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.

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.

Aspartic acid administered neonatally affects ventilation of male and female rats differently

1986 ◽  
Vol 61 (2) ◽  
pp. 780-784 ◽  
Author(s):  
E. H. Schlenker ◽  
M. Goldman
Keyword(s):  
Aspartic Acid ◽  
Ventilatory Response ◽  
Minute Ventilation ◽  
Female Rats ◽  
Male Rats ◽  
Metabolic Rates ◽  
Control Male ◽  
Male And Female ◽  
Male And Female Rats ◽  
Neonatal Administration

In this study ventilation was evaluated in 12-mo-old male and female rats who had received large doses of aspartic acid neonatally. Rats of both sexes treated with aspartic acid were obese, stunted, and exhibited hypogonadism. Although metabolic rates of the aspartic acid-treated rats were not different compared with sex-matched controls, ventilatory patterns were different. Aspartic acid-treated females breathed with a smaller tidal volume (VT), higher frequency (f), and similar minute ventilation (VE) compared with control females. This pattern is commonly observed in many patients who are obese. The aspartic acid-treated females responded to hypercapnic and hypoxic challenges by increasing f more than VT. Tissue pocket gases (PCO2 and PO2) of aspartic acid-treated females were normal. In contrast, aspartic acid-treated males hypoventilated compared with control males. Tissue pocket gas values suggested that aspartic acid-treated males were hypoxemic and hypercapnic. Moreover, the response of aspartic acid-treated males to hypercapnia was parallel to but was less than that of control male rats. The ventilatory response of aspartic acid-treated male rats to hypoxia was blunted. This study has shown that neonatal administration of aspartic acid causes a decreased ventilation and blunted response to hypoxia in adult male but not female rats.

scholarly journals Oestrogenic effects of neonatal administration of raloxifene on hypothalamic-pituitary-gonadal axis in male and female rats

Reproduction ◽  
2001 ◽  
pp. 915-924 ◽  
Author(s):  
L Pinilla ◽  
LC Gonzalez ◽  
F Gaytan ◽  
M Tena-Sempere ◽  
E Aguilar
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Body Weight ◽  
Oestrogen Receptor ◽  
Female Rats ◽  
Male Rats ◽  
Selective Oestrogen Receptor Modulators ◽  
Male And Female Rats ◽  
The Central Nervous System ◽  
Neonatal Administration

Selective oestrogen receptor modulators constitute a family of drugs that are used increasingly in the management of oestrogen-associated pathology. Raloxifene is a selective oestrogen receptor modulator that is used to treat and prevent osteoporosis in post-menopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol concentrations have been widely analysed, but very few studies have investigated the possible actions of this drug on the central nervous system. The central nervous system of the newborn rat is very sensitive to oestrogen action. In this study a series of experiments was conducted to analyse the effects of different doses of raloxifene (50, 100, 250 or 500 microg per rat per day) administered to neonatal rats on days 1-5 of age. Female rats treated with raloxifene showed decreased gonadotrophin secretion, hyperprolactinaemia, advanced vaginal opening, decreased body weight, persistent presence of cornified epithelial cells in vaginal smears, anovulation, inhibition of positive feedback between oestradiol and LH, and infertility. Male rats showed delayed balanopreputial separation, reduced body weight and hyperprolactinaemia. All these changes resemble those obtained after neonatal administration of oestradiol benzoate, thus indicating, for the first time, that raloxifene exerts an oestrogenic action on the hypothalamic-pituitary structures controlling reproductive function in rats.

PREVENTION OF CENTRAL DEFEMINIZATION BUT NOT MASCULINIZATION IN MALE RATS BY INHIBITION NEONATALLY OF OESTROGEN BIOSYNTHESIS

1977 ◽  
Vol 74 (3) ◽  
pp. 375-382 ◽  
Author(s):  
J. T. M. VREEBURG ◽  
PAULA D. M. VAN DER VAART ◽  
P. VAN DER SCHOOT
Keyword(s):  
Sexual Function ◽  
Ovarian Function ◽  
Testosterone Propionate ◽  
Neonatal Period ◽  
Female Rats ◽  
Male Rats ◽  
Normal Male ◽  
Male And Female ◽  
Male And Female Rats ◽  
Copulatory Behaviour

