The Role of Prolactin in the Prostatic Inflammatory Response to Neonatal Estrogen

Abstract

Estrogen exposure in the neonatal rat has been shown to disrupt the normal morphology and development of the prostate gland. The response to this exposure is manifest in adulthood as epithelial dysplasia and chronic inflammation. This inflammatory response consists of infiltrating T-lymphocytes and macrophages, which is typically observed in chronic prostatitis in both rodents and humans. In our rat model, the developmental hormonal milieu is altered following estrogenization, resulting in transient hyperprolactinemia, which begins prepubertally (postnatal d 21) and persists throughout puberty. The purpose of this experiment was to determine the role of prolactin (PRL) in the altered phenotype of the adult rat prostate exposed to neonatal estrogen. Male Sprague Dawley rat pups (n = 104) were randomized at birth to receive oil or estradiol benzoate on postnatal d 1, 3, and 5. They were further randomized to receive bromocriptine (BrC) pellets or placebo at d 15. Animals were killed at d 90. Serum PRL and testosterone levels, prostate lobe, and hormone-dependent and immune-related tissue weights and histology were examined. Animals receiving BrC had significantly lower PRL levels at d 90, regardless of estrogen status. Prostate lobe and testicular weights were significantly reduced in estrogenized animals vs. controls, and BrC did not abate this response, indicating that growth inhibition is not mediated through hyperprolactinemia. Splenic and thymus weights were greater in estrogenized animals, and this was partially reversed with BrC. Neonatal estrogen exposure resulted in a marked infiltration of CD4+ and CD8a+ lymphocytes in the prostate gland, and this was partially reversed by concomitant BrC treatment. In contrast, the estrogen-induced macrophage infiltration of the prostate was not affected by PRL suppression. These findings indicate that prostatic inflammation and immune cell infiltration in the prostate gland of neonatally estrogenized rats is mediated through a PRL-dependent as well as a PRL-independent mechanism. As prostatic inflammation or prostatitis in humans is associated with benign prostatic hyperplasia and prostatic carcinoma, this animal model may provide mechanistic insight with regards to age-associated prostatic lesions.

Sex Hormones Induce Direct Epithelial and Inflammation-Mediated Oxidative/Nitrosative Stress That Favors Prostatic Carcinogenesis in the Noble Rat

“…[32][33][34][35][36] In the NBL rat model, the action of E2 can be indirect and mediated by an elevation in prolactin level from the pituitary gland. 23,37,38 Thus, it is likely that elevated levels of prolactin also contribute to the up-regulation of pro-oxidant/pro-nitrosant/ proinflammatory genes. Interestingly, prolactin has been implicated as a modulator of immune functions and inflammation, and some of its actions have been linked to the regulation of ⅐NO synthesis.…”

Experimental rodent models of prostatitis: limitations and potential

“…145 It is important to note that estrogenization limited to the neonatal period results in both lateral and ventral prostatic inflammation in adulthood, producing a marked prolactin-dependent infiltration of CD4 þ and CD8 þ lymphocytes and a prolactin-independent macrophage accumulation in the adult ventral prostate lobe of Sprague-Dawley rats. 146 Collectively, these findings suggest that hyperplolactenemia may contribute in the 17b-estradiol-induced immune response.…”

Inflammation in prostate carcinogenesis

“…Increased levels of oestrogens, whether from environmental or developmental exposures, have long been linked to the development of prostate cancer 73,74 . Oestrogens affect the growth and development of the prostate, and this occurs through indirect routes on the hypothalamic-pituitary-gonadal axis through prolactin, and also by direct effects mediated by oestrogen receptor-α (ERα), which is expressed primarily in the stroma, and oestrogen receptor-β(ERβ), which is expressed primarily in the epithelium [73][74][75][76] . Oestrogens given to neonatal rodents result in an 'imprinted state' or 'developmental oestrogenization' in which there are developmental defects, including a reduction in prostatic growth.…”