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Topical anti-androgenicity of a new 4-azasteroid in the hamster.

The topical anti-androgenic activity of L-651,580 (methyl 3-oxo-4-methyl-4-aza-5 alpha-androst-1-ene-17 beta-carboxylate) was established in a series of for experiments using castrated male hamsters. During each 21-day experiment, the animals received a daily subcutaneous injection of 40 micrograms testosterone propionate or 20 micrograms dihydrotestosterone propionate. Test compound in 25 microliters of gel was applied daily to the left flank organ. Compounds assayed included L-651,580, WIN 17,665 (17 alpha-propyltestosterone), and SH-434 (17 beta-hydroxy-1 alpha-methyl-17 alpha-propyl-5 alpha-androstan-3-one). Endpoints were flank organ area, sebaceous gland area, and prostate weight. Very similar results were obtained with L-651,580 and WIN 17,665. Daily doses of 0.25 mg or more of either compound usually produced a significant reduction in the areas of treated flank organs and sebaceous glands underlying treated flank organs. Neither compound caused significant changes in the area of the contralateral flank organs and sebaceous glands, which indicated they possess little or no systemic activity at topically effective treatment levels. In direct comparisons, SH-434 was less anti-androgenic than L-651,580 or WIN 17,665, although in one experiment, 0.5 mg/d of SH-434 significantly reduced the area of treated flank organs and sebaceous glands. Neither WIN 17,665 nor SH-434 caused a change in prostate weight; however, in one of four tests, a significant decrease was induced by the 0.5 mg/d level of L-651,580. The results of these experiments show that the topical anti-androgenicity of L-651,580 compares very favorably with that of WIN 17,665 and SH-434. They also indicate that the topical administration of effective dosage levels of L-651,580 causes few, if any, systemic effects.

Administration, Topical↗

Topical canrenoic acid. Quantification of the antiandrogenic activity in the hamster flank organ.

The topical antiandrogenic activity of potassium canrenoate (CAK), compared with that of spironolactone (SP), was assayed in vivo in female golden Syrian hamsters whose flank organs were stimulated by subcutaneous administration of testosterone propionate. Sebaceous glands and hair were measured by a computerized image analyzer. Pigmented spots, sebaceous gland areas, and the diameter of hairs of the treated flank organs were smaller in the groups that received CAK (1.6 mg/day) and SP (0.4 mg/day). The authors' results showed that CAK may act as a topical antiandrogen on the hamster flank organ when applied in concentrations four times greater than the minimal active dosage of SP. Potassium canrenoate may be a useful weak topical antiandrogen, and it could be used in androgen-related skin disorders involving both sebaceous glands and hair, especially in men. These concentrations could be verified by additional clinical investigations.

Administration, Topical↗

Contrasting expression patterns of CCAAT/enhancer-binding protein transcription factors in the hair follicle and at different stages of the hair growth cycle.

Hair follicles undergo repeated cycles of growth and regression, throughout the entire life of the organism. These dynamic changes require closely co-ordinated regulation of gene expression. The CCAAT/enhancer-binding proteins are a family of basic region/leucine zipper transcription factors that regulate gene transcription in various tissues. They have been implicated in epidermal differentiation and may therefore play an important role in the hair follicle. We have investigated the localization of four members of this family--CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153--in both human and murine hair follicles by immunohistochemistry. Furthermore, we examined CCAAT/enhancer-binding protein-alpha, -beta, and -delta immunoreactivity at different stages of the depilation-induced murine hair growth cycle. Distinct immunoreactivity patterns for CCAAT/enhancer-binding protein-alpha, -beta, and -delta, and Gadd153 were observed in the outer root sheath, sebaceous gland, dermal papilla, and connective tissue sheath of human anagen hair follicles. In murine follicles, CCAAT/enhancer-binding protein-alpha was expressed in the outer root sheath, sebaceous gland, and dermal papilla, whereas CCAAT/enhancer-binding protein-beta expression was confined to the matrix, sebaceous gland, and inner and outer root sheaths. Both CCAAT/enhancer-binding protein-alpha and -beta were upregulated during anagen, then downregulated in catagen follicles. In contrast, CCAAT/enhancer-binding protein-delta showed no hair cycle-dependent variation in immunoreactivity. These data suggests that the expression of CCAAT/enhancer-binding protein-alpha and -beta may, in turn, play a part in regulating hair cycle-dependent gene expression. Moreover, as CCAAT/enhancer-binding protein-alpha, -beta, and -delta are crucial in the regulation of adipocyte differentiation and lipid metabolism, their expression in sebocytes suggests they may also play a similar role in differentiation and lipid metabolism of the sebaceous gland.

