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SUMMARY
The metabolism of [4-14C]4-androstene-3,17-dione and [4-14C]5α-androstane-3α,17β-diol were studied in the microsomal fraction and the metabolism of [4-14C]4-androstene-3,17-dione was studied in the 105000 g supernatant fraction of liver from adult male rats castrated at birth or at 14 days of age. Some of these rats were adrenalectomized 6 weeks after castration and given dexamethasone substitution for 14 consecutive days and some were not adrenalectomized and were treated with adrenocorticotrophin for 14 days. Untreated, castrated control rats were also investigated. Adrenalectomy combined with dexamethasone substitution was found to abolish the masculine, imprinted character of the activities of 16α-hydroxylase, 17α- and 17β-hydroxysteroid reductases and 5β-reductase active on 4-androstene-3,17-dione and 2α- and 2β-hydroxylases active on 5α-androstane-3α,17β-diol in liver from male rats castrated at 14 days of age. The type of androgenic regulation characterizing these enzymes was called 'less stable' imprinting. In contrast to these findings, the activities of 5α-reductase and 3β-hydroxysteroid reductase retained their masculine character in male rats castrated 14 days after birth even after adrenalectomy combined with glucocorticoid substitution. The type of programming regulating these enzyme activities was called 'more stable' imprinting.
'Less stable' imprinting could be explained by the increased androgen responsiveness of the neonatally androgenized liver which thus responds more promptly to the enzyme-inducing or suppressing effects of adrenal androgens. Adrenalectomy combined with dexamethasone substitution results in elimination of these effectors and consequently loss of the masculine character of the enzyme activities regulated by 'less stable' imprinting. The activity of 5β-reductase, however, seems to be regulated by unknown central factors. 'More stable' imprinting may be explained by a specific, autonomous, irreversible enzyme induction in liver independent of postpubertal hormonal stimuli.
Corticotrophin treatment generally led to similar but less significant effects upon the hepatic enzyme activities than adrenalectomy combined with dexamethasone substitution. It is speculated that these effects may be attributable to increased glucocorticoid levels in blood possibly through secondary effects on central control mechanism(s) regulating hepatic enzyme activities.
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The presence of ectopic pituitary tissue (derived from an adult rat) in prepubertal male and female rats caused the immature, masculine-type hepatic steroid metabolism to develop into female-type metabolism. It is concluded that the hypothalamus–pituitary system controls the ontogenesis of sex-dependent steroid metabolism in rat liver.
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The metabolism of 4-androstene-3,17-dione by liver microsomes from juvenile rainbow trout, Salmo gairdnerii, was studied in vitro. Hypophysectomy of the fish significantly increased mean hepatic 17-hydroxysteroid oxidoreductase activity when compared with that from sham-operated fish but none of the other enzyme activities investigated were affected. Administration of oestradiol-17β resulted in a significant decrease in mean hepatic 6β-hydroxylase activity and total cytochrome P-450 content but had no effect on the 16-hydroxylation or on the reductive metabolism of androstenedione. The effect of oestradiol-17β on hepatic 6β-hydroxylase activity was as pronounced after hypophysectomy as after sham-operation indicating that these effects of oestradiol-17β are mainly direct and independent of the pituitary gland. The results indicate that hypophysial hormone(s) as well as oestradiol-17β play a role in the regulation of hepatic steroid metabolism in trout.
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The reduction of 4-[1,2-3H]androstene-3,17-dione (androstenedione) in vitro by scrotal skin was measured in samples from nine men (16–34 years old) with hypospadias and from ten male control subjects. The reduction of androstenedione was also studied in axillary and upper arm skin of seven control subjects. Androstenedione was reduced to material with chromatographic characteristics of 5α-androstane-3,17-dione and to 3α- and 3β-hydroxy-5α-androstan-17-one.
No difference in 5α-reductase activity (defined as the sum of these three metabolites formed) was found in scrotal skin from hypospadic and control men.
The mean concentration of 5α-dihydrotestosterone in serum from men with hypospadias was lower than that in serum from control subjects (P< 0·01). The mean ratio of the serum concentrations of testosterone and 5α-dihydrotestosterone was higher in hypospadic men than in control subjects (P< 0·05). No differences between the two groups were found in the mean serum concentrations of LH, FSH, prolactin, dehydroepiandrosterone, androstenedione, testosterone or testosterone-binding globulin.
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The metabolism of 4-[1,2-3H]androstene-3,17-dione in the prepuce, axillary skin and skin from the arm was investigated in 27 boys operated for phimosis (controls) and 13 unselected boys with hypospadias (a congenital defect of the male urethra). In all types of skin investigated, androstenedione was metabolized to 5α-androstane-3,17-dione, 3α-hydroxy-5α-androstan-17-one, 3β-hydroxy-5α-androstan-17-one and testosterone. Conversion to testosterone was found in the prepuce of two out of 11 boys with hypospadias.
Mild forms of hypospadias in the age group 1–4 years had a higher level of 5α-reductase activity in the prepuce than controls in the same age group (P < 0·05); no such differences were found in the few severe cases of hypospadias in this group. No other differences in 5α-reductase activity were found between hypospadic boys and controls. The ratio of 5α-reductase activity in the prepuce: 5α-reductase activity in skin from the arm was significantly higher (P<0·05) in hypospadic boys than in controls in the age group 1–4 years.
Serum levels of LH and FSH were the same in normal and hypospadic boys but the concentration of prolactin in the serum was lower in boys with hypospadias compared with control subjects in the age group 1–4 years (P<0·005). No differences were found in serum concentrations of androstenedione, testosterone, oestradiol and testosterone-binding globulin.
