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[The morphogenesis and functional control of sebaceous glands with reference to free sebaceous glands].

Not very much was known until now about the physiology of sebaceous glands--especially about the regulation of their function. The author divides primary stimuli for the function of sebaceous glands during lifetime from secondary stimuli for the common supply of sebum. Other primary stimuli are a hypophysial sebotropic factor and other hormones of the gonads and adrenal glands. Capillary attraction and the autonomous system (in a low degree) belong to the secondary stimuli. Following the opinion of renowned authors sebaceous glands and production of sebum are just a special secretoric function of the epidermis. The author voices the hypothesis that androgens can stimulate epidermal basal cells to form sebaceous glands and to produce sebum. This is only possible under certain circumstances, above all only in non-keratinised epidermis.

Androgens

Isolation of human sebaceous glands and cultivation of sebaceous gland-derived cells as an in vitro model.

An experimental technique is presented as an in vitro model for the study of human sebaceous gland-derived cells. Intact sebaceous glands were isolated from full-thickness human skin after incubation in dispase (2.4 U/ml) and in deoxyribonuclease (0.02%) by using microsurgical instruments under microscopical observation of the epidermal underface. Subsequently, the ducts of the glands were removed, the isolated gland lobules were seeded on a 3T3-cell feeder layer in Dulbecco's modified Eagle's medium and Ham's F 12 medium (3:1) supplemented with fetal calf serum (10%), L-glutamine, antibiotics, epidermal growth factor (10 ng/ml), hydrocortisone (0.4 microgram/ml), and cholera toxin (10(-9) M), and were then cultivated in a CO2-incubator at 37 degrees C. After 2-3 wk cell outgrowths resulting from the periphery of the gland lobules were obtained and dispersed cells were passaged for three subcultures with or without 3T3-cell feeder layer. The cultured cells preserved in vitro morphologic characteristics and differentiation patterns comparable to those described for normal human sebocytes in vivo, with a high rate of viable cells. Their labeling pattern with MoAb showed close similarities to the pattern reported for sebocytes in vivo but differences to the pattern of keratinocytes in vivo and in vitro. In their cytoplasm oil red and nile red stained droplets were detected, and the observed density and distribution evidenced in vitro lipogenesis. The technique presented here may provide a promising model for further experimental studies on sebaceous gland cell development and function.

Antibodies, Monoclonal

Age-related changes in sebaceous gland activity.

The sebaceous glands of man show age-related differences in their activity as determined by quantitative and qualitative examination of sebum. Sebaceous secretion is low in children and begins to increase in mid- to late childhood under the influence of androgens. This rise continues until the late teens, after which no further significant change takes place until late in life. In elderly men, sebum levels remain essentially unchanged from those of younger adults until the age of 80. In women, sebaceous secretion decreases gradually after menopause and shows no significant change after the 7th decade. The most likely explanation for the decrease in sebaceous gland secretion with age in both men and women is a concomitant decrease in the endogenous production of androgens. Although surface lipid levels fall with age, paradoxically the sebaceous glands become larger, rather than smaller, as a result of decreased cellular turnover. Nonetheless, as the higher surface lipid levels after administration of fluoxymesterone (a synthetic testosterone derivative) indicate, the glands have the capacity to respond to androgens.

Adolescent

Neonatal sebaceous glands: fine structure of sebaceous and dendritic cells.

Ultrastructural features of sebaceous glands in newborns were examined in adnexal polyp lesions of neonatal skin. Material for electron microscopy was obtained from the nipple areola of 10 Japanese newborn babies of both sexes, less than 8 days of age. The cell organization of the neonatal sebaceous acini consisted of undifferentiated, differentiating, and mature sebaceous cells, and the sequence of sebaceous transformation seemed to be consistent with that described in the postnatal acini. The sheet of continuous basal lamina covering the sebaceous acini was neither distorted nor convoluted. This configuration in the basal lamina revealed no convincing evidence for physiological involution of the neonatal sebaceous cells were identified at the outer periphery of the sebaceous glnads. Melanocytes in symbiosis with the sebaceous acini in concurrent presence of Langerhans cells.

