Hormonal therapy of intrinsic aging

Intrinsic skin aging represents the biological clock of the skin cells per se and reflects the reduction processes that are common in internal organs. The reduced secretion of the pituitary, adrenal glands, and the gonads contributes to characteristic aging-associated body and skin phenotypes as well as behavior patterns. Our knowledge of whether there is a direct or indirect connection between hormonal deficiency and skin aging still remains limited. In females, serum levels of 17β-estradiol, dehydroepiandrosterone, progesterone, growth hormone (GH), and its downstream hormone insulin-like growth factor I (IGF-I) are significantly decreased with increasing age. In males, serum levels of GH and IGF-I decrease significantly, whereas it can decrease in late age in a part of the population. Hormones have been shown to influence skin morphology and functions, skin permeability, wound healing, sebaceous lipogenesis, and the metabolism of skin cells. Prevention of skin aging by estrogen/progesterone replacement therapy is effective if administered early after menopause and influences intrinsically aged skin only. Vitamin D substitution and antioxidant treatment may also be beneficial. Replacement therapy with androgens, GH, IGF-I, progesterone, melatonin, cortisol, and thyroid hormones still remains controversial.     

Hormonal effects on skin aging

With aging, there is a decrease in the level of hormones, such as estrogen, testosterone, dehydroepiandrosterone sulfate, and growth hormone. The effect of this decrease on the skin has been poorly documented, although more data are available for estrogen than for other hormones. This article reviews the effect of decreasing hormone levels on the skin and the possible cutaneous benefits of hormone replacement therapy.     

Skin and menopause

Important changes related to declining level of several hormones occur during menopause: vasomotor instability, bone loss, anxiety, sexual dysfunction, skin aging... Our objective was a review of the literature concerning the histological and clinical changes seen in post menopausal skin, and also an analysis of the effect of hormonal replacement therapy in slowing down the aging process. Decline in progesterone increases the impact of androgen on the sebaceous glands and hair. Decreased estrogen slows down mitotic activity in the epidermal basal layer, reduces the synthesis of collagen and contributes to thickening of the dermo-epidermal junction. This hypoestrogenemia may be spontaneously attenuated by local synthesis of oestradiol in peripheral target tissues according to the intracrine process. This new hormonal pattern is associated with skin atrophy, hyperseborrhea, increased pilosity on the cheeks and upper lip, loss of scalp hair, increase in degeneration of elastic tissue, atrophy and dryness of the vaginal mucosa. Estrogen treatment in post menopausal women has been shown to increase collagen content, dermal thickness and elasticity. Biophysical properties are also significantly improved for the parameters reflecting hydration and sebum secretion. However, numerous side effects such as increased incidence of cancer and cardiovascular morbidity limit the use of this treatment. So non hormonal alternatives are proposed. Laser and lifting remain the most important options.     

Beneficial regulation of type I collagen and matrixmetalloproteinase-1 expression by estrogen, progesterone, and its combination in skin fibroblasts.

There is impaired wound healing and loss of type I collagen in skin aging, which can be improved by topical estrogen in vivo. The goal of this study was to determine the effects of estrogen, and progesterone and a combination of estrogen and progesterone as well, on the proliferation and the expression of type I collagen and matrixmetalloprotienase-1 (MMP-1, degrades collagen) in dermal fibroblasts (cells that synthesize collagen and MMP-1) in-vitro. Estrogen, progesterone, and its combination similarly and significantly inhibited cell proliferation and MMP-1 protein levels, and simultaneously stimulated type I collagen expression in the fibroblasts, indicating beneficial modulation.     

