Hormonersättningsterapi (HRT) används för att lindra vasomotoriska och urogenitala symtom associerade med klimakteriet. Eftersom behandling med enbart östrogen förknippats med endometriell hyperplasi och livmodercancer, tillsätts progestagener till östrogen-beredningar i HRT hos kvinnor med intakt livmoder för att motverka den proliferativa effekten av östrogen och förebygga cancerutveckling i livmodern. Sådan kombinerad HRT har emellertid associerats med ökad risk för bröstcancer. Vid kombinerad HRT används olika typer av progestagener och olika behandlingsregimer (kontinuerlig eller sekventiell tillförsel). Syftet med detta arbete var att undersöka vad som ökar risken för bröstcancer vid kombinerad HRT: valet av progestagen-typ eller vilken behandlingsregim (kontinuerlig/sekventiell) som används. Metoden som användes var en litteraturstudie som omfattade sju studier om HRT och bröstcancerrisk, vilka hämtades från databasen PubMed. Utifrån undersökta studier kan man dra slutsats att ökad risk för bröstcancer associeras med kombinerad östrogen-progestagen HRT jämfört med HRT med enbart östrogen och framför allt om man jämför kontinuerlig kombinerad HRT med sekventiell kombinerad HRT med ett dos-responsförhållande som bakomliggande grund. Progestagen-typ kan ha effekt på risken för bröstcancer men detta behöver undersökas ytterligare.

Abstract Estrogen replacement therapy (ERT) has been associated with favorable effects on risk factors for atherosclerosis. In observational studies ERT was also suggested to reduce the risk of cardiovascular disease in postmenopausal women, but the cardioprotective role of estrogen has been challenged after negative results in randomized trials. However, the mechanisms of estrogen action in atherosclerosis development are only partially known. In order to investigate the regulation of plasma low-density lipoprotein (LDL) cholesterol in postmenopausal women and the effects of ERT on cholesterol and glucose metabolism and blood pressure, 79 hysterectomized, non-diabetic postmenopausal women were randomized in a double-blind, double-dummy study to receive either peroral estradiol valerate (2 mg/day) or transdermal 17β-estradiol gel (1 mg estradiol/day) for six months. At baseline the level of LDL cholesterol was related to body mass index, the fractional catabolic rate (FCR) and the production of LDL apolipoprotein B (apo B), but not to cholesterol absorption efficiency. Both peroral and transdermal ERT decreased plasma total and LDL cholesterol, while high-density lipoprotein cholesterol and triglycerides increased only in the peroral group. The LDL-lowering response was related to changes in estrogen levels, which presumably enhance LDL receptor activity shown as an increase in FCR for LDL apo B. In contrast, the determined genetic factors, apo E phenotype, EcoRI and XbaI polymorphisms of the apo B gene and polymorphism of 7α-hydroxylase gene, were not significant in regulation of LDL cholesterol, neither did they modify the response of ERT in these postmenopausal women. Similar outcomes were observed with both peroral and transdermal ERT as regards glucose metabolism and blood pressure. The overall effect of ERT on glucose tolerance was found to be neutral. Blood pressure decreased among non-hypertensive subjects on both estrogens, which could be related, at least in part, to the alterations in vasoactive peptides. The data of the present study suggest an overall favorable effect of both peroral and transdermal estrogen on common cardiovascular risk factors. However, the clinical significance of these findings in the prevention of cardiovascular diseases needs to be proven in long-term, randomized trials.