Female

Circumscribed sebaceous gland hyperplasia: autoradiographic and histoplanimetric studies.

Circumscribed sebaceous gland hyperplasia (sebaceous hyperplasia) is a common benign facial tumor found in adults and aged. Seventeen biopsies of sebaceous hyperplasia from 10 patients, females and males aged 57-87 years were secured which were injected 45 min or up to 15 days prior with tritiated thymidine, and prepared for autoradiography. Specimens were evaluated by cell counts (labeling index, labeled total cells), and histoplanimetric techniques (sagittal section areas and circumference of sebaceous hyperplasia, of sebocytes, and of sebocyte nuclei). Controls were uninvolved sebaceous follicles from the same subjects, from an age-matched group, and from young male adults. In sebaceous hyperplasia the labeling index of basal cells is low with 5.7% +/- 2.3 vs uninvolved sebaceous follicles from the same subject (8.6% +/- 2.4) and the younger subjects with a value of 10.1% +/- 2.0). Labeled cells are retained in the acini much longer than in young adults (slowed down transit and turnover time). The glands of sebaceous hyperplasia are very large, their sebocytes are small, and many more basal cells are found per unit basement membrane length.

Adenoma

The fatty acids of human sebaceous gland phosphatidylcholine.

The fatty acids of human sebaceous gland phosphatidylcholine were examined by gas chromatography and by analysis of the double bond positions in the C-16 and C-18 monoenes. Compared to phosphatidylcholine from other organs, sebaceous gland phosphatidylcholine was found to be deficient in essential fatty acids and poly-unsaturated fatty acids. The relatively large mono-unsaturated fatty acid fraction consisted predominantly of fatty acids with delta6- and delta8-unsaturation. Analysis indicates that the fatty acids of sebaceous gland phospholipids are predominantly of types synthesized in sebaceous glands.

Fatty Acids

Control and function of sebaceous glands.

This review describes the various types of sebaceous glands, their locations, and where possible their different functions. All sebaceous glands are similar in structure and secrete sebum by a holocrine process. However, the nature of this secretion and the regulation of the secretory process seem to differ among the various types of glands. Methods for measuring sebum secretion and assessing sebaceous gland activity are also described. The area of major interest during the last 20 years has undoubtedly been the mechanisms that control sebaceous gland function. Most studies have focused on the endocrine control and in particular on the role of androgens and pituitary hormones, although evidence suggests that nonendocrine factors may also be important. However, many questions remain and during the next few years attention will certainly be given to the role of retinoids and their mode of action in the treatment of acne.

Animals

Control of human sebocyte proliferation in vitro by testosterone and 5-alpha-dihydrotestosterone is dependent on the localization of the sebaceous glands.

Androgens stimulate the activity of sebaceous glands in vivo. In this study the in vitro effect of androgens on the proliferation of cultured human sebocytes derived from facial and non-facial skin were assessed. Human sebocytes from sebaceous glands isolated from the face and the upper and lower legs of five individuals were cultured in vitro with or without testosterone or 5-alpha-dihydrotestosterone (5 alpha-DHT) at different concentrations (10(-11)-10(-5) M). Cell proliferation was assessed in 96-well culture plates using a fluorometric assay. Testosterone and 5 alpha-DHT stimulated the proliferation of human facial sebocytes in a significant dose-dependent manner. In our system 5 alpha-DHT exhibited the strongest effect; on the contrary, the proliferation of non-facial sebocytes was inhibited by testosterone, whereas 5 alpha-DHT enhanced their growth. The stimulatory effect of 5 alpha-DHT was more prominent on facial than on non-facial sebocytes. These results provide first evidence that the effect of testosterone and 5 alpha-DHT on the proliferation of cultured human sebocytes may depend on the localization of the sebaceous glands at different skin regions.

