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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

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 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

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

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

Cell proliferation kinetics of epidermis and sebaceous glands in relation to chalone action.

Median S-phase lengths of pinna epidermis and sebaceous glands, and of epithelia from the oesophagus and under surface of the tongue of Albino Swiss S mice were estimated by the percentage labelled mitoses method (PLM). The 18.4 and 18,8 hr for the median length of S-phase for pinna epidermis and sebaceous glands respectively made it possible for these two tissues to be used experimentally for testing tissue specificity in chalone assay experiments. The 10.0 and 11.5 hr for oesophagus ang tongue epithelium respectively made experimental design for chalone assay difficult when pinna epidermis was the target tissue. The results of the Labelling Index measured each hour throughout a 24-hr period showed no distinct single peaked diurnal rhythm for pinna epidermis and sebaceous glands. Instead a circadian rhythm with several small peaks occurred which would be expected if an S-phase of approximately 18 hr was imposed on the diurnal rhythm. This indicates that there may be very little change in the rate of DNA synthesis. The results are given for the assay in vivo of purified epidermal G1 and G2 chalones, and the 72--81% ethanol precipitate of pig skin from which they could be isolated. These experiments were performed over a time period which took into account the diurnal rhythm of activity of the mice as well as the S-phase lengths. Extrapolating the results with time of action of the chalone shows that the G1 chalone acts at the point of entry into DNA synthesis and that the S-phase length was approximately 17 hr for both the pinna epidermis and sebaceous glands. This may be a more correct value since the PLM method overestimates the median S-phase length as it is known that in pinna skin the [3H]TdR is available to the tissues for 2 hr and true flash labelling does not take place. The previous reports that epidermal G1 chalone acts some hours prior to entry into S-phase resulted from experiments on back skin where the S-phase is shorter and there is a pronounced diurnal rhythm which could mask the chalone effect. The epidermal G2 chalone had no effect on DNA synthesis even at different times in the circadian rhythm. Thus the circadian rhythms and S-phase lengths of the test tissues need to be considered when experiments are performed with chalones. Ideally, the target tissues selected for cell line specificity tests should have the same cell kinetics for the easier and more accurate assessment and interpretation of results. When the tissues have markedly different cell kinetics, experimental procedures and results need to be evaluated accordingly. The point of action of G1 chalone can only be assessed if the effect is measured over the peak of incorporation of [3H]TdR into DNA. The results of the effects of skin extracts are analysed in relation to changes in the availability of [3H]TdR for the incorporation into DNA and to the possibility of there being two distinct populations of proliferating cells.

Animals

Sebaceous gland adenomas in dogs.

In a review of neoplasm registry records at Kansas State University (1961 through 1971), 162 sebaceous gland adenomas were reported in 31 breeds of dogs, representing 5.0% of 3,240 neoplasms recorded. Mean age of the affected dogs was 9.5 years. Females accounted for 56.1% of the recorded sebaceous gland adenomas. The tumors were removed surgically for biopsy in all dogs; 24 dogs had multiple concurrent skin neoplasms of a different cell type, and 7 dogs had recurrence of sebaceous gland adenomas, without metastases, and required further surgery. The skin of the hindquarters, abdomen, and thorax was a principal site (54%) of the sebaceous gland adenomas.

Adenoma

Effect of alpha-melanocyte-stimulating hormone and testosterone on cutaneous and modified sebaceous glands in the rat.

The effects of alpha-MSH and testosterone propionate on sebum secretion, sebaceous gland volume, dermal lipogenesis, and preputial gland weight and lipogenesis were examined in hypophysectomized rats. Hypophysectomy reduced sebum secretion, sebaceous and preputial gland size, and dermal and preputial gland lipogenesis. The greatest effects were seen on the biosynthesis of wax esters and squalene. Testosterone propionate (TP) increased sebum secretion, sebaceous gland volume and preputial gland weight and lipogenic activity, but had no significant effect on the pattern of lipid labelling. alpha-MSH had no effect on sebaceous or preputial gland size, but increased sebum secretion and dermal lipogenesis, especially wax ester biosynthesis. When given together TP and alpha-MSH had a synergistic effect on sebum secretion and on dermal and preputial gland lipogenesis, and the pattern of lipid labelling was shifted towards normal. TP and alpha-MSH also showed synergism in increasing preputial gland weight, but together they had no greater effect on sebaceous gland volume than that achieved with TP alone. These results suggest that TP and alpha-MSH have different actions on the sebaceous glands with alpha-MSH acting predominantly on lipogenesis and TP on cellualr proliferation and turnover leading to an increase in gland size. Preputial glands differ from cutaneous sebaceous glands in their response to alpha-MSH and androgen which could be a reflection of their more specilized function.

