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.

Dissertação apresentada ao Programa de Pós-Graduação em Saúde Coletiva (Mestrado Profissional) da Universidade do Extremo Sul Catarinense - UNESC, como requisito para a obtenção do título de Mestre em Saúde Coletiva. / Os miomas uterinos são os tumores mais comuns do trato genital feminino, afetando as mulheres na sua idade produtiva e reprodutiva. Como seu manejo curativo ainda é eminentemente cirúrgico, o tratamento dos mesmos produz alto impacto econômico, onerando os serviços públicos de saúde. Diante disto, a busca por uma resolução medicamentosa se faz necessária. A comprovação da ação da progesterona, estimulando o crescimento dos miomas suscintou estudos quanto à propriedade dos moduladores seletivos dos receptores de progesterona (SRPM) em reduzir o volume dos miomas e do sangramento por eles provocados. Este trabalho, uma revisão sistemática e metanálise, compara a ação do acetato de ulipristal (um SRPM) com placebo. Uma estratégia de busca foi desenvolvida usando os termos: "ulipristal acetate", "UPA", "uterine myoma", "fibromyoma" e "fibroid tumor". As bases de dados pesquisadas foram MEDLINE, EMBASE, Scopus, Registro Cochrane Central de Ensaios Controlados (CENTRAL), Biomed Central, Web of Science, IBECS, LILACS, Congress Abstracts e literatura cinza (Google Escolar e British Library), para estudos publicados no período de fevereiro de 1990 a fevereiro de 2017. Foram identificadas 438 referências, sendo que 106 delas foram relevantes após o rastreio inicial. Três estudos primários, envolvendo 291 pacientes, preencheram os critérios de inclusão. Neles pode-se observar que houve redução do sangramento vaginal (RR=0,23, IC 95%:0,18-0,30, p<0,00; I²:0%) e do volume dos miomas (RR=0,63 IC 95%:0,40-0,99; p<0,04; I²:74%). Desse modo, constata-se uma superioridade de ação do acetato de ulipristal na diminuição do volume do tumor e na redução do sangramento das portadoras de miomas.

I Sverige är abort en laglig rättighet och det finns flera godkända metoder för regelbunden antikonception. Ändå finns ett behov av akutmetoder för att förhindra oönskad graviditet.  Det finns tre godkända akutpreventivmedelsmetoder; levonorgestrel, ulipristal och kopparspiral. Detta arbetes syfte var att undersöka effektivitet och säkerhet för dessa tre godkända metoder. En litteratursökning gjordes i databasen PubMed,  7 artiklar valdes ut för analys. Artikel 1och 2 undersökte levonorgestrels effektivitet och säkerhet och kunde redovisa graviditetsfrekvenser på 0, 57%  och 0,67 % , samt en graviditetsförebyggande effektivitet på 68 %. Artikel 3 jämförde ulipristal och levonorgestrel och redovisade graviditetsfrekvenser på 1,8 % för ulipristal och 2,6 % för levonorgestrel. Även ”non-inferiority” konstaterades med OR på 0,68. Artikel 4 undersökte levonorgestrels effektivitet och redovisade graviditetsfrekvenser på 2,0 % (12 h- gruppen) och 1,9 % (24 h- gruppen), dessutom redovisades en graviditetsförebyggande effektivitet på 72 % (12 h- gruppen) och 75 % (24 h- gruppen). Artikel 5 jämförde ulipristal och levonorgestrel och fann att ulipristalbehandling  är ”non-inferiority” till levonorgestrelbehandling. Artikel 6 undersökte ulipristals effektivitet och redovisade en graviditetsfrekvens på 2, 1 % och en graviditetsförebyggande effektivitet på  62, 3%. Artikel 7 undersökte kopparspiralens effektivitet och kunde redovisa 100 % graviditetsförebyggande effektivitet. Akutpreventivmedel fungerar inte alltid, men förhindrar oönskade graviditeter. Slutsatsen är att resultaten ger stöd för gällande behandlingsrekommendationer.

