**5.4 Estrogen/androgen ratio**

416 Dyslipidemia - From Prevention to Treatment

PPARs are ligand activated transcription factors, which includes polyunsaturated FAs, eicosanoids, prostaglandins, docosahexaenoic acid, thiozolidinediones, and non-steroidal anti-inflammatory drugs. A recent study by Jiang et al., showed that conditional prostatic epithelial knockout of PPARγ resulted in the inflammation and focal hyperplasia which developed into prostatic intraepithelial neoplasia (Jiang et al.). Increased expression of PPARγ and overall enlargement of the prostate was observed in the rats kept on diet rich in saturated fat (Escobar et al., 2009). We also observed increased cell proliferation and prostatic enlargement in rodents kept on high-fat diet (Vikram et al., 2010b; 2011a; Vikram et al., 2010c). Moreover, pioglitazone (a PPARγ agonist) treatment restored prostate size in these rats (Vikram et al., 2010b; Vikram et al., 2010c). A recent study indicating the dominant uptake of FAs (as compared to glucose) by the malignant as well as non-malignant prostatic cells (Liu et al., 2010) underlines the possible role of PPARγ in the prostatic growth and development. These findings suggest that PPARγ represents a potential link between dietary fat and prostatic growth. However, further studies are needed to characterize its role

Hyperinsulinemia generally develops as a compensatory response to the decreased insulin mediated actions under the insulin-resistant conditions (McKeehan et al., 1984). Experimental (Cai et al., 2001; Escobar et al., 2009; Rahman et al., 2007; Vikram et al., 2010a; b; 2011a; Vikram et al., 2010c) and clinical/epidemiological (Hammarsten et al., 2009; Hammarsten and Hogstedt, 2001; Nandeesha et al., 2006) studies indicate that the hyperinsulinemia is an independent contributor to the prostatic cell proliferation and pathogenesis of the BPH. Further, hyperinsulinemic condition can contribute to the augmented prostatic growth by several ways such as (i) increasing the serum level of IGF-I (Chokkalingam et al., 2002; Nam et al., 1997), (ii) possibility of the binding of insulin with the IGF-I receptor (IGF-IR) under the hyperinsulinemic conditions and (iii) binding of IGF-I to the insulin receptor (IR) (Belfiore and Frasca, 2008; Li et al., 2005). Further, IR has two isoforms, A and B, the former is having metabolic as well as mitogenic effects while B is mainly concerned with the metabolic effects. IR isoforms exhibit difference in the binding affinities to the ligand(s) and downstream signaling cascade (Giudice et al., 2011; Kosaki et al., 1995; Leibiger et al., 2001; Sciacca et al., 2003; Uhles et al., 2003; Vogt et al., 1991). IGF-II binds to the IR-A and mediates its growth promoting effects but not with IR-B (Frasca et al., 1999; Morrione et al., 1997). This means that insulin, IGF-I and IGF-II competes to bind with the IR-A, while only insulin binds with the IR-B. The hybrid receptors, IR-A/IR-B and IR/IGF-I further complicates the molecular diversification of the insulin signaling system. IR-A/IR-B hybrid receptors were found to bind to both insulin and IGF-II and therefore, resemble IR-A homodimers rather IR-B homodimers (Blanquart et al., 2008). The IR/IGF-IR hybrid receptors (Pandini et al., 2002; Soos et al., 1990) are activated by both insulin as well as IGF-I, but the IGF-I effect is predominant, and it resembles IGF-1R homodimers rather IR homodimers (Langlois et al., 1995). The IGF and insulin signaling system has been summarized in figure 1. Prostate is known to have both isoforms of the IR (Cox et al., 2009). Experimental studies investigating the effect of dietary habits (particularly dietary fat) on the expression of IR isoforms and signaling kinetics might provide valuable insight in the understanding of the pathogenesis of the BPH under the insulin-resistant, obese and

**5.2 PPARγ signaling** 

diabetic conditions.

in the normal and pathological growth of the prostate.

**5.3 Hyperinsulinemia: Altered insulin/IGF signaling** 

Androgen deprivation leads to rapid apoptosis of the luminal secretory cells and atrophy of the prostate gland (Ikeda et al., 2000; Vikram et al., 2010c; Vikram et al., 2008). However, with the re-administration of the androgens prostate regains its normal size, and is capable of more than 15 rounds of the regression / regeneration cycle (Wang et al., 2009). Further, administration of either estrogen or dihydrotestosterone leads to hyperproliferation and induction of prostatic hyperplasia in the experimental animals. These simple experiments highlights the crucial role of steroidal hormones in the growth and development of the gland. Aromatase is a CYP450 enzyme which irreversibly converts testosterone to the estradiol, and obesity is associated with increased aromatase activity (Subbaramaiah et al., 2011). Increased aromatase activity in the obese people may lead to rise in the estrogen/androgen ratio and hence the susceptibility for developing BPH. These aspects have been recently reviewed by Nicholson et al., and readers are encouraged to read the review (Nicholson and Ricke, 2011).

Fig. 1. The IGF and insulin receptor signaling system. To avoid confusion, the binding affinity of the ligands and relative effects of hybrid receptors (metabolic and mitogenic) are not depicted in the figure. However, the IGF-IR/IR hybrid resembles IGF-IR homodimer and IR-A/IR-B resembles IR-A homodimers. Lipids are involved in nuclear signaling and can influence transcriptional regulation and thus growth and differentiation. IGF-I/II; insulin-like growth factor-I/II, IGF-IR; insulin-like growth factor-I receptor, IR-A/B; insuln receptor isoform-A/B.

### **6. Summary**

BPH is a highly prevalent condition of prostate in the aging men population. The worldwide increase in the prevalence of BPH has been thought to be associated with obesity and lifestyle changes such as excessive intake of fat-rich diet and physical inactivity. Considering

Lipids in the Pathogenesis of Benign Prostatic Hyperplasia: Emerging Connections 419

and contractility of the prostate gland, and represent important risk factors for the development of symptomatic LUTS / BPH (Fig. 2). ATX-LPA axis, PPARγ signaling, hyperinsulinemia/IGF signaling and steroidal signaling are the emerging mechanisms which explains the association between dietary fat intake, obesity and BPH. However, further mechanistic as well as epidemiology based studies are required to delineate the role of lipids in the pathogenesis of BPH. Future research to investigate the direct effect of different types of FAs on the prostatic growth and isoforms specific characterization of

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**9. References** 

the changing dietary habits and rising incidences of BPH, it becomes increasingly important to delineate the precise roles of lipids in the normal as well as pathological growth of the prostate. Although, experimental and clinical/epidemiological studies suggest that these conditions contribute to the pathogenesis of both insulin-resistance and BPH, the direct role of lipids in the pathogenesis of prostatic enlargement is far from complete understanding. Role of lipids in the progression of insulin-resistance and other disorders and indirect effect on the prostatic growth owing to compensatory rise in the plasma insulin level is essentially correct, but what has emerged is that the lipids might have a direct influence on the normal as well as pathological growth of the prostate.

Fig. 2. Modern lifestyle associated changes including increased consumption of fat-rich diets and decreased physical activities contributes to the development of lipid-disorders and obesity. The present illustration demonstrates the possible influence of these factors on the prostatic growth and development. IR; insulin receptor, IGF-IR; insulin-like growth factor-1 receptor, PPAR-α/γ; peroxisome-proliferator activated receptor alpha/gamma, ATX; autotaxin, LPA, lysophosphatidic acid.
