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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
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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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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.
Faculty of Medicine, Health and Life Sciences