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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Although women constitute more than half of the estimated 34-40 million people living with HIV/AIDS worldwide, little is known about the early events of HIV-1 infection in the female genital tract (FGT). Genital epithelial cells (GECs) line the FGT and act as intrinsic barriers providing mechanical protection against foreign microbes. GECs are also sentient and are capable of sensing and immunologically responding to various types of pathogens including sexually transmitted infections (STIs). These responses play a central role in preventing disease and also help mobilize both innate and adaptive immune cells against invading threats. While it is well understood that GECs exert important physical and immunological protective roles in the FGT, little is known regarding the role of GECs and GEC inflammatory responses in HIV infection. It is estimated that 40% of all new HIV infections are established each year in the FGT. Our understanding of the early events following HIV transmission in the FGT remains particularly elusive in the context of endogenous or exogenous factors found in the genital microenvironment that may influence susceptibility to HIV-1. Inflammation is known to play a critical role in increasing HIV susceptibility, replication as well as initiating and maintaining chronic immune activation, a hallmark of disease progression. Among the key factors in the FGT that are known to or that could influence inflammation are sexually transmitted co-infections and female sex hormones. The work summarized in this thesis examines how GEC innate immune responses to co-infecting microbes or female sex hormones impact HIV infection and replication in the FGT. Our results show that GEC innate immune response against herpes simplex virus type 2 (HSV-2), a common HIV co-infecting agent, consists of elevated proinflammatory cytokines and chemokines in addition to biologically active interferon-β. Furthermore, our results show that these responses require potent viral HSV-2 replication and that proinflammatory cytokine and chemokine responses are enhanced in the absence of the HSV-2 virus host shutoff protein. Based on this work, we decided to investigate whether GEC inflammatory responses to common STIs played a role in regulating HIV replication in T-cells. We found that HIV co-infecting microbes, specifically HSV-1, HSV-2 and Neisseria gonorrhoeae, directly induced HIV replication in T-cells, and caused primary GECs to upregulate inflammatory responses that indirectly increased HIV replication in T-cells. Next we examined a translational aspect of the aforementioned studies by examining whether blocking inflammatory pathways, using the broad anti-inflammatory compound curcumin, could provide prophylactic or therapeutic protection against HIV. We found that curcumin pre-treatment a) protected the genital epithelial barrier against HIV-1-mediated disruption and inflammation, b) prevented the gp120-mediated upregulation of chemokines by GECs that recruit HIV target cells to the FGT, c) blocked GEC innate inflammatory responses to co-infecting microbes and indirect activation of the HIV promoter in T-cells, d) decreased HIV amplification in chronically infected T-cells and e) blocked HSV-2 viral replication in GECs by a mechanism that likely involves NFκB. Lastly, it has long been speculated that female sex hormones can regulate inflammatory responses, and numerous lines of evidence suggest that they may also regulate susceptibility to HIV-1. Thus, we investigated how female sex hormones and the hormonal contraceptive medroxyprogesterone acetate (MPA), used by more than 100 million women worldwide, regulated HIV infection and replication in GECs and whether inflammation played an important role in this regulation. Our results showed that progesterone and in particular MPA increased uptake of HIV-1 and transcytosis, but not replication, across GECs – in the absence of a proinflammatory milieu - and that this enhanced transcytosis resulted in increased infection of HIV target cells. These results demonstrate that sex hormones and co-infection both play an important role in regulating HIV-1 infection and replication in the FGT. Furthermore, our results suggest that anti-inflammatory compounds such as curcumin may offer paradigm shifting prophylactic or therapeutic strategies against HIV-1 infection and future research should investigate its potential benefit in vivo. / Thesis / Doctor of Philosophy (Medical Science)

