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PubMed2004

6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate, a steroid sulfatase inhibitor for the treatment of androgen- and estrogen-dependent diseases.

Steroid sulfatase (STS) offers a new target for the treatment of steroid hormone-dependent diseases, such as breast and prostate cancer and androgen-dependent skin diseases. We here characterize a novel non-estrogenic inhibitor of the enzyme, namely 6-[2-(adamantylidene)-hydroxybenzoxazole]-O-sulfamate (AHBS), with special attention to its potential use in the treatment of acne. The compound blocks STS activity in homogenates of human skin with IC(50)=16 nM. Following a single oral dose (5 mg/kg) in rats, the compound blocks STS in the skin by 95% at 8 h, followed by recovery of activity over 5 days. Following topical application to the skin, both in vitro and in vivo, AHBS passes through the stratum corneum leading to inhibition of STS activity in the dermal compartment with rapid onset and long duration. Topical application of AHBS to Göttingen minipigs for a period of 2 weeks does not induce symptoms of ichthyosis as seen in STS-deficient human subjects, but leads to a reduction of sebum secretion to the skin surface. Based on these data, clinical studies with AHBS in acne patients are warranted, in order to verify the hypothesis on the importance of the sulfatase pathway in androgen-dependent skin diseases.

Absorption↗
PubMed2004

Cultural evolution as a possible triggering or causative factor of common baldness.

Common baldness (alopecia) increasingly affects a higher number of individuals at earlier ages, independently of gender. One of the reasons could be lack of knowledge concerning its etiology. The human being has evolved to become a naked monkey, although there is no apparent reason to continue the evolutionary process up to becoming a bald monkey. According to this theory, common baldness is a degenerative process derived from certain inadequate cultural practices, such as excessive hair cutting or certain types of haircuts that prevent contact among hairs themselves and limit outside contact in ways that would alleviate balding. Blocking the flow of sebum towards the base of the hair follicle - and so interfering with the arrival of the stem cells to the dermal papilla with consequent hair miniaturization - ends up being the first negative physiological effect derived from certain cultural habits. As time goes by, other mechanisms become altered, which leads to a less and less reversibility of the process.

Alopecia↗
PubMed2004

Dependence of fetal hairs and sebaceous glands on fetal adrenal cortex and possible control from adrenal medulla.

Human fetal adrenal development is characterized by rapid growth, high steroidogenic activity, and a distinct morphology, including a unique cortical compartment known as the fetal zone. For most of gestation, the predominant fetal zone accounts for 80-90% of the cortical volume and is the primary site of growth and steroidogenesis, producing 100-200 mg/day of the androgenic steroid, dehydroepiandrosterone sulfate (DHEA-S). The physiological role of this zone during intrauterine life is not well understood. While the glands appear to be capable of DHEA-S synthesis early in gestation (8-10 weeks), we noticed that this event precedes the differentiation of hairs and sebaceous glands. Hairs begin to develop between 9 and 12 weeks and sebaceous glands between 13 and 15 weeks of gestation. Sebaceous glands form an oily secretion - sebum that mixes with desquamated epidermal cells to form vernix caseosa. Vernix caseosa protects the developing skin from constant exposure to amniotic fluid, and hairs helps to hold the vernix caseosa on the skin. We suggest therefore that the human fetal adrenal cortex produces DHEA-S beginning at around 8-10 weeks of gestation in sufficient quantities to influence the growth of hairs and sebaceous glands. Soon after birth, the fetal zone atrophies, and adrenal androgen production decreases to minimal levels. As a consequence, in concordance with the rapid decrease in adrenal androgen levels and in consistent with our hypothesis, fetal hairs are shed and sebaceous glands shrink to small structures. The mechanism that regulates fetal adrenal androgen production is a key unanswered problem in human adrenal biology. Since there exists a close relationship between epinephrine and DHEA-S levels during adrenarche which shows modulatory interactions between adrenal androgen production and adrenomedullary function, we suggest again that adrenomedullary function might play a role in the control of fetal adrenal androgen secretion.

Adrenal Cortex↗
PubMed2005

Melanocortin-5 receptor: a marker of human sebocyte differentiation.

