The Interplay Between Prolactin and Reproductive System: Focus on Uterine Pathophysiology (original) (raw)
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Localization and Temporal Expression of Prolactin Receptor in Human Endometrium
The Journal of Clinical Endocrinology & Metabolism, 1998
Extrapituitary PRL is synthesized by the decidualized endometrial stromal cells from the mid to late secretory phase in the nonpregnant cycle and throughout pregnancy. The function of PRL in the uterus is unknown, but the temporal expression indicates a role in implantation and placentation. PRL is a powerful immunoregulatory agent, and thus, a role in modulating endometrial leukocytes may be envisaged. To investigate the site of action of PRL, immunohistochemistry was conducted to localize the PRL receptor (PRL-R). In addition, ribonucleic acid was extracted and reverse transcriptase-PCR for PRL-R was conducted. PRL-R protein was immunolocalized to the Normal endometrial tissue (menstrual, n ϭ 3; proliferative, n ϭ 7; ovulatory, n ϭ 3; early secretory, n ϭ 3; mid secretory, n ϭ 5; late
Effect of prolactin and dopaminergic drugs on uterine response to chronic estrogen exposure
Journal of Endocrinology, 2002
The aim of this work was to examine the role of prolactin and dopaminergic drugs, which affect prolactin secretion, on proliferative and morphogenetic reactions in the uterus under continuous estrogen treatment. Ovariectomized mice received injections of estradiol dipropionate (2 microg per 100 g, weekly) or vehicle and daily injections of prolactin (0.25 mg/100 g) or saline (0.05 ml) for 30 days. Other groups of mice received injections of estradiol or vehicle and injections of saline, and were allowed to drink bromocriptine (25 mg/l), metoclopramide (25 mg/l), or only tap water for 30 days. Prolactin administration results in a decrease in the incidence of abnormal glands with abnormal epithelium, the incidence of atypical hyperplasia, uterine weight, proliferation (the number of mitotic and bromodeoxyuridine-labeled cells) and the levels of estrogen receptor-alpha, but causes an increase in the level of beta-catenin in uterine tissues of estrogen-treated mice. The effect of metoc...
Biological Significance of Prolactin in Gynecologic Cancers
Cancer Research, 2009
There is increasing evidence that Prolactin (PRL), a hormone/cytokine, plays a role in breast, prostate and colorectal cancers via local production or accumulation. Elevated levels of serum PRL in ovarian and endometrial cancers have been reported indicating a potential role for prolactin in endometrial and ovarian carcinogenesis. In this study, we demonstrate that serum PRL levels are significantly elevated in women with a strong family history of ovarian cancer. We demonstrate dramatically increased expression of PRL receptor (PRLR) in ovarian and endometrial tumors as well as in endometrial hyperplasia signifying the importance of PRL signaling in malignant and premalignant conditions. PRL mRNA was expressed in ovarian and endometrial tumors indicating the presence of an autocrine loop. PRL potently induced proliferation in several ovarian and endometrial cancer cell lines. Binding of PRL to its receptor was followed by rapid phosphorylation of ERK1/2, MEK-1, STAT3, CREB, ATF-2, and p53, and activation of 37 transcription factors in ovarian and endometrial carcinoma cells. PRL also activated Ras oncogene in these cells. When human immortalized normal ovarian epithelial (NOE) cells were chronically exposed to PRL a malignant transformation occurred manifested by the acquired ability of transformed cells to form clones, grow in soft agar, and form tumors in SCIDbeige mice. Transformation efficiency was diminished by a Ras inhibitor providing proof that PRL-induced transformation utilizes the Ras pathway. In summary, we present findings that indicate an important role for PRL in ovarian and endometrial tumorigenesis. PRL may represent a risk factor for ovarian and endometrial cancers.
