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H O Critchley

Publications and source records attributed to H O Critchley.

At least 37 records · Page 2Linked to original sources
PubMed2000

The effect of mifepristone administration on leukocyte populations, matrix metalloproteinases and inflammatory mediators in the first trimester cervix.

Cervical ripening is analogous to an inflammatory reaction characterized by an influx of inflammatory cells and an increase in inflammatory mediators. The anti-gestogen mifepristone is highly effective in inducing cervical ripening in women throughout gestation. However, its mechanism of action is largely unknown. The aim of the study was to investigate the effect of in-vivo administration of mifepristone on inflammatory cells and mediators in the cervix. Cervical biopsies were taken from women undergoing a first trimester termination of pregnancy at 0, 6, 12, 24 and 36 h (n = 6 per group) after mifepristone administration. Biopsies were fixed for immunohistochemistry and also cultured for subsequent analysis of culture media by radioimmunoassay or enzyme-linked immunosorbent assay. After administration of mifepristone (6-24 h), there was an increase in immunostaining for leukocyte common antigen (CD45), neutrophil elastase, monocytes (CD68), and matrix metalloproteinases (MMP)-1, -8 and -9. Immunostaining for MMP-2 and tissue inhibitor of metalloproteinases (TIMP)-1, -2 and -4 were unaffected by mifepristone treatment. Secretion of monocyte chemotactic protein (MCP-1) was significantly (P < 0.05) increased from biopsies taken 6-24 h after mifepristone administration. Cervical biopsies also released interleukin-8 (IL-8), prostaglandin (PG) E(2), PGF(2alpha) and prostaglandin metabolites (PGEM and PGFM) although their secretion was unaffected by mifepristone treatment. This study suggests that mifepristone may, in part, effect cervical ripening by modulating the influx of inflammatory cells into the cervix, up-regulating MMP expression and inducing chemokine secretion by cervical tissue.

Abortifacient Agents, Steroidal↗
PubMed2000

Enhanced sensitivity to steroid-negative feedback during breast-feeding: low-dose estradiol (transdermal estradiol supplementation) suppresses gonadotropins and ovarian activity assessed by inhibin B.

Breast-feeding reduces fertility, and this seems to be related, in part, to an enhancement of the sensitivity of the GnRH system to the negative feedback effects of estradiol related to suckling. Previously, we showed that short-term treatment with small doses of estradiol delivered transdermally suppress plasma gonadotropin concentrations in breast-feeding women. We have now monitored the effects on ovarian function of longer-term low-dose estradiol treatment using plasma inhibin B and inhibin A concentrations and ultrasonography. Breast-feeding women (n = 45) using barrier methods of contraception were enrolled at 6 weeks postpartum and followed up to 18 weeks PP. Nineteen women agreed to being randomized to wear either an estrogen [transdermal estradiol supplementation (TES); n = 10; Estraderm, 50 microg/24 h] or a placebo (PL; n = 9) patch for 12 weeks, whereas the remaining 26 women acted as untreated controls. TES did not significantly increase plasma estradiol concentrations. Plasma FSH levels decreased from 6.1+/-0.8 U/L to 3.3+/-0.6 U/L after 2 weeks of treatment (P < 0.01) and were lower in the TES group compared with the PL group at all times during the treatment (at least P < 0.05). Plasma LH concentrations in the TES group were lower than in the PL group after 4, 6, 8, and 10 weeks of estrogen treatment (at least P < 0.05). Throughout the study, no ovarian follicles detected by ultrasound were greater than 10 mm in diameter. Nevertheless, after 2 weeks of treatment, plasma inhibin B concentrations were significantly lower in the TES group than in the PL group (15.5+/-5.8 vs. 64.9+/-11.1 ng/L; P < 0.01) and remained significantly (P < 0.01) suppressed throughout the treatment, suggesting a suppression of the functional ovarian activity during TES. Inhibin A levels remained low in all groups (3-45 ng/L) but were suppressed further by TES treatment with no levels greater than 7 ng/L. We conclude that low-dose estradiol treatment given as TES suppresses ovarian activity as measured by inhibins B and A by reducing the secretion of LH and FSH during breast-feeding for several weeks. This supports the concept that suckling-induced suppression of the GnRH system is associated with an enhancement of the negative effects of estradiol on the hypothalamic GnRH system. Furthermore, because the contraceptive efficacy of breast-feeding is complicated by the unpredictable early return of ovarian activity in some women, TES could be the basis for the development of a novel contraceptive for breast-feeding women.