Different modes of hippocampal plasticity in response to estrogen in young and aged female rats

Estrogen regulates hippocampal dendritic spine density and synapse number in an N-methyl-D-aspartate (NMDA) receptor-dependent manner, and these effects may be of particular importance in the context of age-related changes in endocrine status. We investigated estrogen's effects on axospinous synapse density and the synaptic distribution of the NMDA receptor subunit, NR1, within the context of aging. Although estrogen induced an increase in axospinous synapse density in young animals, it did not alter the synaptic representation of NR1, in that the amount of NR1 per synapse was equivalent across groups. Estrogen replacement in aged female rats failed to increase axospinous synapse density; however, estrogen up-regulated synaptic NR1 compared with aged animals with no estrogen. Therefore, the young and aged hippocampi react differently to estrogen replacement, with the aged animals unable to mount a plasticity response generating additional synapses, yet responsive to estrogen with respect to additional NMDA receptor content per synapse. These findings have important implications for estrogen replacement therapy in the context of aging.     

A metabolic and functional overview of brain aging linked to neurological disorders

Close correlations have recently been shown among the late onset complications encountered in diabetes and aging linked to neurobiological disorders. Aging in females and males is considered as the end of natural protection against age related diseases like osteoporosis, coronary heart disease, diabetes, Alzheimer’s disease and Parkinson’s disease, dementia, cognitive dysfunction and hypernatremia. Beside the sex hormones other hormonal changes are also known to occur during aging and many common problems encountered in the aging process can be related to neuroendocrine phenomena. Diabetes mellitus is associated with moderate cognitive deficits and neurophysiologic and structural changes in the brain, a condition that may be referred to as diabetes encephalopathy; diabetes increases the risk of dementia especially in the elderly. The current view is that the diabetic brain features many symptoms that are best described as accelerated brain aging. This review presents and compares biochemical, physiological, electrophysiological, molecular, and pathological data from neuronal tissue of aging and hormone treated control and diabetic animals to arrive at the similarities among the two naturally occuring physiological conditions. Animal models can make a substantial contribution to understanding of the pathogenesis, which share many features with mechanism underlying brain aging. By studying the pathogenesis, targets for pharmacology can be identified, finally leading to delay or prevention of these complications. Antiaging strategies using hormone therapy, chemical and herbal compounds were carried out for reversal of aging effects. Neuronal markers have been presented in this review and similarities in changes were seen among the aging, diabetes and hormone treated (estrogen, DHEA and insulin) brains from these animals. A close correlation was observed in parameters like oxidative stress, enzyme changes, and pathological changes like lipofuscin accumulation in aging and diabetic brain.     

Transdermal estrogen replacement therapy and vasomotor response

Previous studies have shown that acute administration of estrogen improves endothelial function in postmenopausal women, but there has been little investigation of the chronic effects of transdermal estrogen replacement therapy. The present study assessed the effect of transdermal estrogen replacement therapy (0.025 mg / day for 4 weeks, the normally applied dosage in Japan) on flow-mediated endothelium-dependent vasodilation of the brachial artery (B-mode ultrasound) and forearm cutaneous blood flow (laser Doppler flowmetry), and plasma hormonal and lipid levels in 12 normolipidemic postmenopausal women. Neither resting vascular diameter, flow-mediated vasodilation, nor time to peak vasodilation, showed significant changes after the estrogen therapy. In contrast, resting forearm cutaneous blood flow decreased significantly after the estrogen therapy. The time to the peak reactive hyperemia in the forearm skin was slightly shortened, and the % change in reactive hyperemia decreased slightly after the therapy. These findings seemed to reflect the inhibition of hot-flush symptoms associated with vasomotor abnormalities in cutaneous tissue. The lack of improvement in flow-mediated vasodilation of the brachial artery despite the inhibitory effect on cutaneous vasomotor abnormalities may be related to the low plasma estradiol concentration obtained with the present transdermal therapy (42.4+/-15.2 pg / ml), a finding which supports the estrogen threshold hypothesis in hormone replacement therapy.     

老年瘙痒症病理机制研究进展

老年瘙痒症发生的病理机制尚未完全阐明。角质细胞间脂质成分改变、膜丝聚蛋白结构不完整、天然保湿因子水平降低、pH值变化及雌激素水平降低等均可导致皮肤屏障功能受损,并在皮肤瘙痒症的发病中起着重要作用。免疫衰老形成的炎性环境、神经的退行性改变与病理性损伤被认为是介导该病发生的自然病因。此外,一些系统性疾病(如慢性肾脏疾病、胆...     

