|dc.contributor.author||Whitaker, Lucy Harriet Ravenscroft||
|dc.description.abstract||Introduction: The human menstrual cycle is regulated by sex-steroid hormones,
including oestrogen (E), progesterone (P4) and androgens which act by ligand binding
to their cognate receptors. Perturbation of the complex series of events governing the
menstrual cycle may lead to heavy menstrual bleeding (HMB). This is a common
debilitating condition and often associated with uterine fibroids. There remains an
unmet need for effective, long-term medical treatment so women avoid surgery and
preserve their fertility.
Selective progesterone receptor modulators (SPRMs, e.g. ulipristal acetate, UPA) are
synthetic ligands that bind the progesterone receptor (PR). Many SPRMs have been
developed but only mifepristone (for the management of unwanted pregnancy) and UPA
are in current clinical use. UPA is licensed for the intermittent treatment of symptomatic
fibroids. SPRMs have potential utility for treatment of HMB as administration rapidly
induces amenorrhoea but the mechanisms by which this is achieved are unknown.
SPRM administration results in unique endometrial morphological changes
(progesterone receptor modulator-associated endometrial changes; PAEC). Despite
endometrial unopposed estradiol exposure these morphological changes do not appear
to be associated with malignancy or pre-malignancy risk. Indeed endometrial cell
proliferation appears reduced despite relative progesterone-antagonism.
Based upon findings with other SPRMs it was hypothesised that: (i) administration of
UPA would have an endometrial specific effect upon the reproductive tract, with regard
to alteration in morphology, localisation of sex steroid receptors (SSR) and cell
proliferation.; (ii) administration of UPA would impact upon progesterone-regulated (Pregulated)
genes in the endometrium.
Methods: The data presented within this thesis are derived from biopsies obtained at
hysterectomy from the endometrium, fallopian tubes and cervices of women with
symptomatic fibroids administered UPA for 8-15 weeks. Samples were obtained for
histological assessment, immunohistochemistry and RNA extraction for subsequent
quantitative RT-qPCR of sex-steroid receptors (SSR) and proliferation markers. In
addition key P-regulated genes within the endometrium were investigated by RT-qPCR
and selected protein expression. To further interrogate the anti-proliferative effect, RNA
was extracted from “paired” endometrial biopsies from the same woman in the
proliferative phase of the menstrual cycle and following subsequent treatment with UPA
for at least eight weeks and microarray gene analyses undertaken.
Results: Morphological alteration of the endometrium with UPA administration was
consistent with previously published data, but with a higher prevalence than previously
described. There was a striking alteration in expression and localization of SSRs,
particularly PR and androgen receptor (AR), and alteration of many P-regulated genes,
consistent with UPA acting with low progesteroneagonism within the endometrium.
There was no alteration of SSR expression within the cervix and proliferation was
unchanged. Fallopian tube morphology and SSR expression was consistent with
proliferative phase but cell proliferation was reduced following UPA administration,
consistent with secretory phase levels.
Microarray analyses identified multiple transcripts altered relative to proliferative
phase, with GREM2 the most significantly down-regulated gene and MUC1 one of the
most significantly upregulated genes. Consistent with low levels of mitotic figures and
cell proliferation, the most down regulated KEGG pathway was the cell cycle. Multiple
elements within this were subsequently validated (RT-qPCR) and included key
regulators of all elements of the mitotic cell cycle, many of which were novel to those
previously described following administration of another SPRM, mifepristone.
In summary the novel data presented in this thesis considerably extend the data
available to date concerning the actions of the SPRM, UPA, on the female reproductive
tract, and increases knowledge regarding a compound with promising utility for the
management of the debilitating complaint of HMB.||en
|dc.contributor.sponsor||Medical Research Council (MRC)||en
|dc.publisher||The University of Edinburgh||en
|dc.relation.hasversion||Murji, A., L. Whitaker, T. L. Chow and M. L. Sobel (2017). "Selective progesterone receptor modulators (SPRMs) for uterine fibroids." Cochrane Database Syst Rev 4: Cd010770.||en
|dc.relation.hasversion||Wagenfeld, A., P. T. Saunders, L. Whitaker and H. O. Critchley (2016). "Selective progesterone receptor modulators (SPRMs): progesterone receptor action, mode of action on the endometrium and treatment options in gynecological therapies." Expert Opin Ther Targets.||en
|dc.relation.hasversion||Whitaker, L. and H. O. Critchley (2016). "Abnormal uterine bleeding." Best Pract Res Clin Obstet Gynaecol 34: 54-65.||en
|dc.relation.hasversion||Whitaker, L. H., A. A. Murray, R. Matthews, G. Shaw, A. R. Williams, P. T. Saunders and H. O. Critchley (2017). "Selective progesterone receptor modulator (SPRM) ulipristal acetate (UPA) and its effects on the human endometrium." Hum Reprod.||en
|dc.relation.hasversion||Whitaker, L. H., A. R. Williams and H. O. Critchley (2014). "Selective progesterone receptor modulators." Curr Opin Obstet Gynecol 26(4): 237-242.||en
|dc.title||Effect of administration of selective progesterone receptor modulators (SPRMs) on uterine and endometrial morphology||en
|dc.type||Thesis or Dissertation||en
|dc.type.qualificationname||MD Doctor of Medicine||en