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Contraceptive Development Network, Center for Reproductive Biology (N.N., S.C., H.O.D.C., D.T.B.), Edinburgh, United Kingdom EH16 4SB; and Shanghai Institute of Family Planning Technical Instruction, International Peace Maternity and Child Health Hospital, China Welfare Institute (S.L., L.C.), Shanghai 200030, People’s Republic of China
Address all correspondence and requests for reprints to: Prof. David T. Baird, Contraceptive Development Network, Chancellor’s Building, 49 Little France Crescent, Edinburgh, United Kingdom EH16 4SB. E-mail: dtbaird{at}ed.ac.uk.
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Abstract |
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0.001) and progesterone receptor (P < 0.05) in endometrial glands and stroma by d 60 of treatment. In contrast, the expression of androgen receptor increased (P < 0.01) in glands, surface epithelium, and stroma compared with the pretreatment sample. These changes were maintained at 120 d of treatment. The expression of estrogen receptor was unchanged in stroma and surface epithelium; however, there was a significant decrease in expression after 120 d of treatment (P = 0.034). As androgens can antagonize estrogen action, enhanced glandular androgen receptor expression induced by mifepristone could play a role in its antiproliferative effects. |
Introduction |
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There is substantial evidence that exogenous androgen can have inhibitory effects on the female reproductive tract (17, 18, 19, 20). It has been suggested that the androgen receptor (AR) could play an important role in the noncompetitive antiestrogenic actions of PR antagonists (21). Slayden et al. (21) demonstrated a significant up-regulation of AR in endometrium after 21–30 d of treatment with PR antagonists. However, there are no data on the expression of AR after long-term treatment with mifepristone.
We previously reported that daily doses of 2 and 5 mg mifepristone for 120 d has contraceptive potential by suppressing ovulation and endometrial cyclicity (4). A striking feature of the endometrium after treatment with low dose mifepristone was a significant reduction in mitotic count and Ki67 immunostaining compared with endometrium on d 12 of control cycles (6). Because Ki67 protein is expressed during several phases of the cell cycle, e.g. G1, S, G2, and M, counts of Ki67-positive nuclei in paraffin sections are numerically greater than mitotic counts, although the Ki67 is usually well correlated with the mitotic index (22, 23). Mifepristone may block completion of the cell cycle at G2-M interphase (24), so that Ki67 protein persists for some time after cell division has been arrested. Therefore, Ki67 counts may fail to reveal that mifepristone treatment suppressed estrogen-dependent proliferation (5). Direct counting of mitotic cells in hematoxylin/eosin-stained sections is a time-consuming process that requires highly skilled observers (25). We evaluated a new marker of phosphorylated proteins associated with mitosis, phospho-H3. This marker has been validated in paraffin-embedded endometrial tissues and shows an excellent correlation with the mitotic count (26). The aim of the present study was to examine endometrial proliferation and steroid receptor content and distribution in women after treatment with low dose mifepristone, with particular emphasis on the role of the AR in mediating endometrial antiproliferative effects.
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Subjects and Methods |
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Mifepristone group
A subset of 16 women, aged 18–40 yr, with regular menstrual cycles (25–35 d) were studied for one pretreatment, four treatment, and one posttreatment cycles from 58 volunteer women from Edinburgh previously reported (4, 6). Subjects were randomly allocated to receive 2 and 5 mg mifepristone daily for the 120 treatment d. Subjects had a mean age of 30.5 yr and a mean body mass index (BMI) of 24.5 kg/m2. Endometrial biopsies were collected using a Pipelle endometrial sampling device (Prodimed, Neuilly-en-Thelle, France) in the late follicular phase of the pretreatment cycle (d 12), after 60 d of mifepristone treatment, and after 120 d of treatment. Specimens were fixed in normal buffered formalin, processed, and embedded in paraffin wax. Endocrine and endometrial findings have been reported previously (4, 6).