Administration, Cutaneous↗
PubMed2000

Progesterone withdrawal up-regulates vascular endothelial growth factor receptor type 2 in the superficial zone stroma of the human and macaque endometrium: potential relevance to menstruation.

Several reports indicate that vascular endothelial growth factor (VEGF) expression is increased in endometrial glands and stroma during the menstrual phase in the human endometrium. Here we report that VEGF receptor type 2 (KDR), normally expressed only in the vascular endothelium, was dramatically up-regulated in the stromal cells of the superficial endometrial zones during the premenstrual phase in both human and macaque endometrium. This increase was detectable by Northern analysis, in situ hybridization, and immunocytochemistry and was cell specific, zone specific, cycle phase specific, and VEGF receptor type specific. That is, it only occurred during the premenstrual/menstrual phase, did not occur in glandular epithelium, endothelium, or stromal cells of the deepest endometrial zones, and was not observed for VEGF receptor type 1. The upregulation of stromal KDR was induced by progesterone (P) withdrawal in both women and macaques, and adding back P 24 h after P withdrawal in macaques blocked stromal, but not vascular, endothelial KDR expression. Promatrix metalloproteinase-1 (MMP-1) was coordinately up-regulated in the same stromal cell population by P withdrawal. Because of reports that VEGF can enhance MMP expression, we hypothesize that VEGF-KDR interactions may influence MMP expression in the superficial zones of the primate endometrium during the premenstrual phase, and that these interactions play a role in the induction of menstruation.

Adult↗
PubMed1999

Factors of importance for implantation and problems after treatment for childhood cancer.

The uterus is of fundamental importance to reproduction; it nourishes the early embryo and accommodates growth and differentiation of the developing fetus. It is thus possible that the modalities employed to treat childhood cancer, that is; chemotherapeutic agents, and particularly irradiation, may result in damage to the uterine structure (musculature and local vasculature), with potential impairment of normal uterine function and thus increased risk of subsequent defective implantation. This may result in an impaired reproductive outcome (increased risk of spontaneous abortion, preterm labour, and low-birth-weight infants). Thus the reproductive problems foreseen following treatment of childhood cancer will be 1) ovarian failure or impaired ovarian activity and 2) uterine/endometrial structural and functional damage. The mode of treatment and age at its administration will be the major determinants of residual ovarian and uterine function. To understand the mechanisms that may be responsible for potential problems in reproductive function after treatment, it is essential to consider the mechanisms governing normal early pregnancy. Ovarian estradiol (E) and progesterone (P) secreted in a cyclical manner orchestrate the spatial and temporal morphological and functional changes in the endometrium required for implantation. In the absence of sex steroids, the endometrium is inactive. Implantation takes place in the midsecretory phase, that is, 5-9 days postovulation. E and P act sequentially to regulate cellular concentrations of their respective receptors and in turn gene transcription events are initiated to prepare the endometrium for implantation. A complex interaction exists between the network of uterine cells (epithelial, stroma, vascular, haemopoietic) and the endocrine system. Several key factors implicated in the implantation process will be addressed. There is published evidence that reports the risk of pubertal failure and early menopause after treatment for childhood cancer and, in those women who continue with ovarian activity and achieve pregnancy, a risk of poor reproductive outcome. It is likely that radiation damage to the uterus will adversely effect pregnancy potential. Our own group has reported impaired uterine characteristics in women after abdominal irradiation. More recently, we have shown that lower doses of radiotherapy (as with total-body irradiation) may be associated with a potential for improved uterine characteristics in response to physiological sex steroid replacement. The outlook after chemotherapy alone may be more optimistic; our early data support a normal uterine morphological response. Reproductive outcome in these patients remains unpredictable, so simple noninvasive assessment of uterine characteristics may provide data of predictive value with respect to future fertility potential.