Adult

Sebaceous gland hyperplasia on rabbit pinna induced by tetradecane.

To investigate the pathologic changes of sebaceous glands during comedo formation induced by topically applied substances in a rabbit pinna model, purified tetradecane was inuncted on the ventral aspect of the rabbit pinnas once a day for a week. Histologically, a marked hyperplasia of sebaceous glands, epidermis, and follicular epithelium was seen. These remarkably enlarged sebaceous glands were examined histochemically and ultrastructurally. The acinus size and cell population of the hyperplastic sebaceous gland were significantly increased over those of the normal sebaceous gland. By N-(7-dimethylamino-4-methyl-3-coumarinyl)maleimide staining, normal distribution patterns of sulfhydryl (SH) and disulfide (SS) were seen in the peripheral to differentiating layers in the hyperplastic sebaceous glands. In the terminally differentiated layer, the brilliant SH fluorescence was gradually decreased and the SS fluorescence was gradually increased in intensity, indicating that most SH groups in the sebaceous cells were converted to SS linkages before holocrine secretion. By transmission electron microscopy, several cell layers of undifferentiated sebaceous cells were observed at the periphery of the large sebaceous gland. The differentiating sebaceous cells produced a large number of lipid droplets, which were produced in either rough or smooth endoplasmic reticulum. These cells were abruptly converted into homogeneously electron-dense cells which formed several layers. These homogeneous cells gradually lost their electron density before holocrine secretion. These findings indicate that the sebaceous cells in the hyperplastic sebaceous glands undergo a magnified step-by-step cell differentiation and play a role in slightly modified lipid formation, and that there may be an increased production of sebum in the rabbit pinna model. This is the first report of sebaceous hyperplasia induced by a topically applied substance on skin surface, except for androgens. The hyperplastic sebaceous glands could serve as a model for investigations of sebaceous cell differentiation and lipid formation.

Administration, Topical

Sebaceous gland carcinoma of the finger.

We report a patient with sebaceous gland carcinoma of the finger. Sebaceous gland carcinomas located outside the ocular adnexa are rare, with fewer than 100 cases documented to date. The majority of these arise in the head and neck where sebaceous glands are plentiful. Because this tumor shows no pathognomonic characteristics, accurate histologic evaluation is essential to its diagnosis. Local excision may not be adequate treatment for a sebaceous gland carcinoma of the digit. Ray amputation was the treatment of choice for this patient.

Adenocarcinoma

Alpha 2u-globulin in modified sebaceous glands with pheromonal functions: localization of the protein and its mRNA in preputial, meibomian, and perianal glands.

alpha 2u-Globulin, the principal urinary protein of the male rat, has extensive sequence homology with many lipid binding proteins. The highest concentration of alpha 2u-globulin is found in the preputial gland, a holocrine secretory organ with pheromonal function. Meibomian and perianal glands are two other modified sebaceous glands with holocrine secretory cycles and pleiomorphic peroxisomes capable of synthesizing pheromonal lipids. Immunocytochemical examination shows the presence of alpha 2u-globulin in the acinar cells of all three of these modified sebaceous glands. Whereas in the preputial gland all of the acinar cells exhibit immunoreactivity, in the meibomian and perianal glands only selective cells contain alpha 2u-globulin. In the case of the preputial gland, in addition to the acinar cells some stratified epithelial cells also were immunoreactive. In the perianal and meibomian glands, keratinocytes lining nearby hair shafts and select cells of accessory oil glands stained for alpha 2u-globulin. In situ hybridization with a cloned cRNA probe confirmed the immunocytochemical data. Presence of the alpha 2u-globulin mRNA in these glands was also established by Northern blot analysis. Immunoelectron microscopic examination of preputial alpha 2u-globulin showed the presence of this protein in secretory granules of various maturational stages. Immunolabeled alpha 2u was also found in attached vesicles containing protein and lipid inclusions. The lytic cells were not only loaded with alpha 2u-globulin but also contained sharp-edged, irregularly shaped electron-dense granules which stained heavily for this protein. Specific localization of alpha 2u-globulin and its mRNA in three pheromone-producing sebaceous glands and its structural homology with known lipid binding proteins indicate a pheromone carrier role of alpha 2u-globulin.

