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Isotretinoin administered subcutaneously to male hamsters results in marked involution of the sebaceous glands of the flank organ without discernible effort on the other androgen-dependent structures, pigmented hair follicles, and dermal melanocytes. Treatment of androgen-stimulated female hamsters with isotretinoin prevented the androgen-induced growth of the sebaceous glands but not the formation of large pigmented hairs and dermal pigment cells. Etretinate, in comparable dosage, did not show the inhibitor effect on sebaceous gland growth. The hamster flank organ seems a promising system for assessment of the sebaceous gland inhibitory activity of retinoids and may be predictive for therapeutic activity in acne.

The effect of subcutaneously administered 13-cis-retinoic acid and an aromatic retinoid (Ro 10-9359) on the sebaceous glands of the hamster flank organ were compared. As previously reported, 13-cis-retinoic acid caused a marked diminution of sebaceous gland size without affecting other androgen dependent structures. The aromatic retinoid derivative showed no effect upon any of the flank organ components. Studies utilizing androgen stimulated female confirmed our previous finding that 13-cis-retinoic acid prevented the growth of sebaceous glands without affecting the development of dermal pigmentation or large pigmented hair follicles. The aromatic retinoid derivative showed slight, if any, effect upon sebaceous gland size and no effect upon pigmentation or pigmented follicle development. The findings with this model system suggest that any efficacy of Ro 10-9359 in the treatment of acne would be by some mode other than the inhibition of sebum production.

In-vitro [14C]testosterone metabolism was investigated in isolated cells of adult male mouse preputial sebaceous glands. Labelled steroids were extracted and chromatographed after a 2-h incubation, and were identified as 5 alpha-dihydrotestosterone, androstenedione, 5 alpha-androstane-3,17-dione, 5 alpha-androstane-3 alpha,17 beta-diol and 5 alpha-androstane-3 beta,17 beta-diol, androsterone and 3-epiandrosterone. In cells separated according to state of maturity (lipid content) by isopycnic centrifugation in a metrizamide gradient, maximal testosterone metabolism occurred in large, nearly mature cells. In this population, mean hydroxysteroid 5 alpha-reductase and 17 beta-hydroxysteroid dehydrogenase activities were 3.8 and 2.3 nmol/10(6) cells per 2h respectively, more than 100-fold greater than in the densest population, comprised of undifferentiated and early differentiating cells. It was also found that the profile of testosterone metabolites was dependent on the proportion of the label metabolized. The metabolite index (MI), i.e. the average number of enzymatic steps undergone per molecule of metabolite, increased with increasing substrate utilization. Metrizamide showed reversible, non-specific inhibition of testosterone metabolism and reduction of the MI. Thus, it was postulated that testosterone is metabolized sequentially by different cells, with metrizamide inhibiting cellular uptake and intercellular substrate transport. This suggested that most of the metabolites would be found in the medium, rather than in the cellular compartment. Further, in incubations run without cell disaggregation, efficient substrate cycling among cells should result in a high MI, independent of metrizamide concentration and substrate utilization. These predictions were all confirmed, providing strong evidence that testosterone metabolism is a co-operative effort among several cells in this tissue.

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.