Ovarian steroid regulation of vascular endothelial growth factor in the human endometrium: implications for angiogenesis during the menstrual cycle and in the pathogenesis of endometriosis

The human endometrium undergoes a complex process of vascular and glandular proliferation, differentiation, and regeneration with each menstrual cycle in preparation for implantation. Vascular endothelial growth factor (VEGF) is an endothelial cell-specific angiogenic protein that appears to play an important role in both physiological and pathological neovascularization. To investigate whether VEGF may regulate human endometrial angiogenesis, we examined VEGF messenger ribonucleic acid (mRNA) and protein throughout the menstrual cycle and studied the regulation of VEGF by reproductive steroids in isolated human endometrial cells. By ribonuclease protection analysis, VEGF mRNA increased relative to early proliferative phase expression by 1.6-,2.0-, and 3.6-fold in midproliferative, late proliferative, and secretory endometrium, respectively. In histological sections, VEGF mRNA and protein were localized focally in glandular epithelial cells and more diffusely in surrounding stroma, with greatest VEGF expression in secretory endometrium. Consistent with these in vivo results, the treatment of isolated human endometrial cells with estradiol (E2), medroxyprogesterone acetate (MPA), or E2 plus MPA significantly increased VEGF mRNA expression over the control value by 3.1-, 2.8-, and 4.7-fold, respectively. The VEGF response to E2 was rapid, with steady state levels of VEGF mRNA reaching 85% maximum 1 h after the addition of steroid. E2 also caused a 46% increase in secreted VEGF protein, and the combination of E2 and MPA caused an 18% increase. VEGF expression in endometriosis, an angiogenesis-dependent, estrogen-sensitive disease was similar to that seen in eutopic endometrium. Peritoneal fluid concentrations of VEGF were significantly higher in women with moderate to severe endometriosis than in women with minimal to mild endometriosis or no disease. VEGF, therefore, may be important in both physiological and pathological angiogenesis of human endometrium, as it is an estrogen-responsive angiogenic factor that varies throughout the menstrual cycle and is elevated in women with endometriosis.     

Expression of katG in Mycobacterium tuberculosis is associated with its growth and persistence in mice and guinea pigs

The integrin alpha(v)beta3 functions in both cell-cell and cell-extracellular matrix adhesion, and has reported roles in platelet aggregation, immune function, tissue repair, tumour invasion, angiogenesis and uterine receptivity. The aim of this study was to use immunohistochemistry to describe the vascular and glandular expression of integrin alpha(v)beta3 in formalin fixed, paraffin embedded endometrium obtained from women with (n = 29) and without (n = 24) endometriosis. The results showed a significant increase in the percentage of vessels expressing alpha(v)beta3 in the endometrium of women with endometriosis compared with controls (P = 0.0001). This difference was more pronounced in the secretory phase (P = 0.001) than the proliferative phase (P = 0.016). There was no correlation between vascular alpha(v)beta3 expression and the endothelial cell proliferation index (P > 0.05). Vascular sprouts were not observed in any of the 53 endometrial tissues obtained from women with or without endometriosis throughout the menstrual cycle. Results from semi-quantitative scoring of gland immunostaining showed that neither controls (P = 0.3329) nor the endometriosis group (P = 0.2260) had any significant changes in terms of alpha(v)beta3 expression between the different stages of the menstrual cycle. There was also no difference in glandular alpha(v)beta3 expression between women with and without endometriosis (P = 0.4302). These results provide evidence for increased endometrial angiogenesis in women with endometriosis compared with controls, and suggest that glandular expression of alpha(v)beta3 is not related to uterine receptivity per se.     

Compartmentalization and cyclic variation of immunoreactivity of renin and angiotensin converting enzyme in human endometrium throughout the menstrual cycle

Renin and angiotensin converting enzymes (ACE) are responsible for the generation of angiotensin II which regulates blood pressure and fluid/electrolyte homeostasis. The cellular localization and cyclic distribution of renin and ACE in human endometrium are demonstrated in this study. Immunohistochemical studies revealed that both renin and ACE were consistently localized in the endometrial glandular epithelia throughout the menstrual cycle; however, the immunostainings respectively for ACE and renin were weak and moderate in stromal cells of proliferative endometrium and negligible in secretory endometrium. No renin immunostaining was detected around endometrial blood vessels. Although endothelial cells consistently stained for ACE, no renin immunoreactivity was detected in these cells during the menstrual cycle. Western blot analysis using ACE antibody directed against human kidney identified a single protein band with a relative molecular mass of approximately 153 kDa. The intensity of this band showed cyclic variation during the menstrual cycle with the highest ACE expression during the late secretory phase and at menses suggesting that ACE plays a role in the initiation of menstruation. The differences in the cellular distribution patterns of these two enzymes further supports our previous proposition that angiotensin II has different functions at the different stages of the menstrual cycle.     

