Prolactin Receptor Levels Research Articles

Disruption of steroid and prolactin receptor patterning in the mammary gland correlates with a block in lobuloalveolar development.

Targeted deletion of the bZIP transcription factor, CCAAT/enhancer binding protein-beta (C/EBPbeta), was shown previously to result in aberrant ductal morphogenesis and decreased lobuloalveolar development, accompanied by an altered pattern of progesterone receptor (PR) expression. Here, similar changes in the level and pattern of prolactin receptor (PrlR) expression were observed while screening for differentially expressed genes in C/EBPbeta(null) mice. PR patterning was also altered in PrlR(null) mice, as well as in mammary tissue transplants from both PrlR(null) and signal transducer and activator of transcription (Stat) 5a/b-deficient mice, with concomitant defects in hormone-induced proliferation. Down-regulation of PR and activation of Stat5 phosphorylation were seen after estrogen and progesterone treatment in both C/EBPbeta(null) and wild-type mice, indicating that these signaling pathways were functional, despite the failure of steroid hormones to induce proliferation. IGF binding protein-5, IGF-II, and insulin receptor substrate-1 all displayed altered patterns and levels of expression in C/EBPbeta(null) mice, suggestive of a change in the IGF signaling axis. In addition, small proline-rich protein (SPRR2A), a marker of epidermal differentiation, and keratin 6 were misexpressed in the mammary epithelium of C/EBPbeta(null) mice. Together, these data suggest that C/EBPbeta is a master regulator of mammary epithelial cell fate and that the correct spatial pattern of PR and PrlR expression is a critical determinant of hormone-regulated cell proliferation.

Suppression of nerve growth factor Trk receptors and prolactin receptors by endocannabinoids leads to inhibition of human breast and prostate cancer cell proliferation.

Anandamide and 2-arachidonoylglycerol (2-AG), two endogenous ligands of the CB1 and CB2 cannabinoid receptor subtypes, inhibit the proliferation of PRL-responsive human breast cancer cells (HBCCs) through down-regulation of the long form of the PRL receptor (PRLr). Here we report that 1) anandamide and 2-AG inhibit the nerve growth factor (NGF)-induced proliferation of HBCCs through suppression of the levels of NGF Trk receptors; 2) inhibition of PRLr levels results in inhibition of the proliferation of other PRL-responsive cells, the prostate cancer DU-145 cell line; and 3) CB1-like cannabinoid receptors are expressed in HBCCs and DU-145 cells and mediate the inhibition of cell proliferation and Trk/PRLr expression. Beta-NGF-induced HBCC proliferation was potently inhibited (IC50 = 50-600 nM) by the synthetic cannabinoid HU-210, 2-AG, anandamide, and its metabolically stable analogs, but not by the anandamide congener, palmitoylethanolamide, or the selective agonist of CB2 cannabinoid receptors, BML-190. The effect of anandamide was blocked by the CB1 receptor antagonist, SR141716A, but not by the CB2 receptor antagonist, SR144528. Anandamide and HU-210 exerted a strong inhibition of the levels of NGF Trk receptors as detected by Western immunoblotting; this effect was reversed by SR141716A. When induced by exogenous PRL, the proliferation of prostate DU-145 cells was potently inhibited (IC50 = 100-300 nM) by anandamide, 2-AG, and HU-210. Anandamide also down-regulated the levels of PRLr in DU-145 cells. SR141716A attenuated these two effects of anandamide. HBCCs and DU-145 cells were shown to contain 1) transcripts for CB1 and, to a lesser extent, CB2 cannabinoid receptors, 2) specific binding sites for [3H]SR141716A that could be displaced by anandamide, and 3) a CB1 receptor-immunoreactive protein. These findings suggest that endogenous cannabinoids and CB1 receptor agonists are potential negative effectors of PRL- and NGF-induced biological responses, at least in some cancer cells.

The endogenous cannabinoid anandamide inhibits human breast cancer cell proliferation.

