle), and further at the cellular level (keratinocyte, melanocyte, fibroblast, dendrocyte, etc.) also shows a patchwork of ageing severity.
The global expression of skin ageing exhibits so many different aspects that chronological ageing is often distinguished from photoageing because ultraviolet (UV) light exposure tremendously influences the process. However, this concept has been challenged because several other factors also alter the global ageing process. Accordingly, seven main influences have been distinguished [1, 2]. They are summarized in Table 1. In these respects, ageing is one single process (the chronological type) that is modulated by each of the six other influences.
Table 1. Types of cutaneous ageing
|Chronological||Passage of time|
|Genetic||Genetics (premature ageing, phototype)|
|Photo-induced||Ultraviolet and infrared irradiations|
|Behavioural||Diet, tobacco, alcoholic abuse, drug addiction, etc.|
|Catabolic||Chronic intercurrent debilitating disease (infections, cancers)|
|Endocrine||Dysfunction or ageing of hormonal systems (ovaries, testes, thyroid, pituitary gland, adrenal glands)|
According to this classification, hormones play an important role in the ageing process. Indeed, the skin is recognized as a hormone-dependent organ . In this review, we report metabolic effects of physiological amounts of hormones on the skin, as well as the intrinsic neuroendocrine activity of the skin. In addition, like any other system in the body, the ageing process affecting the hormonal functions basically results in deteriorations expressed by hormone deficiencies which in turn can influence the ageing machinery operative in the skin. Quite distinct are the skin manifestations of some endocrinopathies which may mimick or interfere with skin ageing [4, 5].
Skin as a target for hormones and neuroendocrine signals
The endocrine and neuroendocrine signals affecting the skin are numerous . The main receptors are listed in Table 2.
Table 2. Neuroendocrine receptors active in the skin
| 1.||Adrenergic receptors|
| 2.||Androgen and oestrogen receptors|
| 3.||Calcitonin gene-related peptide receptor|
| 4.||Cholinergic receptors|
| 5.||Corticotropin releasing hormone and urocortin receptors|
| 6.||Glucocorticoid and mineralocorticoid receptors|
| 7.||Glutamate receptors|
| 8.||Growth hormone receptor|
| 9.||Histamine receptors|
|11.||Miscellaneous neuropeptide receptors|
|16.||Parathormone and PTH-related protein receptors|
|17.||PRL and LH-CG receptors|
|19.||Thyroid hormone receptors|
|20.||Vasoactive intestinal peptide receptor|
|21.||Vitamin D receptor|
Skin as a source of hormones and neurotransmitters
Some hormones and neurotransmitters are synthesized by nerves, as well as by epithelial and dermal cells in the skin . They are listed in Table 3.
Table 3. Hormones and neurotransmitters produced by the skin
|1.||Hypothalamic and pituitary hormones|
|2.||Neuropeptides and neurotrophins|
|4.||Other steroid hormones|
|6.||Sex steroid hormones|
Regulation of the cutaneous neuroendocrine system
A number of environmental and intrinsic factors regulate the level of cutaneous neuroendocrine system activity. Solar radiation, particularly the spectrum of UVA and UVB, is the most prominent environmental factor affecting the skin [6, 7]. Temperature, humidity, as well as diverse chemicals and biological xenobiotics represent other important factors. Some internal mechanisms affecting the neuroendocrine system of the skin may be generated in reaction to some environmental signals or result from local biological rhythms, or from local or general disease processes [3, 8].
The most important endocrine compound produced by the skin is vitamin D, which is a regulator of the calcium metabolism and exhibits other systemic effects as well. For example, epidemiological evidence suggests that sunlight deprivation with associated reduction in the circulating levels of vitamin D3 may result in increased incidence of carcinomas of the breast, colon and prostate . Vitamin D3 and its analogues also modulate the biology of keratinocytes and melanocytes of the skin in vivo .
Ageing of the endocrine system
All endocrine glands are affected by the global ageing process. A few direct consequences interfere with some aspects of skin ageing. They are mostly related to the declined activity of the pituitary gland, adrenal glands, ovaries and testes.
Growth hormone (GH) is secreted by the pituitary gland under the control of several hypothalamic and peripheral modulators that exert either positive or negative influences. The final balance among the modulating factors determines the pulsatile and circadian secretion of GH. Moreover, physiological changes occurring in particular conditions (i.e. puberty, pregnancy, ageing and severe acute illness) affect the GH secretion. The peripheral effects of GH are mainly exerted by insulin-like growth factor (IGF), produced by the liver upon GH stimulation. The circulating IGF-1 is bioavailable and functionally active depending upon its binding with the IGF-binding proteins (IGF-Bps).
The skin is a target of the GH–IGF system, that exerts a significant influence on the dermal and epidermal physiology . GH, IGF-1, IGF-2 and IGF-Bps are present in the skin and are involved in its physiological homeostasis, including the dermo-epidermal cross-talking. Thus, not only systemic but also paracrine and/or autocrine cutaneous activity of the GH–IGF system contributes to skin homeostasis [11–15]. GH supplementation induces skin changes [16–21], a part of which may correspond to some corrective effects on ageing skin .