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SUMMARY
The metabolism of [4-14C]4-androstene-3, 17-dione, [4-14C]5α-androstane-3α, 17β-diol and 1,2-3H]5α-androstane-3α, 17β-diol 3,17-disulphate was studied using the microsomal fraction and the metabolism of [4-14C]4-androstene-3, 17-dione was studied using the 105 000 g supernatant fraction of liver from male and female rats aged 5 months that had been treated with cyproterone acetate before (from day 13 of pregnancy) and after birth (until 3 weeks of age). Nearly all sex-dependent enzyme activities in the treated male rats were changed in a direction characteristic of female rats: 5α-reductase active on 4-androstene-3, 17-dione increased in activity whereas 3β- and 17α-hydroxysteroid reductases and 6β- and 16α-hydroxylases active on 4-androstene-3, 17-dione and 2α-, 2β- and 18-hydroxylases active on 5α-androstane-3α, 17β-diol decreased in activity. Enzyme activities not under gonadal control, i.e. 3α- and 17β-hydroxysteroid reductases active on 4-androstene-3, 17-dione and 7α-hydroxylase active on both 4-androstene-3, 17-dione and 5α-androstane-3α, 17β-diol, were not affected by cyproterone acetate. The liver enzyme activities in treated female rats were generally not affected although significant effects were noted in two cases; in one of these (17α-hydroxysteroid reductase) a testosterone-like effect was observed.
The results obtained are probably best explained in the following way: treatment with the anti-androgen during the neonatal period results in less efficient imprinting of the hypothalamo-hypophysial system leading to less pronounced masculine setting of sex-dependent enzyme levels and also to a relative androgen unresponsiveness. It is suggested that the biochemical methods used in the present investigation may be used for more exact estimation of the degree of neonatal sexual differentiation of the hypothalamo-hypophysial system than biological and psychological methods previously available.
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SUMMARY
The concentrations of LH and FSH were measured by radioimmunoassay in sera from immature male and female rats of various ages. Fairly high levels of FSH were found in both sexes at birth but LH was not detected. FSH peaks appeared in the male at 13 and 19 days of age and in the female at 13 and 17–19 days of age. LH was undetectable in the male before 12 days of age, rose to a peak (440 ± 60 (s.d.) ng/ml) at 13 days of age and fell below the detection level again between 15 and 25 days of age. A further increase then occurred which almost reached adult levels. LH was first detectable in the female rat at 11 days of age with a peak value of 130 ± 35 ng/ml at 12 days. The hormone was undetectable on days 14 and 15, rose to a second peak on day 18 (148 ± 56 ng/ml), and was again absent between 19 and 25 days of age. The concentration rose, as in the male, between days 25 and 28 to a level similar to that of the adult. The results show sexual differences in prepubertal gonadotrophin surges.
The LH peak at 12–13 days in both sexes appears to be light-dependent. The FSH peak at this time was affected by light but was not strictly light-dependent.
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The metabolic syndrome is a complex condition characterized by obesity, insulin resistance, decreased high-density lipoproteins, and hypertension associated with high risk of developing type 2 diabetes and cardiovascular disease. A major increase in the incidence of developing metabolic syndrome and related diseases is observed worldwide in association with a change toward a less active lifestyle and increased food consumption. Estrogen and the estrogen receptors (ERs) are well-known regulators of several aspects of metabolism, including glucose and lipid metabolism, and impaired estrogen signaling is associated with the development of metabolic diseases. This review will describe the key effects of estrogen signaling in metabolic and glucose sensing tissues, including the liver, pancreatic β cells, adipose tissue, and skeletal muscle. The impact on metabolic processes of impaired estrogen signaling and knock out of each ER subtype will also be discussed.
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The metabolism of 4-[4-14C]androstene-3,17-dione in the microsomal fraction of livers from male and female rats was investigated after hypothalamic deafferentation at two levels. It was found that frontal deafferentation at the retrochiasmatic level caused a complete 'feminization' of hepatic steroid metabolism in the male rat but was without effect in the female animal. Transection rostral to the suprachiasmatic nuclei was without effect in both sexes. A complete transition from male to female hepatic steroid metabolism after retrochiasmatic deafferentation was reached on day 4 after the operation and persisted for at least 10 weeks. The present results, taken together with previous investigations, indicate that the release of a 'feminizing' factor from the pituitary gland of the male rat is inhibited by a factor produced in, or transported through, the periventricular anterior hypothalamic region including the suprachiasmatic area. No effect on the hepatic steroid metabolism was observed after blinding of the rats suggesting that a diurnal rhythm is not essential to this control mechanism.
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Obesity has become a major health problem in many parts of the world. Estrogens are known to reduce adipose tissue mass in both humans and animals but the molecular mechanisms are not well characterized. We used gene expression profiling to study long-term effects of estrogen on gene expression in mouse white adipose tissue and hypothalamus. Overall, the effects of estrogen on hypothalamic gene expression were much smaller than the corresponding effects on white adipose tissue gene expression. We characterize in detail estrogenic regulation of glutathione peroxidase 3 (GPX3). Our studies suggest that GPX3 is a direct estrogen receptor α target gene in white adipose tissue. Since obesity is correlated with oxidative stress, and GPX3 has been demonstrated to be lower in obesity and higher after weight loss, we hypothesize that GPX3 is one important mediator of effects of estrogen in relation to fat mass. Additional genes that were affected by estrogen in adipose tissue include cell death-inducing DNA fragmentation factor, α-subunit-like effector A (CIDEA), a gene shown to be related to body fat in mice. We conclude that estrogen has large effects on gene expression in white adipose tissue and hypothesize that GPX3 and CIDEA could be important mediators of the effects of estrogen on fat mass.