Anandamide was the first brain metabolite shown to act as a ligand of "central" CB1 cannabinoid receptors. Here we report that the endogenous cannabinoid potently and selectively inhibits the proliferation of human breast cancer cells in vitro. Anandamide dose-dependently inhibited the proliferation of MCF-7 and EFM-19 cells with IC50 values between 0.5 and 1.5 microM and 83-92% maximal inhibition at 5-10 microM. The proliferation of several other nonmammary tumoral cell lines was not affected by 10 microM anandamide. The anti-proliferative effect of anandamide was not due to toxicity or to apoptosis of cells but was accompanied by a reduction of cells in the S phase of the cell cycle. A stable analogue of anandamide (R)-methanandamide, another endogenous cannabinoid, 2-arachidonoylglycerol, and the synthetic cannabinoid HU-210 also inhibited EFM-19 cell proliferation, whereas arachidonic acid was much less effective. These cannabimimetic substances displaced the binding of the selective cannabinoid agonist [3H]CP 55, 940 to EFM-19 membranes with an order of potency identical to that observed for the inhibition of EFM-19 cell proliferation. Moreover, anandamide cytostatic effect was inhibited by the selective CB1 receptor antagonist SR 141716A. Cell proliferation was arrested by a prolactin mAb and enhanced by exogenous human prolactin, whose mitogenic action was reverted by very low (0.1-0.5 microM) doses of anandamide. Anandamide suppressed the levels of the long form of the prolactin receptor in both EFM-19 and MCF-7 cells, as well as a typical prolactin-induced response, i.e., the expression of the breast cancer cell susceptibility gene brca1. These data suggest that anandamide blocks human breast cancer cell proliferation through CB1-like receptor-mediated inhibition of endogenous prolactin action at the level of prolactin receptor.

Coexpression and cross-regulation of the prolactin receptor and sex steroid hormone receptors in breast cancer.

The sex steroid hormones and PRL interact synergistically to control the neoplastic growth of the mammary gland. The basis for this hormonal synergy is unknown, but may involve cellular coexpression of the sex steroid and PRL receptors, coupled with receptor cross-regulation. To examine this hypothesis the expression of the sex steroid and PRL receptors was examined in 20 human breast cancer cell lines and 123 primary breast cancers. Regulation of sex steroid receptors by PRL and of the PRL receptor by sex steroids was examined in T-47D and MCF-7 breast cancer cells. Northern analysis of the breast cancer cell lines and tumors indicated that the PRL receptor and the sex steroid receptors were coexpressed. The level of PRL receptor expression in the breast cancer cell lines was linearly related to that of the estrogen and progesterone receptors, but not to that of the androgen receptor. In MCF-7 and T-47D cells, acute treatment with progestins and androgens and long term treatment with estrogens increased PRL receptor levels. Analysis of sex steroid receptor messenger ribonucleic acid and binding activity showed that acute PRL treatment produced a time- and concentration-dependent increase in progesterone receptor and a decrease in androgen receptor. These results indicate that receptors for sex steroids and PRL are coexpressed and are cross-regulated, providing a potential mechanism for the observed synergy among estrogen, progesterone, and PRL in the control of tumor growth.

Removal of milk by suckling acutely increases the prolactin receptor gene expression in the lactating mouse mammary gland

To determine the effect of suckling on the prolactin receptor (PRL-R) gene expression, we measured the quantity of PRL-R mRNA in the lactating mouse mammary gland. When the pups were separated from their mother on day 5 of lactation, the long form of PRL-R (PRL-R L) mRNA disappeared with a half-life of 12.5 h for the first 9 h and 3.0 h for the following 9–15 h. By supplying pups to mice which had been weaned for 24 h, PRL-R L mRNA increased 2.5-fold during the next 6 h-period. The increase in PRL-R L mRNA was found in the mammary glands from which the pups removed milk. The number of mammary PRL-R protein decreased or increased following weaning or following the removal of milk by suckling, respectively. From these observations, it was concluded that the removal of milk acutely increases the level of PRL-R L mRNA during lactation.

