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- Mints, Miriam
(författare)
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Idiopathic menorrhagia : studies of angiogenesis and surgical therapy
- 2003
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Background: Excessive menstrual bleeding, menorrhagia (i.e. > 80 nil loss of blood) is a com-mon gynecological problem in women of reproductive age, accounting for over 20% of visits to gynecology outpatient clinics. The disorder may not only cause iron deficiency anemia but also considerable social discomfort and reduction in the quality of life. Although commonly associated with fibroids and carcinoma, approximately 50% of patients with menorrhagia do not show any evidence of uterine pathology. This suggests a defect in the cellular processes and regulatory mechanisms of menstruation. Historically, many women with heavy menstrual bleeding were advised to undergo hysterectomy, which was the only way of enduring a "cure". Hysterectomy is an effective treatment of menorrhagia, but it is associated with substantial postoperative morbidity and convalescence. In the early 1990s, endometrial resection or ablation became a well-established outpatient alternative for the surgical treatment of menorrhagia. The aim of this thesis: This work has mainly been focused on two aspects: firstly, the analysis of transcervical resection of the endometrium (TCRE) as a surgical option for treatment of menorrhagia and, secondly, on the involvement of the vascular endothelial growth factor (VEGF) family in the regulation of anglogenesis in the human endometrium in healthy women and those with idiopathic menorrhagia. In particular, we investigated if the vessel wall anatomy was abnormal and related findings to the expression of VEGF and VEGF receptors in the blood vessels. Results The general clinical outcome in the present studies (papers I and II) showed favorable results with low peroperative and postoperative complication rates: fluid overload occurred in 4% and perforation in 1% of the patients. Most of women who underwent TCRE found this surgery acceptable and approximately 80% of these women have avoided hysterectomy. Second-look hysteroscopy in women after TCRE showed signs of regenerative endometrium. In order to determine why the endometrium regenerates and what regulates this process, we have investigated the expression and distribution of VEGF and its receptors as well as vessel morphology in normal and menorrhagic endometrium (papers III-V). Our data suggest an up-regulation of the agonist-receptor pathway of VEGF in idiopathic menorrhagia: the vascular expression of VEGF-A, VEGFR1, -2, -3 in capillaries was 1.8-, 1.8-, 2.0-, and 1.6-fold higher, respectively, in the menorrhagia group. Since VEGF-A not only stimulates migration and survival of endothelial cells but also induces vascular permeability, we have addressed this aspect by analyzing of vessel morphology. We found that vessels in patients with menorrhagia displayed an unusual morphology with focal regions, gaps. The relative size of the gaps was significantly larger in menorrhagia samples than in controls (P=0.000002). Moreover, the sizes of the gaps correlated positively to the number of endometrial blood vessels expressing VEGF-A (P=0.0002) and VEGFR1 (P=0.03). To our knowledge, this is the first study that demonstrates the presence of endothelial gaps in menorrhagic endometrium and as a part of a specific disease process. Conclusions: TCRE provides a minimally invasive technique for treatment of menorrhagia with good clinical results: about 80% of women have the possibility of avoiding hysterectomy. Therefore, endometrial resection/ablation should be offered as a surgical option to all women with idiopathic menorrhagia who have completed their families. Normal endometrial angiogenesis is perturbed in idiopathic menorrhagia with an up-regulation of the agonist-receptor pathway of VEGF-A, which leads to anatomical differences in blood vessels, manifested inter alia as gaps. Our novel observations may be of significance in order to explain some of the underlying mechanisms that contribute to idiopathic menorrhagia and will provide novel opportunities for therapeutic intervention in the future.
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- Razumova, Z., et al.