Alpha-Globulins

Transfollicular extrusion of sebaceous glands: natural phenomenon or artifact? A case report.

A sebaceous gland tumor on the back of a 28-year-old man underwent periodic exudation of yellowish material in association with local irritation. Pathological examination revealed entire sebaceous gland lobes lying subcorneally in the orifices of sebaceous follicles. This case appears to represent transfollicular extrusion of sebaceous gland lobes as a natural phenomenon rather than as an artifact.

Adult

The effect of various treatments on the size of sebaceous glands of hairless mice and hairless hamsters.

The effect of castration on the size of sebaceous glands of male hairless mice and male hairless hamsters was studied over a period of 4 weeks. Statistically significant decreases in the size of sebaceous glands were observed. The effects of intracutaneous injections of micronized crystalline suspensions of testosterone, testosterone propionate, testosterone phenylpropionate, testosterone decanoate and nandrolone phenylpropionate on the sebaceous glands of castrated hairless mice, castrated hairless hamsters and intact female hairless hamsters were studied over a period of one week. Highly significant increases in sebaceous gland volume were observed 6-7 days after treatment. The effects of subcutaneous and intracutaneous injections of micronized crystalline suspensions of testosterone on the sebaceous glands of intact male and female hairless hamsters were examined at sites local and distal to the injection. Increases in sebaceous gland volume were limited to local sites in the male but increases were observed locally and distally in the female. There was no difference between subcutaneous and intracutaneous injections.

Animals

[Morphological changes in sebaceous glands with aging in human males].

Using a computer stereographic analysis, the normal human forehead skin from 16 males of ages ranging from 7 to 77 years were investigated to known the morphological changes of the sebaceous glands with aging. The volume of sebaceous glands increased abruptly in teens, reaching maximum in the 20s; it was maintained at high levels even at middle ages and then began to decrease gradually in the 60s. The volume of sebaceous glands positively correlated with the number of the sebaceous cells but not with their sizes. Ultrastructually, in the large sebaceous glands, and peripheral cells were cuboidal, whereas they were flat in the small sebaceous glands. It is concluded that the sebaceous glands in males show no morphological change in relation to age between the 20s and 50s.

Adolescent

Stereographic and stereometric study of sebaceous gland hyperplasia in rabbit pinnas induced by topically applied substances.

Tetradecane (TD), testosterone (TS), and dimethyl sulfoxide (DMSO) were separately inuncted on rabbit pinnas once a day; the pinnas were biopsied on days 1, 3, 7, and 28. Untreated pinnas and squalane-treated pinnas were used as controls. Three-dimensional images of sebaceous glands were reconstructed from their serial histologic sections using a computer-image analysis system. By stereometry, the sebaceous gland volumes gradually increased during the course of treatments with TS and DMSO, whereas the volumes of TD-treated sebaceous glands increased, reached the maximum on day 7, and then decreased. The acinus number was increased by all the substances, the DMSO-treated sebaceous glands on day 28 showing the largest number of acini. The volumes of individual acini increased until day 28 with TS treatment, whereas with TD and DMSO treatments they increased, reached the maximum on day 7, and then decreased. Stereographically, each untreated control sebaceous gland was composed of 20-30 pear-shaped acini. On day 28, acini of TS-treated sebaceous glands were swollen and ovoid in shape, DMSO-treated sebaceous glands resembled a bunch of grapes, and acini of TD-treated sebaceous glands were widely scattered and showed globular swelling arising from an elongated tube. Hyperplastic responses of sebaceous glands are quite different according to substances applied topically.

Administration, Topical

Sebaceous gland and sweat gland carcinomas of the skin. Clinicopathological study and significance of c-erbB-2 oncoprotein expression.

