This study was designed to explore the hormonal regulation of CNS opioid peptide levels in female Sprague Dawley rats. Forty-eight animals were divided into 2 equal groups for acute and chronic studies. Each group was further divided into 4 subgroups, each containing 6 animals. Each rat in the control group received an inert pill (in 0.25 ml corn oil daily by gavage); the second group, 15 μg norethindrone (NE, a potent progestin present in the oral contraceptive Micronor®); the third group, 15 μg NE and 1 μg ethinyl estradiol, EE2 (present in the oral contraceptive Modicon®) and the fourth group, 10 times the dose of the third group. Rats were treated either acutely for 5 days or chronically for 7 weeks. Opioid peptides were estimated by radioimmunoassay. Acute administration of 150 μg NE + 10 μg EE2 decreased the levels of methionine-enkephalin (ME), leucine-enkephalin (LE), dynorphin (DYN) and β-endorphin like immunoreactivity (β-EI) by about 50% in the pituitary. The same dose on chronic administration also decreased DYN, but increased the levels of ME and LE in the pituitary by 331 and 69%, respectively. In the hypothalamus, chronic administration of NE + EE2 increased the level of ME (155%) and LE (87%) as well as of DYN (97%). In the striatum, the levels of LE (33%) and DYN (115%) were elevated during chronic administration. It is concluded that the acute administration of NE + EE2, in general, reduces the levels of ME, LE, DYN and β-EI. The extent of this decrease is about the same in the pituitary, hypothalamus and striatum. Chronic administration of these hormones, however, results in a reversal of this decrease (except for β-EI) and actually can increase the levels of ME, LE and DYN in all three tissues.

A prospective study of two combined oral contraceptives was conducted in the Sudan. No pregnancies occurred. Overall incidence of side effects was low. Headache was most frequently reported. Elevations were observed for weight, systolic and diastolic blood pressures, and SGOT and SGPT values while a decrease was seen for hemoglobin levels. Menstrual irregularities were not a problem for the users. Total 6-month use discontinuation rates were low for both pill groups.

The purpose of this study was to determine if a training program consisting of 30 minutes of running on a treadmill, 3 days per week for 6 weeks, would lower serum cholesterol and/or triglyceride concentration in women using oral contraceptives. The intensity of the training was maintained at approximately 75% of the subject's pre-training maximal oxygen uptake. Comparisons were made in the variables triglyceride, cholesterol, maximum ventilation and maximum oxygen uptake, prior to and following training, between subjects who used birth control pills and those who did not. Eighteen women volunteers between the ages of 25-39 years, participated in the training program. Nine women were using oral contraceptives of the combined type. The subjects were free of metabolic diseases and were judged to be sedentary. Fasting blood samples were taken prior to and following the training program for lipid analyses. Maximum oxygen uptake and ventilation were determined by pre-training and post-training stress tests. To isolate training as the factor responsible for any changes in serum lipid concentration, the factors of body weight, skinfold thickness, fasting times and dietary patterns were held constant across the training period. Using multivariate analysis of covariance, one-way classification, to compare the group using oral contraceptives with the group not using them, no significant differences (p < 0.05) were found between the groups for either the blood lipids or the measures of functional capacity. Hotelling’s T² for comparison of pre-test to post~test differences within groups was employed using the linear combinations of the means of maximum ventilation and maximum oxygen uptake. The same analysis was used for the linear combination of the means of triglyceride and cholesterol. Only the group not using oral contraceptives showed significant difference (p < 0.05) in any of the variables. This difference was an increase after training, in maximum ventilation and maximum oxygen uptake. Other changes as a result of training were noted, although differences were not statistically significant at the 0.05 level of probability. These changes were 1) an improvement in the physical working capacity of the group using oral contraceptives, 2) a decrease in serum triglyceride and/or cholesterol levels in subjects whose initial values were in the upper ranges of clinical normality for these lipids. Exercise did not appear to affect the lipid levels of subjects who initially had low or average values. / Doctor of Education