Diagnosing renal artery stenosis: a comparison between conventional renography, captopril renography and ultrasound Doppler in a large consecutive series of patients with arterial hypertension

PROBLEM: Comparison and characterisation of different lymphocyte subsets in the endometrium of endometriosis patients and in healthy women on every day of the menstrual cycle with special emphasis on the CD4:CD8 ratio in the endometrium. METHOD: Immunohistochemical staining of 253 endometrial biopsies of infertile women with and without endometriosis with Anti-Leu4 (CD3), Anti-Leu3a (CD4), Anti-Leu2a (CD8), Anti-Leu7 and Anti-Human-B-cell (CD22) using the immune peroxidase reaction. Identification and counting of positive lymphocyte were performed on cryostat sections. RESULTS: Endometrial lymphocyte subsets show equal quantity and distribution in endometriosis patients and in the control group. After a peak in the early proliferative phase the absolute number of T lymphocytes decreases while a predominance of T-suppressor/cytotoxic T lymphocytes (CD8) compared to T-helper/inducer lymphocytes (CD4) occurs towards the end of the menstrual cycle. CONCLUSION: Endometrium as the potential parent epithelia of endometriosis lesions seems not to be altered in its lymphatic cell content compared to healthy women. Furthermore, endometrium is clearly characterised as part of the mucosa associated lymphatic tissue (MALT). T lymphocytes show specific quantitative changes due to different phases of the menstrual cycle.     

Isolation of rat chromosome-specific paint probes by bivariate flow sorting followed by degenerate oligonucleotide primed-PCR

Angiogenesis is an essential component of endometrial regeneration after menses in preparation for implantation. Vascular endothelial growth factor (VEGF) is a secreted angiogenic peptide with mitogenic activity specific for endothelial and trophoblast cells. VEGF-immunoreactivity was detected in glandular epithelium throughout the menstrual cycle by immunohistochemistry, but, showed cyclic variation in the stroma and the blood vessels. During the early proliferative phase, strong staining was seen in the glandular epithelial cells while staining in the stroma was confined to a subpopulation of stromal cells and endometrial blood vessels appeared negative. In contrast, very intense staining of the endometrial stromal cells was seen in the mid proliferative endometrium possibly due to increased synthesis of VEGF by oestrogen. In the late proliferative endometrium, staining was seen in the endothelial cells and the perivascular stromal cells around the endometrial blood vessels. The greatest degree of immunostaining of stromal cells was observed in the mid to late proliferative endometrium. Throughout the secretory phase no staining was seen around the endometrial blood vessels and staining of endometrial stromal cells was confined to early secretory endometrium. In the late secretory endometrium only the glands were positive to VEGF antibody. The observed increase in the immunostaining of stroma suggests increased production of VEGF from early to mid and late proliferative endometrium which parallels the increase in the oestradiol levels in the proliferative phase of the menstrual cycle. It is proposed that VEGF may serve as a paracrine mediator of the effects of ovarian steroids on endometrial vascular development.     

Endometrial volume change during spontaneous menstrual cycles: volumetry by transvaginal three-dimensional ultrasound

OBJECTIVE: At present, only limited data are available on endometrial volume during the menstrual cycle. Most of these studies deal with animal models and use magnetic resonance imaging for volume measuring. The application of three-dimensional ultrasound in endometrial volume estimation is the subject of this study. SETTING: Patients visiting the outpatient unit of the division of endocrinology and reproductive medicine of a university hospital. PATIENT(S): Twenty patients with a history of a normal menstrual cycle were selected. INTERVENTION(S): Ultrasound examinations were performed during a single menstrual cycle in addition to routine laboratory tests. MAIN OUTCOME MEASURE(S): Uterus-endometrial volume ratio. RESULT(S): Data from 18 patients could be evaluated. In 81 examinations the endometrium volume could be determined. Mean endometrial volume measured by three-dimensional ultrasound was 1.23 cm3. Mean uterus volume was 48.93 cm3. The change of the uterus-endometrial volume ratio showed a good correlation with the day of menstrual cycle. Quadratic regression analysis of volume and cycle length was R2 = 0.432. CONCLUSION(S): Three-dimensional ultrasound allows assessment of volume data of the female internal genitalia. In this study changes of the endometrial volume in menstrual cycles were measured. Additional studies are required to give information on the clinical impact of this new technique of endometrial volume estimation.     