(författare)
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The prognostic role of LRIG proteins in endometrial cancer
- 2019
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Ingår i: International Journal of Gynecological Cancer. - : BMJ Publishing Group Ltd. - 1048-891X .- 1525-1438. ; 29, s. A358-A358
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Background Endometrial cancer (EC) is the most common gynaecological malignancy in Sweden. The disease has several prognostic factors. Still, the high amount of EC develops into more aggressive forms of cancer, even though being first considered to be non-aggressive. The LRIG proteins are a family of three integral surface proteins that have a similar domain organisation. The current study evaluated the role of LRIG proteins as prognostic biomarkers in EC.Methodology The cohort included 75 women who underwent a hysterectomy and bilateral salpingo-oophorectomydue to EC at the Department of Women's and Children's Health, Karolinska University Hospital Solna between 2007 and 2012. The expression of LRIG1, LRIG2, and LRIG3 in paraffin biopsies was analysed by immunohistochemistry (IHC) with applying specific polyclonal antibodies. Evaluation of immunostainings was performed by two senior pathologists without knowledge of the disease outcome. The percentage of positive cells was divided in two groups with median percentage as cut off to have two groups of equal size included in the statistical analysis. Then the groups were assessedin connection with different tumour characteristics and clinical outcomes of EC.Results The majority of women in the cohort had >50% LRIG1-, LRIG2-, and LRIG3-positive cells. Among 6047 person-months of follow-up a total, of 14 incident cases of relapsed EC were identified. A statistically significant association between high LRIG3 expression and superior overall survival was observed in the cohort (IRR=2.559, 95 CI=1.054–6.210, p=0.038). LRIG1 and LRIG2 expression did not significantly correlate with survival.Conclusion Our results support the hypothesis that LRIG3 expression may have a prognostic role in women with EC. The significance of LRIG1 and LRIG2 expression remains to be clarified.
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- Wersäll, Ofra Castro, et al.
(författare)
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Which dietary and everyday life habits affect endometrial cancer recurrence? The machine gives the answer
- 2020
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Ingår i: International Journal of Gynecological Cancer. - : Lippincott Williams & Wilkins. - 1048-891X .- 1525-1438. ; 30:Suppl. 4, s. A32-A33
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction/Background: The increased life expectancy and westernization of the lifestyle are considered the major contributors to a sustainable rise in endometrial cancer (EC) rates. The factors predicting EC recurrence include patient age and tumour characteristics, such as type, differentiation, and depth of invasion. At the same time, recent studies testify the impact of meal and exercises on the course of various diseases. What are the food preferences and activities that could influence the ultimate risk of EC relapse and death?Methodology: The study included 481 women who previously underwent a hysterectomy due to EC at Karolinska University Hospital. The participants filled an extensive questionnaire on their dietary habits and everyday routines. Related clinical data was obtained through the National e-health system. It resulted in a large dataset with more than 180 variables, which was processed using the Random Survival Forest (RSF) approach. The latter is applied to a right-censored data and uses a collection of decision trees to rank the variables by their importance for the occurrence of an event. The top-ranked variables were further investigated with the Cox proportional hazards model. Analyzes were performed using the RandomForestSRC package for Python.Results: The consumption of the fried potatoes significantly increased the risk of EC relapse and death [HR=8.62 (2.22–33.56), p=0.002; HR=6.00 (1.06–34.01), p=0.043, respectively), the latter persisted after adjustment for body mass index, age and smoking status. Besides, each additional serving of sweetened soda drinks increased the risk of death [3.262 (1.834–5.800), p=0.0001]. In contrast, physical activity was beneficial with each additional Metabolic Equivalent per day decreasing the risk of death by 7.3% [HR=0.927 (0.892–0.964), p< 0.0001).Conclusion: We hypothesise that the fried potatoes’ detrimental effect may be related to the acrylamide, which is formed in starch-rich foods under high-temperature conditions. It acts as a carcinogen and endocrine disruptor, causing the endometrial hyperplasia and EC in animal studies. Sweetened beverages cause a rise in insulin, which in turn inhibits sex-hormone binding protein. This results in higher levels of circulating free oestrogens. Also, insulin has mitogenic and anti-apoptotic properties, further inducing the endometrium proliferation. The favorable influence of regular physical activity on EC relapse and death is in accordance with previous studies, including recent meta-analysis.Therefore, we encourage women treated for EC to consider reducing sweetened beverages and fried potatoes consumption and increasing physical activity.
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