Prolactin receptor expression by splenocytes from rats in various hormonal states

Prolactin (PRL) is mitogenic for lymphocytes in vitro, but the responsiveness of lymphocytes depends on the in vivo hormonal status of the rats from which the cells were obtained. Lymphocytes from ovariectomized (OVX) rats, but not from rats in oestrus or from male rats, respond to prolactin; administration of oestradiol to OVX rats diminishes the response. In order to determine if a correlation exists between lymphocyte responsiveness to prolactin and levels of cell surface prolactin receptors (PRL-R) expression, the percentage of splenocytes and each splenocyte subpopulation expressing surface PRL-R from rats of various hormonal states (OVX, oestradiol-injected OVX, oestrus and male) was analysed by single-colour and dual-colour flow cytometric analysis. We found that approximately 20% of splenocytes expressed surface PRL-R regardless of hormonal states (n = 16). The majority (85%) of PRL-R positive splenocytes were B lymphocytes whereas 11.1% and 4.8% of splenocytes expressing the PRL-R were CD4 positive T-helper (TH) and CD8 positive T-cytotoxic (TC) lymphocytes, respectively. B lymphocytes also stained more brightly than T lymphocytes. This distribution of PRL-R expression did not show significant alterations on total splenocytes or TH and TC lymphocytes during various hormonal stages. However, the percentage of PRL-R-positive B lymphocytes increased markedly in OVX rats (twofold), compared to rats at oestrus. In summary, no correlation was found between the responsiveness to prolactin as a mitogen and levels of PRL-R expression by lymphocytes from rats at different hormonal states. This result suggests that sex steroid hormones may control prolactin responsiveness of lymphocytes by affecting the signal transduction pathway through PRL-R rather than by altering the level of the cell surface receptor expression.

Inhibition of Prolactin Receptor Gene Expression by 2,3,7,8-Tetrachlorodibenzo-p-dioxin in MCF-7 Human Breast Cancer Cells

Treatment of MCF-7 human breast cancer cells with 10 nM2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) did not decrease prolactin receptor (PRLR) binding. In contrast, PRLR mRNA levels were significantly decreased within 12 h after treatment with TCDD and persisted for up to 48 h. The effects of TCDD on PRLR mRNA levels were inhibited by the aryl hydrocarbon (Ah) receptor antagonist α-naphthoflavone and were not observed in Ah nonresponsive benzo[a]pyrene-resistant MCF-7 cells. These results suggest that the effects of TCDD were mediated through the Ah receptor. After treatment of MCF-7 cells with 10 nM17β-estradiol (E2), there was a 2.3-fold increase in PRLR mRNA levels, and in cells cotreated with E2 plus TCDD, there was a 72% decrease in E2-induced PRLR mRNA levels. Previous studies have showed that TCDD also effects estrogen receptor (ER) binding and mRNA levels through the aryl hydrocarbon receptor pathway; however, the effects of TCDD on PRLR levels and binding in MCF-7 cells were different from those previously observed for ER.

Prolactin receptor gene expression in rat splenocytes and thymocytes from birth to adulthood

In vivo and in vitro studies have indicated that the anterior pituitary hormone prolactin (PRL) is an immunoregulator and functions in the development of the neonatal immune system. In this study, prolactin receptor (PRL-R) expression from birth to adulthood as well as the effect of milk ingestion on the PRL-R expression were examined in splenocytes and thymocytes of neonatal rats. Three approaches were taken to measure PRL-R expression: (i) polymerase chain reaction (RT-PCR); (ii) antibody to PRL-R and Western blotting; (iii) antibody to PRL-R and flow cytometry. RT-PCR analysis revealed the short and long form of PRL-R mRNA in both spleen and thymus at every age tested. However, the long form of PRL-R mRNA was always more abundant than that of the short form. In addition, antipeptide antibody against the long form of PRL-R recognized 84 and 42 kD proteins in the spleen, but only the 84 kD protein in the thymus. A monoclonal antibody U6 recognized 38 and 40 kD proteins in both the spleen and thymus. Although the mRNA level of PRL-R was relatively low at birth and increased with age in both the spleen and thymus, the levels of protein bands detected with both antibodies correlated with development in the spleen; whereas the levels remained steady in the thymus. Therefore, we concluded that the expression of PRL-R at the protein level is developmentally regulated in the spleen but not in the thymus. Finally, milk ingestion in the first seven hours decreased the percentage of cells expressing cell surface PRL-R, suggesting that milk-borne PRL may have a direct effect on lymphocytes.