Animals↗

Toxicology and Carcinogenesis Studies of 4-Vinyl-1-cyclohexene Diepoxide (CAS No. 106-87-6) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

4-Vinyl-1-cyclohexene diepoxide is used a chemical intermediate and as a reactive diluent for diepoxides and epoxy resins. Toxicology and carcinogenesis studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide (97% pure) in acetone by dermal application to individually housed F344/N rats and B6C3F1 mice for 14 days, 13 weeks, 15 months, and 2 years. Additional studies included evaluation of immune function after a 5-day dermal exposure and evaluation of the oral toxicity of 4-vinyl-1-cyclohexene diepoxide in 16-day and 13-week corn oil gavage studies. Genetic toxicology studies were conducted in Salmonella typhimurium, mouse L5178Y lymphoma cells, and Chinese hamster ovary (CHO) cells. Fourteen-Day Dermal Studies: In the 14-day studies, all rats that received 924 mg/kg or higher (equivalent to 139 mg/rat or higher for males and 112 mg/rat of higher for females) died before the end of the studies. Final mean body weights were lower than those of vehicle controls in males receiving 68 mg/rat and in females receiving 57 mg/rat. Excoriations on the skin at the application site were observed in the groups receiving 57 mg/rat or more. Males receiving 139 mg/rat and females receiving 112 mg/rat had congestion and/or hypoplasia of the bone marrow; most had acute nephrosis. Skin lesions, including epidermal necrosis and ulceration, epidermal hyperplasia, and hyperkeratosis, were found in the 139 and 112 mg/rat group; similar lesions of lesser severity were seen in the two lowest dose groups of each sex. All mice that received 1,787 mg/kg (equivalent to 43/mouse for males and 37 mg/mouse for females) and 3/5 male mice and 5/5 female mice that received 889 mg/kg (equivalent to 19-21 mg/mouse) died before the end of the 14-day dermal studies. Final mean body weights of exposed and vehicle control mice were generally similar. Lesions of the skin at the site of application were seen in 4/5 males and 4/5 females receiving 5 mg/mouse and all mice receiving 10 and 21 (males) or 19 (females) mg/mouse and included epidermal and sebaceous gland hyperplasia, hyperkeratosis, and ulceration. Thirteen-Week Studies: In the 13-week dermal studies, all rats survived to the end of the studies (doses up to 60 mg/rat). The final mean body weights of the 60 mg/rat groups were 9%-14% lower than those of the vehicle controls. Compound-related clinical signs in the 60 mg/rat groups observed during the second half of the studies included redness, scabs, and ulceration at the application site and burrowing behavior after dermal application. Hyperplasia of the sebaceous glands and acanthosis (hyperplasia) and hyperkeratosis of the squamous epithelium were seen at the site of application. In mice, no compound-related deaths occurred after applications of up to 10 mg/mouse in 13-week dermal studies, and final mean body weights of exposed and vehicle control mice were similar. Relative liver and kidney weights increased with dose. Compound-related lesions of the skin included sebaceous gland hyperplasia and acanthosis (hyperplasia) and hyperkeratosis of the stratified squamous epithelium at the site of application; ovarian atrophy was also considered to be compound related. In the 13-week oral studies, the major target organ of toxicity in rats and mice was the forestomach, as indicated by hyperkeratosis and hyperplasia of the stratified squamous epithelium. In female mice, ovarian atrophy was seen in 4-vinyl-1-cyclohexene diepoxide-dosed groups. Two-year studies were conducted by administering 4-vinyl-1-cyclohexene diepoxide in acetone by dermal application, 5 days per week for 105 weeks to groups of 60 rats of each sex at 0, 15, or 30 mg/animal. Groups of 60 mice of each sex were administered 0, 2.5, 5, or 10 mg/animal on the same schedule for 103 weeks. None of the doses selected had produced ulceration of skin in 13-week studies. Ten animals from each group were killed and examined during month 15 for toxicologic evaluation. Immune Function Studies: The immunotoxic effects of 4-vinyl-1-cyclohexene diepoxide were studied in male B6C3F1 mice in male B6C3F1 mice after a 5-day dermal exposure at doses ranging from 2.5 to 10 mg/mouse per day. 4-Vinyl-1-cyclohexene diepoxide was immunosuppressive at 10 mg/mouse and, to a lesser extent, at 5 mg/mouse, as indicated by a decrease in peripheral lymphocytes and the in vitro lymphoproliferative response to phytohemagglutinin and concanavalin A in the high dose group and suppression of the antibody plaque-forming-cell