Sex-role reversal and the absence of extra-pair fertilization in Wilson''s phalaropes

Human endometrial leukocytes undergo regular cyclical changes during the menstrual cycle, with a striking increase in the phenotypically unusual population of CD56+ CD16- endometrial granulated lymphocytes (eGLs) in the late secretory phase and early pregnancy. The factors that regulate this increase in eGL numbers are unclear; their unusual morphology, however, has led to the suggestion that they undergo apoptosis at the end of the menstrual cycle. Apoptosis, bcl-2 expression, and proliferative activity were examined in the stroma of normal cycling, progesterone-treated, and early-pregnancy endometrium. The expression of bcl-2 and the Ki67 proliferation marker by highly purified (> 98% CD56+) eGLs from endometrium during the menstrual cycle and from first-trimester decidua was also studied. Apoptotic cells were rarely observed in the endometrial stroma of any of the samples examined. Stromal bcl-2 expression, however, increased from the proliferative to the premenstrual phase, and double immunohistochemical labeling demonstrated large numbers of bcl-2+ CD56+ eGLs. In contrast, Ki67 expression was high in the endometrial stroma during the proliferative phase, fell during the secretory phase, and rose again premenstrually, because of expression by eGLs. Isolated CD56+ eGLs also showed high bcl-2 and Ki67 expression at the end of the menstrual cycle. Unlike premenstrual endometrium, progesterone-treated endometrium and first-trimester decidua contained few proliferating cells, expressed high levels of bcl-2, and showed no evidence of apoptosis. Thus, eGLs do not undergo apoptosis in premenstrual endometrium, and their regulatory mechanisms remain to be clarified.     

Iron deposition at mineralization fronts and osteoid formation following chronic cadmium exposure in ovariectomized rats

Integrins are heterodimeric glycoproteins that have been found to undergo dynamic temporal and spatial changes in distribution in the endometrium during the menstrual cycle in women. Likewise the extracellular matrix (ECM) ligands for these receptors are likely to play a role in the establishment of a receptive endometrium. To develop primate models to study the role of these molecules in the cascade of molecular events leading to implantation, integrin expression and associated changes in ECM were investigated during the menstrual cycle and in early pregnancy in the baboon. Antibodies specific for the integrins (alpha(1-6) and alpha(v); beta1, beta3, and beta4) and ECM (laminin, collagen IV, fibronectin) were utilized. In addition, cytokeratin and alpha-smooth muscle actin were used as epithelial, stromal, and smooth muscle cell markers, respectively. Endometrium was obtained in duplicate or triplicate during the menstrual cycle and early pregnancy. Changes observed during the natural menstrual cycle were confirmed using ovariectomized, steroid-treated animals. Constitutively expressed integrins on the endometrial epithelium included the collagen/laminin receptors: alpha2, alpha3, alpha6, and beta4. The pattern of expression correlated well with the distribution of ECM in this tissue. Collagen IV was confined to the basement membrane of glandular epithelium and blood vessels. Laminin immunostaining was found in the basement membrane, mostly in the stroma of the basal region, in the glandular endometrium and vasculature. Fibronectin was present throughout the stroma but not in the basement membrane. The collagen receptor alpha1 beta1 and fibronectin receptor alpha4 beta1 appeared in the glandular epithelium in the luteal phase. As in the human, alpha1 and alpha4 disappeared from the glandular epithelium with the establishment of pregnancy. In contrast, the alpha4 beta3 vitronectin receptor appeared in the glandular epithelium only in pregnancy or following long-term steroid treatment with estrogen and progesterone but not during the time of uterine receptivity associated with the initial period of embryo attachment. Osteopontin, an ECM ligand for alpha(v) beta3, was coexpressed with this integrin in invading cytotrophoblasts, glandular epithelium, and decidualizing stromal cells. Decidualization in the baboon was associated with changes in integrin expression similar to those found in humans: there was an increase in alpha1, alpha3, alpha6, beta1, and alpha(v) beta3 in the decidualized stromal cells. Laminin and collagen IV expression also increased at the implantation site and throughout the endometrium. In contrast, fibronectin expression was most evident at the implantation site and corresponded to alpha5 expression on the invading cytotrophoblasts. In summary, marked similarities were found in the expression of ECM and the integrin receptors between the baboon and the human endometrium throughout the menstrual cycle and in pregnancy. Cycle-specific integrins, alpha1, and alpha4, were present on epithelial cells during the secretory phase. Delayed expression of alpha(v) beta3 in baboon endometrial glands correlated closely with the time of enhanced glandular secretory activity in this primate. The baboon appears to be an excellent model for the investigation of the role of integrins and ECM leading to successful implantation.     

