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P. SÖDERSTEN and J. -Å. GUSTAFSSON

Castrated sexually inactive rats were treated with the synthetic androgen 17β-hydroxy-17α-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R 1881), testosterone benzoate (TB), 5α-dihydrotestosterone benzoate (DHTB) or oestradiol benzoate (OB) and tested for sexual behaviour. The synthetic androgen, R 1881, was as potent as TB in stimulating sexual behaviour and OB stimulated all aspects of copulatory behaviour but DHTB had no significant effect. The synthetic androgen, R 1881, is not metabolized by target cells and rapid metabolism could explain the failure of DHTB to stimulate sexual behaviour.

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C D Soontjens, J J Rafter and J-Å Gustafsson

Introduction

Nuclear receptors

The cell's long-term response to environmental stimuli is associated with changes in cellular proliferation, differentiation and metabolism mediated by the modification of the protein content of a cell via differential gene expression. Transcription factors that regulate the activity of specific genes receive such stimuli in different ways. Peptide hormones, growth factors and neurotransmitters bind and activate cell surface receptors, initiating a cascade of intracellular signals by a complex system of secondary messengers that leads to the activation of transcription factors. Other transcription factors that are responsive to steroid and thyroid hormones, retinoids and other signalling molecules belong to the distinct class of nuclear receptors present in the cytoplasm or nucleus. Direct and high affinity binding of a specific signalling molecule or ligand activates the nuclear receptors to exert control on the rate of transcription of target genes via interaction with specific DNA sequences

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A. Mode, J.-Å. Gustafsson, P. Södersten and P. Eneroth

ABSTRACT

Masculine sexual behaviour was induced in castrated sexually inactive but experienced male rats by testosterone-filled constant-release implants or daily injections of the synthetic androgen 17β-hydroxy-17α-methyl-estra-4,9,11-triene-3-one (methyltrienolone, R 1881), which resists metabolism by target organs. Feminization of the hepatic androgen metabolism by subcutaneous implantation of osmotic minipumps, which delivered a constant amount of human GH, did not affect the behavioural response of castrated rats to testosterone. Testosterone implants were only minimally effective in inducing male behaviour in ovariectomized female rats, but R 1881 was as effective in stimulating male behaviour in females as in males. Testosterone-treated but not R 1881-treated females showed pronounced female sexual behaviour in response to progesterone treatment despite the absence of measureable amounts of oestradiol-17β in peripheral blood. The results provide evidence that masculine sexual behaviour can be activated by an androgen in the absence of oestrogenic stimulation and suggest that the sex difference in the behavioural response to testosterone may be due to a sex difference in the metabolism of androgens by the brain.

J. Endocr. (1984) 100, 245–248

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S. Jeffery, C. A. Wilson, A. Mode, J.-Å. Gustafsson and N. D. Carter

ABSTRACT

Rat liver exhibits a reversed sexual dimorphism of its two endogenous soluble carbonic anhydrase (CA) isozymes, CA II and CA III. Normal males have hepatic CA III concentrations ten–twenty times those in the female, while female liver contains two–three times more CA II than the male. Hypophysectomy abolishes this sexual differentiation, having no effect on male liver but producing isozyme concentrations in the female liver similar to those in the male. Infusion of a continuous level of GH into male rats induces a female-like isozyme pattern for both CA II and CA III.

J. Endocr. (1986) 110, 123–126

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A. Mode, E. Wiersma-Larsson, A. Ström, P. G. Zaphiropoulos and J.-Å. Gustafsson

ABSTRACT

The effects of GH on the major constitutive sex-specific forms of cytochrome P-450 (P-45015β and P-45016α) were studied in hypophysectomized rats at the mRNA level. Time-course experiments were performed with or without simultaneous treatment with thyroxine and cortisol. Intermittent administration of GH, mimicking the male secretory pattern, caused complete masculinization of the male specific P-45016α at a pretranslational level in the absence and presence of thyroxine and cortisol. When GH was administered continuously, mimicking the female secretory pattern, the female specific P-45015β was induced, an effect that was dramatically potentiated by simultaneous treatment with thyroxine and cortisol. A synergistic effect of thyroxine and cortisol at a pretranslational level was demonstrated, although the major potentiating effect could be attributed to thyroxine. Thus it was concluded that GH, depending on its secretory pattern is the sole masculinizing factor for cytochrome P-450, and that it is also a feminizing factor, although this activity requires the synergistic action of thyroid hormones and glucocorticoids to reach its full effect.

