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Acute aerobic exercise alters neurotrophic and growth factor concentrations, increases neural activity and improves cognitive and motor function. Additionally, acute exercise increases excitation and reduces inhibition in the motor cortex as assessed via transcranial magnetic stimulation (TMS). The propensity for exercise-induced neuroplasticity may be greater in females, as females show greater neuroplasticity induction following non-invasive brain stimulation (NIBS) compared to males. In females, NIBS yields greater neuroplasticity during ovulation, when estradiol levels are higher, compared to menstruation, suggesting that ovarian hormones may also impact exercise-induced neuroplasticity. To date, it is unknown whether biological sex and ovarian hormones impact neuroplasticity induced by acute aerobic exercise. The present thesis investigated the effects of biological sex and ovarian hormones on the magnitude and direction of neuroplasticity induced by acute aerobic exercise. Fourteen females and fourteen age- and fitness-matched males participated in two sessions in which dependent measures were acquired before and following a single bout of aerobic exercise. Females were tested in the follicular (~day 7) and luteal (~day 21) phases of the menstrual cycle and males were also tested on two occasions separated by ~14 days. The exercise intervention consisted of 5 minutes of warm up, 20 minutes of moderate intensity continuous cycling at 65-70% maximal heart rate, and 5 minutes cool down. TMS was used to obtain motor evoked potential (MEP) recruitment curves and short interval intracortical inhibition (SICI) from the right first dorsal interosseous muscle. Blood measures of estradiol, progesterone, testosterone, and brain-derived neurotrophic factor were assessed before exercise on both testing sessions. Results indicated that only females showed increases in MEP recruitment curve following exercise, and this occurred regardless of menstrual cycle phase. SICI did not change following exercise for males or females on either testing session. The estrogen to progesterone ratio in females was greater in the follicular phase compared to the luteal phase. There was a trend towards greater serum BDNF levels in females in the luteal phase compared to the follicular phase. Sex hormones and BDNF levels did not vary across sessions in males. These findings indicate biological sex, but not ovarian hormones, is an important factor to consider when inducing neuroplasticity using acute exercise. / Thesis / Master of Science (MSc)

Increased HIV susceptibility has been associated with the progesterone-dominant luteal phase of the menstrual cycle and the use of progesterone-only contraceptives, yet the mechanism is poorly understood. Here, we performed mass spectrometry-based analyses of cervicovaginal fluids collected from women with differing ovarian hormone levels as demonstrated by menstrual cycle phase or exogenous progesterone-only contraceptive use. We found that proteins associated with maintaining the integrity of epithelial barrier were enriched during times of high estradiol, whereas during times of high progesterone, there was a loss of barrier integrity proteins and an enrichment of proteins with known roles in inflammatory processes including leukocyte infiltration. Progesterone-based proteomic profiles were also strongly associated with neutrophil signatures with some evidence of CD4+ T cell signatures. This study generates new hypotheses about the potential mechanisms of hormone-associated HIV susceptibility including a weakened epithelial barrier and increased HIV target cell recruitment during times of increased progesterone. / February 2016

Student Number : 9404757K - PhD thesis - School of Physiology - Faculty of Science / Natural secretions of oestrogen and progesterone vary according to menstrual phase in eumenorrhoeic women and have an affect on physiological systems that could consequentially influence exercise performance. In a series of menstrual phase comparative investigations (considering mainly the early follicular (EF), late follicular (LF) and mid-luteal (ML) phase), I aimed to elucidate the physiological relation of oestrogen and progesterone to fat metabolism and ventilation during endurance exercise and exercise performance. I measured plasma free fatty acid (FFA) kinetics during prolonged exercise from an intravenous infusion of K+[1-13C]palmitate in eumenorrhoeic women and found the change in palmitate rate of appearance and disappearance between menstrual phases to be