The role of prolactin in human breast cancer Review
Biochemia Medica
Much of the literature on human breast cancer and prolactin (PRL) appears to be contradictory. PRL has been first recognizedas a hormone that plays an important role in breast cancer initiation and development in rodents, and, at least partly, in humans. Bioactive PRL is synthesized by human breast cancer cells in culture and acts in an autocrine/paracrine stimulatory loop within breast tissue. The actions of this ligand are mediated by PRL receptor (PRLR) isoforms found on, or secreted by, humanbreast epithelium. The PRL/PRLR complex associates with,and activates, several signaling pathways that are shared withother members of the cytokine receptor superfamily. Proximal PRLR signaling is initiated by three tyrosine kinases, namely Jak2, Src, and Tec. Some recent literature data have indicated a functional role forPRL within the nucleus where it acts in a complex with cyclophilin B as a transcriptional inducer. Several epidemiological studies have indicated that PRL mayalso function as a progression factor for human breast cancer. PRL might be an important local growth promoter involved in the pathogenesis of human breast cancer. Hyperprolactinemia could be an indicator of disease progression and poor prognosis and clinical approaches to controlling this disease need to incorporate antagonists of PRL/PRLR interaction or PRL receptor-associated signaltransduction.
2001
Decidualization of endometrial stroma in the rat induces the expression and secretion of rat decidual PRL (rdPRL). Recently, we have generated a nontransformed rat uterine stromal cell line (UIII) that decidualizes spontaneously in culture. In this report, we have established by immunocytochemistry, RT-PCR, Western blot analysis, labeled amino acid incorporation and RIA that these cells express the rat PRL messenger RNA as well as synthesize and secrete PRL. We have also cloned by RT-PCR a 403-bp complementary DNA fragment whose sequence is identical with that of rat pituitary PRL. In addition, UIII cells express the PRL receptor (PRL-R) long form, all the components involved in the PRL signal transduction pathway, estrogen receptor β (ERβ) and α2-macroglobulin (α2-MG), which are known to be PRL-regulated genes. However, when UIII cells were treated with PRL, no regulation of these genes was observed. Moreover, in these cells, the PRL signaling components: the tyrosine kinase Jak2 a...
Effects of metoclopramide-induced hyperprolactinemia on the prolactin receptor of murine endometrium
Fertility and Sterility, 2010
Objective: To evaluate the effects of metoclopramide-induced hyperprolactinemia on the prolactin receptor of murine endometrium. Design: Experimental study using the RNA extraction to detect tissue prolactin receptor isoforms by reverse-transcriptase polymerase chain reaction (RT-PCR). Setting: University-based laboratory. Animal(s): Seventy-two female swiss albino mice (Mus musculus), approximately 100 days old, were divided into six 12-animal groups: (GI) nonoophorectomized mice given vehicle; (GII) nonoophorectomized mice treated with metoclopramide; (GIII) oophorectomized mice treated with metoclopramide; (GIV) oophorectomized mice treated with metoclopramide and 17b-estradiol; (GV) oophorectomized mice treated with metoclopramide and micronized progesterone; (GVI) oophorectomized mice treated with metoclopramide and a solution of 17b-estradiol and micronized progesterone. Intervention(s): Drugs were administered for 50 days. Following euthanasia, the middle portions of the uterine horns were removed, sectioned, and immediately frozen for RT-PCR procedures. Blood was collected for the dosage of prolactin and serum estrogen and progesterone using radioimmune assay. Main Outcome Measure(s): Identification of uterine prolactin receptor isoforms. Result(s): The PRL receptor and its isoform L were identified only in GI (control group) and GII (metoclopramide), the two groups with nonoophorectomized animals. The amount of PRL receptor mRNA and that of its isoform L from GII were the largest. No other isoforms of the prolactin receptor were identified in any of the groups. Conclusion(s): Our results suggest that replacement of estrogen and progestin may not increase the mRNA of endometrial PRL receptor in metoclopromide-induced hyperprolactinemia in rats after castration.