Thirteen sebaceous gland carcinomas and 10 sweat gland carcinomas were examined to elucidate any important histological parameters influencing their prognosis, and the relationship between immunohistochemical expressions of c-erbB-2 oncoprotein and survival of the patients was analyzed. Sebaceous gland carcinomas with vacuolated cytoplasm in more than 50% of whole tumor area, with necrosis, and without lymphoid cell infiltration in tumor nests and stroma had a higher incidence of tumor recurrence and tumor-related death than tumors with vacuolated cytoplasm in 50% or less of whole tumor area (p < 0.01), without necrosis, and with lymphoid cell infiltration in tumor nest and stroma (p < 0.05). Sweat gland carcinomas of all cases with fatal outcomes demonstrated tubular differentiation in 20% or less of whole tumor area, lymphatic permeation and desmoplastic reaction. Three sebaceous gland carcinomas and three sweat gland carcinomas were positive for c-erbB-2 oncoprotein. Two of three sebaceous gland carcinomas, and all three sweat gland carcinomas developed tumor recurrence and ended in tumor-related deaths. Sweat gland carcinomas with c-erbB-2 expression had significantly shorter survival than those with negative immunostain (p < 0.01). Cytoplasmic appearance, tumor necrosis, and lymphoid cell infiltration in tumor nests and stroma of sebaceous gland carcinoma, and tubular differentiation, lymphatic permeation, and growth patterns of sweat gland carcinoma are considered to closely correlate to the prognosis. Immunohistochemically detected c-erbB-2 oncoprotein may be an indicator of bad prognosis.

Adolescent

The lipid composition of sebaceous glands as a reflection of gland size.

Following 4 h incubation in vitro, the patterns of incorporation of [I-14C] acetate into the lipid classes of human sebaceous glands which were dissected from small skin biopsies have been established for glands of different size. It has been shown that in the larger sebaceous glands proportionately more of the labelled acetate is incorporated into squalene at the expense of triglycerides. Experiments are presented as a result of which we conclude that this in vitro phenomenon, observed with [I-14C] acetate incorporation, does reflect parallel changes in the proportions of these lipids actually present in glands of different size. It is suggested that the larger sebaceous glands of the acne patient elaborate sebum which has an enhanced potential for inducing comedo formation by virtue of an increased concentration of squalene. This work also demonstrates that, in the interpretation of in vitro studies of sebaceous gland lipogenesis utilizing labelled precursors, the size of the sebaceous glands must be carefully considered whenever patterns of incorporation are being compared.

Acne Vulgaris

Analysis of lipid composition of isolated human sebaceous gland homogenates after incubation with cutaneous bacteria. Thin-layer chromatography.

The effects of specific species of skin bacteria on human sebaceous gland lipids in vitro were analyzed. Isolated dissected sebaceous glands were pooled, homogenized, and sterilized, then incorporated into peptone-yeast extract medium and used as substrate for growth of Propionibacterium acnes, P. granulosum, and Staphylococcus epidermidis subgroup II. The sebaceous lipids were analyzed by thin-layer chromatography before and after bacterial growth. The most striking effect of bacteria on sebaceous gland lipid composition was the hydrolysis of sebaceous triglycerides. The degree of hydrolysis varied with bacterial strain but was most complete with P. acnes and P. granulosum. Staphylococci were not effective in hydrolyzing sebaceous triglycerides at pH 4.5 although, when the pH of the medium was raised to pH 6.4, some strains of staphylococci were as effective as the propionibacteria in hydrolyzing sebaceous triglycerides to free fatty acids. Thus minor changes in acidity may play asignificant role in controlling the lipolytic activity of staphylococci on skin. Another effect of bacterial action on sebaceous gland lipids was the esterification of sebaceous cholesterol to cholesteryl esters. Thus, bacterial action must be taken into account in evaluating studies of alterations in cutaneous cholesterol and cholesteryl esters in skin surface lipids in normal and disease states.

Bacteriological Techniques