Isabelle Castiel

Androgen glucuronides, instead of testosterone, as the new markers of androgenic activity in women

Despite the long series of cohort studies performed during the last 20 years, the correlation between serum testosterone and any clinical situation believed to be under androgen control in women has remained elusive. This is likely related to the recent finding that the androgens made locally in large amounts in peripheral tissues from the precursor dehydroepiandrosterone (DHEA) act in the same cells where synthesis takes place and are not released in significant amounts in the circulation, thus making unreliable the measurement of serum testosterone as marker of total androgenic activity. The objective is to determine if serum androgen glucuronides can be replaced by testosterone or another steroid as measure of androgenic activity. Since the glucuronide derivatives of androgens are the obligatory route of elimination of all androgens, these metabolites were measured by liquid chromatography tandem mass spectrometry under basal conditions in 377 healthy postmenopausal women aged 55-65 years as well as in 47 premenopausal women aged 30-35 years while testosterone was assayed by gas chromatography mass spectrometry. No correlation was found between the serum concentration of testosterone and that of androsterone glucuronide (ADT-G) or androstenediol glucuronide (3alpha-diol-G), the androgen metabolites which account for the total pool of androgens. The present data show that measurement of the total pool of androgens reflected by the serum levels of ADT-G and 3alpha-diol-G cannot be replaced by serum testosterone or any other steroid, including DHEA or DHEA sulphate. These findings may have implications for women with androgen deficiency involving osteoporosis, obesity, type 2 diabetes, sexual dysfunction, loss of muscular strength and a series of other clinical situations affecting womens health. Measuring ADT-G and 3alpha-diol-G might identify cases of true androgen deficiency and provide an opportunity to offer appropriate androgen therapy.

Metabolism of DHEA in postmenopausal women following percutaneous administration

The marked decline in serum dehydroepiandrosterone (DHEA) with age is believed to play a role in health problems associated with aging, these health issues being potentially preventable or reversible by the exogenous administration of DHEA. In the present study, liquid chromatography/mass spectrometry/mass spectrometry (LC/MS/MS) and gas chromatrography/mass spectrometry (GC/MS) were used to measure the serum levels of DHEA and 11 of its metabolites in seventy-five 60-65-year-old Caucasian women who received 3g of 0.1%, 0.3%, 1.0% or 2.0% DHEA cream or placebo applied twice daily on the face, upper chest, arms and legs. The serum levels of DHEA increased 574% over control at the 2.0% DHEA dose while the sum of the androgen metabolites androsterone glucuronide (ADT-G), 3alpha-androstenediol-3G (3alpha-diol-3G) and 3alpha-diol-17G increased by only 231%. On the other hand, serum testosterone and dihydrosterone were increased by 192% and 275%, respectively, above basal levels compared to 139% and 158% for estrone and estradiol. Such data show that the transformation of exogenous DHEA in postmenopausal women is preferentially into androgens rather than into estrogens. On the other hand, the present data indicate that serum DHEA measurements following DHEA supplementation in postmenopausal women are an overestimate of the formation of active androgens and estrogens and suggest a decreased efficiency of transformation of DHEA into androgens and estrogens with aging.

Long-term expansion of human functional epidermal precursor cells: promotion of extensive amplification by low TGF-β1 concentrations