Adult↗
PubMed1999

Endometrial apoptosis in patients with dysfunctional uterine bleeding.

AIMS: To assess glandular apoptosis in the zona functionalis of proliferative phase endometrium in normal individuals and in patients with dysfunctional uterine bleeding (DUB). METHODS AND RESULTS: Routinely processed, haematoxylin and eosin-stained endometrial biopsies were assessed in 26 patients with symptomatic menstrual abnormality, mainly menorrhagia, and in 24 controls. All biopsies were in the proliferative phase and had been reported as within normal limits and consistent with the menstrual cycle dates provided. Apoptotic and mitotic figures were counted in a minimum of 100 transversely sectioned endometrial glands in all cases. In 16 biopsies (12 DUB and four controls) apoptosis was further assessed using the in situ terminal deoxynucleotidyl-transferase-mediated 2'-deoxyuridine-5'-triphosphate (dUTP) nick-end labelling (TUNEL) method. Apoptotic figures were identified in most control biopsies averaging 5.6/100 glands, and were significantly increased in biopsies from patients with DUB averaging 13.9/100 glands. There was no difference in mitotic figure counts. Apoptoses tended to be clustered within adjacent glands in both groups and individual glands exhibited both mitotic and apoptotic activity. Application of the TUNEL method gave broad agreement with morphological assessment although approximately 20-25% of typical apoptotic figures were not labelled. CONCLUSIONS: Endometrial glandular apoptosis is present in most normal proliferative phase biopsies and appears increased in some cases of DUB. The significance of this finding is not known but increased apoptosis may serve as a morphological marker of abnormal endometrial development in otherwise normal biopsy specimens.

Adult↗
PubMed1999

Regulation of matrix metalloproteinase-9 in endometrium during the menstrual cycle and following administration of intrauterine levonorgestrel.

Remodelling of endometrial tissues is fundamental to the cyclical changes that occur during the menstrual cycle, implantation and, in the absence of pregnancy, at menstruation. The enzyme matrix metalloproteinase-9 (MMP-9) is recognized as important in these processes but its regulation is not well defined. These studies have demonstrated that MMP-9 activity is present in the endometrium and exhibits cyclical changes in its distribution in the glandular and stromal cells. MMP-9 protein is present throughout the cycle with highest expression, as determined by semiquantitative analysis of specific MMP-9 immunoreactivity, in glandular cells during the mid secretory phase. A similar distribution was observed in first trimester decidua. In women with a levonorgestrel intrauterine system (LNG-IUS), which delivers high local concentrations of progestagen to the uterine cavity, MMP-9 is highly expressed in both endometrial glandular and stromal cells, and in the vasculature (in endothelial and perivascular cells). It can be concluded that MMP-9 is stimulated directly or indirectly by progesterone. Furthermore, MMP-9 may play a role in the remodelling of the endometrium that occurs during the menstrual cycle and in the aetiology of the morphological changes and breakthrough bleeding associated with long-term progestagen administration via a LNG-IUS.

Adult↗
PubMed1999

Ovarian and uterine characteristics after total body irradiation in childhood and adolescence: response to sex steroid replacement.