Melanocortin receptors (MC1R-MC5R) and their ligands (melanocyte-stimulating hormone (MSH) and adrenocorticotrophin hormone (ACTH)) have been shown to influence physiological functions of cells and organs, including exocrine glands. Since relatively little is known about MC5R expression and function in the human sebaceous gland, we examined expression of MC5R by immunohistochemistry and RT-PCR in human sebaceous cells in vivo and in vitro. In human skin, MC5R was detected only in differentiating, lipid-laden sebaceous cells but not in basal, undifferentiated sebaceous cells. Similarly, in cultured human sebocytes MC5R was only detectable at the onset of differentiation and in fully differentiated cells displaying prominent lipid granules. The lipid profile of the cultured and differentiated human sebocytes was shown to be human sebum-specific using (14)C-acetate labeling and high performance thin layer chromatography. Our studies suggest that MC5R is a marker of human sebocyte differentiation.

Biomarkers↗
PubMed2005

The role of toll-like receptors in the pathophysiology of acne.

Acne vulgaris is a common cutaneous disorder of the pilosebaceous follicle, affecting more than 45 million people in the United States alone. The pathogenesis of acne is multifactorial, involving abnormal hyperkeratinization, increased sebum production, hormones, cutaneous microbes, and immunological mechanisms. Many of the immunological processes that contribute to the formation of acne lesions take place at the very site of disease, the skin. Skin is an important component of the innate immune system, providing both physical barriers and rapid cellular responses by keratinocytes, Langerhans cells, and other infiltrating inflammatory cells. In this review, we discuss the ability of the innate immune system to use Toll-like receptors (TLRs) to recognize microbial patterns and initiate immune responses in cutaneous disorders. Because TLRs are vital players in infectious and inflammatory diseases, they are potential therapeutic targets. Indeed, the ability of TLRs to combat disease already has been harnessed through the development of drugs that act as TLR agonists. A better understanding of TLRs will allow for the development of new therapeutic options for cutaneous inflammatory diseases such as acne.

Acne Vulgaris↗
PubMed2005

Implications for the role of diet in acne.

Within the dermatology community, a general consensus has emerged that diet is unrelated to the etiology of acne. Except for 2 poorly designed studies, now more than 30 years old, there are few objective data to support this notion. In contrast, a large body of evidence now exists showing how diet may directly or indirectly influence the following 5 proximate causes of acne: (1) increased proliferation of basal keratinocytes within the pilosebaceous duct, (2) incomplete separation of ductal corneocytes from one another via impairment of apoptosis and subsequent obstruction of the pilosebaceous duct, (3) androgen-mediated increases in sebum production, (4) colonization of the comedo by Propionibacterium acnes, and (5) inflammation both within and adjacent to the comedo. This article will provide a review of the currently available literature on the association between diet and acne vulgaris as well as a discussion of the physiologic principles that may underlie this association.

Acne Vulgaris↗
PubMed2006

[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.

Estrogen Replacement Therapy↗
PubMed2003

13-cis-retinoic acid competitively inhibits 3 alpha-hydroxysteroid oxidation by retinol dehydrogenase RoDH-4: a mechanism for its anti-androgenic effects in sebaceous glands?

Retinol dehydrogenase-4 (RoDH-4) converts retinol and 13-cis-retinol to corresponding aldehydes in human liver and skin in the presence of NAD(+). RoDH-4 also converts 3 alpha-androstanediol and androsterone into dihydrotestosterone and androstanedione, which may stimulate sebum secretion. This oxidative 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) activity of RoDH-4 is competitively inhibited by retinol and 13-cis-retinol. Here, we further examine the substrate specificity of RoDH-4 and the inhibition of its 3 alpha-HSD activity by retinoids. Recombinant RoDH-4 oxidized 3,4-didehydroretinol-a major form of vitamin A in the skin-to its corresponding aldehyde. 13-cis-retinoic acid (isotretinoin), 3,4-didehydroretinoic acid, and 3,4-didehydroretinol, but not all-trans-retinoic acid or the synthetic retinoids acitretin and adapalene, were potent competitive inhibitors of the oxidative 3 alpha-HSD activity of RoDH-4, i.e., reduced the formation of dihydrotestosterone and androstandione in vitro. Extrapolated to the in vivo situation, this effect might explain the unique sebosuppressive effect of isotretinoin when treating acne.