Control groups
Two groups of women whose endometrium was exposed to unopposed estrogen were chosen as controls. As unopposed estrogen gives rise to persistent proliferative endometrium, the endometrium from these women could be compared with that of subjects who remained anovulatory with mifepristone.
A group of women (n = 6) with anovulatory infertility due to polycystic ovarian syndrome (PCOS) participating in a study evaluating the effects of low-dose mifepristone on endometrial maturation and proliferation were recruited (5). Subjects had a mean age of 25 yr (range, 23–38 yr) and a mean BMI of 24.5 kg/m2 (range, 18.7–27.6 kg/m2), and all had biochemical and ultrasound evidence of polycystic ovaries (27). All women had an endometrial biopsy taken 21–23 d after a progestogen-induced withdrawal bleed.
A second group of postmenopausal women (1 yr of amenorrhea or using hormone replacement therapy for 2 yr; n = 5) participating in a study evaluating effects of onapristone on postmenopausal endometrium were recruited. The details of the study along with endocrine and endometrial findings have been reported separately (28). Subjects had a mean age of 54.4 yr (range, 49–54 yr) and a mean BMI of 26.6 kg/m2 (range, 20.9–33.8 kg/m2). None of the women had used a hormone preparation within the preceding 6 wk. Women were instructed to take daily 2 mg 17ß-estradiol valerate (Schering UK, Burgess Hill, West Sussex, UK) orally for 8 wk (56 d). Endometrial biopsy was performed in the eighth week of treatment (n = 4). One subject refused endometrial sampling. Endometrial histology was reported as proliferative in all samples.
Immunocytochemistry
Immunocytochemistry was performed for the immunolocalization of phospho-H3 (Upstate Biotechnology, Inc., Lake Placid, NY), Estrogen receptor (ER clone ID5, DAKO, Glostrup Denmark), PR (Abbott-PR ICA, Abbott Laboratories, Inc., North Chicago, IL) and AR (F39, BioGenex Laboratories, San Ramon, CA). ER, PR, and AR immunostaining procedures followed the methods previously described (21, 29, 30). The phospho-H3 immunostaining procedures followed those described by Brenner et al. (26).
Phospho-H3 mitosis marker
Paraffin sections (5 µm) were dewaxed in Histoclear (National Diagnostics, Atlanta, GA), rehydrated through a series of alcohols, and washed with PBS. The slides were then subjected to pressure cooker antigen retrieval in 0.01 M sodium citrate buffer at pH 6 for 5 min. Endogenous peroxidase activity was quenched by immersion in 3% hydrogen peroxide (Merck & Co., Poole, UK) in distilled water for 10 min at room temperature. Nonspecific binding of the primary antibody was blocked by incubating the sections for 20–30 min at room temperature in nonimmune goat serum (NGS; Vector Laboratories, Inc., Peterborough, UK). A variety of dilutions (0.66, 1, and 2 µg/ml) of the primary antibody in NGS were assessed in preliminary studies. The best compromise between signal to noise (specific staining vs. background) for phospo-H3 was 1 µg/ml (1:1000 dilution). Slides were then incubated overnight at room temperature with rabbit polyclonal phopho-H3 antibody (1:1000 dilution in NGS) or similarly with a control rabbit IgG antibody (1:1000 dilution in NGS). An avidin-biotin peroxidase system was used as the detection system. The slides were incubated in biotinylated horse antirabbit secondary antibody (Vector Laboratories, Inc.) in NGS, followed by the avidin-biotin peroxidase complex (Vectastain HRP, Vector Laboratories, Inc.), for 60 min each at room temperature. The peroxidase substrate 3,3'-diaminobenzidine (DAB; Vector Laboratories, Inc.) was used to visualize the reaction.