OBJECTIVE: To study the effect of total body irradiation (14.4 Gray) in childhood and adolescence on ovarian and uterine characteristics, and to investigate the response to physiological sex steroid serum concentrations. DESIGN: All long term post-pubertal female survivors of total body irradiation who had been treated in paediatric centres in Scotland were identified. Their ovarian and uterine characteristics were studied. SETTING: Recruitment was from follow up oncology clinics. SAMPLE: Nine women were identified, eight of whom were assessed and five progressed to detailed investigation. A control population of 12 women treated for acute leukaemia, but not treated with total body irradiation, and five healthy women with no history of childhood malignancy were recruited as controls. METHODS: Ovarian function was determined by measurement of serum gonadotrophins and sex steroids. Uterine response to physiological sex steroid replacement was investigated in women with ovarian failure, and to endogenous sex steroid production in women with ovarian function by ultrasound scan. The physiological sex steroid replacement was achieved with transdermal oestradiol patches and self administered vaginal progesterone pessaries. MAIN OUTCOME MEASURES: Determination of ovarian function and uterine response to physiological sex steroid serum concentrations. RESULTS: Six of eight women treated with total body irradiation had ovarian failure; preservation of function was seen in two girls treated pre-pubertally who had biochemical evidence of incipient ovarian failure. Four women with ovarian failure had reduced uterine volume, undetectable blood supply and absent endometrium at baseline assessment; after three months of physiological sex steroid replacement treatment uterine blood supply and endometrial response were not significantly different from controls; uterine volume improved but remained significantly smaller than controls and correlated with age at total body irradiation. CONCLUSIONS: Ovarian failure after total body irradiation is common and risk relates to age at treatment. Physiological sex steroid replacement improved uterine measures and these women may benefit from assisted reproductive technology.

Adolescent↗
PubMed1999

Role of inflammatory mediators in human endometrium during progesterone withdrawal and early pregnancy.

The role of progesterone (P4) in the regulation of inflammatory mediators interleukin-8 (IL-8), monocyte chemoattractant protein-1, and cyclooxygenase-2 (COX-2) and in the recruitment of leukocyte subpopulations in the endometrium has been examined, by employing a model of P4 withdrawal and maintenance in vivo. Messenger RNA and protein expression have been investigated in endometrial biopsies: 1) during the midsecretory phase (LH+8 to 10); during the maintained luteal phase (P4 administered vaginally for 4 days from LH+8) and biopsies collected 2) 24 h and 3) 48 h post withdrawal of P4; and 4) during pseudo pregnancy (lifespan of corpus luteum extended by 7 days with CG; (decidua collected from women with 5) an ectopic gestation and 6) from women undergoing first-trimester termination of pregnancy). CD56+ large granular lymphocytes remain the major leukocyte subtype, both 24 and 48 h after P4 withdrawal, and in decidua (CG supported or ectopic). Higher numbers (P < 0.05) of macrophages (CD68+) were present in endometrium 48 h post P4 withdrawal and in pseudo pregnant endometrium, compared with normal decidua. Significantly more macrophages (P < 0.01) were present in decidua from an ectopic pregnancy. A significant elevation of IL-8 (P < 0.01) and COX-2 (P < 0.05) messenger RNA was detected 48 h post P4 withdrawal. Evidence is provided for up-regulation of IL-8 and COX-2 in response to P4 withdrawal.

Chemokine CCL2↗
PubMed1999

Localization of interferon regulatory factor-1 (IRF-1) in nonpregnant human endometrium: expression of IRF-1 is up-regulated by prolactin during the secretory phase of the menstrual cycle.

PRL expression in the human uterus is up-regulated during the mid to late secretory phase of the menstrual cycle. This coincides with up-regulation of the expression of the PRL receptor, which is localized primarily to the endometrial glandular epithelial cells. Recent data have demonstrated activation of the Jak (Janus kinase)/Stat (signal transducer and activator of transcription) signaling pathway in the secretory endometrium after stimulation with exogenous PRL. However, the target genes for the action of PRL on the endometrial epithelial cells have not been elucidated. In this study we have investigated the pattern/site of expression of the transcription factor interferon regulatory factor-1 (IRF-1) as well as the effect of exogenous PRL on the transcription of IRF-1 in the human endometrium during the mid to late secretory phase of the menstrual cycle. Expression of the IRF-1 gene was confirmed by RNase protection assays using a 260-bp homologous [alpha-32P]UTP-labeled IRF-1 complementary ribonucleic acid (RNA) probe and 10 microg total RNA extracted from human endometrium (n = 5) collected between days 19 and 26 of the menstrual cycle. Northern and Western blot analyses were conducted on secretory phase human endometrium (n = 3) using human [alpha-32P]dCTP-labeled IRF-1 complementary DNA and antihuman IRF-1 antibody. Expression of the IRF-1 gene in the secretory phase endometrium was encoded by a RNA transcript of approximately 2.1 kb and a protein of 48 kDa. Furthermore, expression of the IRF-1 gene in the secretory phase endometrium was localized by immunohistochemistry predominantly to the glandular epithelial cells as has been shown previously for the PRL receptor. To investigate the effect of PRL on expression of IRF-1, human endometrial biopsies (n = 3) collected between days 24-26 of the menstrual cycle were cultured in the presence of cycloheximide with or without 100 ng/mL human PRL for 2 and 4 h. Culture of endometrial tissue with PRL for 2 and 4 h resulted in 2.9 +/- 0.3-fold (P < 0.01) and 1.7 +/- 0.1-fold induction of expression of the IRF-1 gene, respectively. These data demonstrate the expression of the transcription factor IRF-1 in the glandular epithelium of the endometrium and its regulation by PRL during the secretory phase of the menstrual cycle. Previous observations of the temporal up-regulation of expression of both PRL and PRL receptors in the secretory human endometrium and their localization to the stromal and glandular compartments, respectively, suggest that endometrial PRL mediates transcription of the IRF-1 gene in a paracrine fashion.

