Cecilia H.M. Ng

Female genital mutilation/cutting – towards abandonment of a harmful cultural practice

Globally, the prevalence of, and support for, female genital mutilation/cutting (FGM/C) is declining. However, the entrenched sense of social obligation that propagates the continuation of this practice and the lack of open communication between men and women on this sensitive issue are two important barriers to abandonment. There is limited evidence on the role of men and their experiences in FGM/C. Marriageability of girls is considered to be one of the main driving forces for the continuation of this practice. In some countries, more men than women are advocating to end FGM/C. Moreover, men, as partners to women with FGM/C, also report physical and psychosexual problems. The abandonment process involves expanding a range of successful programs, addressing the human rights priorities of communities and providing power over their own development processes. Anecdotal evidence exists that FGM/C is practised amongst African migrant populations in Australia. The Australian Government supports a taskforce to improve community awareness and education, workforce training and evidence building. Internationally, an African Coordinating Centre for abandonment of FGM/C has been established in Kenya with a major global support group to share research, promote solidarity, advocacy and implement a coordinated and integrated response to abandon FGM/C.

Use of hormonal therapy is associated with reduced nerve fiber density in deep infiltrating, rectovaginal endometriosis

To study the density of nerve fibers in cases of deep infiltrating endometriosis (DIE) of the rectovaginal septum in relation to various clinical factors.

Inflammation and endometrial bleeding

Abstract Most of the key physiological processes in the human reproductive tract involve a significant inflammatory component. These processes include follicle development, ovulation, implantation, pregnancy, labor, postpartum, remodeling and menstruation. In this context, the term ‘inflammation’ usually means an influx of leukocytes (‘immune cells’), often of different types, into a reproductive tract tissue. These examples of inflammation are not overtly associated with any infective process. There may also be evidence that these invading leukocytes have altered their functions to take on specific and relevant local regulatory roles. Specific sequential changes in different leukocytes can be demonstrated within human endometrium during the different phases of the normal menstrual cycle. Leukocytes are fairly sparse in numbers through the proliferative phase, but increase substantially into and through the secretory phase, so much so that around 40% of all stromal cells in the premenstrual phase are leukocytes, mainly uterine natural killer cells, a large granulated lymphocyte. Other leukocytes which play key roles in menstruation appear to be macrophages, mast cells, dendritic cells, neutrophils, eosinophils and regulatory T cells. Premenstrual withdrawal of progesterone increases the endometrial expression of inflammatory mediators, including IL-8 and MCP-1, which are believed to drive endometrial leukocyte recruitment at this time. Macrophages and neutrophils are rich sources of defensins and whey acid protein motif proteins, which play important roles in ensuring microbial protection while the epithelial barrier is disrupted. Mast cells are increasingly activated as the menstrual phase approaches, and leukocyte proteases trigger a cascade of matrix metalloproteinases and degradation of extracellular matrix. Dendritic cells and other antigen-presenting cells (e.g. macrophages) almost certainly facilitate clearance of cellular debris from the uterine cavity, and reduce the amount of viable cellular material transiting the Fallopian tubes. All of these processes are influenced or controlled by regulatory T cells. Many of these leukocytes also have the potential to release regulatory molecules which stimulate endometrial repair mechanisms. Increasing recent evidence also implicates disturbances of immune cells and their cytokine mediators in contributing to symptoms of abnormal uterine bleeding and pelvic pain. These recent findings all point towards the importance of the ‘inflammatory process’ in both normal and abnormal endometrial bleeding.

A Novel Pilot Study of Endometrial Stromal Cells and Immune Cell Populations in Sentinel Uterine-Draining Lymph Nodes During the Menstrual Cycle and in Endometriosis:

Recent studies suggest that changes in certain uterine immune cell populations in endometrium of women with endometriosis are likely to precede changes at ectopic sites. This preliminary study is a first look into the function of uterine-draining lymph nodes (LNs) during the menstrual cycle and in the presence of endometriosis. Paraffin-embedded obturator LNs were obtained from women with (n = 7, mean age 44.3) and without (n = 9, mean age 38.4) endometriosis, who had undergone hysterectomy for cervical or ovarian cancer and in whom LN involvement was not detected. Immunohistochemical staining for endometrial stromal cells and a range of immune cell populations was performed. The CD10+ endometrial stromal cells were detected in uterine-draining LNs throughout the menstrual cycle with numbers peaking during menstruation. The inflammatory process of menstruation was also associated with increased numbers of CD3+, CD4+, Foxp3+, DC-Sign+, CD68+, CD20+, CD79+, and plasma cells. In endometriosis, CD10+ endometrial stromal cells were further increased in numbers, but CD3+, CD4+, DC-Lamp+, FoxP3+, and plasma cells were reduced. This study indicates that efficient immunological responses may be required to contain shed endometrial fragments within the draining uterine LNs thus preventing their further dissemination with establishment of ectopic lesions at distant sites.

Microanatomy and function of the eutopic endometrium in women with endometriosis

Endometriosis is a disease that still presents many puzzles to clinicians and basic research scientists. Until recently, it has been regarded as a condition that arises when normal endometrium adheres to the peritoneal surface and then grows into an ‘inflammatory’ lesion, which adversely influences local reproductive tract function and causes pain. It is now becoming clear that the endometrium within the uterus in these women differs significantly in function from ‘normal’, and that these anomalies probably precede the development of classical ectopic endometriotic lesions. However, the etiology and mechanisms by which endometriosis arises are still far from certain. This review attempts to address the extensive, but fragmented, evidence that demonstrates widespread molecular disturbances in endometrial function and microstructure underlying this complex condition. The review also addresses some of the novel concepts that are being raised by these exciting new discoveries.

