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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 5 1467-1471
Copyright © 1997 by The Endocrine Society

Reproductive Endocrinology

In Vivo Estrogen Regulation of Epidermal Growth Factor Receptor in Human Endometrium

Judith H. McBean, John R. Brumsted and William S. Stirewalt

Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility (J.H.M., J.R.B.), and the Department of Obstetrics and Gynecology, Division of Research (W.S.S.), University of Vermont College of Medicine, Burlington, Vermont 05401

Address all correspondence and requests for reprints to: Judith H. McBean, M.D., Department of Obstetrics and Gynecology, Division of Reproductive Endocrinology and Infertility, University of Vermont College of Medicine, Burlington, Vermont 05401.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The effects of estrogen and progesterone on the expression of epidermal growth factor receptor (EGFR) in human endometrium were studied in hypogonadal women under conditions that simulated a normal menstrual cycle. All women received the same regimen of estrogen and progesterone and underwent serial biopsies. In one group of women (group I), a biopsy was obtained before receiving estrogen (CD0) and after 11 days (CD11) of estrogen replacement. A second group of women was biopsied on CD11 and CD21 to assess the combined effects of progesterone and estrogen (group II). Immunohistochemistry was used to test for the presence of EGFR, and a ribonuclease protection assay was used to assess the amounts of EGFR messenger ribonucleic acid (RNA) relative to ribosomal RNA in the tissue. In group I, a significant increase in EGFR messenger RNA from CD0 to CD11 was observed. A similar increase was observed to occur between CD11 and CD21 in group II. Immunostaining for EGFR was absent in all CD0 biopsies, but was present in all estrogen-exposed endometrium. No difference in immunostaining was noted between CD11 and CD21. We conclude that estrogen stimulates the synthesis of EGFR in human endometrium and that progesterone does not appear to modulate this effect. The examination of other parameters in hormone-replaced hypogonadal subjects will be valuable in understanding the complex physiological regulation of the human endometrium.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE HUMAN endometrium undergoes a complex series of cyclic changes every month. Proliferation and differentiation of both epithelial and stromal cells are under hormonal control by estrogen and progesterone. Little is known about the mechanism of this control. It is hypothesized that estrogen stimulates cell growth through a cascade that includes elevation of growth factors and their receptors (1, 2). Epidermal growth factor (EGF) receptor (EGFR) is a tyrosine kinase receptor that mediates the effects of EGF, transforming growth factor-{alpha}, and related ligands (3). In mammalian cells, binding of EGFR by these ligands leads to both cell proliferation and differentiation (3). In animal studies, EGF and EGFR have been identified in the uterus (4) and throughout the female reproductive tract (5). EGF can replace estrogen in stimulating in vitro growth of mouse uterine cell cultures (6), and when administered to ovariectomized mice, it is a potent uterine and vaginal mitogen (7). The de novo synthesis of EGF does not appear to be estrogen dependent (4). In contrast, 17ß-estradiol (E2) has been shown in rats to increase de novo synthesis of functional receptors (8) and messenger ribonucleic acid (mRNA) for EGFR (9). It appears that estrogen may regulate the mitogenic effects of the EGF family of ligands at the receptor level.

Expression of EGF and EGFR in human endometrium has been reported (10, 11, 12, 13). However, it remains unclear whether EGFR varies throughout the menstrual cycle, as both cyclic (10, 11) and noncyclic (12, 13) expression have been reported. These studies used single endometrial biopsies from spontaneously cycling women to evaluate EGFR expression. The present study was undertaken to evaluate the relative levels of EGFR and EGFR mRNA in serial biopsies of endometrium obtained from hypogonadal women receiving estrogen and progesterone in amounts that simulated the cyclic levels of the steroids that occur during a normal menstrual cycle.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

Fourteen hypogonadal women, aged 25–61 yr, underwent two endometrial biopsies, as described below. The women included in the study lacked endogenous ovarian function as a result of spontaneous menopause (10), premature menopause (1), hypothalamic amenorrhea (2), and female Kallman’s syndrome (1). Informed written consent was obtained from all participants, and the study was approved by the institutional review board at the University of Vermont College of Medicine. Gonadotropin (FSH) and E2 levels were measured at baseline to document the hypoestrogenic hypogonadal state. Women with a history of estrogen replacement therapy were subjected to a progesterone induced withdrawal menses, followed by a 14-day medication-free period before beginning the protocol.