AR
Paraffin sections (5 µm) were dewaxed in Histoclear (National Diagnostics), rehydrated through a series of alcohols, and washed with PBS. The slides were then subjected to pressure cooker antigen retrieval in 0.01 M sodium citrate buffer at pH 6 for 5 min. Endogenous peroxidase activity was quenched by immersion in 3% hydrogen peroxide (Merck & Co.) in distilled water for 10 min at room temperature. Nonspecific binding of the primary antibody was blocked by incubating the sections for 20–30 min at room temperature in nonimmune horse serum (NHS; Vector Laboratories, Inc.). Slides were then incubated at 4 C with monoclonal antihuman AR antibody F39.4 overnight (1:480 dilution in PBS/BSA gel) or similarly with a control mouse IgG antibody (1:600 dilution in PBS/BSA gel). An avidin-biotin peroxidase system was used as the detection system. The slides were incubated in biotinylated horse antimouse secondary antibody (Vector Laboratories, Inc.) in NHS, followed by avidin-biotin peroxidase complex (Vectastain Elite PK 6101, Vector Laboratories, Inc.), for 60 min each at room temperature. The peroxidase substrate DAB (Vector Laboratories, Inc.) was used to visualize the reaction.
PR
Paraffin sections (5 µm) were dewaxed in Histoclear (National Diagnostics), rehydrated through a series of alcohols, and washed with PBS. The slides were then subjected to microwave antigen retrieval in 0.01 M sodium citrate buffer at pH 6 for 10 min. Endogenous peroxidase activity was quenched by immersion in 3% hydrogen peroxide (Merck & Co.) in distilled water for 10 min at room temperature. Nonspecific binding of the primary antibody was blocked by incubating the sections for 20–30 min at room temperature in NHS (Vector Laboratories, Inc.). Slides were then incubated at 37 C for 1 h with mouse monoclonal PR antibody (1:40 dilution in NHS) or similarly with a control mouse IgG antibody (1:6000 dilution in NHS). An avidin-biotin peroxidase system was used as the detection system. The slides were incubated in biotinylated horse antimouse secondary antibody (Vector Laboratories, Inc.) in NHS, followed by avidin-biotin peroxidase complex (Vectastain Elite PK 6101, Vector Laboratories, Inc.) for 30 min each at room temperature. The peroxidase substrate DAB (Vector Laboratories, Inc.) was used to visualize the reaction.
ER
Paraffin sections (5 µm) were dewaxed in Histoclear (National Diagnostics), rehydrated through a series of alcohols, and washed with PBS. The slides were then subjected to microwave antigen retrieval in 0.01 M sodium citrate buffer at pH 6 for 10 min. Endogenous peroxidase activity was quenched by immersion in 3% hydrogen peroxide (Merck & Co.) in distilled water for 10 min at room temperature. Nonspecific binding of the primary antibody was blocked by incubating the sections for 20–30 min at room temperature in NHS (Vector Laboratories, Inc.). Slides were then incubated at 37 C for 1 h with mouse monoclonal ER antibody (1:25 dilution in NHS) or similarly with a control mouse IgG subtype 1 antibody (1:150 dilution in NHS). An avidin-biotin peroxidase system was used as the detection system. The slides were incubated in biotinylated horse antimouse secondary antibody (Vector Laboratories, Inc.) in NHS, followed by avidin-biotin peroxidase complex (Vectastain Elite PK 6101, Vector Laboratories, Inc.), for 60 min each at room temperature. The peroxidase substrate DAB (Vector Laboratories, Inc.) was used to visualize the reaction.
Immunocytochemistry score
Semiquantitative score. The location and intensity of immunostaining were measured using a semiquantitative scoring system. Sections were scored blind by two observers (blind to study groups and to the other’s results). This scoring system is a standard method used in previous studies (29, 30). A high correlation has been demonstrated between objectively measured immunoreactivity (image analysis) and subjective semiquantitative scoring of immunostaining patterns (29). Immunostaining intensity and distribution of epitopes in all tissue sections were assessed on an arbitrary four-point scale: 0 = no staining, 1 = mild staining, 2 = moderate staining, and 3 = intense staining. This method of semiquantitative scoring has been previously validated in our laboratory (29).
