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Biomedical subjects

H O D Critchley

Publications and source records attributed to H O D Critchley.

12 recordsLinked to original sources

Can we achieve international agreement on terminologies and definitions used to describe abnormalities of menstrual bleeding?

BACKGROUND: There is considerable worldwide confusion in the use of terminologies and definitions around the symptom of abnormal uterine bleeding (AUB), and these are leading increasingly to difficulties in setting up multinational clinical trials and in interpreting the results of studies undertaken in single centres. An international initiative was established to develop an agreement process to recommend clear, simple terminologies and definitions with the potential for wide acceptance. METHODS: After widespread consultation with relevant international and national organizations, journal editors and individuals, a modified Delphi process was developed to assess the current use of terminologies followed by a structured face-to-face meeting of 35 clinicians (mostly gynaecologists) and scientists in Washington. Focused small group discussions led to plenary assessment of concepts and recommendations using an electronic keypad voting system. RESULTS: There was almost universal agreement that poorly defined terms of classical origin used in differing ways in the English medical language should be discarded and that these should be replaced by simple, descriptive terms with clear definitions which have the potential to be understood by health professional and patient alike and which can be translated into most languages. The major recommendations were to replace terms such as menorrhagia, metrorrhagia, hypermenorrhoea and dysfunctional uterine bleeding. Suggestions for potentially suitable replacement terms and definitions are made. CONCLUSIONS: A simple terminology has been recommended for the description and definition of symptoms and signs of AUB. This manuscript should be a living document and should be part of an ongoing process with international medical and community debate. Classification of causes, investigations and cultural and quality of life issues should be part of the ongoing process.

Delphi Technique↗

Thyroid hormone signaling in human ovarian surface epithelial cells.

CONTEXT: Ovarian surface epithelial (OSE) cells express multiple nuclear hormone receptor genes, including those encoding thyroid hormone and estrogen receptors (TR and ER, respectively). Ovarian cancer is hormone-dependent, and epidemiological evidence links hyperthyroidism, inflammation of the ovarian surface, and increased risk of ovarian cancer. OBJECTIVE: The objective of this study was to assess T3 action on human OSE cells in vitro, asking 1) is there evidence for (pre)receptor control, 2) is T3 inflammatory, and 3) does T3 affect ER expression? DESIGN: Immunohistochemical analysis of fixed human ovaries and in vitro analysis of human OSE primary cell cultures were performed. PATIENTS: Twelve women aged 29-50 yr (median, 41 yr) undergoing elective gynecological surgery for nonmalignant conditions were studied. RESULTS: Messenger RNA transcripts for TRalpha1, TRalpha2, TRbeta1, and T3 activating deiodinase 2 and inactivating deiodinase 3 were present in primary OSE cell cultures by RT-PCR. TRalpha and TRbeta proteins were also localized to intact OSE by immunohistochemistry. Treatment of OSE cell cultures for 24 h with T3 caused dose-dependent mRNA expression of inflammation-associated genes: cyclooxygenase-2, matrix metalloproteinase-9, and 11betahydroxysteroid dehydrogenase type 1, determined by quantitative RT-PCR. Finally, treatment with T3 dose dependently stimulated ERalpha mRNA expression without affecting ERbeta1 or ERbeta2. CONCLUSION: The ovarian surface is a potential T3 target. T3 exerts direct inflammatory effects on OSE cell function in vitro. OSE cell responses to T3 include increased expression of ERalpha mRNA, which encodes the ER isoform most strongly associated with ovarian cancer. This could help explain suggested epidemiological links between hyperthyroidism and ovarian cancer.

Adult↗

Implantation of the human embryo: research lines and models. From the implantation research network 'Fruitful'.

Infertility is an increasing problem all over the world, and it has been estimated that 10-15% of couples in fertile age have fertility problems. Likewise induced unsafe abortion is a serious threat to women's health. Despite advances made in assisted reproduction techniques, little progress has been made in increasing the success rate during fertility treatment. This document describes a wide range of projects carried out to increase the understanding in the field of embryo implantation research. The 'Fruitful' research network was created to encourage collaborations within the consortium and to describe our different research potentials to granting agencies or private sponsors.

Animals↗

Spontaneous conception in a young woman who had ovarian cortical tissue cryopreserved before chemotherapy and radiotherapy for a Ewing's sarcoma of the pelvis: case report.

