**7. Conclusion**

18 Sex Steroids

Fig. 4. Prochloraz-induced vaginal morphology in adult male rats receiving a 5-day *in utero* exposure. **A**) Panoramic view of a vaginal pouch (forceps inserted) in a male from the 250 mg/kg maternal dosage group. **B**) A close-up of a control female phallus and vaginal opening. **C** and **D**) Vaginal pouch and phallus deformity variations in males from the 250 mg/kg maternal dose group. **E**–**G**) The most severely affected animal from the 125 mg/kg maternal dose group. In this male, an ejaculatory plug (**F**) was found embedded (**E**) in the vaginal opening (**G**). (Noriega et al. 2005) modified with permission from the Society for the

Study of Reproduction.

The terminology used in discussions of endocrinology, evolution and behavior is changing in light of the growing body of knowledge regarding the complexity of hormonal interactions. This chapter is intended to provide the reader with a panoramic snapshot of sex-steroid function compared to what is normally encountered in specialized fields of study. The summaries of concepts presented here will hopefully be catalysts for further investigation of topics in more detail than presented here. Existing paradigms regarding "disruption", "variation" and "adaptation" are increasingly seen as parts of a continuum. Thus the scope of "endocrine disruptor" assessment has already expanded beyond currently established definition parameters (Guillette 2006; Marty et al. 2011; Norris & Lopez 2011a). For example, the term "Endocrine Active Chemical" (EAC) is now used in favor of terms implying "disruption" (Norris & Lopez 2011a).

The claim has long been made that distinctions such as endocrine system vs. nervous system are arbitrary (Roth et al. 1986). Evolutionary constraints lead to reduced variation in reproductive strategies used by birds and mammals compared to evolutionarily older clades represented by fishes, reptiles and amphibians. However, the evolution of complex neuroendocrine systems may provide time and context-specific behavioral avenues for adaptive radiation in the face of external influences on peripheral hormone levels (Wingfield et al. 1997; Adkins-Regan 2008). We have only a brief window of perspective on the cycle of extinction and adaptive radiation. The ability to include expansive, as well as reductionist perspectives may facilitate new thresholds in our evaluation of environmental, social, behavioral and clinical aspects of sex-steroid biology.

#### **8. Abbreviations**

ancSR = Ancestral Steroid Hormone Receptor; AR = Androgen Receptor; CG = Chorionic Gonadotropin; ER = Estrogen Receptor; FSH = Follicle Stimulating Hormone; GR = Glucocorticoid Receptor; hCG = Human Chorionic Gonadotropin; HPA = Hypothalamic-Pituitary-Adrenal; HPG = Hypothalamic-Pituitary-Gonad; HPT = Hypothalamic-Pituitary-Thyroid; insl3 = Insulin-like hormone 3; LH = Lutenizing Hormone; MR = Mineralocorticoid Receptor; SHBG = Steroid Hormone Binding Globulin; TSH = Thyroid Stimulating Hormone;

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**2** 

*USA* 

**Sex Hormone-Binding Globulin as a** 

*4Department of Medicine, Columbia University, New York, N.Y.* 

*3Herbert Irving Comprehensive Cancer Center* 

**Modulator of the Prostate "Androgenome"** 

Scott M. Kahn1,2,3,\*, Nicholas A. Romas1,2 and William Rosner4,5 *1Department of Urology St. Luke's-Roosevelt Institute for Health Sciences 2Department of Urology, Herbert Irving Comprehensive Cancer Center* 

*5Department of Medicine, St. Luke's-Roosevelt Institute for Health Sciences* 

Sex hormone-binding globulin (SHBG) is a sex steroid binding protein, originally described in humans as the major binding protein for estrogens and androgens in plasma (Anderson, 1974; Avvakumov, et al, 2010). By governing equilibrium conditions in plasma between bound and free sex steroids, SHBG regulates the availability of the latter to hormonally responsive tissues. Along with regulating free steroid concentrations in plasma, it is increasingly evident that SHBG also participates in other biological processes. These include, but are not limited to- activation of a rapid, membrane based steroid signaling pathway in tissues such as the prostate and breast (Rosner et al, 2010); spermatogenesis (Selva and Hammond, 2006); and a yet to be determined consequence of co-localization with

Plasma based SHBG is extensively studied, especially in the context of its regulation of free steroid concentrations and epidemiologic associations. The origin of plasma SHBG is, for all intents and purposes, the liver (Khan et al, 1981; Pugeat et al, 2010) (a differentially glycosylated isoform, androgen binding protein (ABP) is synthesized in the testis (Vigersky et al, 1976)). However, we now know that SHBG is also synthesized, albeit to a much lesser degree, in certain hormonally responsive tissues (Kahn et al, 2002). Early studies demonstrated immunoreactive SHBG in the prostate and breast (Bordin & Petra 1980; Tardivel-Lacombe et al, 1984; Sinnecker et al, 1988; 1990; Meyer et al, 1994; Germain et al, 1997), though its origin (local synthesis vs. import from plasma) was unclear. Other studies demonstrated SHBG mRNA in certain nonhepatic tissues (Larrea et al, 1993; Misao et al, 1994; 1997; Moore et al, 1996; Murayama et al, 1999), and one reported both SHBG protein and mRNA together in fallopian tube tissue (Noé, 1999). In 2002, we reported that human prostate tissue expresses both SHBG mRNA and protein, as do prostate cancer cell lines (Hryb et al, 2002), suggesting that SHBG is indeed locally

**1. Introduction** 

\* Corresponding Author

oxytosin in brain cells (Caldwell et al, 2006).

*sciences : an official journal of the Society of Toxicology* Vol. 69, No. 2, pp (344-353), 1096-6080