Lymphatic vessels in peritoneal endometriotic lesions

Purpose While the exact pathogenesis of endometriosis remains unclear, it has been hypothesized that fragments of viable endometrial tissue shed at menstruation can transit via the lymphatic circulation and establish endometriotic lesions at distant sites. Mounting evidence suggests that related parameters such as immune cell densities are altered in peritoneal endometriotic lesions. However, lymphatic vessels in lesions have not been previously investigated. In this study, the presence and distribution of lymphatic micro-vessels were characterized in peritoneal endometriotic lesions and surrounding tissues. Methods Immunohistochemical staining was performed with an antibody specific for lymphatic endothelium (podoplanin, D2–40 clone) on 48 peritoneal endometriotic lesion specimens and 15 samples of normal surface peritoneum. Lymphatic micro-vessel density (LVD) was quantified in and around endometriotic lesions, and in normal surface peritoneum using an automated cellular imaging system. Results LVD in endometriotic stroma (mean ± SD = 31.1 ± 28.8 vessels per mm2) was significantly increased compared to both adjacent (8.8 ± 7.6, P<.001) and distant sub-peritoneum (17.7 ± 12.0, P=.002). In addition, lesion-adjacent LVD was significantly lower than distant (P<.001). No statistically significant differences in LVD were observed between endometriotic stroma and normal surface peritoneum from women without endometriosis (31.1 ± 26.5) or at different phases of the menstrual cycle. Conclusions This is the first report of LVD in peritoneal endometriotic lesions. LVD is increased in the stroma of peritoneal lesions compared to the surrounding sub-peritoneal tissue. Lymphatic micro-vessels play an important role in the trafficking of immune cells within endometriotic lesions and may be involved in lesion establishment.

An investigation of the relationship between pelvic pain and density of nerve fibers in peritoneal lesions of endometriosis

Purpose Endometriosis is a gynecological disease often characterized by severe pelvic pain, including perimenstrual and intermenstrual pain and dyspareunia. Sensory nerve fibers within peritoneal lesions have previously been shown to contribute to generation of pain in endometriosis; however, their association with different types of pelvic pain is currently uncertain. Methods Peritoneal endometriotic lesions (n = 30) were sectioned and stained immunohistochemically with protein gene product 9.5 (PGP 9.5; pan-neuronal marker), neuropeptide Y (NPY; sympathetic), vasoactive intestinal polypeptide (VIP; parasympathetic), substance P (SP; sensory) and nerve growth factor (NGF) to identify nerve fibers and neurotrophin levels. Densities were assessed within stroma of the lesions and in the adjacent peritoneum. Pelvic pain scores were obtained using a visual analogue scale (VAS), and correlation analysis was performed. Results Increased density of nerve fibers was observed within the stroma of lesions. NGF expression was significantly increased in glandular epithelium, compared with stromal regions (p = 0.026) and correlated inversely with menstrual pain scores (p = 0.05). Sympathetic nerve fiber density (NPY) in stroma showed a significant positive correlation with intensity of menstrual pain (p = 0.04). Parasympathetic nerve fiber density (VIP) also showed a strong trend toward a positive correlation with menstrual pain intensity (p = 0.056). Conclusions There is increased neurogenesis in the stromal region. Innervation of lesions correlates to intensity of menstrual pain. NGF in glandular epithelium may promote growth of nerve fibers into the core of lesions; however, the inverse correlation between NGF expression in glandular epithelium and menstrual pain indicates that mechanisms of pain generation in endometriosis are complex.

Peripheral and endometrial dendritic cell populations during the normal cycle and in the presence of endometriosis

Background Dysfunctional immune response may be implicated in endometriosis pathogenesis, and dendritic cells (DC) may play greater roles in this response than previously recognized. This study set out to evaluate peripheral blood and endometrial DC population changes in the presence and absence of endometriosis pathology. Methods Endometrial (n = 83) and peripheral blood samples (n = 30) were subjected to immunohistochemical techniques and flow cytometry, respectively, to assess DC populations in women with and without endometriosis. Three circulating DC subsets (MDC1, MDC2 and PDC, expressing CD1c, CD303 and CD141), and late-stage mature endometrial DCs (using DC-LAMP antibody) were investigated. Results A highly significant reduction in CD1c intensity on MDC1 populations in peripheral blood was observed between normal cycle proliferative and menstrual phases (p = 0.025), but not in women with endometriosis, in whom CD1c intensity was markedly increased at the time of menstruation (p = 0.05). A significant reduction in peripheral blood MDC2 (p = 0.016) and apparent reduction in endometrial DC-LAMP+ DC (trend, p = 0.062) were observed in women with endometriosis compared with controls, consistent with our preliminary DC data. Conclusions Cyclical variation in endometrial and circulating DC populations appears to be crucial during normal menstrual cycles and in the establishment of pregnancy. In endometriosis, circulating and endometrial DC populations are significantly dysregulated at a number of levels, and are likely to contribute to inefficient immunological targeting of endometrial fragments shed at menstruation, facilitating their survival and establishment of endometriosis.

Use of the CryoPredict algorithm to predict live birth from cryopreserved embryos.

Currently, the viability of cryostored blastocysts that are subsequently re‐warmed is determined via the percentage of cell survival. However, the large number of cells that forms the blastocyst can make this estimate difficult and unreliable. Studies have shown that fast re‐expanding blastocysts have superior pregnancy rates.