We report the case of a 14 year old girl who presented with a non-metastatic Ewing's sarcoma involving her superior pubic ramus. She received 14 courses of alkylating agent-based chemotherapy and direct radiation to her hemi-pelvis (55 Gy) and is alive and disease-free 8 years later. Multiple biopsies of ovarian cortical tissue were cryopreserved, with her written consent, before treatment began. Ovarian failure was confirmed on completion of treatment with cessation of menses and persistently elevated serum gonadotrophin and low estradiol levels on repeated measurement over 2 years. HRT was initiated. Irregular vaginal bleeding occurred due to radiation vaginitis. Reimplantation of ovarian cortical tissue was considered at 19 years as fertility was desired, but the decision deferred. A spontaneous conception occurred 1 year later and a healthy boy (birthweight 2.9 kg, 3rd-10th centile) was delivered at term by elective Caesarean section. This is the first case of a spontaneous conception occurring in a young woman with documented ovarian failure in whom ovarian cortical tissue had been cryopreserved. Clinicians should be aware of the possibility of spontaneous conception despite confirmed ovarian failure in young women successfully treated for cancer.

Adolescent↗

Expression and regulation of the prokineticins (endocrine gland-derived vascular endothelial growth factor and Bv8) and their receptors in the human endometrium across the menstrual cycle.

This study investigated the possible role of the newly discovered endocrine gland-derived vascular endothelial growth factors and their cognate receptors in the human endometrium during the menstrual cycle. Endocrine gland-derived vascular endothelial growth factors are also known as prokineticin (PK) 1 and PK2 and their receptors as PKR1 and PKR2. Expression of PK1 was elevated in the secretory compared with the proliferative phase of the menstrual cycle (P < 0.05). There was no temporal variation in expression of PK2, PKR1, or PKR2. PK1 and PK2 and their receptors were localized to multiple cellular compartments, including glandular epithelial, stromal, and endothelial cells in the endometrium and endothelial and smooth muscle cells in the myometrium. The elevation in PK1 expression in the secretory phase of the menstrual cycle indicated potential regulation of PK1 by progesterone. To investigate this, endometrial tissue was treated with 1 microM (micromol/liter(-1)) progesterone for 24 h, and PK1 expression was assessed by quantitative RT-PCR. Treatment with 1 microM ( micromol/liter(-1)) progesterone resulted in 2.91 +/- 0.75-fold elevation in PK1 expression, compared with controls (P < 0.05). These data identify a paracrine role for the PKs and their receptors in endometrial vascular function.

Endometrium↗

Temporal expression and signalling of prostacyclin receptor in the human endometrium across the menstrual cycle.

Prostacyclin (PGI(2)) synthesis and function in the human uterus has been implicated in the regulation of the process of normal and dysfunctional menstruation. PGI(2) synthesis is elevated during normal menstruation and is also associated with blood loss in women who suffer from heavy menses. This study was designed to outline further the role of PGI(2) in menstruation by investigating the temporal pattern and site of expression of prostaglandin I synthase (PGIS) and the prostacyclin receptor (IP receptor) in the non-pregnant human endometrium across the menstrual cycle. Quantitative RT-PCR demonstrated increased expression of PGIS and IP receptor during the menstrual phase of the cycle compared with all other phases (P < 0.05). Furthermore, PGIS and IP receptor were localised to the glandular epithelium, stromal and endothelial cells in the basal and functional layers of the endometrium. Functionality of the IP receptor in the human endometrium was assessed by measuring cAMP generation following treatment with 100 nmol l(-1) of the PGI(2) analogue, iloprost. cAMP generation was significantly higher in endometrial tissue collected during the proliferative compared with the secretory phase of the menstrual cycle (P < 0.05). In conclusion, this study has confirmed increased expression and signalling of PGIS and IP receptor during the menstrual phase and outlines a potential autocrine/paracrine role for PGI(2) on several cellular compartments in the endometrium including the endothelium. This may underscore a pivotal role for PGI(2) receptor signalling in normal and dysfunctional menstruation.

Cyclic AMP↗

Steroid signalling in human ovarian surface epithelial cells: the response to interleukin-1alpha determined by microarray analysis.

