**7. Acknowledgements**

62 Sex Steroids

Waxman, 2004) to identify GH and sex-dependent nuclear proteins in rat liver. Interestingly, of 165 sexually differentiated spots about 40% underwent a female-like change in male rats

The relationship among the components of GH secretion patterns (interpulse periods, GH concentration, pulse amplitude) and the characteristic sex-dependent expression of a number of genes (Mode and Gustafsson, 2006; Waxman and O'Connor, 2006) has been extensively explored during past years. In general, the GH interpulse periods constitute the major determinant of sex-specific genes; GH concentration and pulse amplitudes are also of different importance for the expression of several sex-characteristic CYP isoforms. In addition, a consensus exists that the response to sex-different GH patterns is the major cause of the "liver sexuality", it is also likely that factors other than the sexually dimorphic pattern of GH secretion are behind some sex differences in rat liver. Potential mechanisms that could contribute to "liver sexuality" are the pituitary-independent effects of estrogens

through interaction with ER or GH-JAK2-STAT5 signalling pathway in liver.

**5.4 E2 is a critical regulator of lipid metabolism and insulin sensitivity: Potential** 

Estrogens, acting on both ER and ERare recognized as important regulators of glucose homeostasis and lipid metabolism (Simpson et al., 2005; Faulds et al., 2011). Both male and female ERKO mice develop insulin resistance and impaired glucose tolerance, similar to humans lacking ER or aromatase. ER mainly mediates beneficial metabolic effects of estrogens such as anti-lipogenesis, improvement of insulin sensitivity and glucose tolerance, and reduction of body weight/fat mass. In contrast, ER activation seems to be detrimental for the maintenance of regular glucose and lipid homeostasis. The insulin resistance in ERKO mice is largely localized to the liver, including increased lipid content and hepatic glucose production. Interestingly, the expression of liver lipogenic genes can be decreased after E2 administration to diabetic Ob/Ob or high-fat diet fed female mice. Similarly, the aromatase knockout (ArKO) mouse, which cannot produce E2, has increased intraabdominal adiposity and develops steatosis and an impairment of lipid oxidation in liver. Importantly, GH-GHR-JAK2-STAT5 deficiency in adults causes adiposity and hepatic steatosis suggesting that E2 and GH can regulate a common cellular network related with physiological control of lipid metabolism. In our lab, we have shown that subcutaneous administration of nearly physiological doses of E2 to male rats with GH deficiency (hypothyroid rats), dramatically influenced the hepatic transcriptional response to pulsatile GH administration (male pattern). In this model, E2 was able to increase hepatic transcriptional program in relation to lipid oxidation whereas lipid synthesis was decreased. Most relevant, expression of genes related to endocrine, metabolic, and sex-differentiated

The liver responds in a sex-specific manner to GH and estrogens.GH is a major regulator of growth, somatic development, and body composition. Estrogens have physiological actions which are not limited to reproductive organs in both females and males, and they are recognized as key regulators of liver physiology. Physiologically and therapeutically relevant are estrogen interactions with GH-regulated endocrine (e.g., IGF-I), metabolic (e.g.,

upon continuous treatment with GH.

functions of GH were drastically inhibited by E2.

**crosstalk with GH** 

**6. Conclusion** 

We thank all the authors that have made a contribution to the understanding of the crosstalk between sex hormones and GH signalling in liver. We apologize to those whose work deserves to be cited but unfortunately are not quoted because of space limitations. Research program in the author lab has been supported by grants from the Spanish Ministry of Science and Innovation with the funding of European Regional Development Fund-European Social Fund (SAF2003-02117 and SAF2006-07824).