Immunocytochemical localization of nitric oxide synthase-III in reproductive organs of female rats during the oestrous cycle

Constitutive endothelial nitric oxide synthase (NOS III) expression during the oestrous cycle was mapped immunocytochemically on 5 microns-thick paraffin sections of rat female reproductive organs. Ovarian NOS III immunoreactivity increased with follicular maturation (strongest in dioestrus corpora lutea), suggesting that nitric oxide may regulate folliculogenesis and luteal functions. Oviductal NOS III, localized in mucosal epithelium and muscular wall, was maximal during pro-oestrus and oestrus, suggesting that nitric oxide may impart periovulatory quiescence for reception, retention and fertilization of ovulated oocytes. Uterine NOS III, localized in endometrial and glandular epithelium, and in myometrial smooth muscle cells, was abundantly expressed during pro-oestrus and oestrus. The peri-implantation period in pregnant rats corresponds to the periovulatory period and the elevated NOS, and thus nitric oxide may provide uterine relaxation to facilitate embryo implantation following fertilization. Cervical NOS III, localized in the mucus-secreting epithelium and smooth muscle cells, exhibited enzyme abundance during pro-oestrus and oestrus, probably indicating cervical preparation to facilitate sperm entry following mating. Vaginal NOS III, found in the stratified squamous epithelial lining and in smooth muscle cells, was maximal during oestrus and pro-oestrus, suggesting that nitric oxide may stimulate vaginal secretions. Differential expression of NOS III by different reproductive organs during the oestrus cycle suggests a role for nitric oxide in modulating reproduction.     

Vascular endothelial growth factor (VEGF) in endometriosis

Angiogenesis is likely to be involved in the pathogenesis of endometriosis. According to the transplantation theory, when the exfoliated endometrium is attached to the peritoneal layer, the establishment of a new blood supply is essential for the survival of the endometrial implant and development of endometriosis. From the known angiogenic factors, vascular endothelial growth factor (VEGF) has emerged as a pivotally important regulator of normal angiogenesis and pathological neovascularization. The VEGF protein was evaluated immunohistochemically in the eutopic endometrium of 10 women without endometriosis (group I) at laparoscopy and the eutopic endometrium and peritoneal endometriotic lesions of 43 women with endometriosis (group II). VEGF histological scores were 9.7 +/- 4.3 and 4.0 +/- 2.6 respectively in the epithelium and stroma of the eutopic endometrium of group I women, and 10.3 +/- 2.3 and 3.6 +/- 2.3 respectively in women of group II. In red lesions, the VEGF scores were 11.1 +/- 3.0 in the epithelium and 5.1 +/- 3.0 in the stroma, and in black lesions were 8.6 +/- 2.7 and 1.6 +/- 1.6, respectively. Significantly lower values were observed in black lesions as compared with eutopic endometrium and red lesions, the values of which were similar. Scores were also evaluated according to the phase of the cycle. In eutopic as well as ectopic endometrium, no significant cyclic variations were observed throughout the cycle. However, VEGF content was found to be higher in the eutopic glandular epithelium of women with endometriosis during the late secretory phase, possibly suggesting a more likely tendency to implant. In contrast, significantly higher VEGF content was noted in red lesions as compared with black lesions. During all phases of the cycle, the VEGF content in stromal cells of red lesions was higher than in black lesions. Similarities in VEGF content were observed in the glandular epithelium of the eutopic endometrium of women with endometriosis and red lesions, suggesting that endometriosis probably arises from the peritoneal seeding of viable endometrial cells during retrograde menstruation and that red lesions can be considered as the first stage of implantation. After the attachment phase, the high VEGF levels could provoke an increase in the subperitoneal vascular network and facilitate implantation and viability in the retroperitoneal space. Lower VEGF levels in black lesions explain the decrease in both stromal vascularization, followed by fibrosis and inactivation of the implant.     