The human ovarian surface epithelium (HOSE) is a common site of gynaecological disease including endometriosis and ovarian cancer, probably due to serial injury-repair events associated with successive ovulations. To comprehend the importance of steroid signalling in the regulation of the HOSE, we used a custom microarray to catalogue the expression of over 250 genes involved in the synthesis and reception of steroid hormones, sterols and retinoids. The array included a subset of non-steroidogenic genes commonly involved in pro-/anti-inflammatory signalling. HOSE cells donated by five patients undergoing surgery for non-malignant gynaecological conditions were cultured for 48 h in the presence and absence of 500 pg/ml interleukin-1alpha (IL-1alpha). Total RNA was reverse-transcribed into biotin-labelled cDNA, which was hybridised to the array and visualised by gold-particle resonance light scattering and charge-coupled device (CCD) camera detection. Results for selected genes were verified by quantitative reverse-transcription PCR. In five out of five cases, untreated HOSE cells expressed genes encoding enzymes required for de novo biosynthesis of cholesterol from acetate and subsequent formation of C21-pregnane and C19-androstane steroids. Consistent with the inability of HOSE cells to synthesise glucocorticoids, oestrogens or 5alpha-reduced androgens de novo, CYP21, CYP19 and 5alpha-reductase were not detected. The only steroidogenic gene significantly up-regulated by IL-1alpha was 11beta-hydroxysteroid dehydrogenase type 1 (11betaHSD1). Other cytokine-induced genes were IL-6, IL-8, nuclear factor kappaB (NFkappaB) inhibitor alpha, metallothionein-IIA and lysyl oxidase: inflammation-associated genes that respond to glucocorticoids. The only steroidogenic gene significantly suppressed by IL-1alpha was 3betaHSD1. Other genes suppressed by IL-1alpha were aldehyde dehydrogenase (ALDH) 1, ALDH 10, gonadotrophin hormone-releasing hormone receptor, peroxisome proliferation-activated receptor-binding protein (PPAR-bp) and nuclear receptor subfamily 2 group F member 2. These results define a steroidogenic phenotype of cultured HOSE cells and provide a limited expression profile for genes with associated signalling functions. IL-1alpha co-ordinately induces 11betaHSD1 and a panel of glucocorticoid-regulated, inflammation-associated genes in HOSE cells, providing further evidence that cortisol generated by 11betaHSD1 could participate in the local resolution of inflammation associated with ovulation.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

Evaluation of abnormal uterine bleeding: comparison of three outpatient procedures within cohorts defined by age and menopausal status.

OBJECTIVES: To compare three outpatient methods of endometrial evaluation in terms of performance, patient acceptability and cost-effectiveness. DESIGN: Pragmatic unblinded trial randomised separately within three groups determined by risk of endometrial cancer. SETTING: The gynaecology outpatient clinic of a large city hospital in Edinburgh, Scotland. PARTICIPANTS: Women referred for investigation and management of abnormal bleeding between January 1999 and May 2001. INTERVENTIONS: Investigations were: blind biopsy alone, hysteroscopy with biopsy, ultrasound evaluation including transvaginal ultrasound, and, in the low-risk group, the option of no investigation. Within this design, two devices for obtaining endometrial biopsy were compared, the Pipelle sampler and the Tao brush. MAIN OUTCOME MEASURES: Successful (informative) completion of the investigation, acceptability of the investigation method to women, women's satisfaction with clinic care in the short term and at 10 months and 2 years of follow-up, and cost-effectiveness to the end of investigation. RESULTS: Minor adverse events (e.g. shock, patient distress) did not occur for ultrasound, but occurred in 16% and 10% of women for hysteroscopy and biopsy procedures respectively. Pipelle biopsy provided an acceptable endometrial sample for 79% of moderate-risk women, but only 43% of high-risk women. The Tao brush gave similar performance in moderate-risk women (77%), but was more successful than the Pipelle sampler in postmenopausal (high-risk) women (72%). There were significantly more successful visualizations for ultrasound than for hysteroscopy in both the low-risk and the moderate-risk group, and a similar but non-significant trend in the high-risk group. Ultrasound was significantly better than hysteroscopy at detecting fibroids, but hysteroscopy significantly better for polyps. At the 10-month follow-up, high-risk women who had been investigated by hysteroscopy (with biopsy) had the most positive views of their clinic experience, but this effect had largely disappeared by 24 months. In the moderate-risk group, the subgroup randomised to biopsy alone gave the most negative responses about their clinic experience and health now. Women wishing they had more investigation comprised 22% of moderate-risk women and 38% of low-risk women, but only 14% of postmenopausal women. At follow-up the moderate-risk women (with menstrual bleeding problems), compared with postmenopausal women, had much worse ratings for clinic experience and health now. Resource use tended to be higher in the moderate- and low-risk women. There was minimal difference in cost-effectiveness between investigation options in the high-risk group, with the option involving hysteroscopy being marginally better than ultrasound. The most cost-effective investigation in the moderate-risk group was biopsy alone and in the low-risk group ultrasound. CONCLUSIONS: Decision-making about investigation would be clarified if postmenopausal women were studied separately from premenopausal women with menstrual bleeding problems. For postmenopausal women exclusion of cancer is a main objective, so once investigation has been completed discharge follows, but in the woman with abnormal menstrual bleeding, even if serious pathology is excluded, the original presenting symptoms require management. About 60% of premenopausal women with abnormal bleeding reported that their symptoms were not 'much improved' at 10 months. Research is needed to understand this phenomenon, and to explore ways to integrate patient factors into optimising evaluation and treatment. The significance of benign pathologies in this group also requires clarification. Given the relatively small differences observed in cost-effectiveness, there is justification for allowing other issues (such as clinician preferences and women's perspectives) to influence decisions as to the investigation method. There is scope to make better use of patient factors to inform decisions as to the most efficient and acceptable method of investigation for an individual woman. Additional analyses, using data available as a result of this study, will contribute to this agenda.

