Thesis (MScMedSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Background Individuals who are latently infected with Mycobacterium tuberculosis (M.tb) are able to quell the infection by balancing the innate and adaptive immune responses. Glucocorticoids (GCs) can affect this balance and can increase the risk of reactivation of TB. The three month injectable contraceptive medroxyprogesterone acetate (MPA) is widely used by women in developing countries, where TB is rife. MPA, unlike the two monthly contraceptive norethisterone enanthate (NET), possesses selective glucocorticoid activity, and could therefore alter immune responses to TB. Aims The aim of my investigation was to elucidate the immune modulatory effects of the synthetic progestins, MPA and NET, compared to the endogenous hormones, cortisol and progesterone, in Mycobacterium bovis Bacillus Calmette–Guérin (BCG) or anti-CD3 stimulated peripheral blood mononuclear cells (PBMC). I aim to determine the effects of MPA, NET, cortisol and progesterone on the receptor expression of glucocorticoid and various progesterone receptors. I investigate the effect of the above mentioned hormones on the downstream signalling cascades in the presence or absence of either BCG or anti-CD3. The overall immune modulation will be determined with regard to the cytokine production in PBMCs. Methods The presence of receptors for these steroid hormones in PBMCs was verified and BCG, anti-CD3 and hormone induced changes in receptor expression determined through RT-PCR. The impact of cortisol, MPA, NET and progesterone on BCG or anti-CD3 mediated activation of downstream signalling molecules were determined by Western blot as well as Luminex analysis. Results and Conclusion My results show that BCG and anti-CD3 mediated activation of the T cell receptor associated signalling molecules, Lck, ZAP-70, LAT was inhibited by the steroid hormones. Similarly several kinases including JNK, ERK and p38 and transcription factors including STAT3, STAT5 and CREB were differentially affected by the hormones. The inhibition of phosphorylation seen in the different signalling molecules indicated an inhibition of activation of downstream signalling cascades. To investigate the impact of the hormone induced changes in the signalling cascades on the expression of inflammatory and anti-inflammatory cytokines Luminex analysis was performed on the supernatant of the BCG and anti-CD3 stimulated PBMC cultures. Cortisol and MPA, but not NET and progesterone, significantly inhibited the secretion of IL-1α, IL-1β, IL-6, IL-10, TNF-α, IL-12 and IL-13. These results suggest that the immune suppressive effects of MPA are likely mediated through a combination of direct genomic GR action as well as through direct or indirect inhibition of several signalling molecules. The inhibition of the IFN-γ, IL-12, IL-1and IL-6 secretion by MPA could potentially increase the risk of susceptibility to TB in women using this contraceptive. Therefore the absence of glucocorticoid activity seen with NET could make this contraceptive a better choice for women in TB endemic areas. / AFRIKAANSE OPSOMMING: Agtergrond Individue wat latent met Mikobakterium tuberkulose (M.tb) geïnfekteer is, is in staat om die infeksie te onderdruk deur die ingebore en aanpasbare immuunrespons te balanseer. Glukokortikoïede (GCs) kan hierdie balans beïnvloed en kan die risiko van heraktivering van tuberkulose (TB) verhoog. Die drie maande inspuitbare voorbehoedmiddel medroksiprogestroon-asetaat (MPA) word algemeen gebruik deur vroue in ontwikkelende lande, waar TB volop is. MPA, in teenstelling met die twee maandelikse voorbehoedmiddel noretisteroon enantaat (NET), beskik selektiewe glukokortikoïed aktiwiteit, en kan dus die immuunrespons teenoor TB verander. Doelwitte Die doel van my studie was om die immuunregulerende effekte van die sintetiese progestiene, MPA en NET, toe te lig , in vergelyking met die endogene hormone, kortisol en progesteroon, in Mycobacterium bovis Bacillus Calmette - Guerin (BCG) of anti- CD3 gestimuleerde perifere bloed mononukleêre selle (PBMSe). Ek het beoog om die gevolge van MPA, NET, kortisol en progesteroon op die reseptor uitdrukking van glukokortikoïede en verskeie progesteroon reseptore te bepaal. Ek het ondersoek ingestel op die effek van die bogenoemde hormone op die sein transduksie in die teenwoordigheid of afwesigheid van óf BCG of anti-CD3. Die algehele immuun -modulasie sal bepaal word met betrekking tot die