Quantitative score. Phospho-H3 mitosis marker immunoexpression was assessed separately for glands and stroma using image analysis. The system used a Axistop 2 microscope (x40 objective; Carl Zeiss, Inc., New York, NY) connected to a MacIntosh G3 computer (Apple Computer, Cupertino, CA), using Openab 2.08 image analysis software (Improvision, Coventry, UK). At least 12 fields of view were selected at random from each tissue section. The glands and stroma from each digitized image were interactively dissected. Using Openlab color discrimination software, the total number of phospho-H3-expressing cells (brown product) and the number of those not expressing phospho-H3 (blue hematoxylin) were measured separately for each digitized image. The number of phospho-H3 expressing cells is reported as a percentage of total cells (brown and blue) per sample. This method of image analysis has previously been described and validated in our laboratories (29, 31).
Statistical methods
Statistical analysis was performed using SPSS (SPSS, Inc., Chicago, IL) and Excel 2002 (Microsoft Corp., Redmond, WA). Continuous data are expressed as the mean ± SE, and categorical data are expressed as the median and range. Nonparametric tests (Friedman’s test, Wilcoxon’s signed rank test, and Mann-Whitney test), with and without Bonferroni correction, were used to compare immunostaining scores at various time points. Where there were significant differences in the conclusions, these are noted.
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Results |
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Mitotic activity as indicated by antibody to phosphorylated histone H3 showed a highly significant decrease (P 0.001) in the endometrium by d 60 of treatment (mean ± SEM; glands, 0.89 ± 0.14; stroma, 0.48 ± 0.09; Fig. 1
) compared with pretreatment proliferative endometrium (glands, 3.48 ± 0.42; stroma, 1.57 ± 0.16; Fig. 2, A and B). This decrease was demonstrable in both glands and stroma and was maintained at 120 d (glands, 0.96 ± 0.13; stroma, 0.55 ± 0.11; Fig. 2C). Endometrium from PCOS women showed higher mitotic activity in the glands (4.72 ± 0.74; P = 0.168, not significant), whereas postmenopausal women had a significantly lower mitotic activity in the stroma (0.65 ± 0.13; P = 0.011) compared with proliferative d 12 pretreatment endometrium (Figs. 1 and 2D). The mitotic activity in the stromal compartment (PCO group, 1.21 ± 0.22) and glands (postmenopausal group, 2.00 ± 0.55) was not significantly different from that in proliferative samples.
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Pretreatment proliferative phase endometrium showed a strong expression of AR in the stroma and minimal or absent expression in glands and surface epithelium (Table 1 and Fig. 2E
). There was a significant increase in AR expression in surface epithelium, glands, and stroma after treatment with mifepristone compared with that seen in the proliferative phase pretreatment sample. This increase occurred as early as 60 d (P < 0.05; Fig. 2F) and was maintained on d 120 (Fig. 2G). The increase was most marked in the glandular compartment, where a virtual absence of expression in the proliferative pretreatment sample (Fig. 2E) was replaced by intense immunostaining in posttreatment samples (P < 0.01; Fig. 2, F and G). There was no difference between women treated with 2 or 5 mg mifepristone. Endometrium from PCOS and estrogen-treated postmenopausal women showed strong AR expression in the stroma, with minimal expression in glands and surface epithelium (Fig. 2H). This pattern was similar to that in d 12 pretreatment proliferative phase samples. Expression in glands was significantly greater in the postmifepristone treatment samples than in samples from both PCOS and postmenopausal women (P < 0.05).
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There was a reduction in PR expression in surface epithelium, glands, and stroma by d 60, which was maintained on 120 d (Table 2 and Fig. 2, I–K). There was no difference between women treated with 2 or 5 mg mifepristone. There was strong PR staining in all three endometrial compartments (surface epithelium, glands, and stroma) in PCOS and postmenopausal groups (Fig. 2L). This pattern was similar to that in d 12 pretreatment proliferative phase samples.