Endocrinology, 2001
Decidualization of endometrial stroma in the rat induces the expression and secretion of rat decidual PRL (rdPRL). Recently, we have generated a nontransformed rat uterine stromal cell line (U III ) that decidualizes spontaneously in culture. In this report, we have established by immunocytochemistry, RT-PCR, Western blot analysis, labeled amino acid incorporation and RIA that these cells express the rat PRL messenger RNA as well as synthesize and secrete PRL. We have also cloned by RT-PCR a 403-bp complementary DNA fragment whose sequence is identical with that of rat pituitary PRL. In addition, U III cells express the PRL receptor (PRL-R) long form, all the components involved in the PRL signal transduction pathway, estrogen receptor  (ER) and ␣ 2 -macroglobulin (␣ 2 -MG), which are known to be PRL-regulated genes. However, when U III cells were treated with PRL, no regulation of these genes was observed. Moreover, in these cells, the PRL signaling components: the tyrosine kinase Jak2 and the transcription factor Stat5 were endogenously phosphorylated and their phosphorylation states were not enhanced in the presence of exogenous PRL. To examine whether the endogenously secreted PRL affects the expression of PRL-regulated genes, U III cells were treated with either an anti-PRL receptor antibody or a Jak2 inhibitor, AG490. The anti-PRL receptor antibody decreased ␣ 2 -MG expression. AG490 inhibited Jak2 and Stat5 phosphorylation, prevented Stat5 binding to its DNA consensus sequence, and also caused a dosedependent down-regulation of ␣ 2 -MG and ER expression. In contrast, AG490 enhanced PRL mRNA levels. In summary, we have established that the U III stromal cells of uterine origin produce PRL. Furthermore, we have shown for the first time that decidual PRL may act locally to activate the Jak2/Stat5 pathway and up-regulate important genes involved in decidual growth and placentation. (Endocrinology
Prolactin receptor expression in gynaecomastia and male breast carcinoma
Histopathology, 2008
Aims: Despite the well-established function of prolactin (PRL) in normal breast development, its role in breast cancer pathogenesis is still controversial. PRL activity is dependent on the activation of a transmembrane protein, the PRL receptor (PRLR). The aim was to evaluate and compare PRLR expression in gynaecomastia and male breast carcinoma (MBC).Methods and results: PRLR expression was detected immunohistochemically in 30 cases of gynaecomastia and 30 cases of MBC. The whole series was also assessed for oestrogen receptors (ER), progesterone receptors (PR) and androgen receptors (AR). A cut-off of 10% was used as the criterion for positivity. Histological type and tumour differentiation were evaluated. Pathological stage was assessed [Tumour Node Metastasis (TNM)-International Union Against Cancer system]. Statistical analysis was performed with Fisher’s exact test. PRLR positivity was seen in 20% of gynaecomastia cases and in 60% of MBC cases (P = 0.003). In gynaecomastia immunoreactivity was predominantly observed in luminal cell borders, whereas in MBC the reactivity was heterogeneous and mainly cytoplasmic. There was no statistically significant correlation between PRLR expression and ER, PR, AR, pTNM, or histological grade.Conclusions: PRLR is significantly more expressed in MBC than in gynaecomastia, and with different patterns of reactivity, suggesting a role for PRL in male breast carcinogenesis.
Prostaglandins, leukotrienes, and essential fatty acids, 1997
We studied the in vitro effect of prolactin on the synthesis of prostaglandins PGE and PGF2 alpha in the rat uterus. Uterine tissue was obtained from ovariectomized adult rats with or without estradiol-17 beta treatment. Prolactin (4 IU/ml) enhanced PGE uterine synthesis. At higher concentrations (10-15 IU/ml) prolactin enhanced PGE levels and diminished PGE2 alpha production by uterine tissue from ovariectomized rats. When ovariectomized rats were injected with estradiol-17 beta, we observed a pattern of PGE and PGF2 beta uterine similar to that of ovariectomized rats. However, the stimulatory action of PRL on PGE synthesis was augmented in the estrogenized animals. These results led us to conclude that: 1)-PRL exerts a luteotrophic action by regulating uterine tissue PGE synthesis, 2-estradiol-17 beta potentiates this action.