Blotting, Northern↗
PubMed1999

Perivascular interleukin-8 messenger ribonucleic acid expression in human endometrium varies across the menstrual cycle and in early pregnancy decidua.

Human endometrium and decidua contain large numbers of different leukocyte populations, the concentration of which fluctuates during the menstrual cycle and pregnancy. There is, for example, a large influx of neutrophils into premenstrual endometrium associated with an increased expression of interleukin (IL)-8 protein, which is chemotactic for neutrophils. Our aim in this study was to localize IL-8 messenger RNA (mRNA) expression in endometrium and decidua using in situ hybridization. In situ hybridization was carried out with a 35S-uridine 5'-triphosphate-labeled riboprobe using standard procedures. Late secretory endometrial and decidual biopsies demonstrated clear perivascular localization of IL-8 mRNA, with additional expression colocalized to activated macrophages. Midluteal endometrium showed minimal IL-8 expression, whereas endometrium obtained from women administered progesterone for 4 days from (LH peak + 8 days), to simulate luteal regression, demonstrated significantly increased localization of IL-8 mRNA, 48 h after withdrawal of progesterone. In conclusion, IL-8 mRNA expression is localized to perivascular cells of late secretory endometrium and decidua.

Blood Vessels↗
PubMed1999

Regulation of bcl-2 gene family members in human endometrium by antiprogestin administration in vivo.

It is likely that the changes which occur in the endometrium throughout the menstrual cycle involve apoptosis, and that expression of associated genes, such as the bcl-2 family, are regulated by sex steroids. The aim of this study was to investigate the presence of bcl-2, Bax and oestrogen receptor proteins in secretory endometrium collected from ten patients with normal ovulatory cycles 4 or 6 days after the LH surge, and on the same days in a subsequent cycle in which the formation of secretory changes was inhibited by the administration of the antiprogestin mifepristone (RU486) 2 days after the onset of the LH surge. Since some stromal cells display positive immunoreactivity, leucocyte subpopulations of macrophages (CD68-positive) and large granular lymphocytes (CD56-positive) were identified in serial sections. After administration of mifepristone on day 2 after the LH surge, a significant increase in bcl-2 immunoreactivity was observed in glandular and surface epithelium. A positive correlation (0.874) with nuclear oestrogen receptor immunoreactivity in endometrial glands was demonstrated. Subsets of stromal cells, identified as CD68-positive macrophages and CD56-positive large granular lymphocytes displayed positive immunoreactivity for the bcl-2 epitope, which was unaffected by mifepristone administration. Bax immunostaining was similar in control and antiprogestin-treated endometrium. These data indicate that antiprogestin administration inhibits progesterone downregulation of steroid receptors in endometrial glands, resulting in persistence of a proliferative endometrium and accompanying bcl-2 secretion.

Adult↗
PubMed1999

Cytokines and the regulation of apoptosis in reproductive tissues: a review.

