Hilary O. D. Critchley

FIGO classification system (PALM-COEIN) for causes of abnormal uterine bleeding in nongravid women of reproductive age

There is general inconsistency in the nomenclature used to describe abnormal uterine bleeding (AUB), in addition to a plethora of potential causes—several of which may coexist in a given individual. It seems clear that the development of consistent and universally accepted nomenclature is a step toward rectifying this unsatisfactory circumstance. Another requirement is the development of a classification system, on several levels, for the causes of AUB, which can be used by clinicians, investigators, and even patients to facilitate communication, clinical care, and research. This manuscript describes an ongoing process designed to achieve these goals, and presents for consideration the PALM‐COEIN (polyp; adenomyosis; leiomyoma; malignancy and hyperplasia; coagulopathy; ovulatory dysfunction; endometrial; iatrogenic; and not yet classified) classification system for AUB, which has been approved by the International Federation of Gynecology and Obstetrics (FIGO) Executive Board as a FIGO classification system.

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.

Current knowledge of the aetiology of human tubal ectopic pregnancy

BACKGROUND An ectopic pregnancy is a pregnancy which occurs outside of the uterine cavity, and over 98% implant in the Fallopian tube. Tubal ectopic pregnancy remains the most common cause of maternal mortality in the first trimester of pregnancy. The epidemiological risk factors for tubal ectopic pregnancy are well established and include: tubal damage as a result of surgery or infection (particularly Chlamydia trachomatis), smoking and in vitro fertilization. This review appraises the data to date researching the aetiology of tubal ectopic pregnancy. METHODS Scientific literature was searched for studies investigating the underlying aetiology of tubal ectopic pregnancy. RESULTS Existing data addressing the underlying cause of tubal ectopic pregnancy are mostly descriptive. There are currently few good animal models of tubal ectopic pregnancy. There are limited data explaining the link between risk factors and tubal implantation. CONCLUSIONS Current evidence supports the hypothesis that tubal ectopic pregnancy is caused by a combination of retention of the embryo within the Fallopian tube due to impaired embryo-tubal transport and alterations in the tubal environment allowing early implantation to occur. Future studies are needed that address the functional consequences of infection and smoking on Fallopian tube physiology. A greater understanding of the aetiology of tubal ectopic pregnancy is critical for the development of improved preventative measures, the advancement of diagnostic screening methods and the development of novel treatments.

Innate immune defences in the human endometrium

The human endometrium is an important site of innate immune defence, giving protection against uterine infection. Such protection is critical to successful implantation and pregnancy. Infection is a major cause of preterm birth and can also cause infertility and ectopic pregnancy. Natural anti-microbial peptides are key mediators of the innate immune system. These peptides, between them, have anti-bacterial, anti-fungal and anti-viral activity and are expressed at epithelial surfaces throughout the female genital tract. Two families of natural anti-microbials, the defensins and the whey acidic protein (WAP) motif proteins, appear to be prominent in endometrium. The human endometrial epithelium expresses beta-defensins 1–4 and the WAP motif protein, secretory leukocyte protease inhibitor. Each beta-defensin has a different expression profile in relation to the stage of the menstrual cycle, providing potential protection throughout the cycle. Secretory leukocyte protease inhibitor is expressed during the secretory phase of the cycle and has a range of possible roles including anti-protease and anti-microbial activity as well as having effects on epithelial cell growth. The leukocyte populations in the endometrium are also a source of anti-microbial production. Neutrophils are a particularly rich source of alpha-defensins, lactoferrin, lysozyme and the WAP motif protein, elafin. The presence of neutrophils during menstruation will enhance anti-microbial protection at a time when the epithelial barrier is disrupted. Several other anti-microbials including the natural killer cell product, granulysin, are likely to have a role in endometrium. The sequential production of natural anti-microbial peptides by the endometrium throughout the menstrual cycle and at other sites in the female genital tract will offer protection from many pathogens, including those that are sexually transmitted.

Decidualization of the human endometrial stromal cell: an enigmatic transformation.

