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All animals must integrate internal and environmental information into an appropriate behavior that ultimately aims to increases fitness. In order to investigate the proximate and ultimate mechanisms underlying adaptive behavior, I examined the role of neuroendocrine molecules at three distinct levels of biological organization. At the level of the individual, I demonstrate that steroid hormone receptors play distinct roles in modulating adaptive behavior, physiology and brain gene expression in dominant and subordinate African cichlid fish. At the level of the social community, I investigate how the behavior and physiology of one individual can affect the behavior, physiology, and brain gene expression of other community members. I found striking covariance patterns that implicate identifiable neuroendocrine pathways as mediators of specific social signals, establishing an important model to investigate the molecular basis of how behavioral phenotypes spread through communities. Finally, I investigate how the neurochemistry of the five major vertebrate classes has changed in a way that covaries with sensory integration, life history, and mating strategy. To address this question, I have laid an important theoretical framework to study the evolution of behavior as well as establishing neuroanatomical brain homologies across vertebrate lineages. I show that variation in where neurochemicals (dopamine, steroids, neuropeptides) are produced in the brain varies across vertebrates while where signals are received (ie receptors) are conserved, providing a novel theory of social brain evolution. In summary, I use a multidisciplinary approach to study hormonal contributions to the proximate and ultimate mechanisms of social behavior on many levels of biological organization and have contributed important novel insights that have significantly increased our understanding of the evolution of behavior and its neural and molecular underpinnings. / text

Thesis (Ph.D.)--Boston University / PLEASE NOTE: Boston University Libraries did not receive an Authorization To Manage form for this thesis or dissertation. It is therefore not openly accessible, though it may be available by request. If you are the author or principal advisor of this work and would like to request open access for it, please contact us at open-help@bu.edu. Thank you. / The vagina is a key organ in the peripheral genital arousal response. In animal models, pelvic nerve stimulation increases vaginal wall compliance, blood flow and transudation of fluid. Decreases in ovarian steroids are known to induce structural changes in the vagina, and evidence is mounting that alterations in the hormonal milieu contribute to genital pathophysiology. To date, however, mechanisms by which sex steroids regulate vaginal arousal responses have not been adequately studied. Further, limited data are available on the effects of hormone replacement on tissue morphology, hormone receptor distribution and vaginal innervation. We propose that imbalances in sex steroid hormone levels alter the distribution, expression and actions of steroid receptors and neurotransmitters, leading to structural and functional changes in vaginal tissue and impairment the arousal response. The goal of this study was to assess dynamic changes in vaginal tissue structure with hormone deprivation and administration. Female Sprague-Dawley rats were used as an animal model. Intact animals served as controls. Ovariectomized animals were treated for a two week period with vehicle, estradiol, testosterone, progesterone, or a combination of estradiol plus testosterone or progesterone. To assess changes in vaginal physiology and morphology, physiological and histological techniques were used, including stereological analysis and immunohistochemistry for localization of hormone receptors and various neuronal markers. / 2031-01-01

Estrogens, such as the biologically active 17-b estradiol (E2) have many actions in the male and female brain. Not only does E2 regulate reproductive behavior in adults, it organizes and activates the brains of younger animals in a sex-specific manner. In addition, many human studies have shown E2 to provide protection against a variety of neurological disorders, including stoke. These studies have been controversial and depend largely on the type and timing of hormone replacement. Animal studies are much less controversial and clearly demonstrate a neuroprotective role for E2 following ischemic brain injury. Because much of E2 neuroprotection requires sex steroid hormone receptors, it is essential to understand expression patterns of these receptors. For the current studies, I evaluated estrogen receptor alpha (ER α), estrogen receptor beta (ER β) and androgen receptor (AR) expression in the cortex. It is known that these receptors change in expression at several times in an animal’s life span including during early postnatal development and following ischemic brain injury. Here I used an in vitro cortical explant model to further examine how these receptors change both during development and following injury. This in vitro model is important because it provides a way to investigate changes in receptor expression pattern in the cortex without input from other brain regions. In addition to characterizing this model, I also evaluated the contribution of E2 to changes in receptor expression and on cell death following injury in the explants. To begin to decipher mechanisms for E2 mediated neuroprotection, I added antagonist for each of the receptors before and after injury. In each these experiments, I also examined potential sex differences by separating the female and male brains before I cultured the explants. Overall, these experiments showed that cortical explants are a good in vitro model. Here we found that E2 was protective in female, but not male cortical explants following injury. However, the exact mechanisms of E2-mediated neuroprotection are still to be deciphered.

The aim of this research was to study the correlation between tissue tumor marker expression and HR-HPV infection, smoking, hormonal contraceptive use and sex steroids in women with cervical intraepithelial neoplasia or normal epithelium. The study investigated the expression of 11 tumor markers in cervical biopsies obtained from 228 women with different diagnoses ranging from normal cervical epithelium to various stages of CIN. 188 women were recruited at our colposcopy clinic (out-patient surgery, Department of Obstetrics and Gynecology, Falun Hospital) for laser cervical conization or a directed punch biopsy, either because of a vaginal smear (Pap smear) that showed cytological findings suggesting CIN, or because of repeated findings showing atypical squamous cells of undetermined significance (ASCUS). For 40 volunteers, punch biopsies were taken from the normal cervical epithelium. The time period for this study was 2005-2007. Study I :  228 women, of whom 116 were tested, 64 were positive to HR-HPV. The results showed that Ki67 tumor cell proliferation index was the only marker that independently correlated to both the presence of HR-HPV and the severity of cervical lesions. Study II:  228 women, of whom 83 were smokers (36, 9%). Smokers showed lower expression of p53, FHIT (tumor suppressor markers) and interleukin-10 .Higher expression of Cox-2 and Ki-67 (tumor proliferation markers). Study III:  195 women who were premenopausal. There was increased p53 expression (tumor suppressor) in the progestin-IUD users compared to non-users. Decreased IL-10 expression (immunological marker) was observed in both COC users and any progestin-only users. Study IV: Serum from 80 premenopausal women was available. The main finding was that the increased levels of serum progesterone and estradiol were associated with increased Cox-2 expression (proliferation marker). Serum progesterone and estradiol levels influence cellular and extracellular proteins which have been associated with neoplastic development in normal epithelium and CIN. Conclusion: The results of these studies support previous epidemiological findings on the role of smoking, contraceptive use and sex steroids as co-factors in development of CIN and that tumor marker expression varies in different grades of CIN.