Philosophiae Doctor - PhD / End stage renal disease (ESRD), a more severe form of kidney disease, is considered to be a complex trait that may involve multiple processes which work together on a background of a significant genetic susceptibility. Black Africans have been shown to bear an unequal burden of this disease compared to white Europeans, Americans and Caucasians. Despite this, most of the genetic and epidemiological advances made in understanding the aetiology of kidney diseases have been done in other populations outside of sub-Saharan Africa (SSA). Very little research has been undertaken to investigate key genetic factors that drive ESRD in Africans compared to patients from rest of world populations. Therefore, the primary aim of this Bioinformatics thesis was twofold: firstly, to develop and apply a whole exome sequencing (WES) analysis pipeline and use it to understand a genetic mechanism underlying ESRD in a South African population of mixed ancestry. As I hypothesized that the pipeline would enable the discovery of highly penetrate rare variants with large effect size, which are expected to explain an important fraction of the genetic aetiology and pathogenesis of ESRD in these African patients. Secondly, the aim was to develop and set up a multicenter clinical database that would capture a plethora of clinical data for patients with Lupus, one of the risk factors of ESRD. From WES of six family members (five cases and one control); a total of 23 196 SNVs, 1445 insertions and 1340 deletions, overlapped amongst all affected family members. The variants were consistent with an autosomal dominant inheritance pattern inferred in this family. Of these, only 1550 SNVs, 67 insertions and 112 deletions were present in all affected family members but absent in the unaffected family member. Following detailed evaluation of evidence for variant implication and pathogenicity, only 3 very rare heterozygous missense variants in 3 genes COL4A1 [p.R476W], ICAM1 [p.P352L], COL16A1 [p.T116M] were considered potentially disease causing. Computational relatedness analysis revealed approximate amount of DNA shared by family members and confirmed reported relatedness. Genotyping for the Y chromosome was additionally performed to assist in sample identity. The clinical database has been designed and is being piloted at Groote Schuur medical Hospital at the University of Cape Town. Currently, about 290 patients have already been entered in the registry. The resources and methodologies developed in this thesis have the potential to contribute not only to the understanding of ESRD and its risk factors, but to the successful application of WES in clinical practice. Importantly, it contributes significant information on the genetics of ESRD based on an African family and will also improve scientific infrastructure on the African continent. Clinical databasing will go a long way to enable clinicians to collect and store standardised clinical data for their patients.