response in the 5 and 10 mg/mouse groups. Fifteen-Month Evaluation: Two of 10 male rats that received 30 mg had a squamous cell carcinoma of the skin at or adjacent to the site of application. Acanthosis was seen in exposed rats (mild severity at 30 mg/rat and minimal severity at 15 mg/rat); hyperkeratosis was observed for rats in the 30 mg/rat groups. Compound-related nonneoplastic skin lesions in mice included acanthosis, hyperkeratosis, and sebaceous gland hyperplasia/hypertrophy. Squamous cell papillomas and carcinomas were seen in mice that received 5 or 10 mg/mouse; none was seen in vehicle control or low dose groups (papillomas--male: mid dose, 1/10; high dose, 2/10; female: 1/10; 1/10; carcinomas-- male: 2/10; 8/10; female: 2/10; 5/10). One vehicle control and all exposed female mice had atrophy of the ovary. Hyperplasia of the ovarian surface epithelium was seen in 8/10 females receiving 5 mg/mouse and 9/9 females receiving 10 mg/mouse. Two of nine females receiving 10 mg/mouse had granulosa cell tumors of the ovary, and 1/9 females receiving 10 mg/mouse had an ovarian papillary cystadenoma. Body Weights and Survival in the Two-Year Studies: In general, the body weights and survival were lower in mid and high dose groups than in vehicle controls. The survival was lower in exposed groups, primarily because of neoplasms (survival at week 105--male rats: vehicle control, 7/50; low dose, 8/50; high dose, 4/50; female rats: 27/50; 23/50; 15/50; male mice: vehicle control, 38/50; low dose, 35/50; mid dose, 4/50; high dose, 0/50; female mice: 30/50; 31/50; 15/50; 0/50). All high dose male mice died by week 83; the 10 surviving high dose female mice were killed during week 85. Nonneoplastic and Neoplastic Effects in the Two-Year Studies: Acanthosis and sebaceous gland hypertrophy of skin from the scapula or back were observed at substantially increased incidences in exposed male and female rats. Squamous cell papillomas in male rats and squamous cell carcinomas in male and female rats were observed only in exposed rats (squamous cell carcinomas--male: vehicle control, 0/50; low dose, 33/50; high dose, 36/50; female: 0/50; 16/50; 34/50). The incidences of basal cell adenomas or carcinomas (combined) were increased (male: 0/50; 1/50; 6/50; female: 0/50; 3/50; 4/50). For exposed mice, acanthosis, hyperkeratosis, and necrotizing inflammation of the skin were observed over the scapula or back. Squamous cell carcinomas were found only in exposed mice (male: vehicle control, 0/50; low dose, 14/50; mid dose, 39/50; high dose, 42/50; female: 0/50; 6/50; 37/50; 41/50). Follicular atrophy and tubular hyperplasia of the ovary in female mice were increased (atrophy: 12/50; 43/49; 47/50; tubular hyperplasia: 5/50; 35/49; 38/49; 34/50). Mid and high dose females had benign or malignant granulosa cell tumors (0/50; 0/49; 7/49; 12/50) and benign mixed tumors (0/50; 0/49; 11/49; 6/50). The combined incidences of luteomas, granulosa cell tumors, benign mixed tumors, or malignant granulosa cell tumors in mid and high dose female mice were increased (1/50; 0/49; 17/49; 18/50). The incidences of alveolar/bronchiolar adenomas or carcinomas (combined) in exposed female mice were marginally increased (4/50; 9/50; 11/50; 7/50). Genetic Toxicology: 4-Vinyl-1-cyclohexene diepoxide was mutagenic in S. typhimurium strains TA98, TA100, and TA1535 with and without exogenous metabolic activation; the compound was equivocally mutagenic in strain TA1537 without S9 but gave a positive response in the presence of activation. 4-Vinyl-1-cyclohexene diepoxide induced resistance to trifluorothymidine in mouse L5178Y/TK cells without exogenous metabolic activation; it was not tested with activation. 4-Vinyl-1-cyclohexene diepoxide induced sister chromatid exchanges and chromosomal aberrations in CHO cells in the presence and absence of exogenous metabolic activation. Conclusions: Under the conditions of these 2-year dermal studies, there was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female F344/N rats, as shown by squamous cell and basal cell neoplasms of the skin. There was clear evidence of carcinogenic activity of 4-vinyl-1-cyclohexene diepoxide for male and female B6C3F1 mice, as shown by squamous cell carcinomas of the skin in males and squamous cell carcinomas of the skin and ovarian neoplasms in females; increased incidences of lung neoplasms in females may also have been related to chemical application. Synonyms: 4-vinylcyclohexene diepoxide; 4-vinyl-1,2-cyclohexene diepoxide; 1-vinyl-3-cyclohexene diepoxide; 4-vinylcyclohexene dioxide; 1,2-epoxy-4-(epoxyethyl) cyclohexane; 1-epoxyethyl-3,4-epoxycyclohexane