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Sex-differences in cardiometabolic physiology are evident; however, the inclusion of female participants in research studies for the purposes of exploration of sex-specific physiological responses is limited by the perceived complexity due to hormonal cycles. This dissertation examined the prevalence of sex-specific inclusion in human vascular exercise physiology research, investigate the influence of endogenous and exogenous sex hormones on cardiovascular, respiratory, and skeletal muscle metabolism, and consider sex- and gender-differences in peripheral vascular outcomes. The first study confirmed a sex-specific bias towards male inclusion in vascular exercise physiology research, with perceived hormonal complexity noted as one rationale for sex-specific exclusion. To address this perception, we reviewed the literature and identified a small effect of the menstrual cycle, and a more robust influence of oral contraceptive pills, on macrovascular endothelial function, with no influence on smooth muscle function or arterial stiffness. Our next set of studies objectively evaluated the influence of the natural menstrual and two generations of oral contraceptive pills on a comprehensive suite of cardiovascular, respiratory, and metabolic outcomes, and found largely no influence on these outcomes or the underlying vascular cellular regulation, apart from a small effect elevated endogenous and exogenous sex hormones on brachial artery endothelial function. Another area identified in our initial sex-inclusion review was the absence of gender-based research in vascular exercise physiology. Our final study found that biological sex aligned with gender identity, but not gender expression and influenced cardiovascular markers by including elevating systolic blood pressure, central arterial stiffness and endothelial function in males and men compared to females and women. Altogether, this dissertation provides substantial evidence for the lack of hormonal cycle influence of endogenous and exogenous sex hormones on three organ systems, which will open further incorporating females into research study design. / Dissertation / Doctor of Philosophy (PhD) / Females have been historically understudied in basic science and clinical research. This dissertation set out to explore sex-specific prevalence of research participants in human vascular exercise physiology studies and examined how sex hormones (through the menstrual cycle and oral contraceptive pill use) impact the cardiovascular, respiratory, and skeletal muscle metabolism systems. We found that there is an evident male-bias in vascular exercise physiology research, due in part to the perceived complexity of how sex hormones may impact the cardiovascular system. We also found that the menstrual cycle and oral contraceptive pill cycle have minimal influence on the biological systems examined. While there are evident sex-differences in cardiovascular outcomes, gender expression does not appear to have an impact in young adults. This research is foundational to further the inclusion of female participants in human physiology research and encourage future considerations of how sex/gender may influence physiological outcomes.

Background: HSV-2 was estimated to infect 491 million people worldwide, with women disproportionately affected by HSV-2. Understanding factors that influence susceptibility to HSV-2 in women is important in preventing infections. Through various studies, the progestin-based contraceptive DMPA exhibited immunosuppressive effects, and has shown increased susceptibility to HIV and HSV-2. Studies comparing DMPA to other contraceptives like NET suggest that NET may be safer. In vivo NET effects have not been characterized thoroughly to better understand the effect of NET on susceptibility to HSV-2. Therefore, this study aimed to compare the effects of NET and DMPA in mouse models that affect susceptibility to HSV-2. We hypothesized that NET treated mice will have decreased susceptibility to HSV-2 compared to DMPA but elevated compared to normal mice. Method of study: Ovariectomized mice were treated with DMPA (2mg) and NET (2 mg injections, 2.5 mg pellets or 5 mg pellets) for 10 days and intravaginally immunized with HSV-2 TK-, then intravaginally challenged with WT HSV-2 ~4-7 weeks later. Primary intravaginal WT HSV-2 challenges were conducted in ovariectomized and normal mice after 10 days of DMPA and NET treatment. Viral titers, pathology and survival were examined. Mucus production in the vagina was investigated