Orientador: Adriana Orcesi Pedro / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-27T01:25:39Z (GMT). No. of bitstreams: 1 Carmignani_LucioOmar_D.pdf: 1313710 bytes, checksum: e5a2ce3ebfaf92d14e105ee597ca752a (MD5) Previous issue date: 2015 / Resumo: Objetivos: Comparar os efeitos da ingestão diária de um suplemento alimentar à base de isoflavona de soja, terapia hormonal (TH) de baixa dosagem e placebo sobre a qualidade de vida (QV) em mulheres sintomáticas na pós-menopausa e avaliar a correlação entre a melhora dos sintomas da menopausa e a QV de acordo com o tipo de tratamento e comparar os efeitos de cada uma das intervenções sobre o sistema urogenital da mulher na pós-menopausa. Métodos: Ensaio clínico randomizado, duplo-cego e controlado envolvendo 60 mulheres na pós-menopausa, com idade entre 40 e 60 anos. Foram selecionadas e randomizadas em três grupos: um grupo recebeu um suplemento alimentar à base de soja (isoflavona 90mg/dia), outro grupo recebeu terapia hormonal de baixa dose (estradiol 1mg e acetato de noretisterona 0,5mg) e um grupo-controle que recebeu placebo, por um período de 16 semanas. O Menopause Rating Scale (MRS) foi utilizado para avaliar as mudanças nos sintomas climatéricos. A QV foi avaliada através da Versão Abreviada do Instrumento de Avaliação de Qualidade de Vida da Organização Mundial de Saúde (WHOQOL-BREF). Os instrumentos foram aplicados no início e após 16 semanas de tratamento. As queixas urinárias, vaginais e sexuais foram avaliadas através da subescala urogenital do MRS. A avaliação dos efeitos terapêuticos no sistema urogenital foi realizada através da medida do pH vaginal e calculo do valor de maturação vaginal. A espessura endometrial foi mensurada através da ultrassonografia transvaginal. A análise estatística foi realizada usando-se o teste do qui-quadrado, teste exato de Fisher, teste t de Student pareado, teste de Kruskal-Wallis, teste não paramétrico de Kruskal-Wallis e análise de variância (ANOVA). Para a análise intergrupo dos escores do MRS e da QV foi utilizado ANOVA, teste de Kruskal-Wallis e Kruskal-Wallis seguido de Mann-Whitney. Para a análise de correlação usou-se o coeficiente de correlação de Spearman. Para a comparação intergrupo das subescalas urogenitais do MRS utilizou-se o teste não paramétrico de Kruskal-Wallis seguido de Mann-Whitney. Resultados: A média de idade das participantes foi de 52,4 (±3,9) anos com tempo médio desde a menopausa de 4,1 (±3,1) anos. Os escores de QV aumentaram significativamente no domínio físico da QV nas usuárias da TH e em menor escala no grupo da soja (233,1% x 39,7%; p=0,02). Apenas no grupo que utilizou TH houve correlação significativa entre a melhora dos sintomas climatéricos e a melhora nos domínios físico (p=0,01) e psicológico (p=0,01) da QV e na questão da saúde geral (p<0,01). A avaliação do sistema urogenital mostrou que houve melhora da secura vaginal nos grupos da soja e da TH (p=0,04). As queixas sexuais e urinárias não se alteraram ao longo do tratamento. Apenas no grupo que usou TH houve um aumento significativo no índice de maturação vaginal (p<0,01) e uma diminuição no pH vaginal (p<0,01). Não houve mudança na espessura endometrial e os efeitos colaterais foram semelhantes nos três grupos estudados. Conclusões: O uso da terapia hormonal mostrou-se eficaz na melhora nos escores do domínio físico da qualidade de vida, isto também foi observado com o uso da isoflavona em uma escala muito menor, mas superior ao uso do placebo, porém apenas o grupo que utilizou a terapia hormonal apresentou uma correlação significativa entre a melhora dos sintomas climatéricos e a melhora na qualidade de vida. O uso de suplemento alimentar à base de soja contendo isoflavonas mostrou eficácia comparável à da terapia hormonal na melhora do ressecamento vaginal, sem exercer ação estrogênica no trato urogenital, em mulheres na pós-menopausa, e superior ao placebo / Abstract: Objectives: To compare the effects of a soy-based dietary supplement, low-dose hormone therapy (HT) and placebo on climacteric symptoms and on quality of life (QOL) of symptomatic postmenopausal women, and to evaluate the correlation between the improvement in menopausal symptoms and QOL according to treatment type, and also assess the effects of each intervention on the urogenital system in postmenopausal women. Methods: This was a double-blind, randomized and placebo-controlled clinical trial. Sixty healthy postmenopausal women, aged 40-60, were recruited and randomly assigned to three groups: a soy dietary supplement group (isoflavone 90mg/day), a low-dose HT group (estradiol 1mg plus noretisterone acetate 0.5mg) and a placebo group. Menopausal symptoms changes were evaluated through Menopause Rating Scale (MRS). QOL was measured by the abbreviated version of the World Health Organization¿s Quality of Life instrument (WHOQOL-BREF). These instruments were applied at baseline and after 16 weeks of treatment. Urinary, vaginal and sexual complaints were evaluated by using the urogenital subscale of the MRS. Evaluation of therapeutic effects on urogenital system was performed by vaginal pH measurement and maturation value calculation. Transvaginal sonography was performed to evaluate endometrial thickness. Statistical analysis were performed using the chi-square test, Fisher's exact test, paired Student¿s t-test, Kruskal-Wallis test, Kruskal-Wallis nonparametric test, and analysis of variance (ANOVA). For MRS and QOL scores intergroup analysis were used ANOVA, Kruskal-Wallis test, and Kruskal-Wallis followed Mann-Whitney test. Correlation analysis was performed using the Correlation Spearman Coefficient. For Intergroup comparisons related to MRS urogenital subscale, the Kruskal-Wallis nonparametric test was used, followed by the Mann-Whitney test. Results: The mean age of the patients was 52.4 (±3.9) years, with 4.1 (±3.1) years mean time since menopause. QOL scores increased significantly in the physical health domain of QOL in the users of HT and in a much lesser extent in the soy group (233,1% x 39,7%; p=0,02). It was observed that only in the HT group there was a statistically significant correlation between the improvement of symptoms of total MRS and improvement in the QOL physical (p=0.01) and psychological (p=0.01) domains and also on general health assessment (p<0.01). Urogenital system evaluation showed a significantly improvement in vaginal dryness in the soy group and HT group (p=0.04). Urinary and sexual symptoms did not change with treatment in the three groups. After 16 weeks of treatment, there was a significant increase in maturation value only in the HT group (p<0.01). Vaginal pH decreased only in this group (p<0.01). There were no statistically significant differences in endometrial thickness between the three groups and the adverse effects evaluated were similar. Conclusions: Hormone therapy was effective in improving the physical health domain of QOL, it was also observed with the use of isoflavones on a much lesser extent, but superior to placebo. However, only the HT group showed a significant correlation between the improvement of climacteric symptoms and the improvement in QOL. The use of soy-based dietary supplement containing isoflavones showed an efficacy similar to that of HT in improving vaginal dryness, and greater than placebo, without exerting estrogen action on urogenital tract in postmenopausal women / Doutorado / Fisiopatologia Ginecológica / Doutor em Ciências da Saúde