related to the oestrogen/progesterone (E/P) ratio. Overall the results from this study suggest that oestrogen promotes increases in FFA availability during exercise, while progesterone mitigates this response. Therefore, a high oestrogen concentration and E/P ratio in the ML phase is required in order to produce a favourable FFA metabolic response for endurance events. In order to estimate plasma FFA oxidation rate using carbon-FFA tracers, the acetate correction factor which accounts for carbon-label retention in secondary metabolic pools, must be applied. When I derived the acetate correction factor by measuring fractional recovery of carbon-13 in expired CO2 from a constant infusion of Na+[1- 13C]acetate during submaximal exercise we found the acetate correction factor to be significantly lower in the ML than EF phase (average change from EF phase -1.8± 0.5%, p<0.05). Failure to account for the lower correction factor in the ML phase will result in a 6% underestimation of plasma FFA oxidation rate. Furthermore, since human serum albumin (HSA) routinely used as a carrier for parenteral delivery of FFA tracers has various disadvantages, I tested the feasibility of using 2-hydroxypropyl-b- cyclodextrin (HP-b-CD) as a possible alternative carrier. A comparison of expired CO2 enrichment following HSA-FFA (7.4±2.0 %o) and HP-b-CD-FFA (8.6±2.1%o) infusion during exercise showed that the HP-b-CD does not compromise natural in vivo behaviour of the FFA tracer (p=0.4). Progesterone-induced hyperventilation is occasionally reported during exercise in the luteal phase. I found that the change in ventilatory parameters (minute ventilation and respiratory rate) during exercise from EF to ML phase is related to both the oestrogen and progesterone concentration in the ML phase. However, the associated increase in respiratory rate throughout prolonged exercise in the ML versus EF phase did not increase metabolic demand and therefore could not be expected to exacerbate fatigue. When exercise performance was evaluated by means of a cycling time trial, I found a trend for best performance in the LF phase versus the EF phase (8 of 11 subjects improved by 5.2±2.9%, p=0.027), while no differences occurred between other menstrual phases. Metabolic and performance benefits of oestrogen may be concealed in the ML phase by the coincident increase in progesterone in this phase and thus a significant effect is often only evident with a high E/P ratio in the ML phase. The transient LF phase, characterised by the pre-ovulatory surge in oestrogen, reveals the maximum benefits of oestrogen on metabolism and performance during submaximal exercise.

Due to their phylogenetic position as an outgroup to humans and the other African apes, empirical data from orangutans are an especially valuable comparative tool with which questions about the evolution of human life history and reproductive characteristics can be addressed. Yet few such data are available. In this dissertation, I use endocrinological and behavioral data from 7 female and 3 male orangutans housed at the Woodland Park Zoo in Washington and the Great Ape Trust in Iowa to characterize the ovarian function and reproductive behaviors of captive female orangutans at different points in the life cycle. Ovarian hormone measurements were achieved through the use of non-invasive urine sampling, and assays reveal both intra- and inter-individual variation in hormone production. Results indicate that (1) adolescent females in captivity do not experience a marked period of subfecund estrogen and progesterone levels in association with reproductive maturation, (2) individual females exhibit both "high quality" and "low quality" cycles, including instances of anovulation, in the absence of fluctuating dietary and environmental conditions, (3) mating behaviors vary between individuals and with cycle phase, but are not strongly influenced by absolute ovarian hormone concentrations, and (4) reproductive senescence does not significantly impact the ovarian function and mating behaviors of aging female orangutans. These results demonstrate that many aspects of human reproductive biology and behavior, such as an extended period of mating receptivity, are evolutionarily conserved. They suggest, however, that the decline in human ovarian function in mid-life may be derived and of possible adaptive significance. The potential significance of differences between captive and wild ape populations, and the character, history, and familial relationships of the particular individuals discussed are considered in the interpretation of all data.