The progressive decline in DHEA serum concentration with age, and conversely its supplementation have not demonstrated prominent effects on the skin , except on sebum production.
Both the climacteric period following menopause and the andropause decade may negatively affect the skin [24–26]. Hormone replacement therapy in post-menopausal women may limit these changes [26–30]. However, there is a limitation because it seems to exist with good and poor responders . Smoking habit may also interfere with the treatment result .
Ancillary effect of nutritional deficiency
The elderly often exist on a substandard diet, deficient in many of the nutrients thought to be essential to maintain health. Protein-containing foods such as meat and fish tend to be too expensive or troublesome to prepare. Dietary faddism, confusional states and forgetfulness are also responsible for an inadequate diet. These situations predispose to skin changes that often amplify the alterations induced by age-related hormone deficiencies.
If sufficient fresh fruit and/or vegetables are not eaten, vitamin C deficiency occurs leading to scurvy. In this disorder there is a defect in coagulation and resulting purpura, particularly in a punctate periforllicular pattern on the legs. In the elderly, iron deficiency is also common and may result in anaemia, generalized pruritus and some diffuse hair loss.
Many of the elderly are also deficient in zinc, and it has been suggested that this may be an important factor in preventing wound healing. Zinc supplementation, however, does not improve healing.
Essential fatty acid deficiency due to dietary faddism or deprivation in the elderly causes xerosis. This skin condition has many other origins  including vitamin A deficiency , climatic conditions , diabetes  and other endocrinopathies .
Endocrinopathies and the skin
Several endocrinopathies, through excess or deficiency of hormones, result in changes in cutaneous functions and structures leading to the acceleration of the skin ageing process [4, 5]. Diabetes mellitus and acromegaly are two typical examples [35–42]. However, all aspects of skin ageing are not boosted by these diseases. For instance, decreased skin wrinkling has been reported in association with diabetes .
Acromegaly results from a pathological excess in GH. The major signs of this disorder are those of bone overgrowth combined with dermal and subcutaneous tissue hypertrophy [35, 36, 39, 40]. The hands and feet become particularly enlarged and succulently thickened. The epidermal cells are enlarged and there is an increase in the rate of keratinocyte production. There is also an increased rate of sebum and sweat production. In some patients, skin pigmentation is increased. Conversely, reduction of dermal thickness, decreased skin elasticity and, less frequently, easy ulcerations have been described in growth hormone deficiency . In both pathological conditions, the normalization of altered circulating GH levels only determines a partial reversibility of the skin alterations .
In diabetes, a generalized abnormality of the small blood vessels is due to deposition of glycoprotein in the vessel walls. This condition results in narrowing of the lumina and decreased blood-flow through them. Xerosis of the lower legs is not rare . Skin stiffness and decreased joint mobility have been noted to occur more frequently in diabetics [37, 38, 42] and seem to be due to glycation of collagen and other macromolecules of the dermis.
Thyroid disorders have some impact on elderly skin. The epidermis appears quite responsive to thyroid hormones and this accounts for at least some of the changes noted clinically. The roughness and dryness of the skin in myxœdema and the smoothness in hyperthyroidism may be explained in this way [4, 5]. In hypothyroidism, the faint yellowish tinge to the skin is probably due to the deposition of carotene in the skin. There is also often a reddish blush high on the cheeks, giving the appropriately termed peaches and cream appearance. The skin looks dry and may be roughened and the hair tends to be coarse and thinner than normal in myxœdema. In thyrotoxicosis, the skin feels warm and moist because of the hyperdynamic circulation and increase in sweating. The hair is fine. In addition, some patients complain of persistent generalized itch. Onycholysis may occur in hyperthyroidism and a diffuse pigmentation is also seen in a few patients.
The adrenal glands may be subject to pathological changes resulting in hyperactivity (Cushing syndrome) or hypoactivity (Addison disease). In Cushing syndrome, the glucocorticoids in excess exhibit profound effects on both the epidermis and the dermis. They cause slowing of keratinocyte production, thinning of the epidermis and shrinking of individual keratinocytes. Glucocorticoids also thin the dermis owing to the metabolic inhibition on fibroblasts. The net result of glucocorticoid action is skin thinning closely resembling the effects of age. The livid facial appearance, especially marked on the cheeks, is due to the skin thinning at a site where the subpapillary venous plexus is nearer the surface than in most other body sites. Striae distensae are the results of loosening structure of the dermis at sites of maximal stress and appear to represent elastic fibre failure owing to the stress [44, 45]. These lesions are normally evident to some degree in adolescence and pregnant women, but are more prominent in Cushing syndrome. In addition, the skin looks thin and the subcutaneous veins are obvious, there is skin fragility to minor trauma and purpuric patches occur after trivial knocks.
Hyperpigmentation is the major skin manifestation of Addison disease. The melanoderma is generalized, but especially noticeable in areas that are normally not or only slightly pigmented, particularly the palmar creases and the oral mucosa.
Skin produces and reacts to hormones and neuroendocrine mediators. The physiological declines in hormone productions with age affect the skin physiology. Some endocrinopathies also interfere with the skin biology, and may influence its ageing machinery.