produksie van sitokiene in PBMSe . Metodes Die teenwoordigheid van reseptore vir die steroïedhormone in PBMSe is geverifieer en BCG en anti-CD3 en die veranderinge deurdie hormone in verband met die reseptor uitdrukking bepaal deur RT -PCR. Die impak van kortisol, MPA, NET en progesteroon op BCG of anti- CD3 aktivering van sein transduksie molekules is bepaal deur ‘Western blot’ asook Luminex analise. Resultate en gevolgtrekking My resultate toon dat BCG en anti-CD3 die aktivering van die T-sel reseptor wat verband hou met sein molekules , LCK , ZAP -70 , en LAT word geïnhibeer deur die steroïedhormone . Van die kinases insluitend JNK , ERK en p38 en transkripsie faktore, insluitend STAT3 , STAT5 en CREB is beïnvloed deur die hormone. Die inhibisie van fosforilering gesien in die verskillende sein molekules dui daarop aan dat 'n inhibisie van aktivering van sein transduksie. Die impak van die hormoon veroorsaak veranderinge in die sein transduksie met betrekking tot die uitdrukking van inflammatoriese en anti -inflammatoriese sitokiene Luminex analise is uitgevoer op die supernatant van die BCG en anti-CD3 gestimuleerde PBMS kulture. Kortisol en MPA, maar nie NET en progesteroon , het aansienlik die produksie van IL-1α , IL-1β , IL-6 , IL-10 , TNF-α , IL-12 en IL-13 geïnhibeer. Hierdie resultate dui daarop dat die immuunstelsel se onderdrukkende effekte van MPA is waarskynlik bemiddel deur 'n kombinasie van direkte genomiese GR interaksie sowel as deur direkte of indirekte inhibisie van verskeie sein molekules . Die inhibisie van die IFN-γ, IL-12, IL-1 en IL-6 sekresie deur MPA kan potensieel die risiko verhoog van vatbaarheid vir TB in vroue wat hierdie voorbehoedmiddel gebruik. Daarom oor die afwesigheid van glukokortikoïede aktiwiteit wat gesien is met NET, kan maak laat hierdie voorbehoedmiddel 'n beter keuse vir vroue in TB endemiese gebiede.

Despite its widespread use, little research has been undertaken on the use of progestogen-only injectable contraceptives by South African women. This thesis is comprised of two sections. Section 1 provides the first comprehensive description of injectable contraceptive use among rural South African women. It includes an analysis of the contraceptive method mix, prevalence of injectable contraceptive use, discontinuation patterns and reported side effects. A comparison of depot medroxyprogesterone acetate (DMPA) versus norethisterone oenanthate (NET-EN) focuses on utilization patterns and costs. The second section gives an account of the pharmacokinetics of DMPA including the first ever population analysis. A cross-sectional, community-based household survey was undertaken in the Hlabisa sub-district of KwaZulu-Natal, South Africa. Interviews were held during 1998 and 1999, with 848 randomly selected women (aged 15-49 years) and with 14 focus groups. There was a heavy reliance on injectable contraceptives which were used by 74% of women practising contraception. By contrast, the condom was the current method of only 4%. The injectable method was the most commonly used method among teenagers. However, in most cases, contraceptive use appeared to commence only after the first pregnancy. Slightly more NET-EN (54%) than DMPA (46%) was used, with younger women more likely to use NET-EN than DMPA (p=0.001). No significant differences in self-reported side effects were found between current users of the two injectables. Health workers played an important role in women's decisions to use the injectable, and in product selection, with NET-EN being recommended for younger women on the basis of concerns about method reversibility. While some women used injectables for long periods of time, discontinuation rates at two years were high, most commonly due to menstrual disturbances. Many side effects were reported by users of both DMPA and NET-EN, with amenorrhoea the most common, experienced by 63% of current injectable users. Heavy bleeding was most commonly reported by previous users (38%). Vaginal wetness was also common, mentioned by 18% and 29% of current and previous users respectively. Utilisation patterns of the two injectable products (DMPA and NET-EN) were analysed by means of a Pareto analysis of injectables issued from four South African provincial pharmaceutical depots over three financial years (1997/8, 1998/9 and 1999/2000). Injectables accounted for a substantial share of total state expenditure on drugs. While more DMPA than NET-EN was issued, NET-EN distribution from two