Rol de la prolactina en la prostatitis en ratas

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0013-7227/03/$15.00/0 Printed in U.S.A.

Endocrinology 144(5):2046 –2054 Copyright © 2003 by The Endocrine Society doi: 10.1210/en.2002-0038

The Role of Prolactin in the Prostatic Inflammatory Response to Neonatal Estrogen
JASON P. GILLERAN*, OLIVER PUTZ*, MEGAN DEJONG, SAMUEL DEJONG, LYNN BIRCH, YONGBING PU, LIWEI HUANG, AND GAIL S. PRINS
Department of Urology, College of Medicine,University of Illinois at Chicago, Chicago, Illinois 60612
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 inchronic 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 toneonatal 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. Animalsreceiving 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 partiallyreversed 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 glandof 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. (Endocrinology 144: 2046 –2054, 2003)

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ORMAL DEVELOPMENT,GROWTH, and function of the prostate gland throughout life are dependent on androgens that act in synergy with other modulating hormones such as estrogen and prolactin (PRL; Refs. 1–3). In the rat model, prostate development is initiated late in fetal life and undergoes extensive branching morphogenesis and cellular differentiation during the neonatal period (4, 5). It is during this earlydevelopmental period that hormonal modulation can have a permanent and irreversible effect on the gland’s morphology, cellular organization, and function. Administration of exogenous estrogen between postnatal day (PND) 1–5 has been shown to permanently imprint the prostate resulting in reduced growth, compromised secretory function, and decreased responsiveness to androgens in adulthood (6 – 8). Thisdevelopmental estrogenization leads to prostatic epithelial hyperplasia and moderate-to-severe dysplasia (prostatic intraepithelial neoplasia) with aging and, consequently, is considered to be a predisposing factor for prostatic tumor formation later in life (9 –11). The effects are lobe specific, with the ventral lobe being most prominently affected with regards to growth inhibition, secretory...
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