through immunohistology. Effects of hormones on immune cells were explored in the lymph nodes, spleens, and vaginal tracts through flow cytometry. Results: Increased mucus was consistently observed in the vaginal tracts of mice after treatment with NET 2.5 mg and 5 mg treated mice, but not with DMPA Therefore, NET treated mice displayed reduced viral shedding and delayed pathology compared to DMPA treated mice. No significant changes occurred in immune cells analyzed post DMPA and NET treatment, although there were trends of increased T cells in progestin treated mice. However, more experiments need to be conducted to confirm observed trends. Conclusion: NET treatment in mice results in mucus production in the vaginal tract, a potential mechanism impeding intravaginal HSV-2 infection and could be applied to other STIs. This provides insight into protective effects of NET compared to DMPA allowing women to make informed decisions regarding hormonal contraceptives. / Thesis / Master of Science in Medical Sciences (MSMS)

Past research has shown that mortality salience increases desire for offspring. Additionally, past studies have illustrated that women in a high fertility phase within a menstrual cycle show greater preference for masculine faces while performing facial judgment tasks than do women in a low fertility phase or women using hormonal contraception. However, mortality salience has been shown to influence mate selection. The current study explored whether or not a cue related to fertility salience may produce similar outcomes to cues of mortality salience observed in past studies. In partial replication of a study conducted by Vaughn, Bradley, Byrd-Craven, and Kennison (2010), the current study included 151 heterosexual female participants who self-identified as falling within cyclical high fertility or low fertility categories, or who reported using hormonal contraception. These participants were randomly assigned to either a control condition, a mortality salience condition, or a fertility salience condition and then instructed to judge images of male faces provided by Re, DeBruine, Jones, and Perrett (2013). Participants rated faces in categories of attractiveness, dominance, and health. The study predicted significant interaction effects of salience condition and fertility status on opposite sex facial perceptions. Additionally, participants were asked about procreation preferences. No effects of mortality salience or fertility salience were observed in regard to opposite sex facial perceptions, number of children desired, or preferred age for having a first child. Thus, the current research does not provide support that the fertility salience cue used in the study influences opposite sex perceptions or procreation preferences. / Master of Arts

Neste trabalho foram estudados os perfis renal, hepático, energético, hormonal e de proteínas de fase aguda (proteinograma) para avaliar possíveis interações com o desempenho reprodutivo em bovinos. Para isso, foram delineados três experimentos. No experimento 1 o objetivo foi verificar se a inseminação artificial (IA) causa alterações nos perfis renal, hepático, energético, hormonal e de proteínas de fase aguda e estudar as relações entre esses perfis e a hemodinâmica uterina. Foram utilizadas amostras de sangue de vacas Nelore que foram inseminadas (GIA, n=9) ou não (GC, n=9). As amostras foram coletadas 30 horas antes da IA, 4, 24, 48 e 168 horas após a IA. No experimento 2 o objetivo foi estudar os efeitos da qualidade do sêmen sobre o perfil hepático e proteinograma, e estudar a relação dos perfis renal, hepático, energético, hormonal e proteinograma sobre a vascularização uterina. Foram utilizadas amostras sanguíneas de 362 vacas, que foram divididas em três grupos experimentais de acordo com a qualidade do sêmen: Boa (n=121), Média (n=121) e Regular (n=120). As amostras foram coletadas 30 horas antes da IA, 4 e 24 horas após a IA. Por fim, o experimento 3 é um estudo retrospectivo, realizado com o objetivo de comparar os perfis renal, hepático, energético, hormonal, e proteínas de fase aguda entre animais prenhes e vazios após a IA, e verificar se há relação entre a hemodinâmica uterina e a fertilidade. Neste experimento, os animais foram divididos em dois grupos experimentais de acordo com o resultado da IA (prenhe, n=76 X vazia, n=45). Em todos os experimentos, nos mesmos momentos da coleta de sangue, foram realizadas avaliações ultrassonográficas do útero no modo color Doppler e espectral. As amostras dos experimentos 1, 2 e 3 foram submetidas à quantificação