Study design

All study subjects received the same estrogen (Estraderm, Ciba Pharmaceutical Co., Summit, NJ) and progesterone replacement. Estraderm was selected because transdermally absorbed E2 bypasses the effects of first pass metabolism and results in a physiological serum estradiol/estrone ratio (14). All women received hormone replacement for a total of 25 days, hereafter referred to as cycle days (CD). Estrogen was administered on CD1 through CD25, with the addition of progesterone on CD15 through CD25 in a manner that mimics an endogenous cycle. The pattern of replacement was developed for use in donor oocyte in vitro fertilization cycles (14). On CD1 through CD6, one 50-µg patch was applied, and this was changed every 3 days. On CD7 through CD9, one 100-µg patch was applied, followed by two 100-µg patches on CD10 through CD11. Four 100-µg patches were worn on CD12 through CD14, followed by one 100-µg patch on CD15 through CD17 and two 100-µg patches changed every 3 days from CD18 through CD25. Progesterone was supplied as vaginal suppositories given at doses of 25 mg three times daily on CD15 through CD16, 50 mg three times daily on CD17 through CD21, and 50 mg twice daily on CD22 through CD25 (15).

All biopsies were obtained in an out-patient setting with the Pipelle Endosampler (Unimar Corp., Wilton, CT). A portion of each biopsy was formalin-fixed, paraffin-embedded, and set aside for histology and immunohistochemistry. Slides stained with hematoxylin and eosin were reviewed and used to confirm estrogen-stimulated proliferation of the endometrium and secretory transformation by progesterone and for dating according to the criteria of Noyes et al. (16). The remaining tissue was immediately frozen in liquid nitrogen and stored at -70 C until analysis.

Group I: effects of E2 on the expression of EGFR

Subjects (n = 6) in this group underwent a baseline biopsy before initiation of estrogen replacement. The second biopsy was performed on CD11, which represents the beginning of the midfollicular phase as well as the midpoint of the follicular E2 rise in normal menstrual cycles (17). One subject was excluded because of inadequate RNA for analysis. By obtaining two biopsies within a single menstrual cycle, each subject served as her own control.

Group II: effects of progesterone on EGFR expression in E2-primed endometrium

In this group (n = 8), the effect of progesterone on an estrogen-primed endometrium was evaluated by obtaining biopsies on CD11 and CD21. CD11 represents the midfollicular phase, and CD21 represents the midluteal phase in normal menstrual cycles. CD21 is also the approximate time of implantation and represents the time of maximal progesterone effect. Three subjects in this group were excluded after cervical stenosis prevented the initial biopsy, leaving five subjects for final analysis.

RNA isolation and analysis

Total cellular RNA was isolated from frozen specimens by the single step method of Chomczynski and Sacchi (18) using TRI Reagent (Molecular Research Center, Cincinnati, OH). mRNA was analyzed by ribonuclease protection assay (RPA) using a commercially available kit (RPA II, Ambion, Austin, TX). Templates for EGFR mRNA and ribosomal RNA (rRNA) were synthesized using [{alpha}-32P]CTP and the Maxiscript kit (Ambion). The template for EGFR, a 350-bp complementary DNA fragment of the human EGFR gene that spans exons 12–14 (19), was transcribed to make a high specific activity probe (1 x 109 cpm/µg) using SP6 RNA polymerase. The 18S ribosomal probe was transcribed to make a low specific activity probe (~1 x 107cpm/µg) using T7 RNA polymerase. The probes were gel purified and added simultaneously to 30 µg total RNA. Hybridization was carried out overnight at 45 C. After ribonuclease inactivation and precipitation of the protected probe fragments, the samples were analyzed on a 5% denaturing polyacrylamide gel. Gels were exposed to x-ray film at -70 C for initial visualization of signals. Hybridization signals were then quantified using a phosphorimager (molecular, Bio-Rad, Hercules, CA). Results are expressed as arbitrary densitometric units, related to the intensity of 18S rRNA and are reported as the EGFR/18S rRNA ratio. A radiolabeled RNA ladder was used to size the protected fragments, and yeast RNA served as a negative control for EGFR mRNA. The A431 cell line served as a positive control for EGFR. All samples from a single protocol were run in the same assay, as shown in Fig. 1Go.



