Interpulse interval in circulating growth hormone patterns regulates sexually dimorphic expression of hepatic cytochrome P450.

Abstract

Plasma growth hormone (GH) profiles are sexually differentiated in many species and regulate the sexdependence of peripubescent growth rates and liver function, including steroid hydroxylase cytochrome P450 expression, by mechanisms that are poorly understood. By use of an external pump to deliver to hypophysectomized rats pulses of rat GH of varying frequency and amplitude, a critical element for liver discrimination between male and female GH patterns was identified. Liver expression of the male-specific steroid 2a(orl6a)-hydroxylase P450, designated CYP2C11, was stimulated by GH at both physiological and nonphysiological pulse amplitudes, durations, and frequencies, provided that an interpulse interval of no detectable GH was maintained for at least 2.5 hr. This rmding suggests that hepatocytes undergo an obligatory recovery period after stimulation by a GH pulse. This period may be required to reset a GH-activated intracellular signaling pathway or may relate to the short-term absence of GH receptors at the hepatocyte surface after a cycle of GH binding and receptor internalization. These requirements were distinguished from those necessary for the stimulation by GH of normal male growth rates in hypophysectomized rats, indicating that different GH responses and, perhaps, different GH-responsive tissues recognize distinct signaling elements in the sexually dimorphic patterns of circulating GH.Episodic secretion is a general characteristic of many hormones, including pituitary-dependent hormones, pancreatic islet, and parathyroid hormones (1), and is often crucial to the triggering of hormone-dependent responses in target cells. For growth hormone (GH), secretion by the pituitary is not only intermittent, or pulsatile, but also the frequency of pulsation is sex-dependent. In many species, including the rat, chicken, and human (2-5), pituitary GH secretion is more frequent in females than in males. In the case of the female rat, a high pulse frequency results in GH present in circulation continuously, at levels 2 10-20 ng/ml of plasma. This situation contrasts with the intermittent presence of GH in plasma of male rats (2, 6). Studies in rats (7-10) and mice (11-13) have demonstrated that the expression of a number of sexually differentiated hepatic proteins, including cytochrome P450 (P450)-linked steroid hydroxylases and drugmetabolizing enzymes, is primarily determined by plasma GH profiles and only secondarily regulated by the gonadal hormones through their effects on the hypothalamo-pituitary axis and its control of GH secretion (14-16).The plasma GH profile in a male rat is characterized by a pulse of 200-250 ng of GH per ml every 3-4 hr followed by a 2-to 2.5-hr period when circulating GH is nearly undetectable (.2 nrg/ml). It is unclear, however, just what features in this pattern are recognized as male by the hepatocyte. This critical question is addressed by the present study, which uses a recently developed external pump apparatus (17) for generation of periodic GH pulses of various frequenc...

Divergent roles of STAT1 and STAT5 in malignancy as revealed by gene disruptions in mice

“…Malecharacteristic body growth rates and male-speci®c liver gene expression were decreased to wild-type female levels in Stat5b7/7 males, while female-predominant liver gene products were increased to a level intermediate between wild-type male and female levels. Pulsatile but not continuous GH exposure has been proposed to play a key role in regulating the sexual dimorphism of liver gene expression (Waxman et al, 1995). Although the responses observed in Stat5b7/7 mice were similar to those observed in GH-de®cient Little mice, Stat5b7/7 mice were not GH-de®cient, suggesting that they may be only impaired in sensing GH pulses.…”

Requirement of STAT5b for sexual dimorphism of body growth rates and liver gene expression

“…STAT5b Ϫ͞Ϫ males grew at the lower rate, which is characteristic of wild-type female mice, thereby abolishing the striking sexual dimorphism in body growth rate normally evident from 3 weeks of age. This sex difference in body growth is determined by the sex-specific pattern of pituitary GH secretion (8,40,41), which first emerges at this stage in development (1). At 4 to 5 weeks of age, STAT5b Ϫ͞Ϫ males were 27% lighter than wild-type males, and this difference persisted beyond puberty (Fig.…”

“…The resultant sex differences in plasma GH profiles are particularly striking in rodents (for example, intermittent GH pulses in male rats vs. continuous plasma GH in female rats) and are the major determinant of sex differences in body growth rates and the sexually dimorphic expression in liver of numerous genes, including the major urinary proteins (MUP) (3), prolactin receptors (3,4), and several cytochrome P450 (CYP) enzymes (5)(6)(7). Altering the temporal pattern of plasma GH by GH infusion or by hypophysectomy with GH replacement causes changes in body growth rate and in the patterns of liver gene expression that directly reflect the changes in plasma GH profiles (3,5,8). In mice, GH secretion is pulsatile in both males and females; however, the interval between pulses is longer in males (9), and this period of low or no plasma GH is thought to be an important determinant of the male-specific pattern of liver gene expression (8).…”

“…Altering the temporal pattern of plasma GH by GH infusion or by hypophysectomy with GH replacement causes changes in body growth rate and in the patterns of liver gene expression that directly reflect the changes in plasma GH profiles (3,5,8). In mice, GH secretion is pulsatile in both males and females; however, the interval between pulses is longer in males (9), and this period of low or no plasma GH is thought to be an important determinant of the male-specific pattern of liver gene expression (8).…”

Gender-specific induction of cytochrome P450s in nonylphenol-treated FVB/NJ mice

“…The liver is a sexually dimorphic organ, and the release pattern of growth hormone and its subsequent control of Stat5b regulate several P450s in a gender-specific or gender-predominant manner (Waxman et al, 1991;Park et al, 1999). Other hepatic transcription factors potentially involved in sex-specific expression of P450s include rsl (Krebs et al, 2003), HNF-1α (Cheung et al, 2003), HNF-4α (Wiwi et al, 2004), and RXRα (Cai et al, 2003).…”