Master of Medicine / The number of unwanted pregnancies has not decreased in recent years and this should be addressed. Emergency contraception may be effective when used correctly having the advantage that it can be used after an episode of unprotected sexual intercourse (when regular contraception has failed or was not used). In this research project I set out to explore some of the major reasons why there are still many unwanted pregnancies in Australia. I decided to focus on the use and non-use of emergency contraception, e.g. emergency contraception pill (ECP) “method failures” are not well understood because the actual mechanisms of action are still unclear. There is evidence ECP can effectively interfere with follicle growth and ovulation. It is much less clear is whether ECP is able to interfere with fertilization and implantation, in a way, which may make it acceptable to those who have strong religious beliefs in fertilization being the start of new life. Emergency contraception has the potential to prevent many unwanted pregnancies when unprotected intercourse has occurred. It has relatively high efficacy in many studies, but true method failures are not well understood. By contrast, many unwanted pregnancies occur for “social reasons” where emergency contraception has not been used. I set out to study changes in knowledge and usage of emergency contraception in these groups of Australian women seeking termination of pregnancy: 1. Before a dedicated emergency contraception pill (ECP) pack (Postinor) became available in Australia 2. One year after dedicated ECP became available on prescription 3. One year after the ECP pack became available “over the counter” without prescription. Ninety-nine women were recruited during their presentation with a request for ECP at the six Family Planning Clinics in Australia. All women took LNG 1.5mg in a single dose during the clinic consultation. A blood sample was taken immediately prior to ingestion of the ECP for estimation of serum LH, oestradiol and progesterone levels to calculate the day of the menstrual cycle. Based on these endocrine data we estimated the timing of ovulation to within a ±24-hour period with an accuracy of around 80%. Women were followed up 4-6 weeks later to ascertain pregnancy status. The effectiveness of ECP when taken before and after ovulation was determined. Three women in this study became pregnant despite taking the ECP (pregnancy rate 3%). All three women who became pregnant had unprotected intercourse between day -1 and 0 and took the ECP on day +2, based on endocrine data. Day zero was taken as ovulation day. Among seventeen women who had intercourse in the fertile period of the cycle and took the ECP after ovulation occurred (on day +1 to +2) we could have expected 3 or 4 pregnancies, based on Wilcox et al data. Three pregnancies were observed. Among 34 women who had intercourse on days –5 to –2 of the fertile period, and took ECP before or around ovulation, four pregnancies could have been expected, but none were observed. The major discrepancies between women’s self-report of stage of the cycle and the dating calculation based on endocrine data were observed in this study. These data are supportive of the concept that the LNG ECP has little or no effect on post-ovulation events, but is highly effective before ovulation. Our interpretation of the data in terms of timing of treatment relative to ovulation may explain why EC with LNG works sometimes and fails at other times. A larger study is needed to prove this hypothesis. To investigate other reasons for such a high rate of unwanted pregnancy, which probably has a larger impact we looked into womens knowledge of and attitude towards ECP. Seven hundred and eighteen women participated in this study by answering a questionnaire consisting of 15 questions on their demographic and reproductive characteristics as well as the knowledge about the ECP, e.g. 208 women were enrolled before the ECP was marketed in Australia in 2001, 308 after it was marketed and 202 after it became available over the counter (Group 1, 2, and 3, respectively). We found that the participants who have heard about ECP were significantly younger (p<0.005). The mean age of women who have never heard about of ECP was 29.8 years compared to 26.3 years in women who have heard about ECP. More women were aware about the ECP after it became available over the counter. Women in group 2 had higher educational level in comparison to women in group 2 and 3 (p<0.005). There was significant trend in increased use of ECP in women of higher educational level (p<0.005). The use of ECP did not increase significantly with improved availability and access to the ECP amongst women presenting for termination of pregnancy. Wider availability of he ECP pack in Australia and an easier access to it has increased women’s awareness about the ECP. However, the use of ECP has not increased. This study provides better understanding of mechanism of action of LNG ECP and an explanation to the method failure. It also reveals poor knowledge about ECP despite its wider availability and accessibility. Improving these is a worldwide challenge for family planners and all health professionals.

Memoria para optar al Titulo Profesional de Médico Veterinario / El mono Cebus apella, ha demostrado ser un buen modelo animal para estudios de fisiología reproductiva en primates, fundamentalmente porque posee una gran capacidad para adaptarse y reproducirse en cautiverio y porque el aparato reproductor de la hembra posee semejanzas anatómicas y fisiológicas con el aparato reproductor de la mujer y con el de monas del viejo mundo. Por estas razones pensamos que Cebus apella puede ser un modelo animal adecuado para estudiar el mecanismo de acción de levonorgestrel (LNG), administrado como anticonceptivo de emergencia. En este estudio se determinó el efecto de la administración post - coital de LNG sobre la fertilidad de la mona Cebus apella. Para esto, se administraron una o dos dosis de 0,75 mg de LNG subcutánea (s.c.) u oral (p.o.) durante las primeras 24 horas después de la cópula. Se utilizaron 12 hembras con ciclos menstruales regulares con una duración de 16 a 25 días. Cada hembra contribuyó con dos ciclos tratados con LNG (tratados) y dos ciclos con administración de vehículo (controles), los cuales fueron distribuidos al azar. Los ciclos fueron monitoreados con frotis vaginales para reconocer el período periovulatorio (óptimo para el apareamiento) y para confirmar la cópula. Además, se utilizó ultrasonografía para confirmar la ovulación y la gestación. A las hembras que se preñaron se les interrumpió la gestación con una antiprogestina (mifepristona) y fueron reintroducidas al estudio, al igual que las no preñadas, en el ciclo subsiguiente. La gestación se produjo en 13 de 24 ciclos tratados con LNG y en 13 de 24 ciclos controles. Por lo tanto, la administración post - coital de LNG no reduce el número de embriones que se implantan. Se demuestra, por primera vez en un primate, que el LNG administrado como anticonceptivo de emergencia, no interfiere con procesos posteriores a la fecundación

