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Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates
Thesis (PhD (Medical Immunology))--University of Pretoria, 2019.
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| Format: | Thesis |
| Language: | English |
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University of Pretoria
2019
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| _version_ | 1867613685984264192 |
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| access_status_str | Open Access |
| author2 | Millar, Robert Peter |
| author_browse | Millar, Robert Peter |
| author_facet | Millar, Robert Peter |
| collection | Thesis |
| dc_rights_str_mv | © 2019 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. |
| description | Thesis (PhD (Medical Immunology))--University of Pretoria, 2019. |
| format | Thesis |
| id | oai:repository.up.ac.za:2263/72417 |
| institution | University of Pretoria (South Africa) |
| language | English |
| last_indexed | 2026-06-10T12:40:04.964Z |
| license_str | Other — see source repository |
| provenance_str_mv | Harvested via OAI-PMH from UPSpace — University of Pretoria Institutional Repository |
| publishDate | 2019 |
| publishDateRange | 2019 |
| publishDateSort | 2019 |
| publisher | University of Pretoria |
| publisherStr | University of Pretoria |
| record_format | dspace |
| source_str | UPSpace — University of Pretoria Institutional Repository |
| spelling | oai:repository.up.ac.za:2263/72417 Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates Millar, Robert Peter u27107052@tuks.co.za Newton, Claire Andreson, Ross Leijenaar, Stacey-Lee Medical Immunology GnRH analogues Prostate Cancer Androgen Deprivation Therapy Hot Flushes Bone Loss Estrogen Deficiency Libido UCTD SDG-03: Good health and well-being Thesis (PhD (Medical Immunology))--University of Pretoria, 2019. Prostate cancer (PC) is the second most commonly occurring cancer in men, and the fourth most common commonly occurring cancer overall. Almost all PC begins in an androgen-dependent state with androgen deprivation therapy (ADT) an effective treatment at this stage. PC can overtime develop into an androgen independent state at which point it can no longer be treated with ADT. The focus of this research is on androgen dependent PC and ADT. The hypothalamic–pituitary–gonadal (HPG) axis, controlled by gonadotropin releasing hormone (GnRH) is responsible for regulating reproduction, puberty and the production of spermatozoa and androgens in men. GnRH analogues (which downregulate the axis) are the foremost ADT agents. GnRH analogues may also have direct anti-proliferative effects in some cancers. However, ADT has negative side effects including loss of bone mass, hot flushes and loss of libido, due to a concomitant decrease in estrogen which is synthesised from androgen. We hypothesise that a molecule which retains GnRH receptor (GnRHR) activation while replacing estrogen activity which activates the estrogen receptors (ERs) may be beneficial. Conjugates of GnRH analogue (GnRHag) with 17β-Estradiol (E2C) or genistein (GenC) were studied examining GnRH and estrogen activity in vitro to evaluate their potential as novel PC therapeutics. Synthesis of the conjugates was commissioned from a commercial company. GnRHR activation was tested in HEK 293T cells by determining the generation of inositol phosphate in cells expressing GnRHR. ER activation was determined in MCF-7 cells using an E-screen assay in a cell line expressing ERs. Anti-proliferative effects were assessed in PC cell lines by crystal violet assay. Potential bone-protective capability was measured by ability to inhibit RANKL-induced osteoclast differentiation of Raw 264.7 macrophages. E2C and GenC elicited potent stimulation of GnRHR. The conjugates also had estrogenic activity similar to the unconjugated estrogen and phytoestrogen in the E-screen assay. Their estrogenic activities were confirmed by their ability to inhibit osteoclast differentiation to the same degree as unconjugated 17β-Estradiol and genistein. No direct antiproliferative effects, by the conjugates or GnRH, on PC cells were observed, indicating that GnRHR may not be expressed in these cell lines. The demonstration that E2C and GenC displayed GnRHR and ER activities similar to their unconjugated counterparts suggests they may be efficacious as ADT agents with reduced side effects of estrogen deprivation. Key Words: GnRH analogues, Prostate Cancer, Androgen Deprivation Therapy, Estrogen Deficiency, RANKL, Hot Flushes, Libido, Bone Loss NRF em2026 Immunology PhD (Medical Immunology) Unrestricted SDG-03: Good health and well-being 2019-11-28T07:14:27Z 2019-11-28T07:14:27Z 2020-04-24 2019-11-12 Thesis Leijenaar, SL 2019, Functional Characterisation of Gonadotropin-Releasing Hormone-Estrogen Conjugate, PhD thesis, University of Pretoria, Pretoria http://hdl.handle.net/2263/72417 A2020 http://hdl.handle.net/2263/72417 en © 2019 University of Pretoria. All rights reserved. The copyright in this work vests in the University of Pretoria. No part of this work may be reproduced or transmitted in any form or by any means, without the prior written permission of the University of Pretoria. application/pdf University of Pretoria |
| spellingShingle | Medical Immunology GnRH analogues Prostate Cancer Androgen Deprivation Therapy Hot Flushes Bone Loss Estrogen Deficiency Libido UCTD SDG-03: Good health and well-being Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title | Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title_full | Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title_fullStr | Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title_full_unstemmed | Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title_short | Functional characterisation of gonadotropin-releasing hormone-estrogen conjugates |
| title_sort | functional characterisation of gonadotropin releasing hormone estrogen conjugates |
| topic | Medical Immunology GnRH analogues Prostate Cancer Androgen Deprivation Therapy Hot Flushes Bone Loss Estrogen Deficiency Libido UCTD SDG-03: Good health and well-being |
| url | http://hdl.handle.net/2263/72417 |