PROBLEM: To determine the role of apoptosis-regulating genes bax and bcl-2 in reproduction. METHOD OF STUDY: Review of literature and current data. RESULTS: The bcl-2 family of apoptotic regulatory gene products interact and form dimers of anti- and pro-apoptotic proteins (e.g., bcl-2 and bax respectively), the ratio of which determines cell death or survival. Menses is associated with increased apoptosis in the glands, a change in bcl-2:bax ratio and increased levels of the pro-apoptotic cytokine TNFalpha. Apoptosis occurs in all placental cell types and increases from first to third trimester. Placental apoptosis is induced by TNFalpha in vitro and increased levels in utero characterize most failing pregnancies, intra-uterine growth restriction (IUGR) and labour. An increased bcl-2:bax ratio and apoptosis in the syncytiotrophoblast characterizes failing first trimester pregnancies. Apoptosis in the syncytiotrophoblast is also associated with IUGR. In a rat model, maternal vitamin A deficiency perturbs fetal development. This is associated with a placental infiltrate of TNFalpha positive neutrophils (day 20) and increased placental apoptosis in areas of infiltration. A similar infiltrate occurs in a mouse model of early pregnancy loss. In the fetal membranes, clusters of bcl-2 negative chorion trophoblast cells undergo apoptosis. This may allow passage of myometrial stimulatory factors that induce labour. CONCLUSION: The ratio of bcl-2:bax is crucial in the regulation of apoptosis, particularly in the human placenta. Changes in trophoblast apoptosis characterize (1) early pregnancy failure, (2) IUGR and (3) pre-term and term labour. Regardless of gestational age, TNFalpha plays a major role in the induction of placental apoptosis.

Animals↗
PubMed1998

Regulation of interleukin 8 production in the term human placenta during labor and by antigestagens.

OBJECTIVE: Our purpose was to assess the effects of labor and antigestagens on production of interleukin 8 by the term human placenta and to localize interleukin 8 in first- and third- trimester placentas. STUDY DESIGN: The study was conducted by the Department of Obstetrics and Gynaecology of the University of Edinburgh. Five placentas were collected after spontaneous and cesarean deliveries. Explants were cultured in the presence of mifepristone, lilopristone, or onapristone. The production of interleukin 8 was determined by specific radioimmunoassay, and the immunolocalization of interleukin 8 was determined in sections of first- and third-trimester placentas. RESULTS: All explants produced interleukin 8. Production was significantly increased (P < .05) after spontaneous delivery. In placentas delivered spontaneously, onapristone significantly increased production of interleukin 8 (P < .05), whereas in those from cesarean deliveries lilopristone caused a significant increase in production (P < .05). In the third-trimester placenta interleukin 8 was localized in the perivascular area of fetal vessels. In first-trimester villi it was peripherally located in syncytiotrophoblast. CONCLUSION: The human placenta at term is capable of producing interleukin 8, which is localized around the perivascular area of the villi. Production is increased after spontaneous labor and to varying degrees by the antigestagens studied. Interleukin 8 may have a role in the onset of parturition by recruiting and activating neutrophils at the placental site.

Culture Techniques↗
PubMed1998

Progestin receptor isoforms and prostaglandin dehydrogenase in the endometrium of women using a levonorgestrel-releasing intrauterine system.

This study has examined endometrial tissue in 14 normal women prior to insertion of a levonorgestrel-releasing intrauterine system (LNG-IUS) and thereafter longitudinally for up to 12 months post-insertion. The specific endpoints examined by immunohistochemistry were progesterone receptor (PR) subtypes A + B, oestrogen receptor (ER) and prostaglandin dehydrogenase (PGDH). Two antiprogesterone receptor antibodies, one specific to PR(B) subtype and the other to PR subtype A + B, were employed to examine the localization of both PR isoforms. The activity of PGDH, a progesterone dependent enzyme, was also measured. ER and PR(A+B) and PR subtype B were significantly down-regulated in glands and stroma in the presence of continuous intrauterine LNG delivery. There was an apparent increase in PR(A) immunoreactivity in endometrial glands between 6 and 12 months post-insertion. Consistent with down-regulation of both isoforms of PR was reduced glandular PGDH immunostaining following LNG-IUS insertion, and PGDH activity (as measured by metabolism of excess substrate in vitro). Furthermore, PGDH activity, known to be localized in the glands, significantly increased (P < 0.05) at 12 months post-insertion, coinciding with the observed increase in glandular PR(A+B) immunoreactivity at this time. Since the LNG-IUS suppresses the PR(B) so strongly, PR(A) is likely to be the subtype that mediates long term LNG action in the endometrium. PR(B) is the more suppressed of the two subtypes, and only PR(A) rises along with PGDH activity. Alterations to normal endometrial morphology and function, e.g. perturbation of normal sex steroid receptor expression, following exposure to high concentrations of local LNG, may play a role in the aetiology of bleeding disorders associated with the LNG-IUS. Further elucidation of local uterine mediators involved in the mechanism of bleeding problems is required.