A visibilidade da etapa fértil na mulher é uma questão polêmica e tem sido muito discutida nas últimas décadas. Alguns autores argumentam que no transcorrer da evolução a ovulação ficou oculta. Em paralelo, outros pesquisadores afirmam que a ovulação na mulher não se manifesta de forma tão visível como em alguns primatas que apresentam sinais muito notórios da ovulação, por exemplo, a tumefação vaginal. Mas diversas pesquisas têm fornecido evidência que mostram que o período fértil na mulher é perceptível de maneira sutil, sem que se tenha consciência do processo perceptual envolvido. Os achados destas pesquisas apontam para o fato de diversas características (como a face, a proporção cintura quadril, a simetria de tecidos brandos pareados e o cheiro) serem percebidas como mais atraentes na etapa fértil. O presente estudo teve por objetivo investigar se em alguma etapa (folicular tardia ou lútea) do ciclo menstrual a face da mulher se torna mais atraente para o sexo oposto devido a mudanças morfológicas induzidas pelos níveis hormonais. Foram apresentados, apenas para participantes masculinos, 36 slides com fotografias de faces frontais de mulheres em idade reprodutiva. Em cada slide foram mostradas simultaneamente duas fotos da mesma mulher, uma das fotos obtida na Fase Folicular Tardia (FFT) do ciclo e a outra obtida na Fase Lútea (FL). Os participantes escolheram a face mais atraente e posteriormente avaliaram o grau de atratividade mediante uma escala analógica visual (VAS), cujo extremo esquerdo e direito da escala foram rotulados respectivamente por: nem um pouco atraente e muito atraente. Os resultados mostraram que a atratividade facial feminina muda em função da etapa do ciclo menstrual. As faces das mulheres que não tomavam anticoncepcionais foram julgadas como mais atraentes na etapa fértil do que na etapa infértil do ciclo. E o julgamento de atratividade feito para as faces das mulheres que tomavam anticoncepcionais não diferiram significativamente entre a FFT e a FL. Os resultados obtidos nesta pesquisa e nos estudos realizados previamente proporcionam evidências que demonstram que o período fértil nos humanos não está oculto, pois ocorrem mudanças na face que são detectáveis, mesmo quando o processo de percepção não é ciente. / Visibility of fertile period in women is a controversial topic that has been broadly discussed during the last decades. Some authors argue that ovulation became hidden in the course of evolution. In contrast, some other researchers state that ovulation in woman is not manifested as visibly as in other primates, which present very evident signals of ovulation like, e.g., vaginal tumefaction. However, several studies have provided evidence showing that fertile period in women is perceptible in a subtle way, without being aware of the perceptual process involved. Findings of those works points to the fact that some characteristics such as face, waist hip ratio, paired soft tissues symmetry and smell are perceived as more attractive in the fertile stage. The present work aimed to find out whether in any stage (late follicular or luteal) of menstrual cycle woman face appears more attractive to opposite sex, due to morphological changes induced by hormonal levels. 36 slides with frontal face photographs of woman in reproductive age were shown to male participants. In each slide two pictures of the same woman, one obtained in the late follicular phase and the other obtained in the luteal phase were exposed. Participants chose the more attractive picture and then they assessed the attractiveness through a visual analogical scale (VAS), in whose left and right extremes the legends not attractive at all and very attractive were marked, respectively. Results showed that female facial attractiveness changes as a function of the menstrual cycle stage. Faces of women who did not take contraceptives did not differ significantly between FFT and FL. The results obtained in this research and previous studies provide evidence to demonstrate that the fertile period in humans is not hidden, because on the face occur changes that are detectable even when the process of perception is not aware of.

A visibilidade da etapa fértil na mulher é uma questão polêmica e tem sido muito discutida nas últimas décadas. Alguns autores argumentam que no transcorrer da evolução a ovulação ficou oculta. Em paralelo, outros pesquisadores afirmam que a ovulação na mulher não se manifesta de forma tão visível como em alguns primatas que apresentam sinais muito notórios da ovulação, por exemplo, a tumefação vaginal. Mas diversas pesquisas têm fornecido evidência que mostram que o período fértil na mulher é perceptível de maneira sutil, sem que se tenha consciência do processo perceptual envolvido. Os achados destas pesquisas apontam para o fato de diversas características (como a face, a proporção cintura quadril, a simetria de tecidos brandos pareados e o cheiro) serem percebidas como mais atraentes na etapa fértil. O presente estudo teve por objetivo investigar se em alguma etapa (folicular tardia ou lútea) do ciclo menstrual a face da mulher se torna mais atraente para o sexo oposto devido a mudanças morfológicas induzidas pelos níveis hormonais. Foram apresentados, apenas para participantes