Alcohol Oxidoreductases↗
PubMed1991

Acne vulgaris. Pathogenesis and treatment.

Acne vulgaris is a multifactorial disease involving abnormalities in follicular keratinization, sebum production, proliferation of Propionibacterium acnes, and inflammation. Treatment is directed toward reversing these underlying pathogenic factors. Therapeutic options include topical comedolytics, topical and systemic antibiotics, hormonal manipulations, and oral retinoids.

Acne Vulgaris↗
PubMed1997

Stimulatory effect of progesterone and 5 beta-progesterone on lipid synthesis in hamster flank organs.

In order to study lipid synthesis in female hamster flank organs during the estrous cycle, glands were obtained from different animals during different phases of the cycle. Lipid metabolism of [U-14C]glucose was studied under in vitro conditions. The radioactive lipids formed, were extracted from the glands and quantified. An aliquot of the extract was submitted to TLC to isolate and identify the lipids formed. Lipid synthesis in the glands increased significantly during estrous compared with the diestrous phase, suggesting the influence of sex hormones on lipid metabolism in flank organs. The radioactive lipids isolated and identified were: phospholipids, cholesterol, glycerides, waxes, and cholesterol esters. The percentages of conversation from [U-14C]glucose to cholesterol esters were minor in extracts from glands of diestrous animals as compared to estrous and proestrous animals, whereas glycerides and waxes increased significantly in metestrous and diestrous animals. To verify and evaluate the role of estrogen and progesterone in lipid synthesis, three different groups of gonadectomized female hamsters were injected daily with estradiol, progesterone, and 5 alpha-progesterone. After treatments, glands were incubated with [U-14C]glucose to determine the incorporation of radioactive glucose into lipids under culture conditions. The radioactive lipids synthesized were subsequently extracted and identified. The results showed that estrogen had no effect on in vitro [U-14C]glucose incorporation into lipids by flank organs, compared to the vehicle, whereas progesterone and 5 alpha-progesterone increased radioactive lipid synthesis by the glands significantly (p < 0.05). The radioactive lipids isolated and identified from extracts of gonadectomized female hamster flank organs were: phospholipids, cholesterol, triglycerides, waxes, and cholesterol esters. Gonadectomy increased phospholipid synthesis and decreased that of monoglycerides, diglycerides, and waxes. The percentages of conversion from [U-14C]glucose to cholesterol esters were higher after progesterone and 5 alpha-progesterone treatments than in vehicle and estrogen-treatments. Our data indicate that progesterone and 5 alpha-progesterone-treatments increased the in vitro [U-14C]glucose incorporation into lipids in flank organs from gonadectomized female hamsters. Furthermore, the major lipid synthesized by glands under these stimuli were cholesterol fatty acids. Thus, progesterone and 5 alpha-progesterone alter the consistency of sebum from gonadectomized female glands.

Animals↗
PubMed2003

Defensins and acne.

Acne a disease of the pilosebaceous unit is characterised by hypercornification and hyperkeratosis of outer root sheath (ORS) and sebaceous duct and perilesional infiltrate. Lesions may be characterised as "non"-inflammatory versus inflammatory. Hypercornification of the distal ORS and the pilosebaceous duct in concert with increased sebum production and abnormalities of the microbial flora are considered to be major factors in the pathogenesis of acne vulgaris. However, the basic mechanisms involved in the development of inflammation during acne vulgaris remain unclear. We have investigated the expression patterns of two antimicrobial peptides, human beta-defensin 1 (hBD1) and human beta-defensin 2 (hBD2) in healthy human hair follicles as well as in peri- and intralesional skin of acne vulgaris lesions such as comedones, papules and pustules. Strong hBD1 and hBD2 immunoreactivity was found in all suprabasal layers of the epidermis, and all permanent compartments of the hair follicle including the distal ORS of the hair follicle and the pilosebaceous duct. Moreover, marked hBD1 and hBD2 expression was also detected in the hair follicle stem cell compartment. In contrast, the proximal follicle bulb which undergoes apoptotic regression and is also able to regenerate following injury did not express hBD1 or hBD2. The majority of acne biopsies displayed a marked upregulation of hBD2 IR in the lesional and perilesional epithelium; in particular in pustules, and a less marked upregulation of hBD1 IR. The upregulation of beta-defensins expression in acne vulgaris lesions when compared to controls suggests that beta-defensins may be involved in the pathogenesis of acne vulgaris.