Changes in human endometrium are essential to allow the establishment of pregnancy. These changes are induced in vivo by progesterone, and include appearance within the tissue of a specific uterine natural killer cell, characterized by an abundant expression of CD56. Changes also occur in the stromal cells, which undergo a characteristic decidualization reaction. Decidualized stromal cells are derived from the fibroblast-like cells within the endometrium, which maintain their progesterone receptors in the presence of progesterone. Prolonged exposure to progesterone induces a rounded cell characterized by release of prolactin and insulin-like growth factor binding protein-1 (IGFBP-1), and expression of tissue factor. Additional changes include the secretion of interleukin (IL)-15, vascular endothelial growth factor, and surface expression of zinc dependent metalloproteinases such as CD10 and CD13. In vitro, elevated intracellular cAMP as well as progesterone is necessary for decidualization. In vivo, these conditions may be provided by progesterone from the corpus luteum, by prostaglandin E, a stimulator of adenyl cyclase, and relaxin, which has recently been shown to be a phosphodiesterase inhibitor. Given the co-distribution of uterine natural killer cells and decidualized stromal cells, a mutual interaction might provide the correct regulatory environment for successful implantation, and penetration of the maternal blood vessels by trophoblastic cells.

The endocrinology of menstruation – a role for the immune system

The human endometrium displays characteristic features, both structural and functional, across the menstrual cycle. It is the sex steroid hormones, oestrogen and progesterone, that drive the endometrium through the different phases of the cycle. Oestrogen and progesterone act sequentially to regulate cellular concentrations of their respective receptors, this interaction initiates gene transcription. Thereafter a cascade of local events prepares the endometrium for implantation, but in the absence of pregnancy, progesterone withdrawal leads to menstruation and cyclic repair. Withdrawal of progesterone from an oestrogen-progesterone primed endometrium is the initiating event for the cascade of molecular and cellular interactions that result in menstruation. Progesterone withdrawal first affects cells with progesterone receptors. Early events in the menstrual process are vasoconstriction and cytokine up-regulation. The activation of lytic mechanisms is a later event and involves cells that may lack progesterone receptors, for example, uterine leucocytes and epithelial cells. Hence progesterone withdrawal results in a local increase of inflammatory mediators and the enzymes responsible for tissue breakdown. The total complex of local factors implicated in normal menstrual and aberrant menstrual bleeding are yet to be fully defined.

Expression of Stromal-Derived Factor-1 Is Decreased by IL-1 and TNF and in Dermal Wound Healing

Stromal-derived factor-1 (SDF-1) is a CXC chemokine that is believed to be constitutively expressed by stromal cells of numerous tissues. In this report, we demonstrate that dermal fibroblasts and vessels of noninflamed tissues express SDF-1. Unexpectedly, we found that expression of SDF-1 is regulated by inflammation. Expression of SDF-1 by primary cultures of human gingival fibroblasts is potently inhibited by activated macrophages via secretion of IL-1α and TNF-α. Levels of SDF-1 mRNA also decrease in acutely inflamed mouse dermal wounds. We propose that SDF-1 functions as a homeostatic regulator of tissue remodeling, whose expression stabilizes existing dermal architecture.

Radiation damage to the uterus — Review of the effects of treatment of childhood cancer

At the present time approximately 1 in 1000 young people aged between 16 and 35 years will have been cured of cancer in childhood and some of the treatment regimens used will have predictable effects on their future fertility prospects. In young women who have been exposed to radiotherapy below the diaphragm, the reproductive problems include the risk of ovarian failure and significantly impaired development of the uterus. The magnitude of the risk is related to the radiation field, total dose and fractionation schedule. Premature labour and low birth weight infants have been reported after flank abdominal radiotherapy. Female long-term survivors treated with total body irradiation and marrow transplantation are also at risk of ovarian follicular depletion and impaired uterine growth and blood flow, and of early pregnancy loss and premature labour if pregnancy is achieved. Despite standard oestrogen replacement, the uterus of these young girls is often reduced to 40% of normal adult size. Uterine volume correlates with the age at which radiation was received. Regrettably, it is likely that radiation damage to the uterine musculature and vasculature adversely affects prospects for pregnancy in these women. It has been demonstrated that, in women treated with total body irradiation, sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as re-establishing uterine blood flow. However, it is not known whether standard regimens of oestrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate assisted reproductive technologies are available, a successful pregnancy outcome is by no means ensured. The uterine factor remains a concern and women who are survivors of childhood cancer and their carers must recognize that these pregnancies will be at high risk.