It is known that some psychiatric disorders may deteriorate in relation to the menstrual cycle. However, in some conditions, such as premenstrual dysphoric disorder (PMDD), symptomatology is triggered mainly by the variations in ovarian steroid hormones. Although symptoms induced by fluctuations in ovarian steroids often are affective, little is known about how emotion processing in women is influenced by variations, or actual levels, of ovarian steroid hormones. The general aim of this thesis was to evaluate menstrual cycle effects on reactivity in emotion generating and controlling areas in the corticolimbic system to emotional stimulation and anticipation, in healthy controls and women with PMDD. A second aim was to evaluate corticolimbic reactivity during long-term administration of exogenous ovarian steroids. In study I, III and IV effects of the menstrual cycle on emotional reactivity in women with PMDD was studied. In study I, women with PMDD in displayed higher amygdala reactivity than healthy controls to emotional faces, not in the luteal phase as was hypothesised, but in the follicular phase. No difference between menstrual cycle phases was obtained in women with PMDD, while healthy controls had an increased reactivity in the luteal phase. The results of study I was further elaborated in study III, where women with PMDD were observed to have an increased anticipatory reactivity to negative emotional stimuli. However, no differences in amygdala reactivity to emotional stimuli were obtained across the menstrual cycle. Finally, in study IV the hypothesis that amygdala reactivity increase in the luteal phase in women with PMDD is linked to social stimuli rather than generally arousing stimuli was suggested, tested and supported. In study II, re-exposure to COC induced mood symptoms de novo in women with a previous history of COC-induced adverse mood. Women treated with COC reported increased levels of mood symptoms both as compared to before treatment, and as compared to the placebo group. There was a relatively strong correlation between depressive scores before and during treatment. The effects of repeated COC administration on subjective measures and brain function were however dissociated with increased aversive experiences accompanied by reduced reactivity in the insular cortex.

<p>The human endometrium undergoes dramatic changes in morphology and function during the menstrual cycle. Recurrent angiogenesis (the formation of new blood vessels) is of utmost importance for oxygen supply and nourishment of the rapidly growing endometrial tissue. </p><p>The importance of some growth factors known to stimulate new blood vessel formation both in vivo and in vitro in non-uterine tissues, for endometrial angiogenesis, was studied. Further, the possible relationship between the patterns of expression of some angiogenic growth factors and bleeding disturbances during the use of a progestin-only intrauterine contraceptive device was analyzed. Different ways of determining changes in the endometrial vascular density during the menstrual cycle were also evaluated. </p><p>The expression of the angiogenic growth factors vascular endothelial growth factors (VEGF) A, B, C, and D, fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF) and their receptors was analyzed using immunohistochemistry.</p><p>VEGF-A, -B and -C, FGF-2 and EGF and their receptors were all found to be expressed in normal human endometrium, especially in and/or around blood vessels, supporting the hypothesis that these peptides most probably contribute to the regulation of angiogenesis and blood vessel function in normal human endometrium.</p><p>There were differences in expression of some of the studied ligands and receptors in endometrium from users of an LNG-IUS with and without bleeding disturbances. We conclude that changes in the expression of these growth factors and receptors might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances.</p><p>The three different methods that were applied for calculating endometrial blood vessel density showed similar results and none of them indicated any significant changes during the menstrual cycle. Angiogenesis thus seems to occur mainly by blood vessel elongation and the angiogenic activity is probably related to changes in endometrial thickness and coiling of the spiral arteries.</p>

The human endometrium undergoes dramatic changes in morphology and function during the menstrual cycle. Recurrent angiogenesis (the formation of new blood vessels) is of utmost importance for oxygen supply and nourishment of the rapidly growing endometrial tissue. The importance of some growth factors known to stimulate new blood vessel formation both in vivo and in vitro in non-uterine tissues, for endometrial angiogenesis, was studied. Further, the possible relationship between the patterns of expression of some angiogenic growth factors and bleeding disturbances during the use of a progestin-only intrauterine contraceptive device was analyzed. Different ways of determining changes in the endometrial vascular density during the menstrual cycle were also evaluated. The expression of the angiogenic growth factors vascular endothelial growth factors (VEGF) A, B, C, and D, fibroblast growth factor 2 (FGF-2), and epidermal growth factor (EGF) and their receptors was analyzed using immunohistochemistry. VEGF-A, -B and -C, FGF-2 and EGF and their receptors were all found to be expressed in normal human endometrium, especially in and/or around blood vessels, supporting the hypothesis that these peptides most probably contribute to the regulation of angiogenesis and blood vessel function in normal human endometrium. There were differences in expression of some of the studied ligands and receptors in endometrium from users of an LNG-IUS with and without bleeding disturbances. We conclude that changes in the expression of these growth factors and receptors might be involved in the formation of fragile and dysfunctional blood vessels that subsequently give rise to bleeding disturbances. The three different methods that were applied for calculating endometrial blood vessel density showed similar results and none of them indicated any significant changes during the menstrual cycle. Angiogenesis thus seems to occur mainly by blood vessel elongation and the angiogenic activity is probably related to changes in endometrial thickness and coiling of the spiral arteries.