Der Einfluß von Ovulationshemmern auf die Tumorbiologie und die Prognose des Mammakarzinoms Die Frage eines potentiellen Einflusses von Ovulationshemmern (OH) auf die Tumorbiologie und die Prognose des Mammakarzinoms stellt noch immer ein ungeklärtes Problem dar. Zur Untersuchung dieser Frage wurde eine Fall-Kontroll-Studie aufgelegt, die den Effekt der OH-Einnahme vor der Diagnose des Mammakarzinoms auf dessen Prognosefaktoren und den Verlauf der Erkrankung untersucht. Das mediane Follow-up belief sich auf 10 Jahre. Bei 471 Patientinnen wurde der Einfluß von OH auf konventionelle (Tumortyp, Grading, Tumorgröße, LK-Status, ER, PR) und molekularbiologische (PCNA, EGF-R, c-erbB-2, p53) Prognosefaktoren dargestellt. In Abhängigkeit von der Zeit seit der letzten Einnahme von OH konnten 2 Tumorentitäten charakterisiert werden. Bei OH-Einnahme bis zum Zeitpunkt der Diagnose fanden sich signifikant häufiger LK-positive (OR 2.14), schlecht differenzierte (OR 2.01) und stark proliferierende Tumoren (OR 2.13). Patientinnen mit langer Latenzperiode seit letzter OH-Einnahme zeigten signifikant häufiger ER-positive (OR 21.6-3.69) allerdings auch EGF-R-positive Tumoren (OR 1.73-2.0) mit moderater Proliferationsaktivität (OR 1.64-1.93). In multivaraiaten Überlebensanalysen hatten Patientinnen mit Langzeiteinnahme (mehr als 5 Jahre) und solche mit OH-Einnahme lange vor der Diagnose der Erkrankung (mehr als 96 Monate) ein signifikant besseres Überleben (HR 0.55, 95%CI 0.34-0.90; HR 0.49, 95%CI 0.26-0.92 respektive)als Patientinnen ohne OH-Einnahme. Dagegen hatte Patientinnen bei OH-Einnahme bis zur Diagnose oder Einnahme in den letzten beiden Jahren vor Diagnose ein signifikant schlechteres Überleben als solche ohne OH-Einnahme (HR 2.29, 95%CI 1.02-5.17; HR 3.80, 95%CI 1.45-9.97 respektive). Offenbar ist die OH-Einnahme während eines biologisch sensiblen Zeitraumes der Entwicklung des Mammakarzinomes von größerer Bedeutung als die Dauer der OH-Einnahme. Eine biologische Hypothese wird dargestellt. / Oral contraceptive use and breast cancer: Effect on tumorbiolgy and prognosis The question of whether oral contraceptive(OC) use before diagnosis has an effect on tumorbiology and prognosis of breast cancer remains a subject of discussion. Thus, a case-control study was conducted to investigate the effect of OC use on prognostic factors and the outcome of breast cancer patients. The median follow-up amounted to 10 years. In 471 breast cancer patients histomorphological (tumortype, grading, tumorsize, nodal status, ER, PR) and molecularbiological prognostic factors (PCNA, EGF-R, c-erbB-2, p53) and their association to OC use were studied. 297 (63%) patients were OC users, 113 were short-term users (less than 5 years) and 184 were long-term users. Dependend on the time since last OC use, two different biological tumor entities were characterised. In current users a significant increase in node-positive (OR 2.14) and poorly differentiated tumors (OR 2.01) and of tumors with a high proliferative fraction (OR 2.13) was observed. Past users with a long latency period had significantly more ER-positive (OR 2.16-3.69) but also EGF-R positive tumors (OR 1.73-2.0) with a moderate increase in proliferative activity (OR 1.64-1.93) compared to never users. In multivariate survival analyses long-term OC use (HR 0.55, 95%CI 0.34-0.90) and first OC use more than 96 months before diagnosis (HR 0.49, 95%CI 0.26-0.92) were associated with a significant improvement in survival, whereas current OC use ( HR 2.29, 95%CI 1.02-5.17) or last OC use during the last 2 years before diagnosis (HR 3.80, 95%CI 1.45-9.97) were related to a significant decrease in survival rates. OC use during a biologically sensitive time period seems to be more important than duration of use. A biological hypothesis is beeing suggested.

