Requirement of the Pituitary Gland for Gonadal Hormone Effects on Hepatic Corticosteroid Metabolism in Rats and Hamsters

Colby, Howard D.; Gaskin, Joe H.; Kitay, Julian I.

doi:10.1210/endo-92-3-769

Cited by 69 publications

(27 citation statements)

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“…No consistently reproducible sex dif ference in the specific activity of ethyl morphine N-demethylation could be demon strated for DBA/2J, C57BL/10J, or C3H/HeJ mice in this study. Recent reports have in dicated that pituitary hormones may also influence hepatic enzyme activities (9,12,19,32,33). Other factors that might selectively alter drug metabolism in only one sex could influence the results.…”

Section: Discussionmentioning

confidence: 99%

Mouse Liver N-Demethylase Activity

1978

Pharmacology

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Male-female differences in ethylmorphine N-demethylase activity and cytochrome P-450 content were studied in BALB/cJ, DBA/2J, C3H/HeJ, C57BL/10J and CRL:CD-1 mouse strains. Demethylase activity was greater for male mice than females of the BALB/cJ strain, but the inverse male-female relationship existed for CRJL:CD-1 mice. No consistent sex differences were present in the other strains. However, hepatic microsomal cytochrome P-450 content was greater in male mice of all strains studied. The effect of testosterone administration (1,2 or 5 mg/day, 6 days, s.c.) was investigated in intact female mice of each strain. BALB/cJ mice demonstrated a dose-dependent increase in body and liver weights, whereas all five strains displayed increased microsomal protein content in response to the administration of testosterone. Testosterone produced a dose-related increase in ethylmorphine N-demethylase activity and cytochrome P-450 content of BALB/cJ mice. An increase in cytochrome P-450 content of C3H/HeJ mice was the only other response observed following testosterone treatment. These observations support the following conclusions: (1) only certain mouse strains demonstrate a sex difference in ethylmorphine N-demethylase activity and in those strains males may have higher or lower activity than females; (2) sex differences in cytochrome P-450 content are not accompanied by predictable differences in demethylase activity; (3) testosterone stimulation of hepatic microsomal protein content represents one type of androgen action whereas effects on demethylase activity and cytochrome P-450 content represent another, and (4) hepatic microsomal N-demethylase activity is under genetic control such that androgen effects on this activity in adult mice are strain-specific.

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Section: Discussionmentioning

confidence: 99%

Mouse Liver N-Demethylase Activity

1978

Pharmacology

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“…However, an intact pituitary gland was later found to be required for testosterone and estradiol to regulate hepatic corticosterone metabolism, a sexually dimorphic metabolic activity (Colby et al, 1973). 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).…”

Section: Gonadal and Pituitary Hormonal Determinants Of Hepatic Sex Dmentioning

confidence: 99%

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Waxman

Holloway²

2009

Mol Pharmacol

618

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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“…First, how does administration of exogenous E2 (or similar sex steroid) into an animal produce its effects? As mentioned earlier, it has been shown extensively that effects of exogenously injected E2 depend on generating the "feminine plasma growth hormone pattern" through central hypothalamic/pituitary mechanisms (27,(32)(33)(34)(35)(36)(37)(38)(39)(40) (Figure 1). Specifically, a single injection of E2 into a rodent affects the function of cells in the arcuate and ventromedial nucleus in the hypothalamus and additional nuclei therein (27,(49)(50)(51)(52)(53)(54).…”

Section: The Hypothalamic (Ghrh)-pituitary (Gh)-distal Tissues (Stat5mentioning

confidence: 87%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Requirement of the Pituitary Gland for Gonadal Hormone Effects on Hepatic Corticosteroid Metabolism in Rats and Hamsters

Cited by 69 publications

References 0 publications

Mouse Liver N-Demethylase Activity

Mouse Liver N-Demethylase Activity

Sex Differences in the Expression of Hepatic Drug Metabolizing Enzymes

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

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