In recent years, there have been many updates in hormonal emergency contraception. Levonorgestrel emergency contraception has been available for several years to prevent pregnancy when used within 72 hours after unprotected intercourse or contraceptive failure, and it was recently approved for nonprescription status for patients aged 17 years or older. Current research suggests that the primary mechanism of action is delaying ovulation. Ulipristal is the newest emergency contraception, available by prescription only, approved for use up to 120 hours after unprotected intercourse or contraceptive failure. The primary mechanism of action is delaying ovulation. When compared with levonorgestrel emergency contraception, ulipristal was proven noninferior in preventing pregnancy. Evidence suggests that ulipristal does not lose efficacy from 72-120 hours; however, more studies are warranted to support this claim. Many misconceptions and controversies about hormonal emergency contraception still exist. Research does not support that increased access to emergency contraception increases sexual risk-taking behavior. Several studies suggest that health care providers, including pharmacists, could benefit from increased education about emergency contraception. It is important for pharmacists to remain up-to-date on the most recent hormonal emergency contraception products and information, as pharmacists remain a major point of access to emergency contraception.

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Le rôle des progestatifs et du récepteur de la progestérone (PR) dans la carcinogénèse mammaire est maintenant établi. Le PR est exprimé sous deux isoformes PRA et PRB dont l'expression est équimolaire mais qui différent par leur activité transcriptionnelle des gènes cibles. La surexpression de PRA est associée à un pronostic défavorable du cancer mammaire, et est observée chez les femmes à haut risque génétique de cancer du sein. L'utilisation d'antagonistes pour inhiber l'activité de PR pourrait constituer une stratégie thérapeutique potentielle. L'objectif de cette thèse a été d'évaluer les effets de l'ulipristal acétate (UPA), un anti-progestatif, sur la tumorigenèse mammaire dans deux modèles d'études complémentaires. In vitro, dans la lignée cancéreuse mammaire bi-inductible (MDA-iPRAB) développée au laboratoire. Nous avons démontré qu'UPA inhibe la prolifération cellulaire induite par la progestérone en présence de PRA. L'expression de certains gènes clés de la tumorigenèse mammaire, cibles de PRA a été étudiée. Une corrélation entre avec la prolifération cellulaire et l'expression du facteur anti-apoptotique BCL2-L1 (messager et protéine) a été démontrée. L'activation transcriptionnelle, dépendante de la progestérone et inhibée par l'UPA, s'accompagne d'un recrutement spécifique et sélectif de PRA sur des séquences régulatrices du gène BCL2-L1, comme le démontrent les expériences de ChIP. In vivo, nous avons évalué l'efficacité anti-tumorale de l'UPA ainsi qu'une nouvelle classe d'antagoniste sélective et passive de PR, les « APRns » dans un modèle murin de xénogreffe de tumeur mammaire humaine HBCx34. UPA ralentit la croissance tumorale, diminue la prolifération cellulaire (Ki67, PCNA) et inhibe l'expression de BCL2-L1. L'ensemble de nos résultats démontrent une action antiproliférative et apoptotique de l'UPA ce qui suggère une utilisation potentielle d'antagonistes de PR dans la prise en charge du cancer du sein. / The role of progestins and the progesterone receptor (PR) in breast tumorigenesis has now been elucidated. PR is expressed as two isoforms PRA and PRB, differing by their structure and their transcriptional activity. They are often co-expressed in normal breast tissue but the predominance of PRA expression is associated with mammary carcinogenesis, a bad prognosis and an endocrine-resistance. Antiprogestins inhibit mammary tumor growth in several experimental models. The aim of this thesis was to investigate the effect of a well-known selective PR modulator (SPRM), Ulipristal acetate (UPA) in two complementary breast cancer models. In vitro, we used the newly established bi-inducible breast cancer cell line “MDA-iPRAB”, and demonstrated an anti-proliferative activity of UPA in progesterone-dependent, PRA-specific MDA-iPRAB cell proliferation. We also studied the expression of PRA-target genes involved in mammary tumorigenesis, and showed a correlation between cell proliferation and the expression of the anti-apoptotic factor BCL2-L1 (transcript and protein). The transcriptional activation of BCL2-L1 was stimulated by the progesterone in MDA-iPRA cell line, inhibited by UPA and was associated with a specific and selective recruitment of PRA to BCL2-L1 regulatory regions (ChIP assays). In vivo, we evaluated the anti-tumoral activity of UPA and a new class of selective and passive progesterone receptor antagonist ‘APRns' in patient-derived breast cancer xenograft in nude mice. UPA slowed down mammary tumor growth, decreased cell proliferation (Ki67, PCNA) and inhibited the BCL2-L1 expression. Further investigation are needed to determine the actions of APRns. In summary, UPA has an antiproliferative and a pro-apoptotic activities, which suggests a potential interest of UPA in breast cancer endocrine therapy.