The Role of the Hypophysis in the Regulation of Sex Differences in the Activities of Enzymes involved in Hepatic Steroid Hormone Metabolism

Lax, E. R.; Hoff, Hanns-Georg; Ghraf, Rüdiger; Schröder, E; Schriefers, Herbert

doi:10.1515/bchm2.1974.355.2.1325

Cited by 32 publications

(10 citation statements)

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“…Several other groups later confirmed the requirement of an intact pituitary gland for gonadal hormones to regulate sex-dependent drug metabolism (Denef, 1974;Gustafsson and Stenberg, 1974;Lax et al, 1974). Further investigations implicated GH, a 191-amino acid protein hormone secreted by the anterior pituitary gland, in mediating the effects of gonadal hormones on liver drug and steroid metabolism.…”

Section: Gonadal and Pituitary Hormonal Determinants Of Hepatic Sex Dmentioning

confidence: 93%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Molecular Pharmacology

634

584

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Sex differences in pharmacokinetics and pharmacodynamics characterize many drugs and contribute to individual differences in drug efficacy and toxicity. Sex-based differences in drug metabolism are the primary cause of sex-dependent pharmacokinetics and reflect underlying sex differences in the expression of hepatic enzymes active in the metabolism of drugs, steroids, fatty acids and environmental chemicals, including cytochromes P450 (P450s), sulfotransferases, glutathione transferases, and UDP-glucuronosyltransferases. Studies in the rat and mouse liver models have identified more than 1000 genes whose expression is sex-dependent; together, these genes impart substantial sexual dimorphism to liver metabolic function and pathophysiology. Sex differences in drug metabolism and pharmacokinetics also occur in humans and are due in part to the female-predominant expression of CYP3A4, the most important P450 catalyst of drug metabolism in human liver. The sexually dimorphic expression of P450s and other liver-expressed genes is regulated by the temporal pattern of plasma growth hormone (GH) release by the pituitary gland, which shows significant sex differences. These differences are most pronounced in rats and mice, where plasma GH profiles are highly pulsatile (intermittent) in male animals versus more frequent (nearly continuous) in female animals. This review discusses key features of the cell signaling and molecular regulatory mechanisms by which these sex-dependent plasma GH patterns impart sex specificity to the liver. Moreover, the essential role proposed for the GH-activated transcription factor signal transducer and activator of transcription (STAT) 5b, and for hepatic nuclear factor (HNF) 4␣, as mediators of the sexdependent effects of GH on the liver, is evaluated. Together, these studies of the cellular, molecular, and gene regulatory mechanisms that underlie sex-based differences in liver gene expression have provided novel insights into the physiological regulation of both xenobiotic and endobiotic metabolism.

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Section: Gonadal and Pituitary Hormonal Determinants Of Hepatic Sex Dmentioning

confidence: 93%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Molecular Pharmacology

634

584

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“…Renal 3a-hydroxysteroid dehydrogenase like hepatic 3-hydroxysteroid dehydrogenase activity is androgendependent with male activity higher than female. Both activities react to gonadectomy in the same manner (Ghraf et al, 1975b;Lax et al, 1974). However, whereas oestradiol administration blocks androgenic induction of the hepatic activity in the presence of high exogenous androgen levels, it does not affect androgenic induction of the renal activity.…”

Section: Discussionmentioning

confidence: 99%

Antiandrogenic Effects of Oestradiol on Enzyme Activities of Hepatic Steroid Metabolism

Lax¹,

Baumann²,

Schriefers³

2009

Exp Clin Endocrinol Diabetes

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Intact female rats and gonadectomized rats of both sexes were administered 0.5 mg 5x-dihydrotestosterone s.c. daily for 15 days. On the 16th day the activities of hepatic microsomal 3xand 3ß-hydroxysteroid dehydrogenase and 5x.reductase were determined. Androgen. treatment increased the activity of both hydroxysteroid dehydrogenases and decreased the activity of the 50reductase in all animal models. Simultaneous administration of a steroidal antiandrogen, cyproterone (5mg/day; 15 days s.c.) did not prevent this androgenic effect, whereas oestradiol (5 g/day;15 days s.c.) completely reversed the action of 5-dihydrotesthsterone. The nonsteroidal antiandrogen, flutamide, also exhibited a potent antiandrogenic influence on these enzyme activities in female rats, whereas its antagonizing action in males was limited. The effects of cyproterone, oestradiol and flutam. ide on enzyme activities of hepatic steroid metabolism do not reflect the biological activity of these compounds on the weights of target organs (uterus, seminal vesicle, levator ani).

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“…This may be easily explained, since only after hypophysectomy does the activity of hepatic 5a-reductase reach such low values (Lax et al 1974) that 3-oxo-4-ene-steroids, released from the adrenal after stimulation with ACTH, retain an adequately long half-life (Colby, Malendowicz, Caffrey & Kitay, 1974).…”

Section: Discussionmentioning

confidence: 99%

“…The housing conditions and nutrition have been described by Knappen, Korn, Wilk & Schulz (1973). Gonadectomy was performed on day 25 of life, adrenalectomy by the dorsolateral approach and hypophysectomy by the transauricular approach on day 50 of life (for further details see Lax et al 1974). Adrenalectomized rats received 0-9% (w/v) saline.…”

Section: Methodsmentioning

confidence: 99%

“…Rats in group 1 received a single s.c. dose of 1 ml sesame oil. Those in group 2 were given a single s.c. dose of 1 ml Testoviron Depot (corresponding to 50 mg testosterone); this pharmacological dose is known to correct completely for the weight loss of the seminal vesicles and for the activity decrease of androgen-dependent liver and kidney enzymes after castration (Lax et al 1974;Ghraf et al 1975 ). Rats in group 3 received a single s.c. dose of 01 mg Progynon Depot in 0-2 ml sesame oil.…”

Section: Methodsmentioning

confidence: 99%

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

Ghraf¹,

Lax²,

Wagner³

et al. 1977

Journal of Endocrinology

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The NADP-dependent microsomal kidney enzymes, 3alpha- and 20beta-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 3alpha-HSDH activity in both gonadectomized and hypophysectomized rats of either sex. Administration of 5alpha-dihydrotestosterone (5alpha-DHT) or 5alpha-androstane-3alpha, 17beta-diol to hypophysectomized male rats was equally effective in restoring full 3alpha- and 20beta-HSDH activities whereas 5alpha-androstane-3beta, 17beta-diol was less effective and dehydroepiandrosterone was ineffective. Simultaneous administration of cyproterone acetate did not block the inductive action of 5alpha-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.

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The Role of the Hypophysis in the Regulation of Sex Differences in the Activities of Enzymes involved in Hepatic Steroid Hormone Metabolism

Cited by 32 publications

References 1 publication

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Antiandrogenic Effects of Oestradiol on Enzyme Activities of Hepatic Steroid Metabolism

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

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