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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 1 258-262
Copyright © 1998 by The Endocrine Society

Original Studies

Localization and Temporal Expression of Prolactin Receptor in Human Endometrium

R. L. Jones, H. O. D. Critchley, J. Brooks, H. N. Jabbour and A. S. McNeilly

Department of Obstetrics and Gynecology, University of Edinburgh, and the Medical Research Council Reproductive Biology Unit, Center for Reproductive Biology (J.B., H.N.J., A.S.M.), Edinburgh, Scotland EH3 9EW

Address all correspondence and requests for reprints to: Dr. Rebecca L. Jones, Department of Obstetrics and Gynecology, Center for Reproductive Biology, 37 Chalmers Street, Edinburgh, Scotland EH3 9EW.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
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 glandular epithelium and a subset of stromal cells from the mid to late secretory phase of the menstrual cycle and in early decidua. PRL-R transcripts were also detected from the late secretory phase and first trimester decidua. These findings indicate that the receptor is expressed in a temporal pattern similar to that of PRL. PRL-R expression in the glandular epithelium is consistent with a role in regulating glandular activity. Furthermore, immunoreactivity for PRL-R in a subset of stromal cells may be evidence for paracrine interactions between decidualized cells or an immunoregulatory role for PRL.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
EXTRAPITUITARY PRL is produced and secreted by the decidua during pregnancy (1). The decidualized stromal cells have been conclusively shown to be the sole site of synthesis (2). Furthermore, experimental studies have recognized that PRL is produced by the nonpregnant endometrium from the mid to late luteal phase until menses (3). This corresponds to the initiation of decidualization during which the stromal cells become pseudodecidualized (2), and in vitro decidualization by stimulation of estrogen-primed proliferative endometrial cells with progesterone results in PRL production (4). Indeed, PRL expression is now commonly used as a marker for functional decidualization. Although pituitary and endometrial PRL are identical in structure and function, expression is differentially regulated, which has been attributed to the presence of a distinct promoter region located ~6 kilobases upstream of the pituitary promoter (5, 6).

The significance of PRL expression in the endometrium is uncertain. It is believed that PRL primarily acts as an autocrine or paracrine, rather than endocrine, factor. A similar mechanism has been reported in immune cells, where PRL has a profound immunomodulatory effect (7). The majority of leukocytes ubiquitously express the PRL receptor (PRL-R) (8, 9, 10, 11). Stimulated T cells secrete PRL (10), and in vitro PRL enhances the proliferation of leukocytes previously stimulated with mitogenic factors, including interleukin-2 and T and B cell mitogens (12). Furthermore, this proliferation is inhibited by exposure to anti-PRL antibodies (13). In vivo studies indicate an immunosuppressive action, such as the reduced immune response in lactating or PRL-treated castrated rats (14, 15).

The temporal expression of PRL in the endometrium suggests a role in the preparation for implantation and subsequent placentation. Decidualization is essential for implantation to occur, and the specialized immune environment within the decidua plays a major role in achieving a successful pregnancy. Coincidental with decidualization is the accumulation of leukocytes in the endometrial stroma, the majority of which are the uterine-specific large granular lymphocytes and macrophages (16, 17). These persist into early pregnancy and are believed to have a role in regulating implantation and placentation (18). PRL may be acting as an immunomodulatory agent in the endometrium by stimulation of either leukocyte proliferation or differentiation.

Although the production of PRL by the endometrium has been thoroughly investigated, its site of action in the endometrium has not been fully elucidated. PRL-R have been detected in the amniochorion, where PRL is believed to have an osmoregulatory effect on amniotic fluid volume (19), and additionally in third trimester decidua (20, 21). The exact cellular localization and temporal expression in the nonpregnant and early pregnant endometrium have not been clearly examined. The present study, by means of immunohistochemistry and reverse transcriptase-PCR (RT-PCR), investigates PRL-R expression in the human endometrium at different stages of the menstrual cycle and early pregnancy.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Tissue collection

Normal endometrial tissue (menstrual, n = 3; proliferative, n = 7; ovulatory, n = 3; early secretory, n = 3; mid secretory, n = 5; late secretory, n = 6) was collected from fertile women with regular menstrual cycles (25–35 days) who were undergoing minor gynecological procedures. Decidua parietalis (n = 8) was obtained by curettage before surgical termination of first trimester pregnancies. Written informed consent was received before tissue collection, and ethical approval was received from Lothian research ethics committee. Tissue samples were fixed by immersion in 10% neutral buffered formalin overnight at 4 C and stored in 70% ethanol before routine paraffin embedding. In addition, a sample was snap-frozen in isopentane precooled with dry ice and stored at -70 C. Ribonucleic acid (RNA) was subsequently extracted using Ultraspec RNA Isolation System (Biogenesis, Poole, UK). The RNA yield was estimated by measuring absorbance at 260 nm by spectrophometry, and purity was assessed by the ratio of absorbance at 260:280 nm.