This thesis aims to study the effects of endogenous and exogenous hormones and mammographic breast density (BD) on cellular markers in non-cancerous female breast tissue. Women on the waiting list for breast reduction plastic surgery were recruited (n = 79), and randomized to 2 months of hormone therapy or no therapy before surgery. The women had a mammogram and a needle biopsy 2 months before surgery and tissue samples were obtained at the operation. In premenopausal women, estrogen receptor (ER)α levels were associated with age (p = 0.0002), were similar in the follicular and luteal phases of the menstrual cycle and were higher in parous than in nulliparous women (p = 0.009). Current smokers had lower PR levels than non-smokers (p = 0.019). Women on oral contraception had lower ERα (p = 0.048) and PR (p = 0.007) levels than women in the follicular phase. The ERα levels did not differ significantly between postmenopausal estrogen and estrogen-progestogen users, but PR levels were lower among estrogen-progestogen users (p = 0.03). We found lower expression of the genes for decorin and syndecans 1 and 4 in the luteal phase than in the follicular phase, among parous women. Protein levels of the androgen receptor, syndecan-4 and decorin was lower in premenopausal women who were using oral contraceptives (OC) than in those in the follicular phase (p = 0.002 - 0.02), whereas no significant differences between OC use and the luteal phase were found. In premenopausal women, BD was negatively associated with age and body mass index but was similar for the menstrual phases. Breast density was associated with genetic expression of the androgen receptor and remained significant after adjustment for age (rs = 0.56; p = 0.04). After adjustement for age, breast density was also marginally associated with expression of the caspase 3 gene (0.55; 0.053). However, protein levels of caspase 3 was negatively associated (-0.61; 0.03).

Avaliar a eficácia de duas formulações de contraceptivos orais combinados, uma contendo 20&#61549;g de etinilestradiol e 100 &#61549;g de levonorgestrel (grupo 1) e outra contendo 30&#61549;g de etinilestradiol e 150 &#61549;g de levonorgestrel (grupo 2), no controle da dismenorréia moderada a grave. Ensaio clínico aberto, prospectivo e randomizado. O cálculo amostral evidenciou que 11 pacientes seriam necessárias em cada grupo para detectar uma diferença de 1,5 pontos na escala analógica visual. As pacientes foram avaliadas no início do estudo e com 6 meses de uso de medicação. A escala analógica visual foi usada para avaliar a dismenorréia, a dispareunia e a dor não-cíclica. O questionário de Beck foi usado para avaliar depressão e o Short-Form-36 foi usado para avaliar a qualidade de vida. Outros desfechos avaliados foram os efeitos adversos e o controle do ciclo. No grupo 1, oito pacientes completaram o estudo e no grupo 2, dez pacientes. Não houve diferença, aos seis meses, entre os grupos 1 e 2 nos desfechos avaliados. Ao combinarmos os dois grupos, houve redução significativa dos escores para dismenorréia (p<0,0001), dispareunia (p<0,04) e dor não cíclica (p<0,006) com o uso dos contraceptivos hormonais. Houve melhora da qualidade devida observada em todos os domínios do Short-form 36 e redução dos escores do questionário de Beck em 8 dos 12 questionários analisados. Não ocorreram eventos adversos graves. Os contraceptivos orais de uso contínuo mostraram-se muito eficientes no controle da dismenorréia moderada a grave. Este efeito pode ser medido também pela melhora na qualidade de vida das pacientes tratadas. Como são medicações de baixo custo e com poucos efeitos colaterais, constituem uma das primeiras opções no tratamento de pacientes com dismenorréia moderada a grave. / Evaluate the efficacy of two different oral contraceptive formulations, one containing 20 &#61549;g of etinilestradiol and 100 &#61549;g of levonorgestrel (group 1) and the other with 30 &#61549;g of etinilestradiol and 150 &#61549;g of levonorgestrel(group 2). Methods: This is an open label, prospective and randomized clinical trial. It was calculated that 11 patients in each group were necessary to detect a difference of 1,5 points on the pain scale. After randomization, each group was evaluated at the beginning and at 6 months of treatment. The visual analogue scale was used to assess dysmenorrhea, dyspareunia and non-menstrual pain. To asses quality of life the Short-form 36 questionnaire was used and the beck