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There was no significant change in ER expression in surface epithelium and stroma after treatment with mifepristone (Table 3 and Fig. 2, M–O). Expression in glands was decreased after 120 d (P = 0.034). This failed to reach significance after using Bonferroni’s correction (P < 0.102). There was no difference between women treated with 2 or 5 mg mifepristone. The endometrium in both control groups demonstrated strong ER staining in all three endometrial compartments (Fig. 2P). This pattern was similar to that in d 12 pretreatment proliferative phase samples.
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Discussion |
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Concern has been expressed previously that long-term use of PR antagonists may lead to endometrial hyperplasia and possible malignancy due to exposure of the endometrium to the effects of unopposed estrogen (7, 8, 9). Evidence of estrogenic stimulation of the endometrium has been observed in the rats receiving long-term PR antagonist treatment (32, 33). The nonhuman primate endometrium, however, demonstrates endometrial atrophy and evidence of antiestrogenic activity (10, 34, 35, 36, 37, 38). In women, after high doses of mifepristone (25 and 50 mg/d) variable effects, such as atypical cystic changes, have been described in eutopic endometrium (8, 39). In a study in which women with pelvic endometriosis were treated with 50 mg mifepristone/d for 6 months, there was evidence of endometrial hyperplasia and numerous mitotic figures (8). The occurrence of endometrial gland dilatation in 34% of women receiving chronic treatment with mifepristone (1 mg/d given for 150 d) has also been reported (15). We reported previously that 18–23% of women treated with 2 or 5 mg mifepristone/d developed cystic changes in the endometrium, although the cysts were lined with inactive glandular tissue (6). There is a case report of an adolescent girl, aged 13 yr, with Cushingoid features and morbid osteoporosis who was treated with high doses (400 mg/d) of mifepristone for its antiglucocorticoid effect (7). However, with each of the two 6-month courses of mifepristone, given 9 months apart, she developed massive simple endometrial hyperplasia. There was no evidence of atypia, and ER and PR concentrations were in the normal range. This abnormality resolved on cessation of treatment. Eisenger et al. (9) investigating effects of 5 and 10 mg mifepristone daily for 6 months on uterine leiomyomata noted simple endometrial hyperplasia in 28% of subjects. No atypical hyperplasia was noted. Our findings using phospho-H3, a specific marker of mitosis, confirm that at the doses tested, there is no evidence of endometrial hyperplasia. Although a proportion of the endometrial samples show cystic dilatation, the glands are lined by atrophic inactive epithelium in contrast to the pseudo-stratified appearance in typical cystic glandular hyperplasia (6).
In agreement with previous reports (21, 40, 41), proliferative phase control endometria demonstrated absent or minimal AR expression. Treatment with a PR antagonist enhances stromal and induces glandular AR expression (21). Slayden et al. (21) used ligand binding, immunocytochemistry, and in situ hybridization on the same set of endometria to ascertain the regulation of and localization of AR during normal and hormonally regulated cycles and to evaluate changes in AR in women and nonhuman primates treated with PR antagonist (mifepristone or ZK 137 316). Treatment of macaques with estradiol implants for 28 d significantly increased AR mRNA in stromal cells, but not in the glands. The highest levels of AR mRNA in both stroma and glands were detected after combined treatment with estradiol and PR antagonist (mifepristone or ZK 137 316) treatment. At all stages of the human menstrual cycle, AR staining was localized predominantly in the endometrial stroma, with no or barely detectable staining in the glands. After mifepristone treatment (2 mg/d for 21–24 d), there were distinct and notable increases in AR staining of the glands and surface epithelium plus some enhancement of stromal AR staining (21).