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  		Figure 1. Autoradiograph of multiple probe RPA using total RNA isolated from endometrial biopsies. Samples from all subjects from group I (A) and group II (B) were run in a single assay and are labeled individually. (Note that I-4 was loaded in reverse order.) The EGFR probe protected a 350-nucleotide sequence, as marked. rRNA was used as an internal control to which EGFR data were normalized. The 18S ribosomal RNA probe protected an 80 nucleotide sequence. The two bands observed with the 18S rRNA probe are due to a portion of the antisense probe rehybidizing to its complementary sequence subsequent to denaturation in the loading buffer. Both bands were quantified, and the total signal was used for analysis.

 
Immunohistochemistry

Immunohistochemistry was performed on all biopsies to assess the presence of EGFR protein in the endometrium. Slides were deparaffinized in xylene and rehydrated in ethanol. Tissue sections were preincubated with blocking solution (10% goat serum) and incubated with 1:100 dilution of antiserum overnight in a humidified chamber at 4 C. Primary antibody was detected by means of an avidin-biotin peroxidase complex kit (Oncogene Science, Uniondale, NY). Enzyme activity was detected using the AEC detection method (Zymed, South San Francisco, CA), resulting in a red precipitate. All slides were then evaluated for the presence of EGFR by two reviewers in a blinded fashion. Staining was characterized as absent, light, or dark (0, +1, or +2, respectively). The primary antibody for EGFR was a rabbit affinity-purified polyclonal antibody raised against the peptide that corresponds to amino acid residues 1005–1016 (Oncogene Science) and is human specific. For negative controls, primary antibody was omitted. Sections from normal term placenta served as the positive control (data not shown).

Hormone assays

Serum E2 and progesterone levels were determined by standard RIA using commercially available kits. E2 levels were measured using the Equate RIA system (Binax, South Portland, ME) and were reported as picograms per mL. Progesterone levels were measured using a RIA kit (Diagnostic Systems Laboratories, Webster, TX) and were reported as nanograms per mL. Intra- and interassay coefficients of variation were 8.8% and 7.5% for E2 and 3.7% and 7.6% for progesterone, respectively. All samples for an individual subject were run within a single assay.

Statistical analysis

All hormone levels were reported as the mean ± SD. Statistical analysis of the RPA data was performed using a paired t test. P < 0.05 was considered significant.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Hormone replacement

The effects of estrogen and progesterone replacement on serum levels of the steroids for all study subjects are shown in Fig. 2Go. The levels of E2 and progesterone through the 21-day study period were similar to those achieved in an endogenous cycle (14).



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  		Figure 2. Serum concentrations of E2 (•) and progesterone ({circ}) are shown. Values represent the mean of all subjects in both protocols and are reported as the mean ± SD.

 
EGFR mRNA quantification

All samples of endometrium had detectable levels of EGFR mRNA. Group I was designed to study the in vivo response of EGFR to E2 alone. A significant increase in mRNA levels was seen after E2 treatment in four of five subjects (Fig. 3AGo). The one subject (I-2) who failed to demonstrate an increase in EGFR mRNA had subphysiological serum E2 levels throughout the cycle (E2, 32 pg/mL on CD11) and was excluded from the analysis. Measurements of EGFR mRNA were normalized to 18S rRNA to correct for variabilities in RNA loading between samples (Fig. 1Go).