The adverse effects of hormonal therapy

Estrogen therapy must be cycled with progestin therapy in women with intact uteri in order to prevent uterine cancer. However, these women cannot be expected to benefit (with regard to cardiovascular disease) from any estrogen-induced changes in the lipoprotein profile, as progestins will either negate or overwhelm any estrogen effects. However, such women will definitely benefit from estrogen's effects with regard to menopausal symptoms and bone loss. These clearly beneficial effects of estrogen-progestin therapy are not outweighed by any known risks. However, in women without uteri (approximately 30 per cent of women), unopposed estrogen therapy in the menopause may protect against cardiovascular disease, as well as have beneficial effects on bone metabolism and menopausal symptoms. In this special case, the beneficial effects of unopposed estrogen therapy clearly outweigh any known risk.     

The role of estrogen deficiency in skin ageing and wound healing

The links between hormonal signalling and lifespan have been well documented in a range of model organisms. For example, in C. elegans or D. melanogaster, lifespan can be modulated by ablating germline cells, or manipulating reproductive history or pregnenolone signalling. In mammalian systems, however, hormonal contribution to longevity is less well understood. With increasing age human steroid hormone profiles change substantially, particularly following menopause in women. This article reviews recent links between steroid sex hormones and ageing, with special emphasis on the skin and wound repair. Estrogen, which substantially decreases with advancing age in both males and females, protects against multiple aspects of cellular ageing in rodent models, including oxidative damage, telomere shortening and cellular senescence. Estrogen’s effects are particularly pronounced in the skin where cutaneous changes post-menopause are well documented, and can be partially reversed by classical Hormone Replacement Therapy (HRT). Our research shows that while chronological ageing has clear effects on skin wound healing, falling estrogen levels are the principle mediator of these effects. Thus, both HRT and topical estrogen replacement substantially accelerate healing in elderly humans, but are associated with unwanted deleterious effects, particularly cancer promotion. In fact, much current research effort is being invested in exploring the therapeutic potential of estrogen signalling manipulation to reverse age-associated pathology in peripheral tissues. In the case of the skin the differential targeting of estrogen receptors to promote healing in aged subjects is a real therapeutic possibility.     

Aging and substitutive hormonal therapy influence in regional and subcellular distribution of ERα in female rat brain

Estrogens are not only critical for sexual differentiation it is well-known for the role of 17β-estradiol (E2) in the adult brain modulating memory, learning, mood and acts as a neuroprotector. E2 exerts its actions through two classical receptors: estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). The distribution of both receptors changes from one brain area to another, E2 being able to modulate their expression. Among the classical features of aging in humans, we find cognitive impairment, dementia, memory loss, etc. As estrogen levels change with age, especially in females, it is important to know the effects of low E2 levels on ERα distribution; results from previous studies are controversial regarding this issue. In the present work, we have studied the effects of long-term E2 depletion as well as the ones of E2 treatment on ERα brain distribution of ovariectomized rats along aging in the diencephalon and in the telencephalon. We have found that ovariectomy causes downregulation and affects subcellular localization of ERα expression during aging, meanwhile prolonged estrogen treatment produces upregulation and overexpression of the receptor levels. Our results support the idea of the region-specific neuroprotection mechanisms mediated by estradiol.     

Treatment of the aging skin by dermatologic methods.

Adverse physiologic and biochemical changes in the aging skin are aggravated by unprotected, continuous or repeated exposure to the harmful rays of the sun. Waning hormonal activity contributes to these changes. The associated clinical entities are skin dryness, accentuation of facial lines and wrinkles, hyperpigmentation, and multiple benign or malignant growths. The skin should be protected by sunscreening and sunblocking agents. Overexposure to the sun must be avoided. Repeated applications of moisturizing creams, vegetable oils, and appropriate hormonal cosmetics may be helpful in hydrating the skin and thus improving its external appearance. Chemosurgery (peeling) and dermabrasion may reduce hyperpigmentation and fine facial lines and wrinkles. New growths can be removed by various surgical methods. Biopsy should be performed to determine the presence of a malignant lesion requiring additional x-ray therapy.     