We have previously introduced the concept of high proliferative potential-quiescent (HPP-Q) cells to refer to primitive human hematopoietic progenitors, on which transforming growth factor-β1 (TGF-β1) exerts a pleiotropic effect. TGF-β1 confers to these slow-dividing cells a mitogenic receptorlow phenotype and maintains immature properties by preventing differentiation and apoptosis. However, the effect of TGF-β1 on long-term expansion has not yet been clearly demonstrated. Here, we describe the characterization of a human skin keratinocyte subpopulation, highly enriched for primitive epidermal precursors, on the basis of high adhesion capacity (Adh+++) and low expression of the epidermal growth factor receptor (Adh+++EGF-Rlow). In our standard culture condition without feeder cells, the mean estimated output for cells from an unfractionated population of primary foreskin keratinocytes was 107-108, increasing to 1012-1013 in cultures initiated with selected Adh+++EGF-Rlow precursors. Characterization of these cells revealed a hitherto unknown property of TGF-β1: its addition at a very low concentration (10 pg/ml) in long-term cultures induces a very significant additional increase of expansion. In this optimized system, outputs obtained in cultures initiated with Adh+++EGF-Rlow cells repeatedly reached 1016-1017 (∼60 population doublings, ∼4×1018 keratinocytes produced per clonogenic cell present in the initial population). At the molecular level, this effect is associated with an increase in Smad1, Smad2 and Smad3 phosphorylation and an increase in α6 and β1 integrin expression. No such effect could be observed on mature keratinocytes with low adhesion capacity (Adh-/+). We finally demonstrated that the progeny of Adh+++EGF-Rlow precursors after long-term expansion is still capable of generating a pluristratified epidermis in a model for skin reconstruction. In conclusion, after further characterizing the phenotype of primitive epidermal precursors, we demonstrated a new function of TGF-β1, which is to promote undifferentiated keratinocyte amplification.

Probiotics for Skin Benefits

Publisher Summary Probiotic, as defined by an expert committee, means “living microorganisms, which, when consumed in adequate amounts, confer a health effect on the host.” Specific strains of probiotic lactic acid bacteria have been shown to beneficially influence the composition and/or metabolic activity of the endogenous microbiota. Certain probiotic strains or specific bacterial lysates or extracts exert their effects beyond the gut or topically applied directly to the skin and confer benefits at the skin level. There is indeed emerging evidence that such probiotics alive or in extract forms can contribute to the reinforcement of skin barrier function and modulate the skin immune system, leading to the preservation of skin homeostasis. Probiotics can be consumed in various forms of fermented or nonfermented food products. Probiotics can be used as a component of functional foods. The most often used probiotic genera in humans and animals are enterococci, lactobacilli, and bifidobacteria, which are natural residents of the intestinal tract. Different human trials suggest that probiotic supplementation might be useful in the management of atopic dermatitis. Ingested probiotic bacteria can accelerate the recovery of cutaneous immune homeostasis after UV exposure in humans and may therefore play a role in UV-induced skin damage prevention and photoprotection. Another indication for which the probiotics could be beneficial is to improve reactive skin symptoms.

Bioavailability and Skin Bioefficacy of Vitamin C and E

Publisher Summary Skin is constantly exposed to pro-oxidant environmental stresses from an array of sources, such as air pollutants, solar UV light, chemical oxidants, micro-organisms, cigarette smoke, and ozone, which causes many changes in the skin. The most popular nutrients to alleviate skin changes such as aging, photosensitivity, and dryness are vitamins, carotenoids, polyphenols, and minerals. The blood continuously replenishes the skin with bioactives, which can then be distributed to all skin compartments, that is, epidermis, dermis, subcutaneous fat, and also sebum. This chapter presents the mechanisms involved in the bioavailability of nutrients such as vitamins C and E at the intestinal as well as at the skin level but also their bioefficacies in skin. Vitamin E has been shown to present an antioxidant property, and to play a role in photoprotection and in the prevention of aging, alone or in association with vitamin C. Literature on vitamin C for skin benefits is more abundant, showing evidence for the beneficial effect of this ingredient on dermal matrix formation, or epidermal differentiation, against UV-induced skin damage, and oxidative stress, indicating that vitamin C supplementation may be of interest to target skin aging, photoprotection, and skin xerosis. This chapter reviews current knowledge on the journey of dietary bioactives, that is, vitamin C and vitamin E from the mouth to skin, as well as their biological activities in the skin.

Probiotics and Skin Health

Certain probiotic strains alive exert their effects beyond the gut to the skin level and contribute to the reinforcement of the barrier function and the modulation of immune system.