Short-term treatment with PR antagonist, either during the menstrual cycle or with combined estrogen therapy, leads to elevations of the two main uterine steroid receptors, ER and PR (5, 42, 43). Expression after chronic treatment has been shown to be increased, decreased, or unchanged depending on the dose and duration of treatment (8, 38, 39, 44). We have demonstrated a down-regulation of PR after 60 d of treatment. ER expression decreased in glands, but remained unchanged in surface epithelium and stroma. The mechanisms involved are poorly understood, but could result from either chronic antimitotic activity (24) affecting cellular protein synthesis or androgen-AR interactions.
The endometrium is a target tissue for androgen action. There is ample evidence of antiestrogenic effects of exogenous androgens in vivo (17, 18, 19, 20), and androstenedione can inhibit human endometrial cell growth and secretory activity in vitro (45). Currently, the role of endogenous androgens in the endometrium is not clear, but stromal AR would mediate any possible effects of normal levels of endogenous androgens. Treatment with mifepristone up-regulates AR in glands; hence, androgens could have direct effects on glands in addition to stroma. An increase in AR levels in mifepristone-treated tissues could lead to an increased binding of androgens, which might antagonize the effects of estrogens on endometrial growth. Treatment with flutamide, a pure antiandrogen, blocked the antiproliferative effect of the PR antagonist ZK 137 316 in the nonhuman primate, adding strong support to the hypothesis that this effect of PR antagonist is mediated through changes in AR (46). It is possible that mifepristone itself directly mediates these effects by interacting with AR, for which the relative binding affinity is 13% (47).
The factors regulating the expression of AR in the endometrium are not clear. In the normal cycle, AR is confined to the stroma, with little or no expression in the glands (21, 40, 41). Our observations in postmenopausal women treated with estrogen and in women with PCOS are in keeping with reports in women and nonhuman primates that estrogen stimulates AR expression in the endometrium (38, 48). Increased AR expression in both stroma and glands of endometrium from women with PCO have been reported by others (49). The expression was higher in those with persistent proliferative endometrium and may merely reflect the effect of prolonged exposure to unopposed estrogen. Although this probably contributes to the changes in women treated with long-term mifepristone, it is likely that the massive up-regulation of AR that occurs, especially in the glands, as early as 21 d after starting treatment is a specific effect of the PR antagonist (21). In our study the endometrial biopsy from women with PCO, collected 21 d after progestagen-induced menses, showed little, if any, AR expression in glands and was similar to that observed in estrogen-treated women.
Summary
In summary, we have shown that low dose mifepristone treatment has a significant antiproliferative effect on the endometrium. There is down-regulation of PR and ER and up-regulation of AR. The mechanisms involved are poorly understood. An increase in glandular AR content could mediate the antiestrogenic, antiproliferative effects of PR antagonists. Whether androgens mediate all of these effects or whether PR antagonists interact in concert with other factors remains to be established.
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Acknowledgments |
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Footnotes |
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Abbreviations: AR, Androgen receptor; BMI, body mass index; DAB, 3,3'-diaminobenzidine; ER, estrogen receptor; NGS, nonimmune goat serum; NHS, nonimmune horse serum; PCOS, polycystic ovarian syndrome; PR, progesterone receptor.
Received November 11, 2003.
Accepted February 1, 2004.
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, is present in the vascular endothelium of the human and nonhuman primate endometrium. J Clin Endocrinol Metab 86:1370–1378This article has been cited by other articles:
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A.R.W. Williams, H.O.D. Critchley, J. Osei, S. Ingamells, I.T. Cameron, C. Han, and K. Chwalisz The effects of the selective progesterone receptor modulator asoprisnil on the morphology of uterine tissues after 3 months treatment in patients with symptomatic uterine leiomyomata Hum. Reprod., June 1, 2007; 22(6): 1696 - 1704. [Abstract] [Full Text] [PDF]
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N. Chabbert-Buffet, G. Meduri, P. Bouchard, and I. M. Spitz Selective progesterone receptor modulators and progesterone antagonists: mechanisms of action and clinical applications Hum. Reprod. Update, May 1, 2005; 11(3): 293 - 307. [Abstract] [Full Text] [PDF]
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