Sex-specific action of antiandrogens on androgen induced changes in hepatic microsomal 3β-hydroxysteroid dehydrogenase and 5α-reductase activity in the rat

1981 ◽  
Vol 98 (2) ◽  
pp. 261-266 ◽  
Author(s):  
E. Rodney Lax ◽  
Herbert Schriefers
Keyword(s):  
Enzyme Activities ◽  
Cyproterone Acetate ◽  
Reductase Activity ◽  
Hydroxysteroid Dehydrogenase ◽  
Female Rats ◽  
Male Rats ◽  
Induced Changes ◽  
Intrinsic Effect ◽  
Gonadal Status ◽  
Antiandrogenic Activity

Abstract. The ability of two antiandrogens, cyproterone acetate and flutamide, to block the induction of microsomal 3β-hydroxysteroid dehydrogenase and repression of microsomal 5α-reductase in rat liver following administration of 5α-dihydrotestosterone was investigated in male and female castrated and female gonadintact rats. Although both antiandrogens blocked the effects of 5α-dihydrotestosterone on the seminal vesicles and uteri of gonadectomized rats at the doses employed, cyproterone acetate showed no antiandrogenic activity against the two enzyme activities. On the contrary when cyproterone acetate was administered alone it elicited a response similar to that seen after androgen administration; when given simultaneously with 5α-dihydrotestosterone, the induction of 3β-hydroxysteroid dehydrogenase activity was greater than after either steroid alone. In contrast the non-steroidal antiandrogen, flutamide, which had no intrinsic effect on either enzyme activity, effectively blocked 5α-dihydrotestosterone mediated changes in the enzyme activities of female rats regardless of gonadal status. However the influence of 5α-dihydrotestosterone administration on these enzyme activities in male rats was not prevented.

DEVELOPMENTAL, DIURNAL AND OESTROUS CYCLE-DEPENDENT CHANGES IN THE ACTIVITY OF LIVER ENZYMES

1976 ◽  
Vol 68 (2) ◽  
pp. 265-272 ◽  
Author(s):  
ÅKE STENBERG
Keyword(s):  
Enzyme Activities ◽  
Reductase Activity ◽  
Maximal Activity ◽  
Oestrous Cycle ◽  
Female Rats ◽  
Male Rats ◽  
Supernatant Fraction ◽  
Second Phase ◽  
Developmental Phase ◽  
Male And Female Rats

SUMMARY The metabolism of [4-14C]4-androstene-3,17-dione was studied in the 105000 g microsomal and supernatant fractions of liver from developing rats of both sexes. The following enzyme activities were measured: 5β-reductase (supernatant fraction) and 5α-reductase, 17α- and 17β-hydroxysteroid reductases, 6β-, 7α- and 16α-hydroxylases (microsomal fraction). The activities of the 3α- and 3β-hydroxysteroid reductases were estimated by calculating the ratios of 3α-:5α- and 3β-: 5α-reduced metabolites formed, respectively. Most enzyme activities present at birth (i.e. 5β-reductase, 5α-reductase, 17β-hydroxysteroid reductase, 6β- and 7α-hydroxylase) increased until 20 days of age in both male and female rats. Between 20 and 30 days of age a number of masculine metabolic characteristics appeared in both sexes, i.e. the 16α-hydroxylase and the 17α-hydroxysteroid reductase were induced, the 5β-reductase activity rapidly increased and the 5α-reductase activity slightly decreased. During a third period beginning 30 days after birth the adult male enzyme activity pattern was completed by the induction of 3β-hydroxysteroid reductase and a further increase in the activity of 16α-hydroxylase. After 30 days of age a feminine type of liver metabolism also rapidly developed in female rats; the 16α-hydroxylase and the 17α-hydroxysteroid reductase activities disappeared, the 6β-hydroxylase and the 5β-reductase activities decreased and the 5α-reductase activity increased six times. The developmental patterns of enzyme activities in the rat liver are consistent with a first developmental phase (0–30 days of age) independent of hypophysial control and probably determined primarily by the genome of the liver cell and a second phase (from 30 days onwards) with increasing sexual differentiation under hypophysial control. This control is mediated by some kind of feminizing factor in female rats and possibly by some kind of androgen-elicited secretion of masculinizing factor(s) in male rats. The metabolism of [4-14C]4-androstene-3,17-dione was also studied during different times of the day and during different phases of the oestrous cycle. The 16α-hydroxylase activity showed a diurnal variation with higher values at noon than at midnight. The 5β-reductase activity reached a maximal activity during metoestrus.