Reconstruction of Endometrium from Human Endometrial Side Population Cell Lines

Endometrial regeneration is mediated, at least in part, by the existence of a specialized somatic stem cell (SSC) population recently identified by several groups using the side population (SP) technique. We previously demonstrated that endometrial SP displays genotypic, phenotypic and the functional capability to develop human endometrium after subcutaneous injection in NOD-SCID mice. We have now established seven human endometrial SP (hESP) cell lines (ICE 1-7): four from the epithelial and three from the stromal fraction, respectively. SP cell lines were generated under hypoxic conditions based on their cloning efficiency ability, cultured for 12-15 passages (20 weeks) and cryopreserved. Cell lines displayed normal 46XX karyotype, intermediate telomerase activity pattern and expressed mRNAs encoding proteins that are considered characteristic of undifferentiated cells (Oct-4, GDF3, DNMT3B, Nanog, GABR3) and those of mesodermal origin (WT1, Cardiac Actin, Enolase, Globin, REN). Phenotype analysis corroborated their epithelial (CD9+) or stromal (vimentin+) cell origin and mesenchymal (CD90+, CD73+ and CD45⁻) attributes. Markers considered characteristic of ectoderm or endoderm were not detected. Cells did not express either estrogen receptor alpha (ERα) or progesterone receptor (PR). The hESP cell lines were able to differentiate in vitro into adipocytes and osteocytes, which confirmed their mesenchymal origin. Finally, we demonstrated their ability to generate human endometrium when transplanted beneath the renal capsule of NOD-SCID mice. These findings confirm that SP cells exhibit key features of human endometrial SSC and open up new possibilities for the understanding of gynecological disorders such as endometriosis or Asherman syndrome. Our cell lines can be a valuable model to investigate new targets for endometrium proliferation in endometriosis.

Late effects of the treatment of childhood cancer on the female reproductive system and the potential for fertility preservation

One in 600 children will develop cancer in the first 15 years of life. Unlike the majority of adult cancers, most paediatric cancers are curable using multi-agent chemotherapy in combination with surgery and radiotherapy. The incidence of childhood cancer is 110 to 130 per million children per year and the relative frequencies of paediatric cancers as follows: leukaemia 34%; brain/spinal 24%; embryonal 15%; lymphona 11%; soft tissue 6%; bone 5%; others 5%. Over the last three decades there has been a sustained improvement in survival for most forms of childhood cancer. In the 1960s, acute lymphoblastic leukaemia, the most common childhood malignancy, had a five-year survival rate of less than 10%. Today, 70% of these children may now be cured. Following the demonstration in the 1950s that actinomycin was an effective agent in the treatment of Wilms’ tumour, there has been steady progress in the development of multi-agent chemotherapy regimens for the majority of childhood haematological and solid tumours. Radiotherapy is highly effective in the treatment of many malignancies but the increasing recognition of the morbidity for children from the late effects of radiation exposure has limited its therapeutic benefit. The majority of children with cancer are treated in specialised paediatric oncology centres according to nationally and often internationally agreed protocols. At the start of the 21 century, one in 1000 young adults in their third decade is a survivor of childhood cancer. The number of long term survivors is increasing year by year. The major challenge for this generation of children’s cancer specialists is to sustain the significant improvement in survival rates while at the same time minimising the treatment-induced late effects. The risk of late effects is directly related to the nature of the treatment received. The anticipation of late effects and their detection is important, as they may be amenable to prevention or treatment. The reproductive system is an important site of late effects of anti-cancer treatment. Natural pubertal progression, fertility and successful pregnancy outcome depend on normal hypothalamic, pituitary, ovarian and uterine function. Potential adverse effects on reproductive function in the female may be mediated through the hypothalamo–pituitary–ovarian axis, the ovary or the uterus. One of the more commonly recognised adverse effects of anti-cancer treatments is ovarian failure as a result of depletion of the numbers of primordial follicles leading to a premature menopause. The late effects of the treatment on reproductive function are difficult to predict with certainty. The patient or parents may expect discussion of these potential late effects before treatment commences. Options to preserve reproductive potential are limited in the case of young women and are experimental. Physicians need to be aware of the potential problems so that therapeutic prevention strategies and late effects can be openly discussed with the aim of cure at least cost.