das proteínas de fase aguda e dos componentes metabólicos utilizando analisador bioquímico automático (RX Daytona) e à dosagem hormonal, pela técnica de radioimunoensaio. Os dados foram analisados pelo PROC MIXED (SAS, versão 9.2, 2010). Foram consideradas diferenças estatísticas quando P<0,05. No experimento 1, os grupos não diferiram quanto aos perfis renal, hepático, energético, hormonal e proteinograma, no entanto, o RI apresentou correlações positivas com AST e BHB e correlação negativa com estradiol. O estradiol também foi correlacionado com EV, entretanto essa correlação foi positiva. No experimento 2, os animais inseminados com sêmen B, M ou R apresentaram concentrações semelhantes das variáveis do perfil hepático e proteínograma. O RI foi correlacionado positivamente com colesterol, HDL, LDL, e progesterona, e negativamente com glicose, estradiol, albumina e proteína total. Já o EV apresentou correlações negativas com ureia, GGT e cortisol. No experimento 3, os grupos Vazio e Prenhe foram semelhantes quanto aos perfis renal, hepático, energético, hormonal, proteiograma e hemodinâmica uterina. Sendo assim, conclui-se que o processo da IA e a qualidade do sêmen utilizado não causam alterações sistêmicas, bem como a fertilidade não pode ser explicada por estas alterações. Adicionalmente, a hemodinâmica uterina é correlacionada com diversos parâmetros, no entanto, o padrão vascular do útero não mostrou relação com a fertilidade / In this study, were evaluated kidney, liver, energy, hormonal and acute phase proteins profiles to evaluate the possible interactions with the reproductive performance in cattle. For this, three experiments were designed. In experiment 1 the objective was to verify if artificial insemination (AI) causes changes in renal, liver, energetic, hormonal and acute phase proteins profiles and to study the relationship between these profiles and uterine hemodynamics. Blood samples from inseminated (GIA, n = 9) or non inseminated Nellore cows (CG, n = 9) were used. Samples were collected 30 hours before AI, 4, 24, 48 and 168 hours after AI. In experiment 2 the objective was to study the effects of semen quality on liver and protein profiles and study the relationship of renal, liver, energetic, hormonal and protein profiles on uterine vascularization. Blood samples of 362 cows were used, which were divided into three groups according to semen quality: Good (n = 121), medium (n = 121) and Regular (n = 1200. Samples were collected 30 hours before AI, 4 and 24 hours after AI. Finally, experiment 3 is a retrospective study, carried out in order to compare the renal, liver, energetic, hormonal, and acute phase proteins profiles between pregnant and non pregnant animals after AI, and check for relationship between uterine hemodynamics and fertility. In this experiment, animals were divided into two groups according to the result of AI (pregnant, n = 76 and non pregnant, n = 45). In all experiments, at the same time of blood sampling were performed sonographic evaluations of the uterus in color Doppler and spectral mode. The samples of experiments 1, 2 and 3 were subjected to quantification of acute phase proteins and metabolic components using automatic biochemical analyzer (RX Daytona) and to hormone dosage, by radioimmunoassay. Data were analyzed using PROC MIXED (SAS, version 9.2, 2010). Statistics differences were considered when P<0,05. In experiment 1, the groups did not differ about kidney, liver, energetic, hormonal and protein profiles, however, the RI showed positive correlations with AST and BHB and negative correlation with estradiol. Estradiol was also correlated with EV, however this correlation was positive. In experiment 2, the animals inseminated with semen B, M or R showed similar concentrations of the variables of liver and proteinogram profiles. The RI was positively correlated with cholesterol, HDL, LDL, and progesterone, and negatively with glucose, estradiol, albumin and total protein. EV showed negative correlations with urea, GGT and cortisol. In Experiment 3, the non pregnant and pregnant groups were similar about kidney, liver, energetic, hormonal, proteiogram profiles and uterine hemodynamics. Thus, in this study were not observed systemic changes caused by AI process and by quality of semen, and systemic differences did not notice is between non pregnant and pregnant animals. Additionally, uterine hemodynamic is correlated with various parameters, however, the vascular pattern of the uterus was not correlated with fertility