Immunohistochemistry

The conditions for optimal specific immunoreactivity were determined. Paraffin sections (5 µm) were dewaxed in Histoclear (National Diagnostics, Atlanta, GA) and rehydrated through descending grades of ethanol to distilled water. Endogenous peroxidase activity was quenched by immersion in 3% hydrogen peroxide (H2O2, BDH Laboratory Supplies, Poole, UK) in distilled H2O for 5 min. Nonspecific binding was reduced by a 20 minute incubation with nonimmune goat serum (Vectastain Elite, Vector Laboratories, Peterborough, UK) in a humidified chamber at room temperature, after which the primary antibody (rabbit polyclonal raised against a rat peptide sequence common to the short and long forms of the receptor, supplied by Dr. P. Ingleton, University of Sheffield, Sheffield, UK) (22) was applied at a dilution of 1:50. The slides were incubated overnight (17 ± 1 h) at 4 C. Antibody binding was detected by the sequential application of biotinylated goat antirabbit IgG and an avidin-biotin-peroxidase complex (ABC Vectastain, Vector Laboratories, Peterborough, UK). The substrate 3,3'-diaminobenzidine (Vector Laboratories) was then used to visualize positive immunoreactivity. Finally, sections were counterstained with Harris’s hematoxylin (Pioneer Research Chemicals, Colchester, UK), dehydrated in ethanol, and mounted from xylene (BDH Laboratory Supplies).

Human term fetal membranes were included as a positive control for the PRL-R immunohistochemistry (21). A matching concentration of nonimmunized rabbit IgG was substituted for the primary antibody to exclude the possibility of nonspecific binding.

RT-PCR

Total RNA extracted from tissue collected at all stages throughout the menstrual cycle (proliferative, n = 12; secretory, n = 12) and in early pregnancy (n = 6) was subjected to RT-PCR for PRL-R.

Glyceraldehyde phosphate dehydrogenase (GAP-DH)

To ensure equivalent loading of viable RNA for the PRL-R RT-PCR, the expression level of the housekeeping gene GAP-DH was monitored by RT-PCR. Oligonucleotide primers for GAP-DH (sense, 5'-TGA AGG TCG GAG TCA ACG GAT TTG GT-3'; antisense, 5'-CAT GTG GGC CAT GAG GTC CAC CAC-3') were designed to produce a 1103-bp product. A sample of 400 ng total RNA was reverse transcribed to complementary DNA (cDNA) using avian myeloblastosis virus RT (Promega, Southampton, UK) and subsequently amplified by PCR using AmpliTaq DNA polymerase (Perkin-Elmer, Beaconsfield, UK) for 28 cycles at 94 C for 1 min, 60 C for 1 min, and 72 C for 2 min, followed by a final extension for 10 min at 72 C. Analysis of products by electrophoresis enabled assessment of viability of RNA, and bands of comparable intensity indicated comparable RNA loading into the RT-PCR.

PRL-R

Oligonucleotide primers complementary to the extracellular domain of the PRL-R were used (sense, 5'-GCA GAT GGA GGA CTT CCT ACC AAT TA-3' antisense, 5'-GCA GGT CAC CAT GCT ATA GCC CTT-3'), flanking bp 154–794, to amplify by RT-PCR a 650-bp product. The primers chosen spanned intronic sequences to ensure against the possibility of genomic DNA contamination. Firstly, gene-specific cDNA for PRL-R was generated by the reverse transcription of 400 ng total RNA from stocks identical to those used for GAP-DH, using the antisense oligonucleotide primer at 42 C for 45 min. The total volume of RT products was then amplified by PCR for 30 cycles at 94 C for 1 min, 62 C for 1 min, and 72 C for 2 min, followed by a 10-min final extension at 72 C. Sheep pituitary RNA was included as a positive control for the RT-PCR (23), and the omission of template RNA served as a negative control. The products were analyzed by comparison with a mol wt marker (PCR Marker, Sigma, Poole, UK) on a 1% agarose gel containing ethidium bromide.

The identity of the RT-PCR product was confirmed by subcloning into expression vector pGEM-T Easy Vector (Promega) and sequenced using the dideoxy chain termination method.