Journal of Endocrinology (1989) 120, 311–317

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M. Warner, P. Tollet, M. Strömstedt, K. Carlström and J.-Å. Gustafsson

ABSTRACT

In an effort to understand the physiological functions of cytochrome P-450 in the central nervous system and pituitary gland, we evaluated changes in the level of the enzyme as a function of the endocrine status of rats and the ability of these tissues to synthesize or degrade steroids. The P-450 content of microsomes prepared from the hypothalamic preoptic area (HPOA), the olfactory lobes and the cerebrum was 0·040 ± 0·009 and in the pituitary gland 2·2 ± 0·6 (s.d.) nmol/g tissue. The P-450 content of the HPOA and olfactory lobes, but not of the rest of the cerebrum, was influenced by the endocrine status of rats. In microsomes it increased five- to tenfold over control levels during late pregnancy in the olfactory lobes and during lactation in the HPOA, and in both brain regions treatment of rats with 5α-dihydrotestosterone (DHT) caused an eight- to tenfold increase in the P-450 content. Androstenedione was not a good substrate for brain P-450. The level of androstenedione 19-hydroxylase in the olfactory lobe microsomal fraction was 0·50± 0·06 nmol 19-hydroxyandrostenedione formed/g tissue per h. This activity was tenfold lower in other brain areas and was not detectable in the pituitary gland. The rate of aromatization of androstenedione to oestradiol in the HPOA and olfactory lobe of lactating rats was 0·46 ± 0·14 and 0·38 ± 0·05 pmol/oestradiol formed/g tissue per h respectively. 5α-Androstane-3β,17β-diol (A-5α-3β,17β-diol) was a much better substrate for P-450 throughout the brain and pituitary gland. Catalytic activity was 125 ± 46 and 307 ±108 nmol triols formed/g tissue per h in the brain and pituitary gland respectively. The P-450 responsible for this catalytic activity was isolated and its substrate specificity examined. In addition to A-5α-3β,17β-diol, 5-androstene-3β,17β-diol, dehydroepiandrosterone and DHT were also substrates, with turnover numbers of 27, 8, 12 and 1 mol product/mol P-450 per min respectively. None of these catalytic activities was induced in the rat brain during pregnancy, lactation or DHT treatment. The enzyme was also present in the brains of mice but not guinea-pigs.

The yield of P-450 from the mitochondrial fraction of the HPOA and olfactory lobes in control rats was 0·01–0·02 nmol/g tissue. This increased tenfold during pregnancy. Immunological evidence for the presence of the cholesterol side-chain cleavage enzyme P-450 SCC was found in the HPOA and olfactory lobes of pregnant but not of control rats. However, no SCC catalytic activity was detectable in these brain mitochondrial P-450 fractions. From these studies we conclude that there is a major influence of the endocrine system on the content and quality of P-450 in the brain. However, the function and substrate specificities of these P-450s as well as of those in the pituitary gland remain to be characterized.

Journal of Endocrinology (1989) 122, 341–349

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P. Södersten, P. Eneroth, T. Hansson, A. Mode, D. Johansson, B. Näslund, T. Liang and J.-Å. Gustafsson

ABSTRACT

Sexual behaviour was induced in castrated male rats with oestradiol-17β- or testosterone-filled constant-release implants. Testosterone-induced sexual behaviour was unaffected by treatment with the 5α-reductase inhibitor 17β-N,N-diethylcarbamoyl-4-aza-5α-androstan-3-one (4-MA; 16·7 mg/day) but treatment with the aromatization inhibitor 1,4,6-androstatriene-3,17-dione (ATD; 10 mg/day) prevented testosterone from inducing the behaviour. Sexual behaviour could be activated in castrated rats treated with testosterone plus ATD by treatment with 4-MA or with implants filled with a low dose of oestradiol. Lordosis behaviour induced in ovariectomized rats with testosterone-filled implants and progesterone was blocked by ATD treatment and could not be activated with 4-MA but oestradiol implants restored the display of lordosis in the testosterone plus ATD-treated females. 4-MA inhibited the in-vitro formation of [14C]5α-dihydrotestosterone from [14C]testosterone by combined preoptic and hypothalamic tissue at all doses tested and a high dose of oestradiol exerted a similar effect. The results suggest that androgen aromatization is required for testosterone-activated female sexual behaviour but not for testosterone-activated male sexual behaviour. It is suggested that oestradiol normally acts to control the sexual behaviour of male rats by modifying neural androgen metabolism.