PARTIAL FEMINIZATION OF HEPATIC STEROID METABOLISM IN MALE RATS AFTER NEONATAL ADMINISTRATION OF CYPROTERONE ACETATE

1975 ◽  
Vol 64 (2) ◽  
pp. 267-275 ◽  
Author(s):  
JAN-ÅKE GUSTAFSSON ◽  
MAGNUS INGELMAN-SUNDBERG ◽  
ÅKE STENBERG ◽  
FRIEDMUND NEUMANN
Keyword(s):  
Sexual Differentiation ◽  
Enzyme Activities ◽  
Cyproterone Acetate ◽  
Microsomal Fraction ◽  
Neonatal Period ◽  
Female Rats ◽  
Male Rats ◽  
Supernatant Fraction ◽  
Male And Female Rats ◽  
Neonatal Administration

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.

REGULATION OF THE ACTIVITIES OF THE ENZYMES INVOLVED IN THE METABOLISM OF STEROID HORMONES IN RAT LIVER: THE EFFECT OF 19-NORTESTOSTERONE AND THE INFLUENCE OF CYPROTERONE ACETATE ON THE ACTION OF TESTOSTERONE AND 5α-DIHYDROTESTOSTERONE

1974 ◽  
Vol 77 (2) ◽  
pp. 287-297 ◽  
Author(s):  
Rüdiger Ghraf ◽  
Edmund Rodney Lax ◽  
Hanns-Georg Hoff ◽  
Herbert Schriefers
Keyword(s):  
Weight Loss ◽  
Body Weight ◽  
Rat Liver ◽  
Enzyme Activities ◽  
Cyproterone Acetate ◽  
Hydroxysteroid Dehydrogenase ◽  
Seminal Vesicles ◽  
Normal Male ◽  
Steroid Hydroxylases ◽  
Drug Leads

ABSTRACT The androgens testosterone and 5α-dihydrotestosterone, the anabolic drug 19-nortestosterone and the anti-androgen cyproterone acetate were investigated with regard to their modifying action on the sexual differentiation of the activities of rat liver enzymes involved in steroid hormone metabolism. The activities of the enzymes (Δ4-5α-hydrogenase, 20-ketoreductase, 3α-and 3β-hydroxysteroid dehydrogenase, NAD- and NADP-dependent Δ4-3β-hydroxysteroid dehydrogenase, total steroid hydroxylases, 7α- and 16α-hydroxylase) were determined in cell-free liver fractions of male animals castrated on day 25 of life and killed on day 90; and of castrated animals which, from day 75 to 89 received daily sc injections (0.3 mg/100 g body weight) of the anabolic drug or the androgen only or in combination with cyproterone acetate (3 mg/100 g body weight). With the exception of 7α-hydroxylase castration leads to a feminization of the enzyme activity pattern. However, the degree of feminization varies from enzyme to enzyme. The administration of testosterone or of 5α-dihydrotestosterone reverses the effect of castration. With 5α-dihydrotestosterone activity values were reached which in some cases were significantly higher than those obtained with testosterone. Although both androgens restored the enzyme activities to the normal male values, neither androgen was able to compensate for the weight loss of the seminal vesicles in the dose administered. The administration of 19-nortestosterone in the same dose as testosterone is only 30 % as effective in restoring the weight loss of the seminal vesicles, but leads to identical activities of Δ4-5α-hydrogenase and of hydroxysteroid dehydrogenases as are found for testosterone. 19-Nortestosterone is without influence on the activities of total steroid hydroxylases and of 16α-hydroxylase. 16α-Hydroxylase is the only enzyme in which the activity enhancing effects of testosterone or of 5α-dihydrotestosterone can be completely blocked by the simultaneous administration of the anti-androgen cyproterone acetate. In all other enzyme activities the anti-androgen does not interfere with the effect of the androgens although it blocks their action on the weight restitution of the seminal vesicles by 60–70 %. 7α-Hydroxylase does not exhibit any androgen dependency. Neither castration nor the subsequent administration of the two androgens, or of the anabolic drug leads to any alterations in activity. However, it is interesting to note that the administration of cyproterone acetate does cause an increase in activity.

scholarly journals Different mechanisms of regulation of nuclear reduced nicotinamide–adenine dinucleotide phosphate-dependent 3-oxo steroid 5α-reductase activity in rat liver, kidney and prostate