Journal Article↗

Effect of 13-cis-retinoic acid on the hamster flank organ.

Administration of 13-cis-retinoic acid subcutaneously to mature male hamsters produced a marked decrease in the size of the sebaceous glands of the flank organ, without diminution of other hormonally dependent structures of the flank organs. Subcutaneous administration of 13-cis-retinoic acid to female hamsters treated simultaneously with injections of testosterone enanthate prevented the androgen-induced growth of the flank organ sebaceous glands but did not prevent the growth of other hormonally dependent structures such as the dermal pigment cells and large pigmented hair follicles. The sebaceous gland progressively decreased during 3 weeks of treatment and the effect persisted at least 3 weeks after cessation of treatment but was completely reversed by 6 mos after treatment. In vitro studies of testosterone metabolism by hamster flank organ indicated the lack of inhibition of 5 alpha-reduction by 13-cis-retinoic acid. It seems likely that systemically administered 13-cis-retinoic acid, unlike antiandrogens, exerts a specific extrahormonal effect on the sebaceous glands of the hamster flank organ without affecting other androgen dependent cells.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

Further aspects of the general antimicrobial properties of pinniped skin secretions.

In 2 pinniped species with varying hair densities (the northern fur seal Callorhinus ursinus, and the common seal Phoca vitulina), the enzyme lysozyme and the peptide group beta-defensins are demonstrated for the first time as products of the apocrine glands and the sebaceous glands in the common integument of mammals. These antimicrobial substances are also found in the epithelial lining of the hair follicles, between the corneal lamellae of the epidermis, and in dermal histiocytes. Thus, it becomes obvious that another general defense mechanism against microbes, in addition to free sugars (Meyer et al. [2000] Aspects of general properties of skin secretions in the common seal Phoca vitulina. Dis Aquat Org 41:77-79), is active on the skin surface of haired marine mammals to which glandular lysozyme and defensins are regularly transported, so that this biotope is protected against the proliferation of potential pathogens, e.g. bacteria and fungi.

Animals↗

[Normal and pathologic sebaceous function. Research in a shallow milieu?].

Modern therapeutic approaches allow to control sebaceous secretion but knowledge about the sebaceous gland and its precise function within the pilosebaceous unit is still insufficient. Steroid hormones are the principal albeit not exclusive regulators of the sebaceous glands. Three phases may be distinguished in sebaceous physiology: secretion-production, stocking in the follicular reservoir, and excretion. Human "native" intracellular sebum, before secretion, is composed of squalene, waxes, and triglycerides. Once secreted, the sebum is colonised by various xenobiots whose development is controlled by several defensive humoral mechanisms and by the contact with ambient oxygen. Oxygen and micro-organisms transform "native" sebum, lysis of triglycerides to fatty acids being the most pronounced activity. Certain components of this complex mixture of molecules present in the sebum are clearly cytotoxic or irritant, provoking reactive follicular hyperkeratosis and comedone formation--the first step to acne. Some lipophilic organisms like Malassezia yeast may be highly antigenic and induce chronic inflammatory reactions like in seborrhoeic dermatitis. Demodex is an inrafollicular parasite feeding on sebum that frequently causes blepharitis. Sebum is also a vehicle transporting and transmitting several endogenous and exogenous molecules, including potential regulatory factors of hair follicles. Recent development of in vitro cultures of functional sebocytes should help to better understand several aspects of the sebaceous gland's biology.

Acne Vulgaris↗

The distribution of estrogen receptor beta is distinct to that of estrogen receptor alpha and the androgen receptor in human skin and the pilosebaceous unit.