SUMMARY An inhibitor of aromatization, androsta-1,4,6-triene-3,17-dione (ATD), was administered to newborn male and female rats and various parameters of gonadal and sexual function were examined in adulthood. Males injected with 1 mg ATD on the day of birth (day 1) and on days 3, 5, 10 and 15 postnatally, subsequently (day 55) showed normal male and female copulatory behaviour, but were not able to maintain cyclicity in ovarian transplants. When the ATD was administered by Silastic implants, however, cyclicity in ovarian transplants did occur. Neither form of treatment brought about significant changes in neonatal plasma or testicular testosterone concentrations. Female rats implanted on day 3 of life with Silastic capsules containing ATD and then given an injection of 0·25 mg testosterone propionate on day 5 subsequently showed normal ovarian function, whereas the controls receiving only testosterone propionate showed persistent vaginal cornification, anovulation and polyfollicular ovaries. The results support the view that the central conversion of testicular androgens to oestrogens during the neonatal period is necessary to abolish cyclic gonadotrophin release and to suppress female copulatory behaviour.

Incidence, growth and oestradiol-receptor levels of 7,12-dimethylbenz(a)anthracene-induced mammary tumours in rats: effects of neonatal sex steroids and oestradiol implants

1982 ◽  
Vol 95 (3) ◽  
pp. 357-368 ◽  
Author(s):  
G. Verhoeven ◽  
G. Vandoren ◽  
W. Heyns ◽  
E. R. Kühn ◽  
J. P. Janssens ◽  
...  
Keyword(s):  
Female Rats ◽  
Male Rats ◽  
Intact Female ◽  
Intact Male ◽  
Tumour Incidence ◽  
Tumour Induction ◽  
Male And Female Rats ◽  
Neonatal Administration ◽  
Low Levels ◽  
Intact Rats

The effects of neonatally administered steroids on the sensitivity of the mammary gland to tumour induction by 7,12-dimethylbenz(a)anthracene was studied as a model for delayed (de)differentiating effects of steroid hormones. Immediately after birth male and female rats were gonadectomized and treated with testosterone, oestradiol or oil. Control animals were left intact. On day 45 all the gonadectomized animals and some of the control animals received an implant which delivered continuous low levels of oestradiol. The carcinogen was administered on day 55. The administration of an oestradiol implant, which increased prolactin levels in all animals, markedly reduced tumour incidence in intact female rats and increased tumour incidence in intact male rats. Neonatal administration of testosterone or oestradiol did not significantly influence tumour incidence, histopathology or oestradiol responsiveness in neonatally gonadectomized rats but tended to decrease tumour oestradiol-receptor levels. This lack of effect of neonatal steroids in gonadectomized animals suggests that the effects observed by other authors in intact rats are mediated by changes in gonadal secretions. It is concluded that the hormonal environment during and after tumour induction plays a major role in the development of 7,12-dimethylbenz(a)anthracene-induced mammary carcinomas.

scholarly journals Androgen responsiveness of the liver of the developing rat

1974 ◽  
Vol 144 (2) ◽  
pp. 225-229 ◽  
Author(s):  
J-Å Gustafsson
Keyword(s):  
Testosterone Propionate ◽  
Neonatal Period ◽  
Female Rats ◽  
Male Rats ◽  
Second Phase ◽  
Final Phase ◽  
Male And Female ◽  
Androgen Treatment ◽  
Male And Female Rats ◽  
Developing Rat

The activities of the hepatic microsomal 2α-, 2β-, 7α- and 18-hydroxylase systems active on 5α-[4-14C]androstane-3α,17β-diol were studied in male and female rats which had been castrated at birth and at the age of 7, 13, 21, 27, 34, 43 and 55 days, treated for 5 days with 2mg of testosterone propionate/kg body weight and killed 6 days after castration. The 7α-hydroxylase system was affected very little by androgen treatment at all stages during development. On the other hand it was found that the rat liver passed through three phases during development with respect to androgen responsiveness as judged by changes in the activities of the 2α, 2β- and 18-hydroxylase systems: a first phase (from the neonatal period up to about 19 days of age) with a relative androgen unresponsiveness in both male and female rats, a second phase (from about 27 to about 33 days of age) when male and female rats responded equally well to androgens and a final phase (from about 40 days of age) with a successively decreasing androgen responsiveness in female rats but with a retained responsiveness in male rats. The hypothesis is presented that neonatal imprinting of the liver by testicular androgen(s) determines the development and degree of androgen responsiveness of liver tissue in the rat.

