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SUMMARY
Human skin from forehead, cheek and axilla was incubated in vitro with [7α-3H]dehydroepiandrosterone (DHA), [7α-3H]DHA sulphate, [7α-3H]-androstenedione and [7α-3H]testosterone. The following enzyme activities were detected: 3β-hydroxysteroid dehydrogenase Δ4-5 isomerase, 17β-hydroxysteroid dehydrogenase, 3β-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, 5α-reductase, 5β-reductase, sulphotransferase, sulphatase, steroid hydroxylase. 5α-Reduced steroids were the major metabolites. All four substrates were converted to 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol. In axillary skin, conversion of 17-oxosteroids to 17β-hydroxysteroids was favoured, 5α-dihydrotestosterone and 5α-androstane-3α,17β-diol being major metabolites. In facial skin, formation of 17-oxosteroids predominated with little accumulation of 5α-dihydrotestosterone or 5α-androstane-3α,17β-diol. 5α-Androstane-3β,17β-diol was a metabolite of DHA, androstenedione and testosterone but was found in lower amounts than 5α-androstane-3α,17β-diol. Similarly conversions to epiandrosterone were much lower than to androsterone in all the skin specimens.
It was concluded that the differences in accumulation of 5α-dihydrotestosterone were determined by the differences in 17β-oxidoreduction rather than differences in 5α-reductase, the activity of which was high in all skin specimens.
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SUMMARY
The metabolism of [7α-3H]dehydroepiandrosterone (DHA), [7α-3H]-androstenedione and [7α-3H]testosterone was studied in the ventral sebaceous gland patch of the Mongolian gerbil in vitro. The main enzyme activities found were 17β-hydroxysteroid dehydrogenase, 5α-reductase, 17α-hydroxysteroid dehydrogenase, 3α-hydroxysteroid dehydrogenase, sulphotransferase and hydroxylase. The active androgen 5α-dihydrotestosterone was formed in appreciable amounts from both testosterone and androstenedione. The 17β-hydroxysteroid dehydrogenase actively formed both 17-oxo and 17β-hydroxysteroids in this tissue. The conversion of DHA to C4–5 unsaturated steroids and 5α-steroids was not observed presumably due to a lack of 3β-hydroxysteroid dehydrogenase Δ4–5isomerase. The metabolism was compared with that in human and rat skin and its significance discussed.
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SUMMARY
Testosterone metabolism was studied in tissues associated with a keratin-filled cutaneous cyst. Instead of the 5α-reduced metabolites usually associated with skin steroid metabolism, considerable amounts of 5β-reduced steroids were found. These included 5β-androstane-3,17-dione, 17β-hydroxy-5β-androstan-3-one, and 5β-androstane-3β,17β-diol. This change in metabolic pattern is discussed.
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The distribution of androgen metabolism in human skin was studied using tissues isolated either by direct dissection of axillary skin or by dissection of collagenase-digested forehead and axillary skin. All tissues (epidermis, sweat glands, sebaceous glands, hair follicles and dermis) were found to contain 17β-, 3β- and 3α-hydroxysteroid dehydrogenase (HSD) activities, 3β-hydroxysteroid dehydrogenase-Δ4–5 isomerase (Δ5-3β-HSD) activity and 5α-reductase activity. All tissues converted testosterone into 5α-dihydrotestosterone. In confirmation of previous histochemical studies, over 90% of the Δ5-3β-HSD of forehead skin was found in the sebaceous glands. In forehead skin, 40–66% of the 5α-reductase activity was in the sebaceous glands, while in axillary skin 50–70% was in the sweat glands, especially the apocrine glands. There was a more even distribution of 17β-HSD activity in skin tissues than histochemical studies have indicated previously. Knowledge of the distribution of these enzymes has helped in the understanding of the function of androgen metabolism in skin.