Southern hybridization

The identity of the amplified PRL-R products were further confirmed by Southern hybridization (24). Representative RT-PCR products, amplified from RNA extracted at different stages throughout the menstrual cycle, were selected for analysis. The products were separated by electrophoresis on a 1% agarose gel and blotted overnight onto a nylon membrane by capillary transfer. Hybridization was conducted overnight at 42 C with a 562-bp cDNA, labeled with [{alpha}-32P]deoxy-CTP by random priming, encoding the conserved extracellular domain (82% homology with human PRL-R cDNA) of the red deer PRL-R (between bp 96 and 657) (25). Posthybridization washes in SSC (standard saline citrate) and SDS were conducted with increasing stringency, and the membrane was thereafter exposed to autoradiographic film for 3 weeks.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Specific immunoreactivity for PRL-R was detected in endometrium and decidua by immunohistochemistry (Fig. 1Go). In the proliferative and early secretory phases of the nonpregnant cycle, immunostaining was weak or absent in the stroma, with minimal immunoreactivity visible in the luminal region of the glandular epithelium. From the mid to late secretory phase and in early pregnancy, intense immunoreactivity was apparent in both the glands and a subpopulation of stromal cells. In addition, positive immunostaining was identified in the blood vessels of some of the decidualized endometrial tissues. Fetal membranes included to act as a positive control exhibited positive immunoreactivity in the amniotic epithelium, chorion-laeve trophoblast, and decidual layer as previously reported (21). Substitution of the primary antibody with rabbit IgG resulted in an absence of staining in fetal membranes and endometrial and decidual sections.



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  		Figure 1. PRL-R immunolocalization in human endometrium. Minimal immunoreactivity is observed in the proliferative phase (A) and early secretory phase (B) endometrium. In the mid to late secretory phase (C), intense immunostaining is present in the epithelial glands and a subpopulation of stromal cells. This pattern persists in first trimester decidua (D), and at higher power (E) the decidualized stromal cells clearly exhibit strong immunoreactivity. Immunostaining is also apparent in the decidual vasculature (v). The negative control (F), in which the primary antibody was substituted with nonimmune rabbit IgG, results in an absence of staining. G, Glandular epithelium. Scale bars = 50 µm.

 
After PRL-R RT-PCR, a single band of 650 bp was detected by gel electrophoresis, corresponding to the region of the PRL-R gene amplified. Confirmation of its identity was obtained by Southern hybridization (Fig. 2Go), and sequence analysis verified that the amplicon encoded human PRL-R. A band representing PRL-R was detected in the tissue biopsied during the menstrual phase (days 1–4). During the proliferative and early secretory stages, the signal was either weak or absent. From the mid to late secretory phase, however, a strong signal was detected, with increasing intensity in samples obtained from early pregnancy (Fig. 3Go). A GAP-DH signal of comparable intensity (1103 bp) was obtained from all samples, indicating that equivalent amounts of RNA were loaded into the RT-PCR (Fig. 3Go). Furthermore, the presence of a GAP-DH signal in the absence of a PRL-R signal indicated that this was not due to an absence of viable RNA, but to the inability to detect PRL-R messenger RNA in the RNA sample. Overall, although this method is not totally quantitative, these data suggest that PRL-R expression is up-regulated in the mid to late secretory phase and continues in early pregnancy.



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  		Figure 2. RT-PCR for PRL-R generated a 650-bp amplified product, as identified by comparison with a mol wt marker. The identity of the amplicon was confirmed by Southern blotting (SB) and hybridization with a 562-bp cDNA probe raised against the conserved extracellular domain. LS, Late secretory; DE, decidua.

 


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  		Figure 3. RNA extracted from tissues from each stage of the menstrual cycle and early pregnancy was subjected to RT-PCR to determine the temporal expression of PRL-R. The upper panel shows representative RNA samples amplified for GAP-DH (amplicon size, 1103 bp), indicating the comparable loading of viable RNA into the PRL-R RT-PCR. The lower panel shows the same RNA samples amplified for PRL-R (amplicon size, 650 bp). No signal was obtained in the menstrual (Me), proliferative (P), ovulatory (OV), or early secretory (ES) phases. From the mid and late secretory phases (MS/LS), a signal was achieved, which increased in intensity in early pregnancy (DE, decidua). Pituitary (Pit) RNA was included as a positive control, yielding a band of identical size. No signal was observed for the negative control (-).

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
This study confirms the expression of the PRL-R in endometrium and decidua. Immunohistochemical localization revealed that the PRL-R is strongly expressed by the glandular epithelium and stromal cells in pseudodecidualized and decidualized endometrium. Immunostaining was minimal or absent in proliferative and early secretory phase endometrium. This temporal pattern of expression was confirmed by the amplification of PRL-R messenger RNA by RT-PCR, with the detection of a strong signal from the mid to late secretory phase of the nonpregnant cycle and in early pregnancy. Thus, the temporal expression of the receptor appears to mirror that of PRL by the decidualized endometrium.