Chimeric human epidermal reconstructs to study the role of melanocytes and keratinocytes in pigmentation and photoprotection

OBJECTIVE: To compare the ability of peripheral blood monocytes (PBM) and peritoneal macrophages (PM) to mediate the in vitro cytolysis of endometrial cells from eutopic and ectopic endometrium in women with endometriosis. DESIGN: Prospective study of immune function. SETTING: Institute for the Study and Treatment of Endometriosis and university-based research laboratories. PATIENT(S): Twenty-four women with endometriosis (15 in stage I/II, 9 in stage III/IV) and 4 patients treated with GnRH agonists. INTERVENTION(S): Peritoneal fluid and peripheral blood were sampled and eutopic and ectopic endometrium were biopsied during diagnostic laparoscopy. MAIN OUTCOME MEASURE(S): Lysis of autologous endometrial cells. RESULT(S): Peripheral blood monocytes were significantly more cytolytic than peritoneal macrophages against autologous uterine endometrial cells. However, PBM and PM displayed a similar degree of cytolysis against a hepatoma cell line. Ectopic endometrial cells were significantly more resistant to cytolysis by autologous PBMC than were matched eutopic endometrial cells, and were completely resistant to cytolysis by autologous PM. CONCLUSION(S): The reduced capacity of PM from women with endometriosis to mediate the destruction of endometrial cells coupled with the increased resistance of ectopic endometrial cells to macrophage-mediated cytolysis may facilitate the survival of these cells within the peritoneal cavity of women with endometriosis.     

Cell-cell interactions influence oligosaccharide modifications on mucins and other large glycoproteins

OBJECTIVE: To investigate human endometrial interleukin-6 (IL-6) expression and effects thereon by IL-1 beta. DESIGN: Prospective. SETTING: Academic medical center. PATIENT(S): Endometrial biopsy specimens from normal volunteers (n = 20) at four specific menstrual stages were used for in vivo study. Endometrial specimens for in vitro study were obtained from patients (n = 19) undergoing gynecologic surgery. INTERVENTION(S): Time and dose-response treatment of endometria with IL-1 beta in tissue culture. MAIN OUTCOME MEASURE(S): In vivo IL-6 messenger RNA expression by Northern analysis and in vitro endometrial IL-6 protein production by assay of the conditioned media. RESULT(S): Midsecretory and late secretory phase endometria expressed more IL-6 messenger RNA than late proliferative phase endometria in vivo. Similarly in vitro, in pg/mg endometrium per hour secretory endometria IL-6 protein production, 25.7 +/- 7.1 (mean +/- SEM), exceeded that of proliferative endometria, 4.7 +/- 1.0. With IL-1 beta treatment, secretory endometria IL-6 protein production exceeded that of proliferative endometria. Interleukin-1 beta stimulated endometrial IL-6 protein production in time- and dose-dependent manners. CONCLUSION(S): Human endometrial IL-6 expression varies with the menstrual cycle, occurs more highly in secretory endometria, and in vitro is stimulated by interleukin-1 beta. Human endometrial IL-6 may therefore mediate some actions of IL-1 beta involving the endometrium and trophoblast.     

Levonorgestrel-releasing intrauterine device-wearing women express contraceptive glycodelin A in endometrium during midcycle: another contraceptive mechanism?

Intrauterine devices (IUDs) exert contraceptive action by interfering with sperm transport, ovum development, fertilization and implantation. Glycodelin A (GdA) is a uterine glycoprotein that has local contraceptive activity by inhibiting sperm-egg binding. GdA is normally absent from endometrium during the fertile midcycle and it is not expressed until the fifth postovulatory day. The phase of menstrual cycle addressed in this study covers the phase when conception is most likely to follow an unprotected intercourse and when GdA is normally absent. We present here evidence that levonorgestrel-releasing IUD (LNg-IUD) is accompanied by 'inappropriate' expression of GdA in endometrium between days 7 and 16 of the menstrual cycle (six out of six cases). The same was also found in copper-releasing IUD (Cu-IUD)-wearing women, but less frequently (four out of 11 cases, P < 0.0345, Fisher's exact test). In-situ hybridization localized GdA mRNA into endometrial glands in the midcycle endometrium, confirming the cellular site of synthesis. Based on the potent inhibitory activity of GdA on sperm-egg binding, the presence of GdA in uterine glands of IUD wearers may lead to prior exposure of sperm to contraceptive GdA, thus contributing to the contraceptive activity of the IUD.     