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  		Figure 3. Graphic representation of the relative changes in EGFR mRNA in each subject in group I (A) and group II (B). Results are expressed as ratios of densitometric units of the EGFR mRNA and 18S rRNA phosphoimaged signals. The legends show the serum E2 (group I) and E2 and progesterone levels (group II) for each individual. In group I there was a significant (P < 0.05) increase in EGFR mRNA between CD0 and CD11. A similar increase in EGFR mRNA was observed between CD11 and CD21 in group II (P < 0.02).

 
Biopsies in group II were timed to evaluate the effects of progesterone on an estrogen-primed endometrium in vivo. We noted an increase in EGFR mRNA between CD11 and CD21 (P < 0.02). The one subject with a decrease in the level of EGFR mRNA between CD11 and CD21 was also noted to have a marked decrease in E2 (Fig. 3BGo). Overall, progesterone appeared to have little effect on EGFR independent of E2, as discussed below.

Immunohistochemistry

Expression of EGFR was examined by immunohistochemistry in all samples. Representative sections are shown in Fig. 4Go. Immunostaining for EGFR was associated with both stromal and epithelial cell types, and no specific differences between cell types were noted. In the absence of E2 (CD0), the endometrium exhibited scant glands and stroma with complete absence of immunostaining in all subjects. Moderate to dark staining was seen in all biopsies exposed to estrogen (CD11 and CD21). Estrogen resulted in an increase in immunostaining between CD0 and CD11; no differences were noted between CD11 and CD21.



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  		Figure 4. Immunohistochemistry for EGFR was performed on all biopsies as described in Materials and Methods; tissues were not counterstained. These pictures show representative examples from one study subject from each group (A: group I, CD0; B: group I, CD11; C: group II, CD11; D: group II, CD21). All CD0 biopsies demonstrated scant atrophic tissue, as seen by hematoxylin and eosin staining (data not shown) and complete absence of EGFR immunostaining (A). All CD11 (B and C) and CD21 (D) biopsies showed moderate to dark immunostaining for EGFR.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
In this study we have shown an increase in the expression of EGFR and its mRNA in endometrium in response to estrogen using an in vivo human model. The model was designed to avoid the normal variation observed between individual menstrual cycles and between individual women by obtaining serial biopsies in hormone-replaced hypogonadal women. The subjects received doses of estrogen and progesterone appropriate to simulate serum levels of the steroids during a normal menstrual cycle. This replacement regimen was reasoned to result in physiologically normal endometrium during a cycle, as evidenced by its ability to support pregnancy in donor oocyte in vitro fertilization (14). To the best of our knowledge, the study reported here is the first to report the in vivo responses of endometrial EGFR and EGFR mRNA to exogenously administered hormones in a human model.

The processes by which estrogen influences the growth and development of uterine tissues is unknown, but appears to involve modulation of the levels of growth factors and their receptors. In the rat, E2 increases the level of functional EGF receptors as well as EGFR mRNA (8, 9). In the present study the administration of E2 in physiological concentrations to women in the hypoestrogenic state resulted in a significant increase in EGFR in vivo. This was documented by an increase in both receptor mRNA and protein. Although immunohistochemical techniques do not permit accurate quantification, the absence of EGFR staining in all baseline biopsies and the presence of staining in all E2-exposed tissues support the hypothesis that exposure to E2 results in an increase in EGFR protein as well as EGFR mRNA. These data are consistent with in vivo animal data.