Both estrogens and androgens play important parts in skin and hair physiology, although studies of estrogen action in human skin have been rather limited. Recently, a second estrogen receptor (beta) has been identified in many nonclassical target tissues, including androgen-dependent tissues. Therefore, we have revisited the role of estrogens in human skin and hair by comparing the pattern of expression by immunohistochemistry for both estrogen receptors (alpha and beta) and the androgen receptor. Immunolocalization of androgen receptors was only seen in hair follicle dermal papilla cells and the basal cells of the sebaceous gland. Little specific staining of estrogen receptor alpha was seen anywhere except the sebaceous gland. In contrast estrogen receptor beta was highly expressed in epidermis, blood vessels, and dermal fibroblasts, whereas in the hair follicle it was localized to nuclei of the outer root sheath, epithelial matrix, and dermal papilla cells. Serial sections also showed strong nuclear expression of estrogen receptor beta in the cells of the bulge, whereas neither estrogen receptor alpha or androgen receptor was expressed. In the sebaceous gland, estrogen receptor beta was expressed in both basal and partially differentiated sebocytes in a similar pattern to estrogen receptor alpha. There was no obvious difference in the expression of either estrogen receptor in male or female nonbalding scalp skin. The results of this immunohistochemical study propose that estrogen receptor beta and not estrogen receptor alpha is the main mediator of estrogen action in human skin and the hair follicle. Further studies with androgen-dependent skin are required to determine whether estrogen receptor beta has a regulatory role on androgen receptor expression in the hair follicle in parallel with its role in other androgen-dependent tissues.

Estrogen Receptor alpha↗

NTP Toxicology and Carcinogenesis Studies of Lauric Acid Diethanolamine Condensate (CAS NO. 120-40-1) in F344/N Rats and B6C3F1 Mice (Dermal Studies).