EFFECT OF NEONATAL ADMINISTRATION OF STEROIDS OR GONADECTOMY UPON OESTRADIOL-INDUCED LUTEINIZING HORMONE RELEASE IN RATS OF BOTH SEXES

1980 ◽  
Vol 85 (1) ◽  
pp. 69-74 ◽  
Author(s):  
F. GOGAN ◽  
I. A. BEATTIE ◽  
M. HERY ◽  
E. LAPLANTE ◽  
C. KORDON
Keyword(s):  
Luteinizing Hormone ◽  
Sexual Differentiation ◽  
Female Rats ◽  
Male Rats ◽  
Ovariectomized Rats ◽  
Hormone Release ◽  
Adult Rats ◽  
Luteinizing Hormone Release ◽  
Neonatal Administration ◽  
Lh Secretion

SUMMARY Implantation of oestradiol into adult rats of both sexes induced different patterns of LH secretion depending on the time at which gonadectomy or testosterone injection were performed. Castration 2 h after birth allowed an LH peak to occur daily at 18.00 h, but its amplitude was lower than that of adult gonadectomized female rats treated with oestradiol. Castration 24 h after birth elicited two kinds of response; a circadian discharge of LH lower than that of male rats gonadectomized 2 h after birth or a steady low level of LH. The LH rhythmicity induced by implantation of oestradiol was not seen after castration at 8 weeks of age. Neonatal administration of testosterone to female rats prevented the LH peak induced by oestradiol that was seen in adult ovariectomized rats. Neonatal or adult ovariectomy did not interfere with the rhythmical response of LH after implantation of oestradiol. Thus, it is concluded that sexual differentiation of the hypothalamus is primarily of masculine origin.

INFLUENCE OF ADRENAL STEROIDS ON LIVER ENZYMES OF NEONATALLY CASTRATED RATS

1974 ◽  
Vol 63 (1) ◽  
pp. 103-116 ◽  
Author(s):  
JAN-ÅKE GUSTAFSSON ◽  
ÅKE STENBERG
Keyword(s):  
Enzyme Activities ◽  
Microsomal Fraction ◽  
Liver Enzymes ◽  
Male Rats ◽  
Supernatant Fraction ◽  
Secondary Effects ◽  
Hepatic Enzyme ◽  
Adrenal Androgens ◽  
Androgenic Regulation ◽  
Central Factors

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.

EFFECTS OF DIHYDROTESTOSTERONE AND OESTRADIOL ON SEXUAL DIFFERENTIATION IN MALE RATS

1980 ◽  
Vol 84 (3) ◽  
pp. 397-407 ◽  
Author(s):  
P. VAN DER SCHOOT
Keyword(s):  
Sexual Differentiation ◽  
Testosterone Propionate ◽  
Neonatal Period ◽  
Combined Treatment ◽  
Female Rats ◽  
Male Rats ◽  
Normal Male ◽  
Oestradiol Benzoate ◽  
The Brain ◽  
Copulatory Behaviour

Adult male rats which had been castrated at birth and treated with the non-aromatizable androgen dihydrotestosterone propionate (DHTP) showed incomplete copulatory behaviour. When tested with oestrous female rats during treatment with testosterone propionate (TP) they readily mounted these females and showed frequent penile intromissions but rarely ejaculated. In a long series of observations the proportion of ejaculating rats in tests of 30 min did not exceed 50%. Neonatally castrated rats treated with DHTP during infancy thus seemed to be capable of ejaculation in adulthood during treatment with TP, but the threshold for the occurrence of the ejaculatory reflex seemed to be higher than in normal male rats. By replacing treatment in adulthood with TP by a combined treatment with DHTP and oestradiol benzoate (OB), the frequency of ejaculation was not increased. It was concluded that the incomplete copulatory behaviour was not due to reduced efficiency of aromatization of androgen within the brain of these rats. The addition of OB to DHTP during the neonatal period of treatment enhanced the frequency of ejaculation in adulthood. The combined treatment of 0·1 mg DHTP on days 1, 3 and 5 with 0·01 mg OB on day 1 made adult copulatory behaviour during treatment with TP indistinguishable from that of rats castrated on day 10 or rats castrated at birth and treated with TP during infancy. It was concluded that the masculine organization of systems and structures involved in the display of male copulatory behaviour occurs under the influence of both non-aromatizable androgen and oestrogen, oestrogen being most likely the substance required to 'organize' the central nervous aspects of the regulation of this behaviour. The absence neonatally of nonaromatizable androgen and/or oestrogen results in specific deficiencies in adult copulatory behaviour as compared with the behaviour of normal male rats.

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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