Regulation of prolactin receptor mRNA expression in peripheral lymphocytes in rats in response to changes in serum concentrations of prolactin

In the present study we have evaluated the absolute number of the two forms of prolactin (PRL) receptor mRNA in rat peripheral blood lymphocytes and the modulation of receptor mRNA induced by changes in serum levels of endogenous PRL or by administration of ovine PRL. Lymphocytes expressed low levels of both forms of PRL receptor transcripts. Repeated treatments with ovine PRL significantly reduced levels of mRNA encoding the long form PRL receptor, whereas expression was markedly increased by repeated doses of bromocriptine. In contrast, the mRNA level of short form PRL receptor was unchanged by both treatments. The expression of long form transcripts was also markedly decreased in lymphocytes from pituitary-grafted rats. Therefore it appears that in rat peripheral lymphocytes PRL has a negative effect on the expression of its own receptor.

Regulation of prolactin receptor mRNA expression in peripheral lymphocytes in rats in response to changes in serum concentrations of prolactin.

In the present study we have evaluated the absolute number of the two forms of prolactin (PRL) receptor mRNA in rat peripheral blood lymphocytes and the modulation of receptor mRNA induced by changes in serum levels of endogenous PRL or by administration of ovine PRL. Lymphocytes expressed low levels of both forms of PRL receptor transcripts. Repeated treatments with ovine PRL significantly reduced levels of mRNA encoding the long form PRL receptor, whereas expression was markedly increased by repeated doses of bromocriptine. In contrast, the mRNA level of short form PRL receptor was unchanged by both treatments. The expression of long form transcripts was also markedly decreased in lymphocytes from pituitary-grafted rats. Therefore it appears that in rat peripheral lymphocytes PRL has a negative effect on the expression of its own receptor.

Morphine-induced prolactin release precedes a down-regulation of prolactin receptors in the male rat choroid plexus and hypothalamus

In previous studies we provided evidence for changes in prolactin (PRL) receptor levels in the male rat brain after continuously infusing morphine using subcutanously implanted miniosmotic pumps. In this work we have studied the binding of PRL in the male rat brain following morphine administration by both subcutaneous (s.c.) and intracerebroventricular (i.c.v.) injections. The binding in the choroid plexus and the hypothalamus was measured using iodinated ovine PRL (oPRL) as a radiolabel. The results indicated that the density of the PRL-binding sites in the hypothalamus and the choroid plexus were significantly decreased 4 h and 24 h after s.c. injections, and also 30 min and 4 h after i.c.v. injections. However, no decrease in PRL-binding was observed 15 min after i.c.v. injection of morphine. The plasma levels of PRL were measured by radioimmunoassay (RIA) and were found to be significantly increased after 30 min and 4 h in all treated animals. Following i.c.v. injection a significant increase in plasma PRL was observed after just 15 min. It was suggested that the down-regulation in PRL binding to some extent at least resulted from receptor overstimulation caused by the morphine-induced elevation in the concentrations of the endogenous hormone.