masculinos, 36 slides com fotografias de faces frontais de mulheres em idade reprodutiva. Em cada slide foram mostradas simultaneamente duas fotos da mesma mulher, uma das fotos obtida na Fase Folicular Tardia (FFT) do ciclo e a outra obtida na Fase Lútea (FL). Os participantes escolheram a face mais atraente e posteriormente avaliaram o grau de atratividade mediante uma escala analógica visual (VAS), cujo extremo esquerdo e direito da escala foram rotulados respectivamente por: nem um pouco atraente e muito atraente. Os resultados mostraram que a atratividade facial feminina muda em função da etapa do ciclo menstrual. As faces das mulheres que não tomavam anticoncepcionais foram julgadas como mais atraentes na etapa fértil do que na etapa infértil do ciclo. E o julgamento de atratividade feito para as faces das mulheres que tomavam anticoncepcionais não diferiram significativamente entre a FFT e a FL. Os resultados obtidos nesta pesquisa e nos estudos realizados previamente proporcionam evidências que demonstram que o período fértil nos humanos não está oculto, pois ocorrem mudanças na face que são detectáveis, mesmo quando o processo de percepção não é ciente. / Visibility of fertile period in women is a controversial topic that has been broadly discussed during the last decades. Some authors argue that ovulation became hidden in the course of evolution. In contrast, some other researchers state that ovulation in woman is not manifested as visibly as in other primates, which present very evident signals of ovulation like, e.g., vaginal tumefaction. However, several studies have provided evidence showing that fertile period in women is perceptible in a subtle way, without being aware of the perceptual process involved. Findings of those works points to the fact that some characteristics such as face, waist hip ratio, paired soft tissues symmetry and smell are perceived as more attractive in the fertile stage. The present work aimed to find out whether in any stage (late follicular or luteal) of menstrual cycle woman face appears more attractive to opposite sex, due to morphological changes induced by hormonal levels. 36 slides with frontal face photographs of woman in reproductive age were shown to male participants. In each slide two pictures of the same woman, one obtained in the late follicular phase and the other obtained in the luteal phase were exposed. Participants chose the more attractive picture and then they assessed the attractiveness through a visual analogical scale (VAS), in whose left and right extremes the legends not attractive at all and very attractive were marked, respectively. Results showed that female facial attractiveness changes as a function of the menstrual cycle stage. Faces of women who did not take contraceptives did not differ significantly between FFT and FL. The results obtained in this research and previous studies provide evidence to demonstrate that the fertile period in humans is not hidden, because on the face occur changes that are detectable even when the process of perception is not aware of.

Submitted by Irene Nascimento (irene.kessia@ufpe.br) on 2016-07-29T17:41:36Z No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de doutorado Noranege.pdf: 2102537 bytes, checksum: 369a984689437961ceddacbe025eaf15 (MD5) / Made available in DSpace on 2016-07-29T17:41:36Z (GMT). No. of bitstreams: 2 license_rdf: 1232 bytes, checksum: 66e71c371cc565284e70f40736c94386 (MD5) Tese de doutorado Noranege.pdf: 2102537 bytes, checksum: 369a984689437961ceddacbe025eaf15 (MD5) Previous issue date: 2016-02-25 / Facepe / Há evidências clínicas e experimentais de que os hormônios ovarianos exercem profundas e duradouras ações sobre o cérebro, tanto durante o seu desenvolvimento, quanto após essa fase (cérebro adulto). Algumas dessas ações repercutem de forma importante sobre a excitabilidade cerebral. Em trabalho anterior, filhotes de ratas Wistar aos 7 dias pós-natais foram submetidas à ovariectomia bilateral (grupo ovx) ou pseudo-cirurgia de ovariectomia (grupo sham) ou nenhuma cirurgia (grupo ingênuo). Quando os filhotes alcançaram a idade adulta (90-120 dias) o grupo ovx e os dois grupos controles (sham e ingênuo-na fase proestro) foram submetidos ao registro da Depressão Alastrante Cortical (DAC), fenômeno que é influenciado pela excitabilidade do cérebro. No grupo ovx, a DAC se propagou com velocidades significativamente menores em comparação aos dois grupos controle. Neste trabalho continuou-se essa linha de investigação. Inicialmente, demonstrou-se que a ovariectomia na vida adulta não se acompanha dos efeitos, observados em ratas com ovariectomia precoce. Esses dados, juntados àqueles obtidos durante o mestrado, originaram um artigo publicado na revista “International Journal of Developmental Neuroscience”. Em seguida, estudou-se os efeitos, sobre a DAC, da interação entre a administração de hormônios ovarianos e condições desfavoráveis de lactação (amamentação em ninhadas de grande tamanho). Ratas Wistar foram tratadas com estradiol ou progesterona ou ambos dos 7 aos 21 dias de vida ou submetidas, na vida adulta, a aplicações tópicas, no córtex cerebral, de diferentes concentrações de estradiol ou progesterona durante o registro da DAC. Ao contrário