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第22726号 / 医博第4644号 / 新制||医||1045(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 戸口田 淳也, 教授 柳田 素子, 教授 滝田 順子 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Late-onset hypogonadism (LOH) is a pathological disorder that develops in males over the age of 40 and is diagnosed upon strict criteria that requires that the individual have total serum testosterone (T) below the normal limits as well as three symptoms of sexual dysfunction. Recommended therapy for young males with hypogonadism is testosterone replacement therapy (TRT). Treatment of LOH with TRT has increased significantly in the past several years, but studies showing adverse risks associated with TRT have led to a growing concern about the safety of such a treatment. This systematic review will give an overview of the pathology of LOH, clinical diagnosis of LOH, and comorbidities associated with this dysfunction. Benefits of TRT in elderly hypogonadal men have included improvement in cardiovascular function, reduced all-cause mortality, increased sexual function, increased bone mineral density, improved body composition, increased muscle strength, improved quality of life, and improvement in metabolic parameters. However, risks associated with TRT have included infertility, worsening lipid panel parameters, polycythemia, increased risk of prostate cancer, and in some cases, increased risk of adverse cardiovascular events.

京都大学 / 0048 / 新制・課程博士 / 博士(工学) / 甲第19009号 / 工博第4051号 / 新制||工||1623(附属図書館) / 31960 / 京都大学大学院工学研究科高分子化学専攻 / (主査)教授 岩田 博夫, 教授 田畑 泰彦, 教授 秋吉 一成 / 学位規則第4条第1項該当 / Doctor of Philosophy (Engineering) / Kyoto University / DGAM

The start of the menopausal transition involves the introduction of various somatic, urogenital, and psychological symptoms; of the symptoms, irritability is one of the main complaints reported by women. The use of bioidentical hormone replacement therapy has become more prevalent in society, specifically treating the somatic and urogenital symptoms of the menopausal transition. This study aims to determine the effects of bioidentical hormone replacement therapy (BHRT) on irritability in menopausal women. To test the hypotheses, an online survey was distributed to women via social media and word-of-mouth. Participants were asked to respond to various questions, which were then analyzed based on BHRT use. An independent samples t-test was used to analyze the data. The results exemplified no significant relationship between BHRT and irritability; using BHRT does not significantly reduce irritability scores.

京都大学 / 新制・課程博士 / 博士(医学) / 甲第24787号 / 医博第4979号 / 新制||医||1066(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 松田 秀一, 教授 森本 尚樹, 教授 安達 泰治 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

Oral iron replacement therapy is often used as a first-line modality for the treatment of iron deficiency anemia (IDA). Oral iron replacement options include tablets, capsules, and liquid formulations. Esophagitis due to iron tablet administration is a well-documented phenomenon, yet peptic ulcer disease secondary to iron tablet administration is less well-known. An 83-year-old female with a past medical history of chronic kidney disease stage V, anemia of inflammatory disease, heart failure with preserved ejection fraction, and gastroesophageal reflux disease presented to the hospital with diffuse abdominal pain and dark red emesis. She was started on ferrous sulfate supplementation two weeks ago and described progressive abdominal pain and nausea since beginning the medication. She was not taking nonsteroidal anti-inflammatories (NSAIDs), antiplatelets, or anticoagulants. Six months ago, she had an unremarkable upper endoscopy performed for new-onset gastroesophageal reflux disease. Laboratory studies revealed a hemoglobin of 7.3 mg/dL and due to a concern for rapid blood loss, she was given one unit of packed red blood cells. A non-contrast computed tomography was performed showing wall thickening of the stomach and the first two portions of the duodenum. A possible ulcer was seen in the distal posterior stomach. The patient was made NPO, and twice daily intravenous pantoprazole was started. An upper endoscopy was performed which revealed a 2.5 cm clean-based ulcer in the duodenal bulb. Biopsies showed acute inflammation and positivity for iron debris but were negative for Helicobacter pylori. Once daily pantoprazole was continued, and her ferrous sulfate tablets were discontinued. Her symptoms did not return. Ferrous sulfate may erode and ulcerate the gastric and duodenal mucosa like that of a chemical burn. Iron deposits may be seen on biopsies performed with Prussian blue staining. Brown crystalline deposits may be seen on hematoxylin and eosin staining. Iron injury may be seen in pill or capsule formulations due to a concentration effect, but this is typically not seen with solution forms. Treatment includes discontinuation of tablet or capsule formulations and substitution with liquid forms.