Prolactin receptors in human pituitary adenomas

In the rat, prolactin receptors (PRL-R) have been identified in normal pituitary cells and in anterior pituitary tumours induced by oestradiol. No published data are available concerning PRL-R in the human pituitary. The aim of our study was therefore to detect the presence of PRL-R in the normal human pituitary gland and human pituitary adenomas. Evaluation of free and total PRL-R in the normal pituitary gland and different pituitary tumours characterized by immunocytochemical analysis. Twenty-six unselected patients (14 M, 12 F) who underwent surgery for pituitary adenoma (3 prolactinomas, 4 GH-PRL adenomas, 5 GH adenomas, 1 ACTH adenoma, 9 glycoprotein and/or alpha-subunit adenomas, 4 null cells adenomas) were studied. Nine pituitaries from subjects whose death was unrelated to brain and endocrine diseases, were also studied as a control group in the PRL binding studies. Free PRL-R in microsomal membranes were determined by in-vitro radioreceptor assay using 125I-labelled human PRL as ligand. Total PRL-R were also measured in the same membrane fractions by removing endogenous PRL bound to its receptors using 4 M MgCl2. Serum PRL levels were also evaluated in all patients before surgery using an IRMA method. Specific binding values for PRL (free PRL-R) were 0.39 +/- 0.03% (range 0-1.96%) in the pituitary adenomas. These binding values were identical to those observed in normal pituitaries (0.38 +/- 0.07%, range 0.1-0.78%). Elevated PRL binding (1.25% and 1.96%) was found in two patients with PRL secreting adenomas and very high serum PRL levels (5768 and 11240 mU/I. No PRL binding was shown in 4 patients. Treatment of membranes with 4 M MgCl2 increased the specific binding (total PRL-R) in both pituitary tumours (0.5 +/- 0.11%; P < 0.001) and normal pituitaries (0.47 +/- 0.07%; P < 0.02). Our data have demonstrated the presence of prolactin receptors in normal cadaveric pituitary and in most pituitary adenomas, irrespective of histological classification. In particular, elevated prolactin receptor levels were shown in PRL-secreting tumours from patients with markedly increased serum PRL levels. Our study may support several lines of experimental evidence for a specific functional role for PRL in the growth of some pituitary adenomas.

Prolactin receptor levels on lymphocytes vary with menstrual cycle in women.

Prolactin exerts effects on the immune system, potentiating T-cell growth in response to various stimuli. These effects are felt to be mediated by specific receptors present on lymphocytes for prolactin. While the presence of prolactin receptors (PRLRs) on lymphocytes is well accepted, potential fluctuations in these receptor levels in individuals have not been studied. Here we present evidence that lymphocyte prolactin levels vary throughout the menstrual cycle in females. Lymphocyte PRLR levels varied up to 10-fold as determined by radioreceptor assay on the different days of the menstrual cycle. A semi-quantitative PCR technique was used to measure message levels, and these generally correlated with radioreceptor results. We conclude that lymphocyte PRLR levels vary throughout the menstrual cycle and that these variations are due at least in part to variations in PRLR mRNA levels.

Prolactin binds to human endometrial fibroblasts and inhibits mitogenicity of an endometrial carcinoma extract.

Uterine endometrial carcinoma has been reported to synthesize and secrete a putative peptide mitogen that elicits a potent proliferative response in endometrial fibroblasts. The extract from endometrial carcinoma stimulated [3H]thymidine incorporation into human endometrial fibroblasts in a dose-dependent manner. Concomitant exposure of the fibroblasts to prolactin (PRL) led to a remarkable inhibition of the extract-stimulated mitogenic activity of the fibroblasts. This inhibition was dependent on PRL dose, and maximal effect occurred at 1 microM of PRL. PRL (10 nM) suppressed an apparent maximal activity of the extract by 50%, and the half-maximal stimulated effect of the extract on thymidine incorporation was observed at the same concentration in the absence or presence of PRL. This noncompetitive manner may imply that PRL acts at a stage after the interaction of the mitogen in the extract with the specific receptor for mitogen. When the fibroblasts were first exposed to the extract for 12 hr and then to PRL, PRL suppressed the mitogenic activity with no lag. The rapid growth-inhibitory effect of PRL was mimicked by prostaglandin E1, but the combination of both types of ligand was not additive in the inhibitory action on growth. PRL and prostaglandin E1 may inhibit a similar mitogenic signaling cascade. Specific receptor sites for PRL were detected in the endometrial fibroblasts, showing high binding affinity (Kd = 16.1 nM) and low binding capacity (Bmax = 1.59 pmol/mg protein). Treatment of the fibroblasts with the endometrial carcinoma extract induced no changes in the level of PRL receptor, excluding the possibility that PRL competes for the binding sites with the mitogen. These findings would suggest that PRL may block the mitogenic activity of the fibroblasts stimulated by the endometrial carcinoma-derived mitogen via a PRL receptor-mediated mechanism, perhaps prostaglandin production.