1974 ◽  
Vol 142 (2) ◽  
pp. 273-277 ◽  
Author(s):  
Jan-Åke Gustafsson ◽  
Åke Pousette
Keyword(s):  
Testosterone Propionate ◽  
Reductase Activity ◽  
Nicotinamide Adenine Dinucleotide Phosphate ◽  
Female Rats ◽  
Male Rats ◽  
Regulatory Mechanisms ◽  
Oestradiol Benzoate ◽  
Liver And Kidney ◽  
Reduced Nicotinamide Adenine Dinucleotide ◽  
Hydroxy Steroid

The regulatory mechanisms involved in the control of the nuclear NADPH-dependent 3-ketosteroid 5α-reductase (5α-reductase) activity were studied in liver, kidney and prostate. The substrate used was [1,2-3H]androst-4-ene-3,17-dione (androstenedione) (for liver and kidney) or [4-14C]androstenedione (for prostate). The hepatic nuclear 5α-reductase activity was greater in female than in male rats, was greater in adult than in prepubertal female rats, increased after castration of male rats, but was not affected by treatment with testosterone propionate or oestradiol benzoate. These regulatory characteristics are in part different from those previously described for the hepatic microsomal 5α-reductase. The renal nuclear metabolism of androstenedione, i.e. 5α reduction and 17β-hydroxy steroid reduction, was relatively unaffected by sex, age, castration and treatment with testosterone propionate. However, treatment of castrated male rats with oestradiol benzoate led to a significant increase in the 5α-reductase activity and a significant decrease in the 17β-hydroxy steroid reductase activity. Finally, the nuclear 5α-reductase activity in prostate was androgen-dependent, decreasing after castration and increasing after treatment with testosterone propionate. In conclusion, the nuclear 5α-reductase activities in liver, kidney and prostate seem to be under the control of distinctly different regulatory mechanisms. The hypothesis is presented that whereas the prostatic nuclear 5α-reductase participates in the formation of a physiologically active androgen, 5α-dihydrotestosterone, this may not be the true function of the nuclear 5α-reductase in liver and kidney. These enzymes might rather serve to protect the androgen target sites in the chromatin from active androgens (e.g. testosterone) by transforming them into less active androgens (e.g. 5α-androstane-3,17-dione and/or 5α-dihydrotestosterone).

Abstract WP153: Post-Stroke Physical Exercise Improves Cognition in Middle-Aged Female Rats

Stroke ◽  
2020 ◽  
Vol 51 (Suppl_1) ◽  
Author(s):  
Sharnikha Saravanan ◽  
Weizhao Zhao ◽  
Kunjan R Dave ◽  
Miguel A Perez-Pinzon ◽  
Ami P Raval
Keyword(s):  
Enzyme Activity ◽  
Physical Exercise ◽  
Cognitive Decline ◽  
Fear Conditioning ◽  
Enzyme Activities ◽  
Female Rats ◽  
Male Rats ◽  
Mitochondrial Enzyme ◽  
Post Stroke ◽  
Activity Measurements

Background: A woman’s risk of a stroke increases exponentially following the onset of menopause, andpost-stroke cognitive decline is a significant consequence of stroke survivors. Our earlier study demonstrated that physical exercise (PE) reduced post-stroke brain injury and improved cognitive functions in male rats. The focus of our study is on the improvement of post-stroke cognitive function in female rats. Methods: Reproductively senescent Sprague-Dawley female rats were exposed to transient middle cerebral artery occlusion (tMCAO; 90 min) and randomly assigned to either PE or sham-PE groups. After 3-5 days, rats underwent sham-PE (0m/min speed) or PE (15m/min speed) for 30 mins either every day (continuous) or alternate day for five times on treadmill. The rats that underwent the alternate day paradigm were treated with ER-β agonist (DPN; 1mg/kg) or vehicle-DMSO immediately following PE/sham-PE sessions to determine the synergistic effect. Twenty-one days after the last PE/sham-PE, rats were tested for hippocampal-dependent contextual fear conditioning and freeze time was measured. Rat brains were processed for histology and infarct area was measured with MCID software. From a separate cohort of rat subjected to PE or sham-PE, brain tissue was harvested for various biochemical assays and mitochondrial enzyme activity measurements. Results: Post-tMCAO continuous PE did not reduce ischemic damage. However, alternate PE regimen with or without ER-β agonist reduced infract volume by 20% (p < 0.05) and 23% (p < 0.05), respectively as compared to no-PE. Similarly, alternate PE showed increased freezing on the second day of fear conditioning by 15% (p < 0.05), indicating improved spatial memory. Individual mitochondrial complex I, II, III and IV enzyme activity measurements demonstrated significant improvement in complex III-IV enzyme activities in the alternate PE treated group as compared to sham-PE. Conclusion: An alternate day PE paradigm and ER-β activation improves post-stroke mitochondrial enzyme activities and cognition in reproductively senescent female rats. Future studies delineating underlying mechanism could help identify therapies to prevent/reduce cognitive decline in menopausal female stroke patients.

