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Editorial: Pulsatile Hormone Patterns Governing Transcription Factor Function.

Since it was established that pituitary GH is secreted in a pulsatile pattern (1, 2), the physiological importance of the GH secretion pattern has been sought. Mechanisms by which pulsatile GH secretion is determined by hypothalamic factors has been extensively studied (3–6), but the direct physiological consequences of GH secretion patterns are less clear. Critical insight into such physiology stemmed from observations that the pattern of GH secretion was different in male and female rats (7), in males characterized by abrupt peaks and deep troughs with a periodicity of 3–4 h between peaks (pulsatile secretion), and in females, less pronounced peaks and troughs (often referred to as continuous secretion). Elucidation of these differences in GH secretion patterns led to appreciation that they correspond with sexual dimorphism in some responses to GH, particularly body growth (8) and activities of male-specific and female-specific enzymes of hepatic steroid metabolism (9). Sexual dimorphism of other liver proteins dependent on pulsatile vs. continuous GH include the induction of major urinary proteins by pulsatile GH in male mice, and of liver PRL/GH receptors by continuous GH in female mice (10). Experimental models mimicking the male and female GH secretion patterns in vivo and in vitro have established that a subset of genes encoding liver cytochrome P450 (CYP) enzymes of steroid metabolism in the CYP2 and CYP3 families are useful models for analysis of sexually dimorphic genes whose expression is determined by the differences in GH secretion patterns between males and females (11–14). The CYP story is rather complex, however, because pulsatile GH induces some but suppresses other CYP genes, and continuous GH induces some and suppresses other CYP family genes, whereas others are unaffected by GH. One of the most consistent observations in regulation of sexually dimorphic hepatic genes by the GH secretory pattern is involvement of the signal transducer and activator of transcription (STAT) 5b as a mediator. Pulsatile GH activates STATs 5a and 5b (15, 16) and, for example, determines the activation of the male-specific enzyme CYP2C11 (11, 12). Conversely, continuous GH induces CYP2C12 expression in females (as well as suppressing CYP2C11) (12), and induces low-level STAT 5a and 5b activation (17). Other male-specific CYP genes, but not all, are reported to be regulated by STAT5 (18, 19). In addition, the male-specific hepatic expression of the sex limited protein (C4-slp) gene is also determined by male GH secretion (20, 21), and utilizes STAT5 (22). Analysis of mice deficient in STAT5b showed that male-specific liver gene expression (major urinary proteins and various CYP genes) decreased to female levels and that female-specific liver gene products were increased. Body growth rate in STAT5b-deficient males was reduced to wild-type female levels. Thus, loss of STAT 5b is associated with loss of sexual dimorphism of body growth rates and liver gene expression (23). Disruption of the STAT 5a gene did not impair hepatic male-specific gene expression, while in female mice loss of STAT 5a or STAT 5b similarly increased hepatic expression of female-specific genes (24). Mice deficient in both STAT 5a and 5b also showed impairment of male-specific hepatic gene expression as observed in STAT 5b knockouts, and loss of male-specific body growth rate (25). Thus STAT 5b appears to be a major determinant of sexual dimorphism of hepatic gene expression and body growth, which is determined by pulsatile vs. continuous GH secretion patterns characteristic of male vs. female rodents, respectively. An elegant link in establishing physiological relevance of STAT5 activation in direct relation to spontaneous, endogenous GH pulses in males and females has recently been provided by the laboratories of Tannenbaum and of Waxman, as presented in this issue of Endocrinology (25a). Correspondence of levels of liver STAT5 binding activity with spontaneous episodes of endogenous GH secretion was shown in individual freely moving adult male and female rats. In males, the highest STAT5 binding activity was observed during the initial phase, on the upswing or at a peak of GH secretion, and the lowest activity at troughs, with intermediate STAT5 binding measured during the downswing of GH pulses. In females, the STAT5 binding activity during the initial phase of a GH secretory episode was lower than in males, corresponding with lower GH levels, and during the trough was similar to the baseline in males. The results of these studies of relatively simple design, using a well characterized but elaborate animal model in conjunction with a standard test of hepatic STAT5 binding activity, provide support that STAT5 binding activity is temporally related to spontaneously occurring GH pulses under physiological conditions. Emerging from these observations are implications that GH signaling and consequent regulation of expression of at least some genes using STAT5 may also be pulsatile.