inventory was used to measure depression. Adverse events and bleeding episodes were also recorded. On group 1 a total of eight patients completed the study and on group 2 there were ten patients. There was no statistical difference between the two groups after six months of treatment on all outcomes evaluated. Combining the two groups, there was a significative reduction of dysmenorrhea (p<0,0001), dyspareunia (p<0,04) and non-menstrual pain (p<0,006) with the oral contraceptives and there were no major adverse events. It was also observed an important improvement on all short-form 36 domains and reduction on 8 out of 12 Becks questionnaires. Conclusion: Continuous oral contraceptive use is very effective on the management of moderate to severe dysmenorrhea. This effect could also be seen on quality of life improvement after the treatment. Because of the low cost and few side effects of the medication, oral contraceptives should be used as first line treatment.

Avaliar a eficácia de duas formulações de contraceptivos orais combinados, uma contendo 20&#61549;g de etinilestradiol e 100 &#61549;g de levonorgestrel (grupo 1) e outra contendo 30&#61549;g de etinilestradiol e 150 &#61549;g de levonorgestrel (grupo 2), no controle da dismenorréia moderada a grave. Ensaio clínico aberto, prospectivo e randomizado. O cálculo amostral evidenciou que 11 pacientes seriam necessárias em cada grupo para detectar uma diferença de 1,5 pontos na escala analógica visual. As pacientes foram avaliadas no início do estudo e com 6 meses de uso de medicação. A escala analógica visual foi usada para avaliar a dismenorréia, a dispareunia e a dor não-cíclica. O questionário de Beck foi usado para avaliar depressão e o Short-Form-36 foi usado para avaliar a qualidade de vida. Outros desfechos avaliados foram os efeitos adversos e o controle do ciclo. No grupo 1, oito pacientes completaram o estudo e no grupo 2, dez pacientes. Não houve diferença, aos seis meses, entre os grupos 1 e 2 nos desfechos avaliados. Ao combinarmos os dois grupos, houve redução significativa dos escores para dismenorréia (p<0,0001), dispareunia (p<0,04) e dor não cíclica (p<0,006) com o uso dos contraceptivos hormonais. Houve melhora da qualidade devida observada em todos os domínios do Short-form 36 e redução dos escores do questionário de Beck em 8 dos 12 questionários analisados. Não ocorreram eventos adversos graves. Os contraceptivos orais de uso contínuo mostraram-se muito eficientes no controle da dismenorréia moderada a grave. Este efeito pode ser medido também pela melhora na qualidade de vida das pacientes tratadas. Como são medicações de baixo custo e com poucos efeitos colaterais, constituem uma das primeiras opções no tratamento de pacientes com dismenorréia moderada a grave. / Evaluate the efficacy of two different oral contraceptive formulations, one containing 20 &#61549;g of etinilestradiol and 100 &#61549;g of levonorgestrel (group 1) and the other with 30 &#61549;g of etinilestradiol and 150 &#61549;g of levonorgestrel(group 2). Methods: This is an open label, prospective and randomized clinical trial. It was calculated that 11 patients in each group were necessary to detect a difference of 1,5 points on the pain scale. After randomization, each group was evaluated at the beginning and at 6 months of treatment. The visual analogue scale was used to assess dysmenorrhea, dyspareunia and non-menstrual pain. To asses quality of life the Short-form 36 questionnaire was used and the beck inventory was used to measure depression. Adverse events and bleeding episodes were also recorded. On group 1 a total of eight patients completed the study and on group 2 there were ten patients. There was no statistical difference between the two groups after six months of treatment on all outcomes evaluated. Combining the two groups, there was a significative reduction of dysmenorrhea (p<0,0001), dyspareunia (p<0,04) and non-menstrual pain (p<0,006) with the oral contraceptives and there were no major adverse events. It was also observed an important improvement on all short-form 36 domains and reduction on 8 out of 12 Becks questionnaires. Conclusion: Continuous oral contraceptive use is very effective on the management of moderate to severe dysmenorrhea. This effect could also be seen on quality of life improvement after the treatment. Because of the low cost and few side effects of the medication, oral contraceptives should be used as first line treatment.

