Steroid Hormone Pathways Regulating BPH and LUTS

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Aging is a major risk factor for benign prostate hyperplasia (BPH), a progressive disease that occurs with increasing prevalence as men age, affecting 70% of men in their sixties and 90% of men in their eighties. Quality of life is severely impacted by BPH, which leads to bladder outlet obstruction and lower urinary tract symptoms (LUTS) presenting as reduced flow through the prostatic urethra and incomplete bladder emptying resulting in more frequent urination, especially at night (nocturia). Molecular mechanisms responsible for BPH/LUTS are unclear, which has delayed treatment development. Age-related changes in relative serum testosterone (T) and estradiol (E2) levels are associated with BPH/LUTS. T and E2 are major contributors to BPH/LUTS initiation and progression that act through 1) nuclear receptors to regulate gene expression (classical signaling pathway) or 2) membrane receptors that rapidly activate kinase cascades and alter cellular processes (nonclassical signaling). Our preliminary studies identify a new paradigm to explain sustained prostatic smooth muscle contraction that causes restriction of urine flow and LUTS. Using 3 models of BPH/LUTS with aged levels of T and E2, we found consistent altered expression of protein phosphatase 1 regulators (PPP1r) that decrease or are predicted to decrease activity of myosin light chain phosphatase (MLCP) required for prostatic smooth muscle (SM) relaxation and bladder voiding. This important advance identifies PPP1r proteins and other SM relaxation regulators as targets for therapies to reverse aging associated BPH/LUTS. In Aim 1, we will identify PPP1r proteins and other members of the relaxation promoting pathway that are differentially regulated in aged mouse prostate models and human BPH tissues/cell cultures. In Aim 2, we will identify the T- and E2-mediated pathways required to initiate and sustain BPH and LUTS by using our transgenic mice having only classical or only nonclassical E2 signaling or only classical T signaling. Our results will provide a mechanistic explanation for sustained SM contraction around the prostatic urethra, restriction of urine flow and LUTS including voiding dysfunction that occurs with aging-related altered hormone levels. Our findings will identify pathways and processes required for BPH/LUTS progression and identify new targets for LUTS therapies.