Acne Vulgaris↗
PubMed1983

Estrous cycle modulation of the attraction to odors in female golden hamsters.

Receptive female Syrian hamsters were significantly attracted to the odors of other hamsters but not to odors obtained from certain foods. Estrous female attraction scores were larger in response to male Syrian flank gland sebum (SMFG) than to estrous hamster vaginal discharge (HVD) obtained from either Syrian (SHVD) or Turkish (THVD) hamsters. On Day 3 of their estrous cycle, nonreceptive Syrian hamsters were significantly attracted to food-related odors but not to the odors of other hamsters (SMFG, SHVD, or THVD).

Animals↗
PubMed1982

Changes in lipid metabolism during retinoid administration.

Administration of oral vitamin A and the synthetic retinoids to humans and experimental animals has been accompanied by changes in lipid metabolism. these changes include alterations in serum, liver, and skin surface lipids. While the immediate cause(s) of the serum and liver changes remain(s) obscure, the skin surface lipid alterations appear to be secondary to changes in sebum production. The most marked effect of retinoid feeding seen in clinical or animal studies is that of hypertriglyceridemia. The increased serum triglycerides are found primarily in the very low-density lipoprotein (VLDL) fraction of the blood and occur during both the fasted and fed state. In rats, oral all-trans-retinoic acid, 13-cis-retinoic acid, and natural vitamin A have resulted in hypertriglyceridemia, while in man, 13-cis-retinoic acid, etretinate, and natural vitamin A have been reported to elicit this response. Current studies using the rat indicate that elevated serum triglycerides may be secondary to both increased liver secretion and decreased extrahepatic breakdown. Ongoing work from our laboratory and the possible primary causes of the systemic lipid changes are discussed.

Animals↗
PubMed1986

Rational therapy for acne vulgaris: an update on topical treatment.

Acne vulgaris is a disorder of sebaceous follicles that usually begins at the time of the sharp increase in androgen production that occurs in adolescence. This disease is most prevalent among teenagers, but it does occur in patients in their twenties and thirties. Three major areas of pathophysiology have been identified in acne: hyperkeratinization and obstruction of sebaceous follicles, resulting from abnormal desquamation of follicular epithelium; an androgen-stimulated increase in the production of sebum; and proliferation of Propionibacterium acnes, which generates inflammation. Disruption of the preclinical precursor lesion known as the microcomedo produces inflammation, which leads to the pustules and papules of clinical disease and may eventually result in scarring. Rational therapy for acne should be directed at the three factors involved in the pathophysiology of the disease. Tretinoin (all-trans-retinoic acid) acts to normalize desquamation of follicular epithelium, promote drainage of comedones, and inhibit formation of new ones. Salicylic acid is also comedolytic, but to a much lesser degree. Benzoyl peroxide and topical or systemic antibiotics work by decreasing the follicular population of P. acnes, thus reducing inflammation. Direct injection of corticosteroids may be used to reduce large inflammatory lesions. Physical removal of comedones is also useful. Severe nodulocystic acne and other cases that fail to respond to these measures may be treated systemically with isotretinoin (13-cis-retinoic acid).

Acne Vulgaris↗
PubMed1987

Evolution of a strategy for the treatment of acne.

The management of skin disease may differ in different parts of the world, but in most countries, acne should be a most treatable disease. Acne therapy has not evolved in the most logical fashion, but this article reviews our demonstration of risk factors in the treatment of acne. Young patients, male patients, truncal acne, a marked seborrhea, and a low dose (500 mg/day or less) of tetracycline are factors associated with a poorer response and, when oral therapy is stopped, a greater relapse rate. One gram a day of tetracycline, given for 6 months, is the minimum course of oral therapy and should be given along with topical therapy. One of the most widely used topical treatments is benzoyl peroxide, and this presentation was given in honor of Dr. William Pace, who was possibly the first dermatologist to be aware of the benefit of benzoyl peroxide--a fact not adequately recorded in dermatologic history. A small number of patients do not respond well to conventional therapy, but alternative treatments should bring about a successful outcome. Alternative treatments include hormonal therapy (i.e., 2 mg cyproterone acetate plus 50 micrograms ethinyl estradiol; spironolactone, 100 mg twice daily; or isotretinoin, 1 mg/kg). The success of all these treatments bears some relationship to their effect in modulating the etiologic factors of acne: an enhanced sebum production, increased ductal cornification, abnormal bacterial colonization, and the production of inflammation. Isotretinoin is the most beneficial of all drug regimens, and this fact no doubt relates to its favorable effect on all etiologic factors.