Age-related changes in estrogen receptor beta in rat hypothalamus: a quantitative analysis

Although the estrogen receptor beta (ER beta) is a major target for actions of estrogen on the brain, little is known about its neural expression during aging, when levels and the mode of estrogen release undergo substantial changes. Therefore, in the present study we examined effects of aging and estrogen treatment on the number of cells expressing the ER beta in female rats. Two regions relevant to reproductive function were analyzed: the anteroventral periventricular nucleus (AVPV) and the principal nucleus of the bed nucleus of the stria terminalis (pBST). The numbers of ER beta-expressing cells were quantified using an unbiased stereological approach. Female rats were used at three ages [young (3-4 months), middle-aged (10-12 months), and old (24-26 months)], with or without estrogen replacement. Because the estrogen milieu impacts the function of neurotransmitter receptors such as the N-methyl-D-aspartate receptor in the brain, we also investigated the colocalization of ER beta and the obligatory N-methyl-D-aspartate receptor subunit, NR1. We observed a significant age-related decrease in ER beta cell number in the AVPV, but not the pBST. No significant effect of estrogen on ER beta cell number was detected in either brain region at any age. Approximately 10% and 3% of cells expressing ER beta also coexpressed NR1 in AVPV and pBST, respectively, and this did not differ with age or treatment. Taken together, our results demonstrate 1) there are age-related changes in ER beta cell number that are region specific; 2) this expression is not altered by estrogen replacement; and 3) a subset of ER beta-positive cells coexpresses NR1.     

The role of selective estrogen receptor modulators in the prevention and treatment of osteoporosis

Osteoporosis can affect almost everyone in the population, and although clinical outcome of fracture is manifested in late life, the disease process begins in the early postmenopausal years in women. The pharmacologic agents currently available for osteoporosis prevention and treatment act by inhibiting bone resorption, and include estrogen or hormone replacement therapy (estrogen with progestin), bisphosphonates, salmon calcitonin nasal spray, and selective estrogen receptor modulators (SERMs). Raloxifene is a benzothiophene SERM that has estrogen against effects in bone and on serum lipid metabolism and estrogen antagonist effects on breast and uterine tissue. This article summarizes the effects of these antiresorptive agents, as measured by changes in bone mineral density, biochemical markers of bone turnover, and incident fractures in postmenopausal osteoporosis.     

Photoaging as a consequence of natural and therapeutic ultraviolet irradiation—studies on PUVA-induced senescence-like growth arrest of human dermal fibroblasts

Premature aging of the skin is a prominent side effect of psoralen photoactivation, a therapy widely and successfully used for different skin disorders. Recently, we demonstrated that treatment of fibroblasts with 8-methoxypsoralen and ultraviolet A irradiation resulted in growth arrest with morphological and functional changes reminiscent of replicative senescence. In this minireview we will focus on the similarities between intrinsic and extrinsic aging and PUVA-induced senescence-like growth arrest both resulting in the loss of the structural integrity of the dermal connective tissue as a hallmark of intrinsic aging and photoaging (extrinsic aging) of the skin, and we will discuss the important role of oxidative stress related telomere attrition in the PUVA-induced phenotype of dermal fibroblasts.With the PUVA-induced growth arrest of fibroblasts a new model has been added to the growing number of in vitro models with longterm growth arrest upon exposure to sublethal stressors (i.e. hyperoxia, hydrogen peroxide, ethanol), which are characterized by morphological and functional changes common for cellular senescence. This model may be particularly suited for further studies addressing mechanisms of stress-induced senescence-like growth arrest in vitro and in vivo, since many dermatological patients are treated with PUVA allowing the analysis of putative stress-induced premature senescence in vivo.     