ENDOCRINE REGULATION OF SEX-DEPENDENT HYDROXYSTEROID DEHYDROGENASE ACTIVITIES IN RAT KIDNEY: NADP-DEPENDENT MICROSOMAL 3α- AND 20β-HYDROXYSTEROID DEHYDROGENASE

1977 ◽  
Vol 73 (2) ◽  
pp. 289-300 ◽  
Author(s):  
R. GHRAF ◽  
E. R. LAX ◽  
W. WAGNER ◽  
H. SCHRIEFERS
Keyword(s):  
Rat Kidney ◽  
Hydroxysteroid Dehydrogenase ◽  
Thyroid Stimulating Hormone ◽  
Female Rats ◽  
Male Rats ◽  
Normal Female ◽  
Female Rat ◽  
Endocrine Regulation ◽  
Hypophysectomized Rats ◽  
Stimulating Hormone

SUMMARY The NADP-dependent microsomal kidney enzymes, 3α- and 20β-hydroxysteroid dehydrogenase (HSDH), which exhibit considerable sex differences in their activities (male: female activity ratios, 16:1 and 30:1 respectively), were investigated after interference with the pituitary–gonad and pituitary–adrenal systems. Prepubertal gonadectomy as well as hypophysectomy of mature male rats led to a decline in HSDH activity to almost that found in the normal female rat, whereas activities in female rats were unaffected. Testosterone induced typical male 3α-HSDH activity in both gonadectomized and hypophysectomized rats of either sex. Administration of 5α-dihydrotestosterone (5α-DHT) or 5α-androstane-3α, 17β-diol to hypophysectomized male rats was equally effective in restoring full 3α- and 20β-HSDH activities whereas 5α-androstane-3β, 17β-diol was less effective and dehydroepiandrosterone was ineffective. Simultaneous administration of cyproterone acetate did not block the inductive action of 5α-DHT. Administration of chorionic gonadotrophin, pregnant mare serum gonadotrophin or a combination of luteinizing hormone and follicle-stimulating hormone to hypophysectomized male rats all led to parallel increases in the weight of the seminal vesicles and in both renal enzyme activities; administration of growth hormone, prolactin or thyroid-stimulating hormone was ineffective. Adrenalectomy of gonadectomized, but not of hypophysectomized male rats, caused a further drop in activity to the normal female level. Adrenalectomy of otherwise intact rats did not affect either enzyme activity. The hypophysis was involved in the regulation of the two NADP-dependent renal HSDH activities through its gonadotrophic function in male rats; adrenal secretions were of little physiological significance.

TESTOSTERONE Δ4-REDUCTASE ACTIVITY IN RAT LIVER: HORMONAL CONTROL IN VIVO

1974 ◽  
Vol 63 (1) ◽  
pp. 181-189 ◽  
Author(s):  
D. C. PATTERSON ◽  
A. F. CLARK ◽  
C. E. BIRD
Keyword(s):  
Rat Liver ◽  
Reductase Activity ◽  
Enzyme Level ◽  
Hormonal Control ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Rate Limiting Step ◽  
Level Of Activity

SUMMARY The rate-limiting step in the metabolism of testosterone by the liver is reduction of the double bond in ring A. Using a spectrophotometric assay we have studied the effects of some hormonal manipulations on the levels (per mg protein) of testosterone Δ4-reductase activity in rat liver. While the levels of enzyme activity were higher for adult female rat liver than for adult male liver, there were no further changes in livers from female rats at day 15 of gestation. In male rats, castration increased, hypophysectomy decreased and adrenalectomy had no effect on the level of activity. Administration of oestradiol valerate increased the activity in intact and adrenalectomized animals and had no effect in the hypophysectomized or castrated groups. Administration of testosterone enanthate decreased the levels of activity in the castrated and adrenalectomized groups and had no effects in unoperated or hypophysectomized animals. When given together, the two hormones were antagonistic. Prolactin had no significant effects in either intact or hypophysectomized animals. Experiments with actinomycin D and cycloheximide indicated that the synthesis of new protein was involved in the effects of oestradiol in intact rats. All the changes reflected alterations in the microsomal enzyme level.