depots increased over the period of analysis, even though DMPA was the cheaper option. The pharmacokinetic analysis was undertaken amongst DMPA users routinely attending family planning services in three Durban clinics in 1996. Medroxyprogesterone acetate levels at the end of the dosing interval were analysed for 94 women. In addition a population pharmacokinetic analysis of 291 serum levels from 111 DMPA users was undertaken. This involved the use of Non Linear Mixed Effect Modelling (NONMEM) to fit the data and determine the pharmacokinetic parameters, apparent clearance (CLIP) and apparent volume of distribution (VIP), and to estimate the influence of covariates on CLIP and VIP (where P is the bioavailability). The final model estimates for CLIP and VIP were 1080 (95% confidence interval: 994, 1166) litres/day and 86200 litres (95% confidence interval: 68246, 104154) respectively. No significant relationships were found between the covariates tested and CLIP and VIP. Concerns raised in the literature about the influence of weight or ethnicity on the pharmacokinetics of DMPA were shown to be unfounded. In the context of South Africa's HIV epidemic, the heavy reliance on injectable contraceptives, which offer no protection against HIV, should be addressed by expanding the contraceptive method mix to include barrier methods such as the female condom. Health providers are influential in contraceptive decision-making and should be encouraged and supported to redress the dependence on the injectable method alone, taking into account the need of many for dual protection against HIV and unwanted pregnancy. Provider counseling should also focus on adherence to dosing regimens, improving continuation rates, and should provide appropriate advice for women complaining about vaginal wetness with injectable use. Promotion of one injectable product over another to younger women is not appropriate. Since DMPA is the cheaper product, provider training about the rational use of injectable contraceptives should include cost considerations. / Thesis (Ph.D.)-University of Natal, 2003.

Thesis (M.A.)--Northern Kentucky University, 2006. / Made available through ProQuest. Publication number: AAT 1435883. ProQuest document ID: 1140194581. Includes bibliographical references (p. 22-24)

Thesis (MScMedSc)--Stellenbosch University, 2014. / ENGLISH ABSTRACT: Individuals latently infected with Mycobacterium tuberculosis (M.tb) contain the infection without showing signs of illness. Steroid hormones such as glucocorticoids (GCs) however can lead to reactivation of TB. Currently two different injectable contraceptives are available in South Africa, medroxyprogesterone acetate (MPA) and norethisterone enanthate (NET). MPA is able to bind to and activate the glucocorticoid receptor (GR) and possesses selective GC activity, a pharmacological characteristic absent in NET. The aim of this study was to investigate the immune modulatory effects of the two contraceptives MPA and NET on immune responses to mycobacteria in vitro and in vivo. Human peripheral blood mononuclear cells (PBMCs) were infected with BCG (M. bovis Bacille Calmette-Guérin) and treated with MPA, NET, progesterone or cortisol and cytokine expression was measured in order to determine whether the synthetic progestins mimic endogenous progesterone or the GC cortisol. MPA, but not NET suppressed the expression of IFN-γ, IL-1α, IL-1β, IL-2, IL-12p40 and IL-13 similarly to cortisol. Furthermore expression of miRNAs, small double stranded RNA molecules that bind to complementary sequences in mRNAs of target genes and cause their degradation, was determined under the different experimental conditions. The expression of several miRNAs including miR-30c, miR-222, miR-454 and miR-331-3p were differentially influenced by MPA, cortisol and/or NET in PBMCs stimulated with BCG. For example, BCG induced the expression of miR-454 (p=0.003) which was then inhibited to basal levels by cortisol (p=0.008), MPA (p=0.002) and NET (p=0.002). These results demonstrate that steroid hormones including the contraceptives MPA and NET can modulate immune responses to mycobacteria at the miRNA level. To determine the effect of MPA and NET on BCG-induced expression of miRNAs in vivo a mouse model was used. C57BL/6 mice were injected weekly with either MPA or NET using a dose equivalent to humans and then infected with BCG. Mice treated with MPA had a higher spleen bacterial load 21 days after infection compared to both