Acne Vulgaris↗
PubMed1987

Drug-induced photo-onycholysis. Three subtypes identified in a study of 15 cases.

We have studied 15 patients with photo-onycholysis induced by tetracyclines, psoralens, or fluoroquinolones. Three distinct clinical subtypes of onycholysis were seen. Type I showed a half-moon-shaped separation that was concave distally. Type II had a circular notch opened distally and shaped as if the distal nail plate had acted as a convex lens. In type III the changes were located in the central part of the nail bed with no connection to the margins. Ultraviolet (UV) irradiation of normal fingernails with various wavelengths showed that 3% to 20% of the irradiation could penetrate the nail. The different patterns of photodamage might be caused by the nail acting as a lens. Less protection by lack of melanin and absence of sebum and stratum granulosum may favor penetration of UV irradiation and explain why the skin was not always affected.

Adult↗
PubMed2003

Lead-revealed lipid organization in human hair.

Human hair lipids form a complex mixture of composition close to that of sebum. Part of these lipids appears in an organized state that has been studied by diffraction techniques in the literature. Nevertheless, information on the structure of these lipids remains very scarce due to their low contribution to global hair diffraction pattern. Here we show that appropriate lead treatment considerably enhances organized lipid features observed by microbeam synchrotron radiation diffraction experiments. We attribute these features to the formation of lead soaps of free fatty acids. Specific orientation of hair "lipid crystals" in planes parallel to the hair axis is clearly demonstrated. Inclusion of these lipids in the bulk of the hair shaft is shown by diffraction experiments following removal of the cuticular outermost layer of hair. Moreover, microfluorescence and diffraction experiments are consistent with part of the lipids being present as calcium soaps in native hair. We therefore consider lead fixation as a powerful tool to evaluate the lipid organization in human hair for medical, environmental and archaeological purposes, including lead poisoning.

Calcium↗
PubMed2001

The influence of hormone replacement therapy on skin ageing: a pilot study.

OBJECTIVES: We studied the effect of hormonal treatment on skin ageing in menopausal women. METHODS: Twenty-four patients (45-68 years; mean age, 54.9 years) without hormone treatment for at least 6 months were included. Patients were assigned to three therapy groups: 1, oestrogen only (Estraderm TTS 50) (n=6); 2, transdermal oestrogen and progesterone (Estraderm TTS 50 and 0.4 mg progesterone vaginal suppository) (n=7); and 3, oral oestrogen and progesterone (2 mg Progynova and 0.4 mg progesterone vaginal suppository) (n=8). One group without therapy was included as a control group (n=3). Treatment was continued for 6 months. Three patients, one from group 2 and two from group 3, discontinued therapy before the study endpoint. The following skin parameters were measured at monthly intervals during treatment: skin surface lipids, epidermal skin hydration, skin elasticity and skin thickness. Concomitant clinical evaluation included a subjective clinical evaluation form, a patient questionnaire and laboratory tests for oestradiol, progesterone and follicle stimulating hormone. RESULTS: Mean levels of epidermal skin moisture, elasticity and skin thickness were improved at the end of treatment based on both subjective and objective evaluation in patients with hormone replacement therapy (HRT). Skin surface lipids were increased during combined HRT, which may reflect stimulatory effects of the progestagen component on sebaceous gland activity, while oestrogen alone has a sebum-suppressive action. In the HRT groups, the questionnaire for climacteric complaints demonstrated significant improvements, while laboratory tests showed increases in oestradiol and progesterone and decreases in FSH. CONCLUSIONS: HRT with the mentioned regimes significantly improved parameters of skin ageing.

Administration, Cutaneous↗