Prolactin and interrenal hormone balance in adult specimens of Xenopus laevis exposed to hyperosmotic stress for up to one week.

Adult female specimens of Xenopus laevis were exposed to diluted artificial seawater for up to 1 week. Statistically significant increases were observed in serum levels of aldosterone and corticosterone, concomitant with a drop in levels of prolactin (PRL) receptors in the cell membranes of the epidermis and kidney, which can be taken as an indicator of the levels of circulating PRL. The changes in hormone levels were detected after 1 day, being followed by a gradual restoration of the initial mean levels of these hormones when the exposure to hyperosmotic stress was extended for up to 2 or 7 days. Comparison of the above results with those previously obtained in Xenopus after longer exposure (15 days) to brackish water substantiates the necessity of recording possible initial fluctuations, as well as any changes that occur over the course of longer exposure during which time adaptation to environmental changes are likely to take place. The reverse responses, which may be not independent of one another, in terms of levels of corticoids and PRL in the animals exposed to hyperosmotic stress, are discussed. A survey of the literature suggests that, in Xenopus, as in the case of other less strictly water-dwelling amphibians, PRL is one of the hormones required for life in fresh water.

The effect of progestins on prolactin receptor gene transcription in human breast cancer cells.

The sex steroid hormone progesterone modulates the developmental and lactogenic activity of prolactin in the mammary gland. Regulation of the level of prolactin receptor (PRLR) provides one possible mechanism by which this may occur, prompting this investigation of the molecular mechanisms involved in progestin regulation of prolactin receptor levels. Treatment of T-47D and MCF-7 human breast cancer cells with 10 nM of the synthetic progestin ORG 2058 for 24 hr resulted in an increase in all four PRLR mRNA transcripts detected. The effect of ORG 2058 was shown in T-47D cells to be time- and concentration-dependent and resulted in an approximate two-fold increase in PRLR mRNA after 24 hr of treatment with 10 nM or 100 nM ORG 2058. Nuclear run-on assays indicated that ORG 2058 increased the rate of T-47D PRLR gene transcription at all times between 1 hr and 28 hr of treatment. The protein synthesis inhibitors cycloheximide and puromycin abrogated the induction of PRLR gene transcription at 1 hr and 2 hr, which demonstrated that on-going protein synthesis was required for the ORG 2058 effect and suggested that progestins may exert some transcriptional effects via the induction of an intermediary protein. These experiments demonstrated that progestin induced a transcriptionally based increase in PRLR gene expression and provided a mechanism by which progesterone may modulate the mitogenic activity of prolactin during mammary gland development.

Expression of prolactin (PRL) receptor gene and PRL-binding sites in rabbit intestinal epithelial cells.

Specific binding sites for PRL were identified on isolated intestinal epithelial cells from both male and female rabbits. These receptors exhibited a very high affinity for PRL (Kd = 5 x 10(-11) M) and were immunologically very similar to the well characterized mammary PRL receptor. About 3500 PRL receptors/cell were expressed on isolated epithelial cells from rabbit jejunum. These receptors were distributed in precise portions of the gut, being highly expressed in the proximal small intestine (duodenum and jejunum), moderately expressed in the ileum, and barely detectable in the colon. The levels of intestinal epithelial PRL receptors were low in 15-day-old rabbits, moderate at 1 month, and reached adult levels at 2 months, indicating enhanced PRL receptor expression in the intestine as development proceeded. The PRL receptor gene was specifically and highly expressed in the rabbit intestine, and four PRL receptor transcripts were detected that were identical to the transcripts characterized in the mammary gland. In individual intestinal segments, the expression of PRL-binding sites was always highly correlated with the level of PRL receptor mRNA. These results show that isolated intestinal epithelial cells express the PRL receptor gene as well as specific binding sites with a high affinity for PRL. They suggest that PRL regulates intestinal functions by exerting direct actions on the intestinal epithelial cells.