Animals

[Sebaceous gland tumors in dogs].

Histologically were investigated 37 cases of neoplastic growths and 2 cases of hyperplasia in canine sebaceous glands. From this number 24 tumours of circumanal glands (20 adenomas and 4 carcinomas) and 13 tumours of sebaceous glands in extraanal localization were found. The average age of affected dogs was 9 years. In the neoplastic tissue of circumanal adenomas three differentiation degrees of sebaceous cells were identified. Biological behaviour is favourable, tumours destructured the tissue only topically. Malignant neoplasias consisted of tumorously proliferated, lowly differentiated sebaceous cells. Tumours observed in the ear and external ear canal are histologically similar to human cutaneous sebaceous gland adenomas and therefore from the viewpoint of comparative oncology they are important. In therapy, surgical extirpation is applied with possible estrogen combination.

Adenoma

Immunohistochemical distribution of aromatase and 3B-hydroxysteroid dehydrogenase in human hair follicle and sebaceous gland.

Human hair follicles (HF) and sebaceous glands (SG) were assessed for the presence and distribution of the cytochrome P-450-aromatase (AR) and 3B-hydroxysteroid dehydrogenase (3B-HSD) enzymes. Immunohistochemical methods were used to examine both enzymes in male and female human skin specimens at various ages and different body sites. AR was found in the external root sheath of anagen, terminal HF, and in SG, whereas the 3B-HSD was found only in the SG. AR was rarely found in telogen HF. The expression of both enzymes, AR and 3B-HSD, did not vary with body site or sex. Localizing AR in the external root sheath of anagen HF suggests that AR may have a function in the HF cycle. We hypothesize that AR may be one of many enzymes or factors that play a role in the HF cycle by regulating the level of androgens formed locally, whereas 3B-HSD is localized in SG, converting weak androgen precursors to potent androgens, stimulating lipogenesis.

3-Hydroxysteroid Dehydrogenases

The effects of a nonsteroid antiandrogen, flutamide, on sebaceous gland activity.

Flutamide (alpha,alpha,alpha-trifluoro-2-methyl-4'-nitro-m-propionotoluidide), at daily oral doses of 20 mg/day for 24 days, reduced the number and size of skin sebaceous gland cells, and reduced sebum production in ovariectomized, testosterone-stimulated rats. The weight of the preputial glands was also reduced. Unilateral topical application of flutamide (0.1-3.0 mg/day) to flank organs (androgen-sensitive cutaneous sebaceous structures) of testosterone propionate-treated female hamsters for 14 days resulted in bilateral reductions in flank organ weight and in inhibition of in vitro incorporation of 14-C from sodium [1--14C]acetate into lipids. Flutamide inhibition of flank organ weight paralleled the drug effect on lipogenesis. Unilateral topical application of flutamide to flank organs of intact male hamsters for 14 days resulted in significant bilateral reductions of flank organ weight at doses as low as 0.375 mg/day (the lowest dose tested). These weight changes were marked by reduction in sebaceous gland size, accompanied by focal cytoplasmic degeneration, and reductions in cytoplasmic organelles and in the size of the lipid bodies. Flutamide did not, however, seemingly alter the pattern of endogenous total lipids in sebaceous glands, nor did it alter the pattern of 14-C-incorporation into the lipids of male flank organ epidermis and isolated sebaceous glands, when compared to control, untreated preparations.

Acetates

[Indices of mitotic cell division in sebaceous glands].

The main indices of mitotic cell division in rat sebaceous glands (external auditory meatus and tarsales gl.) were studied autoradiographically using H3-thymidine and with colchicine method. The duration of mitotic cycle and its separate phases, the number of cells involved in the proliferative pool, as well as the turnover of terminals of the epithelium in both the glands were stated to be nearly identical. The duration of the mitotic cycle was: T -- 28.1 hour; tG1 -- 18.64; tS -- 6.3; tG2 -- 1.80; tM -- 1.34 hours. The proliferative pool (Pc) -- 31.45%, turnover of the basal layer cells -- 89.25 hours. These indices for the stratified epithelium of excretory ducts were respectively; T -- 33.0 hours; tG1 -- 21.74; --8.06; tG2 -- 1.6; tM -- 1.6; Pc -- 26.8% and the turnover for the cells of the basal layer -- 123 hours. Thus, the sebaceous glands are to be regarded as organs where a rapid renovation of epithelia cells occurs.

Animals