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A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins. / Zoe Bentham

Swansea University Author: Zoe Bentham

Abstract

Background: Natural progesterone is currently unavailable for the treatment of endometrial hyperplasia. The first line of treatment for this condition is with the synthetic progestins Medroxyprogesterone Acetate (MPA) and Levonorgestrel (LNG). However, these hormones frequently trigger side effects...

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Published: 2015
Institution: Swansea University
Degree level: Doctoral
Degree name: Ph.D
URI: https://cronfa.swan.ac.uk/Record/cronfa42514
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last_indexed 2019-10-21T16:47:57Z
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spelling 2018-08-29T14:29:54.1453351 v2 42514 2018-08-02 A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins. 8adcd1e8f07a7bda244497af87b65f2f NULL Zoe Bentham Zoe Bentham true true 2018-08-02 Background: Natural progesterone is currently unavailable for the treatment of endometrial hyperplasia. The first line of treatment for this condition is with the synthetic progestins Medroxyprogesterone Acetate (MPA) and Levonorgestrel (LNG). However, these hormones frequently trigger side effects which occur as a result of adverse gene and protein regulation. The current unavailability of natural progesterone is down to its poor bioavailability which is due to the low aqueous solubility and extensive first-pass metabolism of this compound. Aims: The first aim of this thesis is to compare natural progesterone with MPA and LNG in their regulation of a subset of genes and proteins in the endometrium whilst also assessing the selected proteins in biopsies from patients with endometrial hyperplasia before and after progestin therapy. The second aim is to study progesterone metabolism within the gastrointestinal tract and liver in order to direct the production of progesterone amorphous solid dispersions. Methodology: During this thesis both microbiological and pharmacological laboratory techniques were used. For microbiology investigations immunohistochemistry, polymerase chain reaction, InCell Analysis and enzyme-linked immunosorbent assay were the key research methods. For pharmacological research the main methods used were stability assays analysed by tandem mass spectrometry and high performance liquid chromatography, solvent emulsion evaporation, powder x-ray diffraction and scanning electron microscopy. Conclusions: Amorphous solid dispersions are an attractive option for the future production of a natural progesterone oral formulation with enhanced solubility. Such a formulation can be targeted for delivery to the distal small intestine where progesterone metabolism is reduced compared to other intestinal regions. This formulation would be of particular benefit to patients with endometrial hyperplasia as the most commonly used progestins to treat this disease were shown to differentially regulate genes and proteins in the human endometrium compared to the natural product. E-Thesis Pharmacology.;Endocrinology. 31 12 2015 2015-12-31 COLLEGE NANME Swansea University Medical School COLLEGE CODE Swansea University Doctoral Ph.D 2018-08-29T14:29:54.1453351 2018-08-02T16:24:29.5249906 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Zoe Bentham NULL 1 0042514-02082018162500.pdf 10801744.pdf 2018-08-02T16:25:00.5070000 Output 37196358 application/pdf E-Thesis true 2018-08-02T16:25:00.5070000 false
title A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
spellingShingle A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
Zoe Bentham
title_short A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
title_full A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
title_fullStr A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
title_full_unstemmed A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
title_sort A novel progesterone oral formulation for the treatment of endometrial hyperplasia with reduced adverse signalling compared to synthetic progestins.
author_id_str_mv 8adcd1e8f07a7bda244497af87b65f2f
author_id_fullname_str_mv 8adcd1e8f07a7bda244497af87b65f2f_***_Zoe Bentham
author Zoe Bentham
author2 Zoe Bentham
format E-Thesis
publishDate 2015
institution Swansea University
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 1
active_str 0
description Background: Natural progesterone is currently unavailable for the treatment of endometrial hyperplasia. The first line of treatment for this condition is with the synthetic progestins Medroxyprogesterone Acetate (MPA) and Levonorgestrel (LNG). However, these hormones frequently trigger side effects which occur as a result of adverse gene and protein regulation. The current unavailability of natural progesterone is down to its poor bioavailability which is due to the low aqueous solubility and extensive first-pass metabolism of this compound. Aims: The first aim of this thesis is to compare natural progesterone with MPA and LNG in their regulation of a subset of genes and proteins in the endometrium whilst also assessing the selected proteins in biopsies from patients with endometrial hyperplasia before and after progestin therapy. The second aim is to study progesterone metabolism within the gastrointestinal tract and liver in order to direct the production of progesterone amorphous solid dispersions. Methodology: During this thesis both microbiological and pharmacological laboratory techniques were used. For microbiology investigations immunohistochemistry, polymerase chain reaction, InCell Analysis and enzyme-linked immunosorbent assay were the key research methods. For pharmacological research the main methods used were stability assays analysed by tandem mass spectrometry and high performance liquid chromatography, solvent emulsion evaporation, powder x-ray diffraction and scanning electron microscopy. Conclusions: Amorphous solid dispersions are an attractive option for the future production of a natural progesterone oral formulation with enhanced solubility. Such a formulation can be targeted for delivery to the distal small intestine where progesterone metabolism is reduced compared to other intestinal regions. This formulation would be of particular benefit to patients with endometrial hyperplasia as the most commonly used progestins to treat this disease were shown to differentially regulate genes and proteins in the human endometrium compared to the natural product.
published_date 2015-12-31T03:53:07Z
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score 11.018911

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