Water is absolutely essential for the normal functioning of the skin and especially its outer layer, the stratum corneum (SC). Loss of water from the skin must be carefully regulated, a function dependent on the complex nature of the SC. The retention of water in the SC is dependent on two major components: (1) the presence of natural hygroscopic agents within the corneocytes (collectively referred to as natural moisturizing factor) and (2) the SC intercellular lipids orderly arranged to form a barrier to transepidermal water loss (TEWL). The water content of the SC is necessary for proper SC maturation and skin desquamation. Increased TEWL impairs enzymatic functions required for normal desquamation resulting in the visible appearance of dry, flaky skin. There have been recent discoveries regarding the complex mechanisms of skin hydration. In particular, it has been discovered that glycerol, a well-known cosmetic ingredient, exists in the SC as a natural endogenous humectant. Hyaluronan, which has been regarded mainly as dermal component, is found in the epidermis and is important for maintaining normal SC structure and epidermal barrier function. More importantly, the discovery of the existence of the water-transporting protein aquaporin-3 in the viable epidermis and the presence of tight junction structures at the junction between the stratum granulosum and SC have brought new insights into the mechanisms of skin water distribution and barrier function.

Estrogens have a profound influence on skin. The relative hypoestrogenism that accompanies menopause exacerbates the deleterious effects of both intrinsic and environmental aging. Estrogens clearly have a key role in skin aging homeostasis as evidenced by the accelerated decline in skin appearance seen in the perimenopausal years. Estrogens improve skin in many ways. Among these, they increase collagen content and skin thickness and improve skin moisture. However, despite the knowledge that estrogens have such important effects on skin, the cellular and subcellular sites and mechanisms of estrogen action are still poorly understood. Estrogen receptors (ERs) have been detected in skin, and recent studies suggest that estrogens exert their effect in skin through the same molecular pathways used in other non-reproductive tissues. Although systemic hormone replacement therapy (HRT) has been used for many years, recent trials have reported a significant increased risk of breast cancer and other pathologies with this treatment. This has led to reconsider the risks and benefits of HRT. For this reason, systemic HRT cannot be recommended today to treat skin aging. Currently, intensive research is conducted to develop new drugs called selective ER modulators (SERMs). These drugs exert mixed estrogenic and antiestrogenic effects depending on the tissue and cell type. One might expect in the future such a drug targeting specifically the skin without systemic side effects.

In this study, we investigated the effects of estradiol on the proliferation of neonatal keratinocytes, the expression of estrogen receptor isoforms, and the signaling mechanisms by which estradiol mediates cell growth. We demonstrate that estradiol binds neonatal keratinocytes with high affinity (Kd=5.2nM) and limited capacity (Bmax of 14.2fmol/mg of protein), confirming the presence of estrogen binding sites. Using specific antibodies, we demonstrate that keratinocytes express both estrogen receptor (ER)-alpha and ER-beta. At physiological concentrations, estradiol up-regulates the level of ER-alpha receptors in keratinocytes and induces keratinocyte proliferation. The proliferative effect of estradiol requires the availability of functional estrogen receptors, as it is abrogated by anti-estrogen administration. Estradiol effect on keratinocyte proliferation is most likely mediated in part by activation of a nongenomic, membrane-associated, signaling pathway involving activation of the extracellular signal regulated kinases 1 and 2 and in part by the genomic signaling pathway through activation of nuclear receptors.

Estrogens have a profound influence on skin. The relative hypoestrogenism that accompanies menopause exacerbates the deleterious effects of both intrinsic and environmental aging. Estrogens prevent skin aging. They increase skin thickness and improve skin moisture. Beneficial effects of hormone replacement therapy (HRT) on skin aging have been well documented, but HRT cannot obviously be recommended solely to treat skin aging in menopausal women. Topical estrogen application is highly effective and safe if used by a dermatologist with expertise in endocrinology. The question of whether estrogen alternatives such as phytoestrogens and selective estrogen receptor modulators are effective estrogens for the prevention of skin aging in postmenopausal women remains unanswered. However, preliminary data indicate that such treatment may be of benefit for skin aging treatment.