NET treated and control mice (p=0.023). In whole blood, MPA and NET treatment suppressed the BCG-induced production of miR-100 and miR-509-3p to basal levels. In contrast to NET, MPA induced expression of miR-99a expression independent of BCG infection. In the lung, the site of disease, a total number of 22 out of 377 miRNAs tested were differentially expressed 21 days after infection. The results of this study indicate that both synthetic progestins altered the immune response to BCG at the level of cytokine expression as well as the miRNA level. MPA was found to mimic cortisol by inhibiting secretion of inflammatory cytokines whereas NET appeared to have more progestogenic properties. Each of the steroid hormones was observed to induce a characteristic miRNA expression profile, both in vitro as well as in vivo, although not identical. These results highlight that the two contraceptives – although used interchangeably by women in developing countries - are pharmacologically unique and differentially modulate immune responses to mycobacteria. These data support the urgent need for further research into the link between hormonal contraceptives and susceptibility to infectious diseases. / AFRIKAANSE OPSOMMING: Individue wat latent met Mycobacterium tuberculosis ( M.tb ) geïnfekteer is, onderdruk die infeksie en wys geen simptome van die siekte nie. Steroïed hormone soos glukokortikoïede (GKe) kan egter tot die heraktivering van TB lei. Daar is tans twee verskillende inspuitbare voorbehoedmiddels beskikbaar in Suid-Afrika, medroksiprogesteroon-asetaat (MPA) en noretisteroon enantaat (NET). MPA is staat om aan die glukokortikoïed reseptor (GR) te bind en dit te aktiveer. MPA beskik ook selektiewe GK aktiwiteit, 'n farmakologiese eienskap wat afwesig is in NET. Die doel van hierdie studie was om die immuun-regulerende effekte van die twee voorbehoedmiddels, MPA en NET, op immuunresponse teen mikobakterieë in vitro en in vivo te ondersoek. Menslike perifêre bloed mononukleêre selle (PBMSe) is met BCG geïnfekteer en met MPA, NET, progesteroon of kortisol behandel. Sitokien uitdrukking was gemeet om vas te stel of die sintetiese progestiene, endogene progesteroon of die GK kortisol naboots. MPA, maar nie NET, onderdruk die produksie van IFN-γ, IL- 1α, IL- 1β, IL- 2, IL- 12p40 en IL- 13 soortgelyk aan kortisol. Verder is uitdrukking van miRNAs, klein dubbelstring RNS molekules wat aan komplimentêre volgorde in mRNAs van teiken gene bind en wat hul degradering veroorsaak, bepaal in elk van die verskillende eksperimentele toestande. Die uitdrukking van verskeie miRNAs insluitende miR-30c, miR-222, miR-454 en miR-331-3p is differensieël beïnvloed deur MPA, kortisol en/of NET in PBMSe wat met BCG gestimuleer is. Byvoorbeeld, BCG veroorsaak die uitdrukking van miR-454 wat dan geïnhibeer word tot agtergrondvlakke deur kortisol, MPA en NET. Hierdie resultate toon dat steroïed hormone, insluitend die voorbehoedmiddels MPA en NET, die immuunrespons teen mikobakterieë op miRNA-vlak affekteer. Om die effek van MPA en NET op BCG-geïnduseerde uitdrukking van miRNAs in vivo te bepaal, is ʼn muismodel gebruik. C57BL/6 muise is weekliks met 'n dosis van MPA of NET, ekwivalent aan dosisse gebruik in die mens, ingespuit en met BCG geïnfekteer. Muise wat met MPA behandel is, het 'n hoër bakteriële lading in die milt 21 dae na infeksie in vergelyking met NET-behandelde muise en kontrole muise. In hul bloed, onderdruk MPA en NET behandeling die BCG-geïnduseerde produksie van miR-100 en miR-509-3p tot basale vlakke. In teenstelling met NET, induseer MPA die uitdrukking van miR-99a onafhanklik van BCG infeksie. In die long is 'n totaal van 23 miRNAs differensieël uitgedruk 21 dae na die infeksie. Die resultate van hierdie studie dui daarop dat beide sintetiese progestien die immuunrespons teen BCG verander op sitokien sowel as miRNA vlak. MPA boots hoofsaaklik kortisol na deur inhibering van sitokien-produksie terwyl NET meer progesterone eienskappe het. Op miRNA vlak veroorsaak elk van die steroïed hormone 'n kenmerkende miRNA uitdrukkingsprofiel, beide in vitro asook in vivo. Hierdie resultate beklemtoon dat die twee voorbehoedmiddels - alhoewel hulle afwisselend gebruik word deur vroue in ontwikkelende lande - farmakologies uniek is en differensieël die immuunrespons reguleer teen Mycobacterium. Hierdie data ondersteun die dringende behoefte aan verdere navorsing in verband met hormonale voorbehoedmiddels en vatbaarheid vir aansteeklike siektes.