Photoaging as a consequence of natural and therapeutic ultraviolet irradiation--studies on PUVA-induced senescence-like growth arrest of human dermal fibroblasts

Premature aging of the skin is a prominent side effect of psoralen photoactivation, a therapy widely and successfully used for different skin disorders. Recently, we demonstrated that treatment of fibroblasts with 8-methoxypsoralen and ultraviolet A irradiation resulted in growth arrest with morphological and functional changes reminiscent of replicative senescence. In this minireview we will focus on the similarities between intrinsic and extrinsic aging and PUVA-induced senescence-like growth arrest both resulting in the loss of the structural integrity of the dermal connective tissue as a hallmark of intrinsic aging and photoaging (extrinsic aging) of the skin, and we will discuss the important role of oxidative stress related telomere attrition in the PUVA-induced phenotype of dermal fibroblasts. With the PUVA-induced growth arrest of fibroblasts a new model has been added to the growing number of in vitro models with longterm growth arrest upon exposure to sublethal stressors (i.e. hyperoxia, hydrogen peroxide, ethanol), which are characterized by morphological and functional changes common for cellular senescence. This model may be particularly suited for further studies addressing mechanisms of stress-induced senescence-like growth arrest in vitro and in vivo, since many dermatological patients are treated with PUVA allowing the analysis of putative stress-induced premature senescence in vivo.     

Demonstration of estrogen receptors in the skin

The occurrence of high affinity and limited capacity estrogen receptors in skin specimens was investigated and the concentrations of cytoplasmic and nuclear receptors were studied in 14 normal and 22 castrated women. The skin estrogen receptor levels were low in all cases examined, although they usually exceeded the limit value used for estrogen receptor levels in breast cancer tissue. The cytoplasmic and nuclear receptor concentrations in normal women varied from 2.4 to 9.0 and from 1.5 to 7.0 fmol/mg cytosol protein, respectively. The receptor was present as a very high affinity binding component (KD = 0.2-1.6x 10(-9)M). The estrogen receptor concentrations in the skin during estriol succinate and estriol valerate therapy were at roughly the same level as during the normal menstrual cycle. The patients who received no replacement therapy after castration displayed the lowest skin estrogen receptor levels. The share of nuclear receptors seemed to be smaller on average during the normal menstrual cycle and in castrated patients not given estrogen therapy than in women treated with estriol succinate or estradiol valerate.     

Age-related reduction in estrogen receptor-mediated mechanisms of vascular relaxation in female spontaneously hypertensive rats

Hypertension increases with aging, and changes in vascular estrogen receptors (ERs) may play a role in age-related hypertension in women. We tested whether age-related increases in blood pressure in female spontaneously hypertensive rats (SHRs) are associated with reduction in amount and/or vascular relaxation effects of estrogen and ER. Arterial pressure and plasma estradiol were measured in adult (12 weeks) and aging (16 months) female SHRs, and thoracic aorta was isolated for measurement of active stress, 45Ca2+ influx, and ERs. Arterial pressure was greater and plasma estradiol was less in aging females than in adult females. In aorta of adult females, Western blots revealed alpha- and beta-ERs that were slightly reduced in aging rats. In endothelium-intact vascular strips, phenylephrine (Phe; 10(-5) mol/L) caused greater active stress in aging rats (9.3+/-0.2) than in adult rats (6.2+/-0.3x10(4) N/m2). 17beta-estradiol (E2) caused relaxation of Phe contraction and stimulation of vascular nitrite/nitrate production, which was reduced in aging rats. In endothelium-denuded strips, E2 still caused relaxation of Phe contraction, which was smaller in aging rats than adult rats. KCl (51 mmol/L), which stimulates Ca2+ influx, produced greater active stress in aging rats (9.1+/-0.3) than in adult rats (5.9+/-0.2x10(4) N/m2). E2 caused relaxation of KCl contraction and inhibition of Phe- and KCl-induced 45Ca2+ influx, which were reduced in aging rats. Thus, aging in female SHR is associated with reduction in ER-mediated NO production from endothelial cells and decrease in inhibitory effects of estrogen on Ca2+ entry mechanisms of smooth muscle contraction. The age-related decrease in ER-mediated vascular relaxation may explain the increased vascular contraction and arterial pressure associated with aging in females.