Adult↗

Effect of long-term treatment with low-dose mifepristone on the endometrium.

BACKGROUND: Mifepristone in low daily doses has contraceptive potential by inhibiting ovulation and menstruation. Because follicular development is maintained, the endometrium is exposed to estrogen for prolonged periods unopposed by progesterone. METHODS: Endometrial biopsies were collected from 90 women in Edinburgh and Shanghai before (late proliferative) and 60 and 120 days after taking 2 or 5 mg mifepristone per day for 120 days. RESULTS: Ovulation and menstruation were inhibited in >90% of cycles and estrogen production was similar to that observed during the follicular phase of the control cycle. By 120 days, endometrial thickness increased significantly in women in Edinburgh but decreased in Shanghai. Endometrial histology showed inactive proliferative or cystic changes with dense stroma. There was a significant decrease in markers of proliferation, i.e. mitotic index and Ki67 staining. There were no pregnancies in a total of 200 women-months in 50 sexually active women who used no other method of contraception. CONCLUSIONS: We confirm that ovulation and menstruation were suppressed in the majority of cycles and there was asynchrony between ovarian activity and endometrial histology, which showed no signs of hyperplasia or atypia. These preliminary data suggest that daily low-dose mifepristone is potentially a safe estrogen-free contraceptive pill which has the added health benefit of amenorrhoea.

Adult↗

Prolactin induces ERK phosphorylation in epithelial and CD56(+) natural killer cells of the human endometrium.

Functional PRL receptors are expressed in the human endometrium during the secretory phase of the menstrual cycle in which PRL stimulates tyrosine phosphorylation of Janus kinase 2 and STAT (signal transducer and activator of transcription) 1 and 5. In this study, we investigated the effect of PRL on the MAPK/ERK pathway in the human endometrium. Human endometrial tissue was collected during the mid to late secretory phase of the menstrual cycle. Western blot analysis performed on proteins, extracted after up to 30 min culture with PRL, demonstrated rapid tyrosine and threonine phosphorylation of ERK 1 and 2 MAPKs. The phosphorylation of ERK, in response to PRL, was localized by immunohistochemistry to glandular epithelial cells and a subset of stromal cells. Using immunofluorescence histochemistry, PRL-induced phosphorylation of ERK in the stromal compartment was localized to the uterine-specific CD56(+) natural killer (NK) cells. We have demonstrated that the PRL receptor is expressed in uterine CD56(+) NK cells in situ by immunofluorescence and in purified decidual CD56(+) NK cells by RT-PCR and Western blotting analysis. We have further demonstrated phosphorylation of ERK 1 and 2 in cultures of purified uterine CD56(+) NK cells, in response to PRL. Our data demonstrate that PRL stimulates the ERK pathway in multiple cellular compartments of the human endometrium and identify uterine CD56(+) NK cells as novel PRL target cells.

CD56 Antigen↗