This study examines the effect of progesterone-only injectable contraceptives, and medroxyprogesterone acetate (Depo-Provera) in particular, on the cells of the uterine cervix. Cervical and vaginal smears were taken before commencement of therapy and at 3 and 6 month intervals thereafter on 79 asymptomatic women attending a family planning clinic. Results of hormonal and cellular measurements before and after therapy were compared. menstrual cycling was also studied. The effect on Methods used were hormonal maturation indices, image analysis measurements and microscopic observation of cellular . features. The latter included anisocytosis, anisokaryosis, karyomegaly , plaque formation, cytoplasmic wrinkling, nuclear grooving, hypertrophy, atrophy, cytoplasmic moulding and density, retarded maturation and nuclear protrusions. Squamous, endocervical and metaplastic cells were examined. Analysis of the results showed that progesterone-only contraceptives produce all of the above to a greater or lesser degree resulting in an increased relative nuclear area which may be confused with intraepithelial neoplasia. This is due to the production of a folate deficiency at target organ level which interferes with cell division and slows the maturation process. This effect enabled further observations to be made leading to the establishment of the origin and content of the nipple-like protrusions which occur in endocervical cells in response to hormonal activity. Physiological effects included amenorrhoea and irregular menstrual cycling. Most women showed evidence of interference with normal cycling to a varying degree. The documented cellular changes were shown to modify the expression of common inflammatory and neoplastic conditions of the uterine cervix. These included trichomoniasis, herpesvirus cervicitis, human papillomavirus infection, folate deficiency, cervical intraepithelial neoplasia and invasive carcinoma as well as multiple pathologies. The potential for diagnostic error was examined. New diagnostic criteria were formulated based on the comparison of cellular features found in the presence of the contraceptive with those found under normal conditions. It is anticipated that these criteria will facilitate the cytological diagnosis of pathological conditions of the uterine cervix in users of depo-medroxyprogesterone acetate (DMPA), leading to increased accuracy and improved and better directed patient management. / Thesis (M.Med.Sc.)-University of Natal, Durban, 1993.

Thesis (M. A. (Communication Studies)) -- University of Limpopo, 2019 / Globally, over the years, health promotion organisations have developed communication campaigns geared towards addressing most major public health issues with the intention of preventing risky sexual behaviour. Teenage pregnancy is a major health, social, systemic and economic challenge, not only for the basic education sector but also, crucially for national development in general. The use of modern contraceptives, specifically implant contraceptives, has the potential to alleviate unintended teenage pregnancies. Modern contraceptives such as implant contraceptives have proven to be highly effective from 24 hours after insertion up to three years. Theoretically, the Health Belief Model and the Theory of Planned Behaviour have been applied to guide the study. A quantitative, descriptive survey was used in this study, with data collected using questionnaires. Purposive sampling of six secondary schools under the Mankweng Circuit in the Limpopo province where 306 participants were randomly selected was employed. Data were analysed using the SPSS version 26. The study revealed that that 34% of the participants were willing to use the implant contraceptive method based on the benefits found to be associated with the method. However, 66% were not willing to use the method regardless of the benefits found in using the implant contraceptives. In addition, it was found that only 3.9% of the participants were using implant contraceptives as a tool to prevent unintended pregnancies. This study makes a contribution to existing literature on implant contraceptives uptake among young women in South Africa. It would be informative to organisations and the National Department of Health who propose the use of implant contraceptives to stem increasing teenage pregnancies.