The effect of progesterone on EGFR has been studied both in vitro and in vivo with variable results. No effect on receptor is seen after the administration of progesterone to ovariectomized immature rats (8, 9). In the adult mouse uterus, progesterone has been shown to cause an increase in EGFR (20); however, the progesterone-treated animals failed to show EGFR bioactivity, and E2 was found to be essential for EGFR bioactivity. Our results provide no evidence that progesterone modulates the changes in EGFR mRNA levels in the first 21 days of a simulated cycle in humans. The magnitude of the increase between CD0 and CD11 in response to estrogen was similar to that observed between days 11 and 21 when both estrogen and progesterone were present. These findings are consistent with the results from animal studies and support the hypothesis that estrogen plays the primary role in regulating EGFR in endometrium, but do not take into account other potential regulatory factors. Recently, differential expression of full-length (EGFR-fl) and truncated (EGFR-tr) forms of the receptor have been reported in endometrium (21). When present in excess, EGFR-tr appears to bind EGFR-fl to form an inactive heterodimer (22). The probe used in our current study would have detected both EGFR-fl and EGFR-tr and could not be used to distinguish between them. It is possible that progesterone may result in a relative increase in EGFR-tr, thereby decreasing potential EGFR activity without affecting receptor number. Further studies will be needed to clarify this issue.

The results of the present study indicate that E2 administration increases the level of EGFR mRNA in human endometrium in vivo. A more detailed evaluation of the early time course of this effect and its relationship to the pleotropic growth that occurs in the tissue is required. The hormone-replaced hypogonadal subjects would appear to offer a valuable model for studying this and other steroid hormone actions in the human endometrium.

Received August 22, 1996.

Revised December 11, 1996.

Accepted January 21, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Murphy LJ, Ghahary A. 1990 Uterine insulin-like growth factor-I: regulation of expression and its role in estrogen-induced uterine proliferation. Endocr Rev. 11:443–453.[Medline]
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  7. Nelson KG, Takahashi T, Bossert NL, Walmer DK, McLachlan JA. 1991 Epidermal growth factor replaces estrogen in the stimulation of female genital-tract growth and differentiation. Proc Natl Acad Sci USA. 88:21–25.[Abstract/Free Full Text]
  8. Mukku VR, Stancel GL. 1985 Regulation of epidermal growth factor receptor by estrogen. J Biol Chem. 260:98209824.
  9. Lingham RB, Stancel GM, Loose-Mitchell DM. 1990 Estrogen regulation of epidermal growth factor receptor in the endometrium during the menstrual cycle. Mol Endocrinol. 2:230–235.[Abstract]
  10. McBean JH, Johnson JV, Stirewalt WS. Epidermal growth factor receptor (EGFR) in human endometrium. Proc of the 50th Annual Meet of the Am Fertil Soc. 1994; P-177.
  11. Imai T, Kurachi H, Adachi K, et al. 1995 Changes in epidermal growth factor receptor and levels of its ligands during menstrual cycle in human endometrium. Biol Reprod. 52:928–938.[Abstract]
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  14. Droesch K, Navot D, Scott R, Kreiner D, Hung-Ching Lui, Rosenwaks Z. 1988 Transdermal estrogen replacement in ovarian failure for ovum donation. Fertil Steril. 50:931–934.[Medline]
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  17. Shaw ST, Roche PC. 1985 The endometrial cycle: aspects of hemostasis. In: Mechanism of menstrual bleeding. Serono Symposia; In: Baird DT, Michie EA eds. New York: Raven Press; 7–27.
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  19. Haley J, Whittle N, Bennet P, Kinchington D, Ullrich A, Waterfield M. 1987 The human EGF receptor gene: structure of the 110kb locus and identification of sequences regulating its transcription. Oncogene Res. 1:375–396.[Medline]
  20. Das SK, Tsukamura H, Paria BC, Andrews GK, Dey SK. 1994 Differential expression of epidermal growth factor receptor (EGF-R) gene and regulation of EGF-R bioactivity by progesterone and estrogen in the adult mouse uterus. Endocrinology. 134:971–981.[Abstract]
  21. Tong BJ, Das SK, Threadgill D, Magnuson T, Dey SK. 1996 Differential expression of the full-length and truncated forms of the epidermal growth factor receptor in the preimplantation mouse uterus and blastocyst. Endocrinology. 137:1492–1496.[Abstract]
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