Adult↗
PubMed1998

Morphological and functional features of endometrial decidualization following long-term intrauterine levonorgestrel delivery.

Irregular bleeding remains a common reason for the discontinuation of progestin-only contraception. The levonorgestrel releasing intrauterine system (LNG-IUS) has profound morphological effects upon the endometrium. Specific features are gland atrophy and extensive decidual transformation of the stroma. Morphological changes in the endometrium may be associated with perturbation of mechanisms regulating normal endometrial function. This study describes endometrial stromal and glandular features prior to and up to 12 months following insertion of the LNG-IUS. Comparison is made with first trimester decidua. In order to elucidate further mechanisms governing endometrial function with local intrauterine delivery of LNG, we here report histological features consistent with decidualization; a significant increase in granulocyte-macrophage colony stimulating factor (GM-CSF) immunoreactivity in decidualized stromal cells; glandular and stromal prolactin receptor expression and an infiltrate of CD56 + large granular lymphocytes and CD68 + macrophages. We are unaware of previous reports which have documented longitudinally both morphological and functional observations in endometrium exposed to local intrauterine levonorgestrel delivery. These studies demonstrate that long-term administration of intrauterine levonorgestrel results in features of altered morphology and function. No correlation was apparent between the end points in the study and the bleeding patterns described by the subjects. Further evaluation of these features in the context of menstrual bleeding experience may contribute to a better understanding of this troublesome side-effect which often leads to dissatisfaction and discontinuation of the intrauterine system.

Adult↗
PubMed1998

Progesterone receptor subtype B is differentially regulated in human endometrial stroma.

Two anti-progesterone receptor (PgR) antibodies, a new one specific to PgRB, the other to PgR subtypes A + B, have been used to examine the cellular location of PgR subtypes A and B in normal endometrium throughout the menstrual cycle and in early human decidua by standard immunohistochemical techniques. PgR(A+B) is the receptor detected by the antibody recognizing both isoforms of the receptor. PgRB is the receptor detected by the new antibody specific to the B isoform. Since it is not possible to raise antibody specific to PgR subtype A, all immunohistochemical analysis of the PgRA subtype is by subtractive inference. Thus we refer to PgRA as the subtype responsible for positive immunoreactivity when the PgRB subtype cannot be specifically detected. Endometrial biopsies were collected from 40 women with regular menses (n = 5 each stage of cycle: menstrual; early, mid and late proliferative; ovulatory; early, mid, and late secretory). Decidual tissue was obtained from 10 women undergoing first trimester surgical termination of pregnancy. As previously reported, the PgR(A+B) antibody stained glandular and stromal nuclei during the proliferative phase but only stromal nuclei during the secretory phase and early pregnancy. The new PgRB antibody also stained both cell types intensely during the proliferative phase, but failed to stain either stromal or glandular nuclei strongly during the secretory phase and early pregnancy. We concluded that, while both PgR subtypes were present in glands and stroma in the proliferative phase, and both subtypes were dramatically reduced in the glands during the secretory phase, PgRA remained as the predominant type in the stroma during the secretory phase and early pregnancy. The profound effects of progesterone on endometrium during the secretory phase and early pregnancy appear to be mediated primarily by PgRA in the stroma.

Adult↗
PubMed1998

Localization and temporal expression of prolactin receptor in human endometrium.

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.

Decidua↗