It seems likely that progesterone has a role in the regulation of PRL-R expression (26). It is unlikely to be a direct regulation, however, as is the case for PRL, whose production is stimulated and maintained by the progesterone-mediated decidualization of the endometrium (27, 28). Regulation via decidua-derived factors (29) or even PRL itself may be envisaged (30, 31, 32). An indirect regulation by progesterone is firmly supported by the absence of progesterone receptors in the glandular epithelium when PRL-Rs are expressed.

The detection of strong immunoreactivity for the receptor in the epithelial glands suggests a paracrine action for PRL. During the early secretory phase, the endometrial glands become tortuous and actively produce uterine secretions, which are vital for preparing the endometrium for implantation (33). During the decidualization of the uterine stroma and continuing into pregnancy, the glandular epithelium becomes atrophic, and glandular secretory activity ceases. PRL has been reported to possess osmoregulatory activity, and the large amounts of PRL detectable in amniotic fluid act as a regulator of amniotic fluid volume. This was demonstrated by a link between defective PRL-R expression in amniotic epithelium and the incidence of polyhydramnios (19). The presence of PRL-R in the glandular epithelium during decidualization implicates a similar role for PRL, i.e. in the down-regulation of glandular activity.

Additional immunoreactivity was observed in a subset of stromal cells. The identity of these stromal cells is unknown, although the majority display morphological characteristics of decidualized stromal cells. This further supports the likelihood of the existence of an autocrine and/or paracrine interaction between PRL and its receptor. Further colocalization studies are required to determine whether the PRL-producing cells concurrently express the receptor. Positive immunostaining for the receptor was detected in the vasculature of some decidualized endometrial samples examined. The perivascular cells frequently exhibited immunostaining as expected, as this is the site of initiation of decidualization in the endometrium. Occasional staining was also observed that appeared to be endothelial in nature. A 16-kDa N-terminal fragment of human PRL has been noted to be a potent inhibitor of angiogenesis (34), and a high affinity binding site has been previously identified on endothelial cells (35).

PRL has important immunoregulatory functions in the peripheral immune system, including leukocyte proliferation, differentiation, and function. An important feature of the premenstrual endometrium and first trimester decidua is the accumulation of leukocytes within the decidualized stroma. These are believed to be essential for successful implantation and placentation (16), but the mechanism responsible for the increase in the secretory phase is not fully understood. Of particular interest are the uterus-specific large granular lymphocytes. It has been speculated that PRL may have a role in their proliferation and/or differentiation, especially after the discovery that these cells, although clearly under the influence of progesterone (36), do not express sex steroid receptors (37). The effect of PRL treatment on these decidual lymphocytes has been examined (36, 37), but both studies failed to observe a resultant proliferation or differentiation. It is not unlikely, however, that PRL may have an effect on decidual leukocytes, acting indirectly through autocrine/paracrine factors produced by neighboring cells.

It is probable that the migration of specific leukocytes from the peripheral circulation also contributes to the increase in leukocyte numbers. This is supported by the elevated levels of the chemokines interleukin-8 and monocyte chemoattractant protein-1 in the endometrium during leukocyte accumulation (38). PRL may be involved in enhancing this recruitment, as recent data reveal that the production of monocyte chemoattractant protein-1 is stimulated by PRL in ovarian tissue (39). A number of roles for PRL in the immunomodulation of the uterine leukocytes can thus be visualized, with a potential for augmenting lymphocyte migration, differentiation, and proliferation. It remains to be determined whether the endometrial leukocytes express the PRL-R.

In third trimester amniochorion, PRL has been implicated in the enhancement of matrix metalloproteinase activity (21, 40). During menses and placentation in early pregnancy, a dramatic reorganization of extracellular matrix must occur to allow endometrial shedding and trophoblast invasion, respectively. These processes invariably involve the action of matrix metalloproteinases, and it is possible that PRL may participate as one of the factors capable of altering the activities of these enzymes in the endometrium.

In summary, this study clearly demonstrates the expression of PRL-R in decidualized nonpregnant and pregnant endometria, with a temporal pattern similar to that of PRL. Immunohistochemical studies have isolated the glands and a subset of stromal cells as sites of action for PRL. PRL has multiple functions throughout the body, including roles in growth, differentiation, and immune response, and it is therefore difficult to isolate a single function for PRL in the uterus. It is, however, likely that PRL plays an important role in immunoregulation and additionally in the decidualization of both stromal and glandular cells of the endometrium.


   Acknowledgments
 
We extend our thanks to Miss Joanne McVerry and Miss Sheila Boddy for their technical assistance, and to Mr. Tom McFetters and Mr. Edward Pinner for all their help with the figures. Additionally, we acknowledge the help of Dr. Rodney Kelly in the RT-PCR studies.

Received April 3, 1997.

Revised July 11, 1997.

Revised September 24, 1997.

Accepted September 30, 1997.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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