Lauric acid diethanolamine condensate is widely used in cosmetics, shampoos, soaps, and related consumer products, to which there is extensive human exposure. Because of the lack of information about potential risks associated with long-term exposure, lauric acid diethanolamine condensate, coconut oil acid diethanolamine condensate, and oleic acid diethanolamine condensate were selected as representative of the class of diethanolamides for evaluation of prechronic toxicity and carcinogenic potential. Male and female F344/N rats and B6C3F1 mice were exposed to lauric acid diethanolamine condensate dermally for 14 weeks or 2 years. Genetic toxicology studies were conducted in Salmonella typhimurium, L5178Y mouse lymphoma cells, cultured Chinese hamster ovary cells, and mouse peripheral blood erythrocytes. 14-WEEK STUDY IN RATS: Groups of 10 male and 10 female rats were admin istered 0, 25, 50, 100, 200, or 400 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 14 weeks. All animals survived until study termination. Final mean body weights and body weight gains of males receiving 200 or 400 mg/kg were significantly less than those of the vehicle control group. Irritation of the skin at the site of application was observed in males receiving 100 mg/kg or greater and in females receiving 200 or 400 mg/kg. Kidney weights of females administered 200 or 400 mg/kg were significantly greater than those of the vehicle control group. There were dose-dependent increases in the incidences of nonneoplastic lesions of the skin at the site of application, including epidermal and sebaceous gland hyperplasia, chronic inflammation, parakeratosis, and ulcer. 14-WEEK STUDY IN MICE: Groups of 10 male and 10 female mice were admin istered 0, 50, 100, 200, 400, or 800 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 14 weeks. All animals survived until the end of the study, and final mean body weights and body weight gains of dosed mice were generally similar to those of the vehicle control groups. Irritation of the skin at the site of application was observed in all males and females administered 400 or 800 mg/kg. The kidney weights of males receiving 100, 400, or 800 mg/kg and females receiving 800 mg/kg were significantly greater than those of the vehicle controls. Liver weights of females administered 200 mg/kg or greater were significantly greater than those of vehicle controls. Increased incidences of nonneoplastic lesions of the skin at the site of application, including epidermal and sebaceous gland hyperplasia, chronic inflammation, parakeratosis, and ulcer, were observed in males and females receiving 200 mg/kg or greater. 2-YEAR STUDY IN RATS: Groups of 50 male and 50 female rats were admin istered 0, 50, or 100 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 104 or 105 weeks. Survival and Body Weights There were no significant differences between vehicle control and dosed males or females in survival or mean body weights. Pathology Findings There were no chemical-related differences in neoplasm incidences. Dose-related increases occurred in the incidences of nonneoplastic lesions of the skin at the site of application, including epidermal and sebaceous gland hyperplasia, hyperkeratosis, chronic inflammation, parakeratosis, and ulcer. 2-YEAR STUDY IN MICE: Groups of 50 male and 50 female mice were admin istered 0, 100, or 200 mg lauric acid diethanolamine condensate/kg body weight in ethanol by dermal application for 105 or 106 weeks. Survival and Body Weights There were no significant differences in survival between vehicle control and dosed males or females. Mean body weights of females that received 200 mg/kg were less than those of the vehicle controls beginning at week 33. Pathology Findings The incidences of hepatocellular adenoma or carcinoma (combined) were significantly increased in dosed females compared to the vehicle controls, as was the incidence of hepatocellular adenoma in the 100 mg/kg female group. There were dose-related increases in the incidences of nonneoplastic lesions of the skin at the site of application, including epidermal and sebaceous gland hyperplasia, hyperkeratosis, chronic inflammation, and parakeratosis. Dosed males had greater incidences of thyroid gland follicular cell focal hyperplasia than did the vehicle controls. GENETIC TOXICOLOGY: Lauric acid diethanolamine condensate was not mutagenic in Salmonella typhimurium strain TA97, TA98, TA100, or TA1535, with or without S9 metabolic activation enzymes. No increase in the frequency of mutant colonies of L5178Y mouse lymphoma cells was noted after exposure to lauric acid diethanolamine condensate, with or without S9. In cytogenetic tests with cultured Chinese hamster ovary cells, lauric acid diethanolamine condensate was shown to induce sister chromatid exchanges, but not chromosomal aberrations, with and without S9. In vivo, no increase in the frequency of micro nucleated normochromatic erythrocytes was observed in peripheral blood samples from male and female mice treated dermally with lauric acid diethanolamine condensate for 14 weeks. CONCLUSIONS: Under the conditions of these 2-year dermal studies, there was no evidence of carcinogenic activity of lauric acid diethanolamine condensate in male or female F344/N rats administered 50 or 100 mg/kg or in male B6C3F1 mice administered 100 or 200 mg/kg. There was some evidence of carcinogenic activity in female B6C3F1 mice based on increased incidences of hepatocellular neoplasms. These increases were associated with free diethanolamine, which was present as a contaminant of lauric acid diethanolamine condensate. Dermal administration of lauric acid diethanolamine condensate to rats and mice for 2 years resulted in increased incidences of epidermal and sebaceous gland hyperplasia, hyperkeratosis, chronic inflammation, and parakeratosis at the site of application. Lauric acid diethanolamine condensate administration also resulted in increased incidences of thyroid gland follicular cell hyperplasia in dosed male mice. Synonyms: N,N-bis(2-hydroxyethyl) dodecanamide; N,N-bis(hydroxyethyl) lauramide; N,N-bis(b-hydroxyethyl) lauramide; bis(2-hydroxyethyl) lauramide; coco diethanolamide; coconut oil amide of diethanolamine; diethanollauramide; N,N-diethanollauramide; N,N-diethanollauric acid amide; lauramide DEA; lauric diethanolamide; lauroyl diethanolamide; lauryl diethanolamide; LDA; LDE Trade names: Clindrol 200 L; Ninol AA62; Onyxol 345; Rewomid DLMS; Rewomid DL 203/S; Richamide 6310; Rolamid CD; Standamidd LD; Steinamid DL 203 S; Super amide L-9A; Super amide L-9C; Synotol L-60; Unamide J-56; Varamid ML 1.

Journal Article↗

Targeting of sebocytes by aminolevulinic acid-dependent photosensitization.

Photodynamic therapy using 5-aminolevulinic acid-induced protoporphyrin IX has been developed as a very useful therapeutic modality. Recently, several authors have reported on the efficacy of this procedure for acne. This approach is based on the fact that 5-aminolevulinic acid-induced protoporphyrin IX has strong selectivity for sebaceous glands. We used the immortalized human sebaceous gland cell line SZ95 to investigate cellular mechanisms of photodynamic therapy using 5-aminolevulinic acid-induced protoporphyrin IX. Quantification of induced protoporphyrin IX production showed dependence on the applied 5-aminolevulinic acid dose. When SZ95 sebocytes were differentiated by arachidonic acid treatment, there was no difference between them and the control cells with respect to both the amount of 5-aminolevulinic acid-induced protoporphyrin IX and the phototoxic effects. We altered protoporphyrin IX formation rates by growing cells scattered as single cells in the culture dishes. Single cells produced significantly lower protoporphyrin IX levels than those grown with intercellular contacts. Intracellular localization of protoporphyrin IX was imaged using confocal laser scanning microscopy. The differentiation-specific lipid droplets were virtually excluded from protoporphyrin IX fluorescence. In addition to weak mitochondrial and strong membrane fluorescence, distinctive spots with strong fluorescence were observed. These did not colocalize with fluorescent probes for mitochondria, lysosomes or the Golgi apparati.