Ontogeny of nitric oxide in the pulmonary vasculature

The vasodilator molecule nitric oxide is critically involved in the successful cardiopulmonary transition from fetal to postnatal life. It is produced in the pulmonary endothelium by the endothelial isoform of the enzyme nitric oxide synthase. The expression of endothelial nitric oxide synthase in the lung increases dramatically during late gestation, optimizing the capacity for nitric oxide production at the time of birth. Studies in cultured cell models indicate that the developmental upregulation may be mediated by estrogen, and that the expression of the enzyme is also upregulated by oxygen. Pulmonary endothelial nitric oxide synthase expression is diminished in models of congenital diaphragmatic hernia and neonatal pulmonary hypertension induced by fetal ductal ligation. Thus, there is normally a marked developmental upregulation in endothelial nitric oxide synthase expression in the lung during late fetal life, and attenuated expression of the enzyme may contribute to the pathophysiology of a variety of forms of neonatal pulmonary vascular disease.     

17Beta-estradiol potentiates the stimulatory effects of progesterone on cadherin-11 expression in cultured human endometrial stromal cells

Cadherin-11 (cad-11) is a novel member of the cadherin gene superfamily of calcium-dependent cell adhesion molecules. To date, the factors capable of regulating this cell adhesion molecule remain poorly characterized. We have recently determined that cad-11 expression in the human endometrium is tightly regulated during the menstrual cycle. The spatiotemporal expression of cad-11 in the stromal cells of the human endometrium during the menstrual cycle suggests that gonadal steroids regulate the expression of this endometrial cell adhesion molecule. In view of these observations, we have examined the ability of progestins, estrogens, and androgens, alone or in combination, to regulate cad-11 expression in isolated human endometrial stromal cells using Northern and Western blot analyses. In these studies, we have determined that progesterone, but not 17beta-estradiol or dihydrotestosterone, is capable of regulating cad-11 messenger RNA and protein expression levels in isolated endometrial stromal cells. In addition, 17beta-estradiol, but not dihydrotestosterone, was capable of potentiating the stimulatory effects of progesterone in a dose-dependent manner. Taken together, these observations suggest that both 17beta-estradiol and progesterone are required for maximal cad-11 expression in human endometrial stromal cells in vitro.     

Immunohistochemical characterization of proliferation, oestrogen receptor and progesterone receptor expression in endometriosis: comparison of eutopic and ectopic endometrium with normal cycling endometrium

Recent studies examining oestrogen and progesterone receptor status and the proliferative activity of endometriotic lesions have produced conflicting reports. This study aimed to clarify the receptor status and proliferative activity of eutopic and ectopic endometrium from women with endometriosis and endometrium from normal women. Progesterone and oestrogen receptor expression and proliferative activity were studied in eutopic and ectopic endometrium from 30 women with endometriosis and in endometrium from 30 normal cycling women using microwave-pretreated paraffin-embedded sections stained with an avidin-biotin peroxidase technique. Progesterone and oestrogen receptor expression in the control endometrium did not differ from that of eutopic endometrium from women with endometriosis. Oestrogen receptor expression in ectopic endometrium increased from the proliferative to the late secretory phase. Epithelial progesterone receptor expression decreased during the cycle. Oestrogen receptor expression in both epithelium and stroma of ectopic endometrium was significantly higher than in eutopic endometrium throughout the cycle. In contrast, stromal progesterone receptor expression tended to be reduced in ectopic endometrium compared with eutopic tissue. Epithelial progesterone receptor expression was increased in ectopic endometrium but only in the late secretory phase. Although proliferative activity in the epithelium of control and eutopic endometrium was reduced from the proliferative to the late secretory phase, stromal activity did not vary. The proliferative activity in ectopic endometrium remained low and constant throughout the cycle. In the proliferative and early secretory phases, the proliferative activity of eutopic endometrium was increased compared with ectopic endometrium, but in the late secretory phase, levels were comparable. These findings challenge previous reports which have suggested that oestrogen receptors are reduced in ectopic tissue. This may have clinical implications for the development of novel treatments for endometriosis.