L’hypothèse de l’hormono-dépendance du mélanome cutané est en débat dans la littérature depuis de nombreuses années. Dans ce contexte, il est essentiel de mieux connaître l’influence potentielle de la prise de traitements hormonaux sur le risque de ce cancer.L’objectif de ce projet de thèse était d’étudier l’influence de la prise de traitements hormonaux (contraceptifs oraux, traitements de l’infertilité, progestatifs pris seuls avant la ménopause et traitements hormonaux de la ménopause) sur le risque de mélanome cutané chez les femmes.Le projet a été conduit principalement à partir de la cohorte prospective E3N (Étude épidémiologique auprès de femmes de l’Éducation nationale) portant sur environ100 000 femmes âgées de 40 à 65 ans à l’inclusion en 1990. L’étude E3N inclut des données détaillées sur le profil pigmentaire, l’exposition solaire et la prise de traitements hormonaux des participantes, ainsi que sur la survenue éventuelle de mélanome cutané, dont les cas ont été confirmés par histologie (761 cas confirmés entre 1990 et 2011). Des données complémentaires sur l’exposition solaire, disponibles pour une fraction de la cohorte E3N, ont également été utilisées. Ces données détaillées sont issues de l’enquête cas-témoin nichée E3N-SunExp menée en 2008. Les analyses ont ensuite été étendues au consortium de cohortes européennes prospectives EPIC (European Prospective Investigation into Cancer and Nutrition), sur près de 334 500 femmes parmi lesquelles 1 734 cas de mélanomes incidents ont été diagnostiqués.Les résultats mettent en évidence des associations modestes entre la prise de traitements hormonaux et le risque de mélanome et ne soutiennent pas l’hypothèse de l’hormono-dépendance de ce cancer. Cependant, ils suggèrent un comportement d’exposition intentionnelle aux UV chez leurs utilisatrices, ce qui ouvre une nouvelle perspective pour les recherches futures dans ce domaine. / The hypothesis of a hormonal dependence of cutaneous melanoma has been debated in the literature over past decades. Within this context, it is critical to increase our knowledge on the influence of exogenous hormone use on the risk of this cancer.The aim of this project was to explore the influence of hormonal treatments (oral contraceptives, fertility drugs, premenopausal use of progestogens, and menopause hormone therapy) on the risk of cutaneous melanoma in women.The project was mainly based on the large E3N (Étude épidémiologique auprès de femmes de l’Éducation Nationale) prospective cohort, which included about 100,000 women aged 40-65 years at inclusion in 1990. The cohort collected data on pigmentary phenotype, sun exposure, hormonal treatment use, and medical data including cutaneous melanomas, which were ascertained through pathology reports (761 incident cases between 1990 and 2011). Additional information on sun exposure, available for a portion of the E3N cohort, was used. These detailed data were collected as part of the E3N-SunExp case-control study launched in 2008.Analyses were extended to the EPIC consortium (European Prospective Investigation into Cancer and Nutrition), which includes about 334 500 women and 1,734 incident melanoma cases.The results arising from this project show modest associations between exogenous hormone use and melanoma risk and suggest no strong direct influence of hormones on melanoma development. However, results suggest intentional UV exposure behaviors in exogenous hormone users, which opens new perspectives for future investigations in this field.

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