Aminolevulinic Acid↗

Androgen-induced delay of hair growth in the golden Syrian hamster.

The golden Syrian hamster flank organ has been used to study the stimulatory effect of androgens on sebaceous glands and hair. Androgens cause the sebaceous glands and hair follicles in this organ to grow. We have made the novel observation that exogenously administered androgen, testosterone propionate (TP), suppresses hair growth in the area surrounding the flank organ. When given in a time-release (systemic) subcutaneous dosage form (pellet), 25 mg TP inhibited the regrowth of clipped hair in peri-flank organ skin for up to 21 days; however, by 28 days hair grew back to the same extent as in controls. The peak serum level of testosterone in TP-treated animals occurred at 14 days, and declined thereafter. When two separate TP pellets (25 mg/pellet) were administered 14 days apart in order to maintain high serum levels for 28 days, the amount of hair regrowth after 35 days was identical to animals receiving a single TP pellet or placebo. This suggests that the systemic level of testosterone was not the only factor in hair regulation. Hair growing within the flank organ appeared to be unaffected by TP administration. In the golden Syrian hamster, androgen, as in humans, can exert stimulatory and inhibitory effects on hair growth depending on the body site. We conclude that this animal model could serve as a useful system to investigate the mechanisms responsible for the opposing effects of androgen on hair growth.

Analysis of Variance↗

Sebaceous lymphadenocarcinoma of parotid gland.

The sebaceous lymphadenocarcinoma of the salivary glands is extremely rare and represents carcinomatous transformation of sebaceous lymphadenoma. There are only four reported patients in the medical literature. A patient who presented with a recent increase of a left infraauricular mass, of more than 10 years duration, underwent surgery. The microscopic examination revealed a typical sebaceous lymphadenoma with transition to a sebaceous adenocarcinoma. After postoperative adjuvant radiotherapy, the patient remains disease-free at 24 months postoperatively. We here report a fifth case of this tumor and the youngest age at diagnosis among reported cases.

Adenocarcinoma, Sebaceous↗

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.

Attenuated familial adenomatous polyposis and Muir-Torre syndrome linked to compound biallelic constitutional MYH gene mutations.Peculiar dermatologic manifestations are present in several heritable gastrointestinal disorders. Muir-Torre syndrome (MTS) is a genodermatosis whose peculiar feature is the presence of sebaceous gland tumors associated with visceral malignancies. We describe one patient in whom multiple sebaceous gland tumors were associated with early onset colon and thyroid cancers and attenuated polyposis coli. Her family history was positive for colonic adenomas. She had a daughter presenting with yellow papules in the forehead region developed in the late infancy. Skin and visceral neoplasms were tested for microsatellite instability and immunohistochemical status of mismatch repair (MMR), APC and MYH proteins. The proband colon and skin tumors were microsatellite stable and showed normal expression of MMR proteins. Cytoplasmic expression of MYH protein was revealed in colonic cancer cells. Compound heterozygosity due to biallelic mutations in MYH, R168H and 379delC, was identified in the proband. The 11-year-old daughter was carrier of the monoallelic constitutional mutation 379delC in the MYH gene; in the sister, the R168H MYH gene mutation was detected. This report presents an interesting case of association between MYH-associated polyposis and sebaceous gland tumors. These findings suggest that patients with MTS phenotype that include colonic polyposis should be screened for MYH gene mutations.

Adenomatous Polyposis Coli↗

Multiple follicular hamartomas with sweat gland and sebaceous differentiation, vermiculate atrophoderma, milia, hypotrichosis, and late development of multiple basal cell carcinomas.

We describe a 46-year-old woman with multiple symmetrical papulocystic lesions on the face, neck, chest, back, and upper arms since childhood. Vermiculate atrophoderma, entropion, and progressive loss of eyelashes was also noted. Since the age of 30, 12 basal cell carcinomas have developed on the face. Histopathologic examination revealed multiple anastomosing nests and strands that arose from the lower part of a hair follicle in early lesions. In more advanced lesions, multiple keratinizing microcysts within a moderately sclerotic stroma were noted in the upper and mid dermis. In some biopsy specimens, focal areas showing sweat gland (ductal) and sebaceous differentiation were also observed. Basal cell carcinomas developed from the basaloid component of the hamartomatous proliferation.