do observado anteriormente em ratas ovariectomizadas, o tratamento sistêmico ou tópico com ambos os hormônios acelerou a propagação da DAC, em comparação com ratas controle, tratadas com o veículo. No caso da aplicação tópica, o efeito apresentou-se reversível e dependente da dose aplicada. Sugere-se que tais efeitos estão relacionados com a açzão dos hormônios ovarianos sobre a excitabilidade cerebral. / There is experimental and clinical evidence that ovarian hormones exert profound and lasting action on the brain, both during its development, and after this phase (adult brain). Some of these actions have repercussions significantly on brain excitability. In previous work, offspring of female rats at 7 postnatal days were subjected to bilateral ovariectomy (OVX group) or ovariectomy pseudo- surgery (sham group) or no surgery (naive group). When the pups reached adulthood (90-120 days) the OVX group and the two control groups (sham and naive in the proestrus phase) were subjected to the recording of Cortical Spreading Depression (CSD), a phenomenon that is influenced by the excitability of the brain. In the OVX group, the CSD spread with significantly lower rates compared to the two control group.it was demonstrated that ovariectomy in the period of brain development reduced the spread of cortical spreading depression (CSD), a phenomenon which is influenced by brain excitability. This work continued this line of research. Initially, it was demonstrated that ovariectomy in adult life is not accompanied by the effects observed in rats with early ovariectomy. These data, coupled to those obtained during the master, gave an article published in the "International Journal of Developmental Neuroscience" journal. Then studied the effects on the CSD, the interaction between the administration of ovarian hormones and unfavorable conditions of lactation (suckling in large litters). Wistar rats were treated with estradiol or progesterone or both from 7 to 21 days or submitted in adult life, topical applications, the cerebral cortex, different concentrations of estradiol or progesterone during registration of CSD. Unlike the previously observed in ovariectomized rats, the systemic or topical treatment with both hormones accelerated the velocity of the CSD compared to control rats treated with the vehicle. In the case of topical application, the effect is reversible and showed dependent on the applied dose. It is suggested that these effects are related to the action of ovarian hormones on brain excitability.

There are robust sex differences in brain anatomy, function, as well as neuropsychiatric and neurodegenerative disease risk (1-6), with women approximately twice as likely to suffer from a depressive illness as well as Alzheimer’s Disease. Disruptions in ovarian hormones likely play a role in such disproportionate disease prevalence, given that ovarian hormones serve as key regulators of brain functional and structural plasticity and undergo major fluctuations across the female lifespan (7-9). From a clinical perspective, there is a wellreported increase in depression susceptibility and initial evidence for cognitive impairment or decline during hormonal transition states, such as the postpartum period and perimenopause (9-14). What remains unknown, however, is the underlying mechanism of how fluctuations in ovarian hormones interact with other biological factors to influence brain structure, function, and chemistry. While this line of research has translational relevance for over half the population, neuroscience is notably guilty of female participant exclusion in research studies, with the male brain implicitly treated as the default model and only a minority of basic and clinical neuroscience studies including a female sample (15-18). Female underrepresentation in neuroscience directly limits opportunities for basic scientific discovery; and without basic knowledge of the biological underpinnings of sex differences, we cannot address critical sexdriven differences in pathology. Thus, my doctoral thesis aims to deliberately investigate the influence of sex and ovarian hormones on brain states in health as well as in vulnerability to depression and cognitive impairment:Table of Contents List of Abbreviations ..................................................................................................................... i List of Figures .............................................................................................................................. ii Acknowledgements .....................................................................................................................iii 1 INTRODUCTION .....................................................................................................................1 1.1 Lifespan approach: Sex, hormones, and metabolic risk factors for cognitive health .......3 1.2 Reproductive years: Healthy models of ovarian hormones, serotonin, and the brain ......4 1.2.1 Ovarian hormones and brain structure across the menstrual cycle ........................4 1.2.2 Serotonergic modulation and brain function in oral contraceptive users .................6 1.3 Neuropsychiatric risk models: Reproductive subtypes of depression ...............................8 1.3.1 Hormonal transition states and brain chemistry measured by PET imaging ...........8 1.3.2 Serotonin transporter binding across the menstrual cycle in PMDD patients .......10 2 PUBLICATIONS ....................................................................................................................12 2.1 Publication 1: Association of estradiol and visceral fat with structural brain networks and memory performance in adults .................................................................................13 2.2 Publication 2: Longitudinal 7T MRI reveals volumetric changes in subregions of human medial temporal lobe to sex hormone fluctuations ..............................................28 2.3 Publication 3: One-week escitalopram intake alters the excitation-inhibition balance in the healthy female brain ...............................................................................................51 2.4 Publication 4: Using positron emission tomography to investigate hormone-mediated neurochemical changes across the female lifespan: implications for depression ..........65 2.5 Publication 5: Increase in serotonin transporter binding across the menstrual cycle in patients with premenstrual dysphoric disorder: a case-control longitudinal neuro- receptor ligand PET imaging study ..................................................................................82 3 SUMMARY ...........................................................................................................................100 References ..............................................................................................................................107 Supplementary Publications ...................................................................................................114 Author Contributions to Publication 1 .....................................................................................184 Author Contributions to Publication 2 .....................................................................................186 Author Contributions to Publication 3 .....................................................................................188 Author Contributions to Publication 4 .....................................................................................190 Author Contributions to Publication 5 .....................................................................................191 Declaration of Authenticity ......................................................................................................193 Curriculum Vitae ......................................................................................................................194 List of Publications ................................................................................................................195 List of Talks and Posters ......................................................................................................196

Projeções do núcleo pré-óptico medial (MPN) para a porção ventromedial do núcleo ventromedial do hipotálamo (VMHvl) compõe um circuito de controle do comportamento sexual feminino (CSF) influenciado por pistas endógenas e exógenas. Este CSF no adulto só ocorre se o sistema nervoso se desenvolveu corretamente, por meio da ação de hormônios esteroidais. Por isso, objetivamos estudar as projeções do MPN para o VMHvl em fêmeas controle (GC) e ooforectomizados (GO). O GC aos 90 dias de idade foi submetido à cirurgia estereotáxica para injeção iontoforética do traçador anterógrado Phaseolus vulgaris no MPN. Já o GO aos 30 dias de idade, foi submetido à ooforectomia bilateral e aos 90 dias de idade submetido à mesma cirurgia que o GC. Como resultado, nos dois grupos observamos marcação anterógrada no VMHvl, assim como para outras regiões que integram o circuito do CSF; porém observamos uma possível redução das projeções no GO. Sendo assim, estabelecemos a conectividade do MPN com o VMHvl, contudo observamos que no GO há uma alteração na densidade e extensão dessas projeções. / Medial preoptic nucleus (MPN) outputs to the ventromedial portion of the ventromedial hypothalamic nucleus (VMHvl) participates in the female sexual behavior (FSB) control circuit influenced by endogenous and environmental cues. This FSB in adults only occurs if the nervous system has developed correctly, through the action of steroid hormones. Thus, our goal is to study the MPN outputs to the VMHvl in control (CG) and ovariectomized (OG) female animals. For the control group (CG), at 90 days of age, these females underwent stereotactic surgery for iontophoretic injection of the anterograde tracer Phaseolus vulgaris into the MPN. The oophorectomized group (OG), at 30 days of age, underwent oophorectomy and when they reach 90 days of age they underwent the same surgery as CG. As a results, in both experimental groups, we observed anterograde labeling in VMHvl, as well as for other regions that are part of the FBS circuit; but in these nuclei, we observed a possible reduction in the density of the projections on the OG. Thus, we establish the connectivity of the MPN with the VMHvl, however we observe that in the GO there is a change in the density and extension of these projections.