Potentiation of medroxyprogesterone acetate antineoplastic activity by histodine in rat mammary tumours

The antitumour activity of arginine, histidine and medroxyprogesterone acetate (MPA) was studied in female rats with dimethylbenzanthracene (DMBA)-induced mammary adenocarcinomas. After 15 days of treatment, regression was observed in 4 of 19 (21%), 3 of 18 (16.7%) and 22 of 59 (37.3%) tumours taken from rats given arginine, histidine or MPA, respectively. A total of 17 rats with tumours that had been non-responsive to MPA were then treated with MPA plus histidine for 15 more days; the growth of 3 lesions (17.6%) was arrested, and 5 tumours (29.4%) regressed markedly. The antineoplastic activity of MPA was found to be related to the oestrogen-(ER) and progesterone-receptor (PgR) concentrations measured in the tumours before the start of treatment, whereas that of arginine and histidine appeared to be independent of receptor status. A significant reduction in serum prolactin (PRL) levels occurred in rats that were responsive to MPA alone or to MPA plus histidine. In tumours taken from the same rats, the PRL receptor content was also significantly increased in comparison with that in non-responsive tumours. In contrast, serum PRL levels increased significantly in rats with tumours that were non-responsive to MPA, whereas no change in serum PRL or PRL receptor levels was observed in rats treated with arginine or histidine. Histidine showed the ability to increase the number of ERs and PgRs in responsive tumours; this could have been responsible for the unexpected potentiation of MPA antineoplastic activity. In contrast, the levels of ER and PgR in uteri taken from the same rats were not modified. Furthermore, the addition in vitro of histidine to cytosols obtained from tumours of control animals did not influence ER and PgR concentrations. These results suggest that the effect of histidine on ER and PgR levels is probably specific for tumour tissue and is not due to a direct activity.

Influence of Neonatal Diethylstilbestrol Treatment on Prolactin Receptor Levels in the Mouse Male Reproductive System

Neonatal exposure to the synthetic estrogen, diethylstilbestrol, is known to affect the structure of the male reproductive system; thus, changes may also occur in the levels of hormone receptors. Prolactin receptor levels from the reproductive systems of male BALB/c mice exposed neonatally to diethylstilbestrol were analyzed. Neonatal exposure to diethylstilbestrol caused significant decreases (i) in prolactin receptor levels in the seminal vesicle, ductus deferens, and anterior and ventral prostates and (ii) in tissue weight and protein content in reproductive organs other than the ventral prostate.

Effects of medroxyprogesterone acetate on serum prolactin levels and liver prolactin binding capacity in the rat

Modifications in liver prolactin (PRL) receptor levels and serum PRL concentration induced by administration of medroxyprogesterone acetate (MPA) were investigated in rats of both sexes. MPA induced a reduction both of the levels of PRL in the serum and of liver PRL receptors in the female rat. The reduction of the number of PRL receptors caused by MPA was rapid and almost complete after 10 days of treatment and appeared earlier than that of serum PRL levels. Furthermore the MPA-induced decrease in PRL receptors was specific, since insulin binding to the same liver membranes was not affected. MPA given simultaneously with oestradiol (which increases both the number of liver PRL receptors and the serum PRL levels in the male rats) was able to counteract the increase in PRL binding induced by oestradiol. On the contrary, the oestrogen-induced increase in serum PRL was not affected by MPA treatment. Similar results were obtained using tamoxifen, a well known antioestrogenic drug. In conclusion, our results show that the reduction of PRL receptor levels induced by MPA in rat liver is specific, not correlated to serum PRL concentration, and seems to depend on the antioestrogenic activity of the drug.