**5. Acknowledgements**

This work is dedicated to the memory of our friend and colleague, Dr. Daniel Hryb, who devoted much of his life to understanding the biology of SHBG. The authors would like to thank Dr. Atif Nakhla and Dr. Saeed Khan for their invaluable contributions to this work. We also appreciate the terrific assistance of many collaborators, including Dr. Yu Hua Li, Dr. Richard Friedman, Dr. Zhaoying Xiang, Dr. Xinsheng Wang, Dr. Jonathan St. George, Dr. Kristina Maletz, Janice Cheong, Dr. Teri Reynolds, Dr. Amy Kappelman, Nomi Levy, Stephanie Meng, and Dr. Hisashi Koga.

## **6. References**

Anderson DC. Sex-hormone-binding globulin. Clin Endocrinol (Oxf). 1974 Jan;3(1):69-96.


It is intriguing to also speculate that, in addition to the prostate, locally expressed SHBG plays a functional role in the hormone response of other tissues. We have preliminary evidence that endogenously expressed SHBG can modulate the estrogen response of human breast cells (Kahn et al, 2008). And, if plasma SHBG levels provide a clue into how altered SHBG expression may contribute to the disease state at a cellular level, it will be of great interest to investigate whether there is a connection between tissue specific SHBG expression and Type 2 diabetes. This does not detract in any way from the importance of plasma SHBG levels on androgen and estrogen responsiveness in humans. Instead, it serves to broaden the scope of SHBG influence on the response to sex steroids to the individual

This work is dedicated to the memory of our friend and colleague, Dr. Daniel Hryb, who devoted much of his life to understanding the biology of SHBG. The authors would like to thank Dr. Atif Nakhla and Dr. Saeed Khan for their invaluable contributions to this work. We also appreciate the terrific assistance of many collaborators, including Dr. Yu Hua Li, Dr. Richard Friedman, Dr. Zhaoying Xiang, Dr. Xinsheng Wang, Dr. Jonathan St. George, Dr. Kristina Maletz, Janice Cheong, Dr. Teri Reynolds, Dr. Amy Kappelman, Nomi Levy,

Anderson DC. Sex-hormone-binding globulin. Clin Endocrinol (Oxf). 1974 Jan;3(1):69-96. Avvakumov GV, Cherkasov A, Muller YA, Hammond GL. Structural analyses of sex

Bordin S, Petra PH. Immunocytochemical localization of the sex steroid-binding protein of

Caldwell JD, Suleman F, Chou SH, Shapiro RA, Herbert Z, Jirikowski GF. Emerging roles of

Germain P, Egloff M, Kiefer H, Metezeau P, Habrioux G. Use of confocal microscopy to

Gurel B, Iwata T, Koh CM, Yegnasubramanian S, Nelson WG, De Marzo AM. Molecular

Hammond GL, Underhill DA, Smith CL, Goping IS, Harley MJ, Musto NA, Cheng CY,

steroid-binding globulins. Horm Metab Res. 2006 Apr;38(4):206-18.

hormone-binding globulin reveal novel ligands and function. Mol Cell Endocrinol.

plasma in tissues of the adult monkey Macaca nemestrina. Proc Natl Acad Sci U S

localize the SHBG interaction with human breast cancer cell lines--a comparison with serum albumin interaction. Cell Mol Biol (Noisy-le-grand). 1997 Jun;43(4):501-8. Gershagen S, Lundwall A, Fernlund P. Characterization of the human sex hormone binding

globulin (SHBG) gene and demonstration of two transcripts in both liver and testis.

alterations in prostate cancer as diagnostic, prognostic, and therapeutic targets.

Bardin CW. The cDNA-deduced primary structure of human sex hormone-binding globulin and location of its steroid-binding domain. FEBS Lett. 1987;215:100–104. Heemers HV, Tindall DJ. Androgen receptor (AR) coregulators: a diversity of functions

converging on and regulating the AR transcriptional complex. Endocr Rev. 2007

tissue and cellular level.

**5. Acknowledgements** 

**6. References** 

Stephanie Meng, and Dr. Hisashi Koga.

A. 1980 Oct;77(10):5678-82.

2010 Mar 5;316(1):13-23. Epub 2009 Sep 11.

Nucleic Acids Res. 1989;17:9245–9258

Adv Anat Pathol. 2008 Nov;15(6):319-31.

Dec;28(7):778-808. Epub 2007 Oct 16.


**1. Introduction** 

and O'Connor, 2006; Vidal et al., 2007).

**3** 

*1Spain 2Denmark* 

**Estrogens in the Control of** 

*1University of Las Palmas de Gran Canaria,* 

*Pharmacology Unit, Las Palmas de G.C., 2Novo Nordisk Center for Protein Research,* 

*University of Copenhagen,* 

**Growth Hormone Actions in Liver** 

*Faculty of Health Sciences, Clinical Sciences Department,* 

Leandro Fernández-Pérez1 and Amilcar Flores-Morales2

The liver responds in a sex-specific manner to Growth Hormone (GH) and sex hormones. GH is the main regulator of body growth, somatic development, body composition, and sexdifferentiated functions in liver (Butler and Le Roith, 2001; Mode and Gustafsson, 2006; LeRoith and Yakar, 2007; Lichanska and Waters, 2008; Vijayakumar et al., 2010). GH is mainly produced in the pituitary gland and acts distantly on target tissues through the activation of the transmembrane GH receptor (GHR). The liver shows the highest levels of GHR expression and, therefore, is a major target for GH, but virtually all human tissues are responsive to GH. GH regulates glucose, lipid, amino acid, and endo-xenobiotic metabolism. The sex-specific secretion release from pituitary has been shown to have a great impact on hepatic transcriptional regulation (Flores-Morales et al., 2001b; Tollet-Egnell et al., 2001; Tollet-Egnell et al., 2004; Lichanska and Waters, 2008; Waxman and Holloway, 2009). Global expression analysis of GH actions in liver using microarrays clearly indicates that most of the known physiological effects of GH can be explained through its effects on the transcription of specific genes. To this end, GH is known to activate a network of transcription factors in liver that include, among others, nuclear receptors/transcription factors such as Hepatocyte Nuclear Factors (4, 6, 3, Peroxisome Proliferator-Activated Receptor alpha (PPAR, Constitutive Androstane Receptor (CAR), Farnesoid X Receptor (FXR), Small Heterodimer Partner (SHP), Sterol Regulated Element-Binding Protein (SREBP), CRBP, C/EBP, and Signal Transducer and Activator of Transcription (STAT)-5b. The latest is of particular importance in the regulation of endocrine, metabolic, and sexdifferentiated actions of GH in liver (Udy et al., 1997; Wiwi and Waxman, 2004; Waxman

17-Estradiol (E2), a major natural estrogen in mammals, has physiological actions which are not limited to reproductive organs in both females and males (Simpson et al., 2005). Estrogens exert their physiological effects through two estrogen receptor (ER) subtypes, ER and ER, which belong to the nuclear receptor family of ligand-activated transcription