Introdução: A prescrição da pílula anticoncepcional passa a ser realizada no Brasil a partir de 1962. Sua prática trouxe transformações políticas e sociais ao país: a pílula passa a ter grande aceitabilidade das mulheres e permanece como o método anticoncepcional mais utilizado por elas até a atualidade. Seu uso influenciou na queda da taxa de fecundidade e compõe, atrelada a uma série de outros fatores, um conjunto de transformações que modifica a formulação de políticas públicas referentes à saúde reprodutiva e à saúde sexual feminina. Objetivo: Compreender como a prescrição da pílula anticoncepcional por médicos ginecologistas era realizada no Brasil na época em que começa a ser utilizada no país. Metodologia: Trata-se de uma pesquisa qualitativa, tendo como material empírico as narrativas de seis médicos ginecologistas que atuaram na década de 1960, no estado de São Paulo. Resultados e Discussão: A partir das entrevistas, foram identificados quatro eixos temáticos de análise, que contemplaram a descrição Introdução: A prescrição da pílula anticoncepcional passa a ser realizada no Brasil a partir de 1962. Sua prática trouxe transformações políticas e sociais ao país: a pílula passa a ter grande aceitabilidade das mulheres e permanece como o método anticoncepcional mais utilizado por elas até a atualidade. Seu uso influenciou na queda da taxa de fecundidade e compõe, atrelada a uma série de outros fatores, um conjunto de transformações que modifica a formulação de políticas públicas referentes à saúde reprodutiva e à saúde sexual feminina. Objetivo: Compreender como a prescrição da pílula anticoncepcional por médicos ginecologistas era realizada no Brasil na época em que começa a ser utilizada no país. Metodologia: Trata-se de uma pesquisa qualitativa, tendo como material empírico as narrativas de seis médicos ginecologistas que atuaram na década de 1960, no estado de São Paulo. Resultados e Discussão: A partir das entrevistas, foram identificados quatro eixos temáticos de análise, que contemplaram a descrição sobre o primeiro contato dos médicos com a pílula, seguido das diferentes formas de utilização da pílula anticoncepcional como uma nova tecnologia. Também foi identificada a relação entre a prescrição médica e a indústria farmacêutica, assim como o uso da pílula anticoncepcional e a construção do discurso médico sobre o corpo feminino. Esses achados foram analisados à luz dos estudos sobre medicalização do corpo feminino, e como a sua prescrição foi sendo incluída na clínica médica a partir da década de 1960. Considerações Finais: O uso da pílula anticoncepcional apresentou-se como uma nova tecnologia de controle da reprodução e dos corpos femininos. Compreender a história da prescrição da pílula é levar em consideração os múltiplos agentes, interesses e práticas que ainda se inscrevem sobre os corpos das mulheres / Introduction: The prescription of the contraceptive pill began in Brazil in 1962. This practice brought political and social changes to the country: the pill becomes highly accepting of women and remains the contraceptive method most used by them until nowadays. The pill use has influenced the fall in fertility rate and, based on a series of other factors, is a set of transformations that modifies the formulation of public policies regarding reproductive health and female sexual health. Goal: To understand how the prescription of the contraceptive pill happened in Brazil, carried by gynecologists at the time when it begins to be used in the country. Methodology: This is a qualitative research, having as empirical material the narratives of six gynecologists who worked in the 1960s, at São Paulo state. Results and Discussion: From the interviews, four thematic axes of analysis were identified, which included the description of the first contact of the doctors with the pill, followed by different ways of using the contraceptive pill as a new technology. Also, were identified the relationship between medical prescription and the pharmaceutical industry, as well as the use of the contraceptive pill and the construction of the medical discourse about the female body. These findings were analyzed in light of the studies on medicalization of the female body, and how the contraceptive pill prescription was included in the medical clinic from the 1960s. Final Considerations: The use of the contraceptive pill was presented as a new technology for the control of Reproduction and of female bodies. Understanding the history of pill prescription is to take into account the multiple agents, interests, and practices that are still inscribed on women\'s bodies