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Human forehead skin incubated in vitro is known to metabolize testosterone to 17-oxosteroids faster than the reverse reaction, while axillary skin rapidly metabolizes androstenedione to 17β-hydroxysteroids, such as testosterone and 5α-dihydrotestosterone, While this has been confirmed using a larger number of patients, some indication has been found that 17β-hydroxysteroid oxidoreductase activity declines with age in the axilla. The relative rates of 17β-oxidation and reduction (direction of operation of skin 17β-hydroxysteroid oxidoreductase activity) were not altered by a variety of incubation conditions. Large amounts of a membrane-bound 17β-hydroxysteroid oxidoreductase, showing preference for NAD as coenzyme and testosterone (rather than androstenedione) as steroid substrate, were found in forehead skin from one patient. On the other hand, the main axillary skin enzyme in skin from another patient was soluble and showed preference for NADP and androstenedione. It is postulated that 17β-oxidation and reduction in skin is controlled by the relative amount, the coenzyme preferences and the kinetic properties of these two enzymes.
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SUMMARY
Fresh scalp, genital, chest and axillary skin from human foetuses of 12–41 weeks' maturity was incubated in Krebs' improved Ringer I medium with [7α-3H]dehydroepiandrosterone, [7α-3H]testosterone and [7α-3H]androstenedione. The metabolites identified were androstenedione, 5α-androstane-3,17-dione, androsterone, 3-epiandrosterone, 5α-dihydrotestosterone, 5α-androstane-3α,17β-diol, 5α-androstane-3β,17β-diol, 5-androstene-3β,17β-diol and testosterone. The results provide evidence for the presence of 3β-hydroxysteroid dehydrogenase, Δ4–5 isomerase, 17β-hydroxysteroid dehydrogenase, Δ4-3-oxosteroid-5α-reductase and 3α-hydroxysteroid dehydrogenase in human foetal skin. There were quantitative differences in the various enzyme activities between different body sites and skin specimens of different gestational age. 5α-Reductase activity was particularly high in genital skin. 3β-Hydroxysteroid dehydrogenase Δ4–5 isomerase activity was low in skin from a 12-week foetus, but high in skin specimens from 28-, 38- and 41-week foetuses. 17β-Hydroxysteroid dehydrogenase activity was already high in the skin of the 12-week foetus and remained so in the older foetuses. These results were correlated with the development of the foetal sebaceous glands, and were in general agreement with a parallel enzyme histochemical study. The role of androgen metabolism in human foetal skin is discussed.
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The metabolism of testosterone and 5α-dihydrotestosterone has been studied in vitro in preputial glands of posterior hypophysectomized, totally hypophysectomized and control sham-operated rats. The level of C19 steroid 5α-reductase activity/unit of preputial gland DNA did not fall after removal of the neurointermediate lobe and rose after total hypophysectomy. It was concluded from this that the androgen unresponsiveness of the preputial glands of hypophysectomized rats was not due to a near-total lack of 5α-reductase and hence that the combined synergistic action of testosterone and α-melanocyte-stimulating hormone (α-MSH) on preputial gland activity was unlikely to be due to an α-MSH-mediated restoration of 5α-reductase levels in hypophysectomized rats. Levels of 3α-and 3β-hydroxysteroid dehydrogenase but not of 17β-hydroxysteroid dehydrogenase appeared to be altered by hypophysectomy.
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Abstract
Although the action of gastric inhibitory polypeptide (GIP) on the β cells of the pancreas is well documented, the effect of this hormone on insulin secretion in patients who are hypothyroid has not been studied. Hypothyroid patients demonstrate increased serum immunoreactive insulin levels in response to oral glucose when compared with euthyroid subjects. We postulated that a delayed and exaggerated response of GIP could account for the hyperinsulinaemic response. Nine thyroidectomized patients (aged 44·9 ± 3·6 years) who were otherwise healthy but undergoing re-evaluation for recurrence of thyroid carcinoma, were given a 75 g oral glucose tolerance test (OGTT). These subjects were studied 6 weeks after thyroid hormone replacement had been stopped and while on hormone treatment. The serum glucose and plasma GIP responses to oral glucose were similar in the euthyroid and hypothyroid states. The serum insulin response as well as the areas under the curve for insulin following OGTT were significantly elevated (P<0·01) during hypothyroidism. Solid-phase gastric emptying times studied in six patients who were euthyroid and hypothyroid were not different (35 ± 12 versus 36 ± 14 min respectively). None of the subjects had detectable levels of serum thyroglobulin, microsomal or parietal cell antibodies. In summary, we have confirmed a hyperinsulinaemic response to an OGTT and normal solid-phase gastric emptying rates in this form of hypothyroidism. We did not find significant differences in serum glucose or GIP responses and postulate this as evidence of resistance to the effects of endogenous insulin. The mechanism of alterations in carbohydrate tolerance in the hypothyroid state continue to remain unknown.