J. Endocr. (1986) 111, 455–462

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B. Chatterjee, W. F. Demyan, J.-Å. Gustafsson, M. W. Harris, T. Hökfelt, G. Norstedt and A. K. Roy

ABSTRACT

Anterior hypothalamic deafferentation and infusion of human GH (hGH) in the normal male rat caused a marked reduction in the hepatic concentration of α2u-globulin, an androgen-dependent protein. Although s.c. injections of hGH (twice-daily) resulted in more than a 50% reduction in the hepatic level of α2u-globulin, the same dose of hGH when administered continuously through osmotic minipumps caused a threefold greater inhibition. The decreased hepatic concentration of α2u-globulin after hGH administration was associated with corresponding changes in the hepatic level of translatable α2u-globulin messenger RNA. Continuous infusion of hGH through osmotic minipumps and removal of the anterior hypothalamic influence on GH secretion by deafferentation also caused a marked reduction in the cytoplasmic androgen-binding activity of the rat liver. These results suggest that alterations in the level and pattern of GH secretion may influence hepatic androgen-binding activity and α2u-globulin synthesis.

J. Endocr. (1986) 108, 351–355

Open access

K L Gustafsson, K H Nilsson, H H Farman, A Andersson, V Lionikaite, P Henning, J Wu, S H Windahl, U Islander, S Movérare-Skrtic, K Sjögren, H Carlsten, J-Å Gustafsson, C Ohlsson and M K Lagerquist

Estrogen treatment has positive effects on the skeleton, and we have shown that estrogen receptor alpha (ERα) expression in cells of hematopoietic origin contributes to a normal estrogen treatment response in bone tissue. T lymphocytes are implicated in the estrogenic regulation of bone mass, but it is not known whether T lymphocytes are direct estrogen target cells. Therefore, the aim of this study was to determine the importance of ERα expression in T lymphocytes for the estrogenic regulation of the skeleton using female mice lacking ERα expression specifically in T lymphocytes (Lck-ERα−/−) and ERαflox/flox littermate (control) mice. Deletion of ERα expression in T lymphocytes did not affect bone mineral density (BMD) in sham-operated Lck-ERα−/− compared to control mice, and ovariectomy (ovx) resulted in a similar decrease in BMD in control and Lck-ERα−/− mice compared to sham-operated mice. Furthermore, estrogen treatment of ovx Lck-ERα−/− led to an increased BMD that was indistinguishable from the increase seen after estrogen treatment of ovx control mice. Detailed analysis of both the appendicular (femur) and axial (vertebrae) skeleton showed that both trabecular and cortical bone parameters responded to a similar extent regardless of the presence of ERα in T lymphocytes. In conclusion, ERα expression in T lymphocytes is dispensable for normal estrogenic regulation of bone mass in female mice.

Free access

L Lundholm, G Bryzgalova, H Gao, N Portwood, S Fält, K D Berndt, A Dicker, D Galuska, J R Zierath, J-Å Gustafsson, S Efendic, K Dahlman-Wright and A Khan

The aim of this study was to validate the role of estrogen receptor α (ERα) signaling in the regulation of glucose metabolism, and to compare the molecular events upon treatment with the ERα-selective agonist propyl pyrazole triol (PPT) or 17β-estradiol (E2) in ob/ob mice. Female ob/ob mice were treated with PPT, E2 or vehicle for 7 or 30 days. Intraperitoneal glucose and insulin tolerance tests were performed, and insulin secretion was determined from isolated islets. Glucose uptake was assayed in isolated skeletal muscle and adipocytes. Gene expression profiling in the liver was performed using Affymetrix microarrays, and the expression of selected genes was studied by real-time PCR analysis. PPT and E2 treatment improved glucose tolerance and insulin sensitivity. Fasting blood glucose levels decreased after 30 days of PPT and E2 treatment. However, PPT and E2 had no effect on insulin secretion from isolated islets. Basal and insulin-stimulated glucose uptake in skeletal muscle and adipose tissue were similar in PPT and vehicle-treated ob/ob mice. Hepatic lipid content was decreased after E2 treatment. In the liver, treatment with E2 and PPT increased and decreased the respective expression levels of the transcription factor signal transducer and activator of transcription 3, and of glucose-6-phosphatase. In summary, our data demonstrate that PPT exerts anti-diabetic effects, and these effects are mediated via ERα.