The role of neonatal and pubertal gonadal hormones in regulating the sex dependence of the hepatic microsomal testosterone 5-reductase activity in the rat

1985 ◽  
Vol 106 (1) ◽  
pp. 71-79 ◽  
Author(s):  
R. C. K. Pak ◽  
K. W. K. Tsim ◽  
C. H. K. Cheng
Keyword(s):  
Enzyme Activity ◽  
Adult Female ◽  
Reductase Activity ◽  
Gonadal Hormones ◽  
Female Rats ◽  
Male Rats ◽  
Female Rat ◽  
Similar Treatment ◽  
Control Value ◽  
Level Of Activity

ABSTRACT Hepatic microsomal testosterone 5-reductase activity was approximately fourfold higher in adult female rats than in males. This discrepancy was only partly androgen-dependent since gonadectomy of male rats at 68 days of age resulted in only a partial increase of the enzyme activity. This increase was reversible by the administration of testosterone. Similar treatment, however, produced no effect in the female rat, indicating that there is a sex difference in testosterone responsivity. Castration of newborn male rats resulted in a marked increase in the basal enzyme activity. This increase was not affected by treating the adults with testosterone. Giving testosterone to male rats immediately after neonatal gonadectomy, or to newborn female rats, did not produce the male pattern of both the basal enzyme activity and the testosterone responsivity in adulthood. These results suggest that a brief exposure to neonatal androgen is not critical for the expression of the male type of enzyme activity, but that the continuous presence of the male gonads up to and including the pubertal period is essential. Exposure of pubescent female rats to testosterone during the period from 35 to 50 days of age resulted in a significant increase in testosterone sensitivity when tested at 90 days of age, suggesting that pubertal exposure to androgen is important for the expression of testosterone responsivity in adulthood. The sensitivity was potentiated when the animals were ovariectomized before puberty. Furthermore, the enzyme activity in prepubertally ovariectomized female rats was significantly lower than that in adult gonadectomized animals. The decreased level of activity returned to the control value when oestrogen was replaced during puberty, indicating that peripubertal oestrogen exposure is required for maintaining the high level of activity found in adult female rats. The present findings suggest that the pubertal period represents a sensitive phase during which sex hormones act to regulate the sexual differentiation of testosterone 5-reductase activity in the rat. J. Endocr. (1985) 106, 71–79

SEXUAL DIFFERENCE IN THE EFFECT OF CYPROTERONE ACETATE AND GLUCOCORTICOIDS ON α2u-GLOBULIN IN GONADECTOMIZED RATS

1978 ◽  
Vol 79 (1) ◽  
pp. 135-136 ◽  
Author(s):  
G. VANDOREN ◽  
W. HEYNS ◽  
G. VERHOEVEN ◽  
P. DE MOOR
Keyword(s):  
Cyproterone Acetate ◽  
Sexual Difference ◽  
Testosterone Propionate ◽  
Female Rats ◽  
Male Rats ◽  
Ovariectomized Rats ◽  
Major Protein ◽  
Intact Male ◽  
Male And Female Rats ◽  
Pituitary Glands

Laboratorium voor Experiméntele Geneeskunde, Katholieke Universiteit Leuven, Rega Instituut, Minderbroedersstraat 10, B-3000 Leuven, Belgium (Received 28 March 1978) The synthesis of α2u-globulin, the major protein found in the urine of adult male rats (Roy & Neuhaus, 1966; Roy, Neuhaus & Harmison, 1966), is controlled by several hormones. Androgens, growth hormone, thyroxine and glucocorticoids promote the synthesis of this protein, whereas oestrogens and a factor secreted by ectopically transplanted pituitary glands suppress it (Roy & Neuhaus, 1967; Roy, 1973; Kurtz, Sippel & Feigelson, 1976; Vandoren, Van Baelen, Verhoeven & De Moor, 1978). Cyproterone acetate (CA), a potent antiandrogen, inhibits the androgenic induction of α2u-globulin in ovariectomized rats, but does not suppress its synthesis in intact male rats (Roy, 1976). In the present experiments, the influence of CA on the induction of α2u-globulin by testosterone propionate (TP) in the serum of gonadectomized male and female rats was compared. Evidence is presented for

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