Journal of Endocrinology (1994) 140, 309–312
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SUMMARY
The main objective of the study was to determine the rate at which Graafian follicles of sheep that had been treated with exogenous gonadotrophin acquire the ability to secrete oestrogen in vitro. Follicles were explanted from sheep 5 min to 24 h after injection of pregnant mare serum gonadotrophin (PMSG) and kept individually in culture for 7 days. The mean daily output of oestrogen by follicles from PMSG-treated sheep was higher than that secreted by follicles from untreated sheep. However, only a certain proportion of the follicles from each sheep secreted significant amounts of oestrogen in vitro; these follicles were called 'stimulated'. The proportion of stimulated follicles was 5% for control sheep, 20–30% for follicles explanted from sheep 5 min to 12 h after injection with PMSG, and 80% for follicles explanted from sheep that had been injected with PMSG 24 h previously.
In the second part of the study, the pattern of oestrogen and progesterone secretion by stimulated follicles of different sizes explanted from PMSG-treated sheep at various stages of the oestrous cycle was determined. Up to the 14th day, oestrogen production in vitro by follicles over 4·5 mm in diameter reached a maximum 2 days after PMSG injection and decreased thereafter; progesterone production rose steadily as the oestrogen levels declined. In contrast, follicles of less than 4·5 mm diameter secreted considerable amounts of oestrogen for the first 5 days in culture, but produced only small quantities of progesterone. In follicles explanted on day 15, oestrogen secretion decreased steadily from the beginning of the culture period and was very low by the 4th day. Most follicles explanted at oestrus secreted only small amounts of oestrogen in vitro but secreted large amounts of progesterone.
Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Department of Pharmacology, University of Cambridge, Cambridge, UK
Department of Pharmacology, University of Chicago, Chicago, Illinois, USA
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Several proteins play a role in the mechanism of insulin exocytosis. However, these ‘exocytotic proteins’ have yet to account for the regulated aspect of insulin exocytosis, and other factors are involved. In pancreatic exocrine cells, the intralumenal zymogen granule protein, syncollin, is required for efficient regulated exocytosis, but it is not known whether intragranular peptides similarly influence regulated insulin exocytosis. Here, this issue has been addressed using expression of syncollin and a syncollin-green fluorescent protein (syncollinGFP) chimera in rat islet β-cells as experimental tools. Syncollin is not normally expressed in β-cells but adenoviral-mediated expression of both syncollin and syncollinGFP indicated that these were specifically targeted to the lumen of β-granules. Syncollin expression in isolated rat islets had no effect on basal insulin secretion but significantly inhibited regulated insulin secretion stimulated by glucose (16.7 mM), glucagon-like peptide-1 (GLP-1) (10 nM) and glyburide (5μM). Consistent with specific localization of syncollin to β-granules, constitutive secretion was unchanged by syncollin expression in rat islets. Syncollin-mediated inhibition of insulin secretion was not due to inadequate insulin production. Moreover, secretagogue-induced increases in cytosolic intracellular Ca2+, which is a prerequisite for triggering insulin exocytosis, were unaffected in syncollin-expressing islets. Therefore, syncollin was most likely acting downstream of secondary signals at the level of insulin exocytosis. Thus, syncollin expression in β-cells has highlighted the importance of intralumenal β-granule peptide factors playing a role in the control of insulin exocytosis. In contrast to syncollin, syncollinGFP had no effect on insulin secretion, underlining its usefulness as a ‘fluorescent tag’ to track β-granule transport and exocytosis in real time.