Atrophy↗

Malignant eyelid tumours in Taiwan.

AIMS: To describe the clinical characteristics of patients with eyelid cancers in Taiwan. METHODS: Between 1980 and 2000, 127 (58 males and 69 females) patients (mean age 62.6; range 10-91 years) with histologically confirmed eyelid cancers were retrospectively evaluated at the National Taiwan University Hospital and Far Eastern Memorial Hospital in Taiwan. Clinical data of all patients were reviewed from medical records. The mean follow-up period was 62.4 months (range 3-240) for 113 patients. RESULTS: The 127 eyelid cancers included 79 basal cell carcinomas (62.2%), 30 sebaceous gland carcinomas (23.6%), 11 squamous cell carcinomas (8.7%), five malignant melanomas (3.9%), one Kaposi's sarcoma (0.8%), and one metastatic cancer (0.8%). Tumours developed more commonly in the lower (37.0%) than the upper eyelid (33.9%). The clinical accuracy in predicting eyelid malignancy was 90.5%. Primary treatment modality was mainly surgical excision. The recurrence, metastasis, and mortality rates at 5 years were 15.2, 11.7, and 7.3%, respectively, for all eyelid malignancies. Rates of sebaceous gland carcinoma recurrence, metastasis, and mortality were significantly higher (P<0.05) than those of basal cell carcinoma. The mean interval of recurrence or metastasis after primary treatment was 26.3 months (range 4-112) for all eyelid cancers. CONCLUSIONS: Although basal cell carcinoma is the most common eyelid cancer in Taiwan, sebaceous gland carcinoma is also common. Of the two, basal cell carcinoma has a better prognosis and sebaceous gland carcinoma has a higher mortality and therefore should be treated much more aggressively. Long-term follow-up is needed after treatment of malignant eyelid tumours.

Adolescent↗

Ultrastructural localization of gap junction protein connexin 43 in normal human skin, basal cell carcinoma, and squamous cell carcinoma.

The expression and localization of connexin 43 (Cx43) were investigated in normal human epidermis, pilosebaceous apparatus, basal cell carcinoma, and squamous cell carcinoma by immunofluorescence as well as by immunoelectron microscopy. In the normal epidermis the immunofluorescence was weak in the basal layer, increased in spinous layer and negative in the horny layer. In the sebaceous gland, peripheral lobular cells showed weak cell membrane dotted pattern. Cell membrane and cytoplasmic fluorescence was strong in the central lobular cells. In the lower hair follicle, the cortex, inner and outer root sheath cells showed cell membrane fluorescence. As cortical cells underwent keratinization, they lost Cx43 epitopes. Basal cell carcinoma and squamous cell carcinoma were poorly stained, and eccrine and apocrine glands were unstained. In immunoelectron microscopy, close membrane appositions of typical gap junctions were often observed in the spinous layers of the epidermis and the immunolabeling for Cx43 was seen along the gap junction structures. Circular and long gap junctions often were found in follicular root sheaths and sebaceous glands. Gold particles labeling Cx43 in these gap junctions were found on the gap junctions or localized in the cytoplasm near the gap junction membranes. Basal cell carcinoma and squamous cell carcinoma had a small number of small gap junctions, and gold particles were not only localized to gap junctions but scattered in the cytoplasm. No gap junctions were labeled in eccrine and apocrine glands. These findings confirmed that 1) long, curved or circular membrane appositions found in hair follicle and sebaceous gland are true gap junctions, 2) immature cells such as epidermal basal cells, peripheral germinative cells of sebaceous gland and basal and squamous cell carcinoma cells do not have fully developed gap junctions, and 3) Cx43 or its precursors are present in the cytoplasm as well as on poorly developed gap junctions in these immature cells. Immunofluorescence findings generally corresponded to ultrastructural distribution and structural maturity of gap junctions.

Adult↗

[Effect of testosterone on the skin and its appendages].

The response of the target cells of the skin (sebaceous glands, hair follicles) to androgens is bound to the influence of different hormones. Pituitary hormones permit the action of testosterone on the sebaceous glands by influencing its conversion to 5 alpha-dihydrotestosterone. The sebaceous glands of the rat have proved a useful experimental model.

Acne Vulgaris↗