We exposed a native endangered species, bonytail chub (Gila elegans), to graded concentrations of secondarily-treated effluent. At the end of each treatment period, we collected water from all raceways and samples were analyzed for the presence of 83 organic wastewater compounds. We extracted blood plasma from control and treatment fish in each raceway and samples were analyzed for hormones, 17β-estradiol and 11-ketotestosterone, and the egg yolk protein, vitellogenin.17β-estradiol concentrations were consistently lower in treatment females than those detected in control females. The 17β-estradiol and vitellogenin concentrations were always higher in treatment males than those found in control males. Concentrations of 11-ketotestosterone were consistently lower in treatment males than those detected in control males.Endocrine disrupting effects occurred in male and female fish exposed to low concentrations of effluent. Changes in hormone levels suggested a feminizing effect in treatment male fish and an androgenizing effect in treatment female fish.

Human pregnancy is characterized by significant increases in central ventilatory drive and perceived respiratory discomfort (breathlessness). The physiological mechanisms of hyperventilation and breathlessness in pregnancy remain largely unknown and understudied. Objective: The main purpose of this research was to elucidate the mechanisms of maternal hyperventilation, and to systematically examine the contribution of alterations in central ventilatory drive, static/dynamic respiratory mechanics and their interaction with respect to the intensity of perceived breathlessness during exercise in pregnancy. General Methods: Experiments were conducted between 34-38 wks gestation and again 4-5 months post-partum in a total of 35 healthy, young women. A comprehensive mathematical model of ventilatory control was used to examine the role of alterations in wakefulness and central chemoreflex drives to breathe, acid-base balance and female sex hormones in maternal hyperventilation. The effects of pregnancy on detailed ventilatory (breathing pattern, airway function, operating lung volumes, esophageal pressure-derived indices of respiratory mechanics) and perceptual (breathing and leg discomfort) responses to incremental cycle exercise to the limits of tolerance were also examined. Results: Maternal hyperventilation resulted from a complex interaction between alterations in arterial and central acid-base balance and other factors that directly affect ventilation, including increased wakefulness and central chemoreflex drives to breathe, increased metabolism and decreased cerebral blood flow. Mechanical adaptations of the respiratory system, including recruitment of resting inspiratory capacity and reduced airway resistance, accommodated the increased demand for tidal volume expansion during exercise in pregnancy, while preserving effort-displacement and breathlessness-ventilation relationships. Variation in the severity of gestational breathlessness could not be explained by respiratory mechanical/muscular factors, but ultimately reflected variation in the amplitude of maternal hyperventilation and temporal desensitization to the sensory consequences of increased ventilation. Conclusion: Our results indicated that 1) the hyperventilation and attendant hypocapnia/alkalosis of pregnancy can be explained by alterations in wakefulness and central chemoreflex drives to breathe, acid-base balance, metabolic rate and cerebral blood flow; 2) mechanical adaptations of the respiratory system obviated the anticipated rise in perceived breathlessness for a given ventilation during exercise in pregnancy, and helped to ensure that peak aerobic working capacity was admirably preserved, even in late gestation; and 3) gestational breathlessness ultimately reflected the normal awareness of increased ventilation and contractile respiratory muscle effort. / Thesis (Ph.D, Kinesiology & Health Studies) -- Queen's University, 2008-08-28 16:01:40.78

Background: The aim of this thesis was to study the relationship of pre-diagnostic circulating concentrations of sex steroid hormones (androgens, estradiol, 17-hydroxyprogesterone, and progesterone), growth factors (insulin-like growth factor-I (IGF-I), placental growth hormone (GH)), sex hormone binding globulin (SHBG), and anti-Müllerian hormone (AMH) with risk of epithelial ovarian cancer (EOC) overall, and by tumor invasiveness and histology. A longitudinal study was used to assess patterns of hormonal changes during a single pregnancy, and in two consecutive pregnancies. Materials & Methods: A case-control study was nested within the Finnish Maternity Cohort and the Northern Sweden Maternity Cohort. A total of 1 052 EOC cases were identified through linkages with the cancer registries in both countries. For each case, 2-3 controls were selected. Cases and controls were matched on cohort, age and date at blood draw, as well as for parity at blood draw and at diagnosis (n=2 695). Odds ratios (OR) and corresponding 95% confidence intervals [CI] were estimated using conditional logistic regression. The longitudinal study was based on 71 pregnant Finnish women, who donated blood samples in each trimester of pregnancy. Results: Higher androgen concentrations were associated with an increased risk of overall EOC (e.g., testosterone ORT3 vs. T1: 1.56 [1.30-1.87], ptrend<0.0001), while the risk of endometrioid tumors increased with higher estradiol concentrations (ORT3 vs. T1: 2.76 [1.04-7.33], ptrend=0.03). Higher IGF-I was associated with a non-significant decrease in risk for invasive (ORT3 vs. T1: 0.79 [0.62-1.02], ptrend=0.07) and endometrioid tumors (ORT3 vs. T1: 0.55 [0.28-1.07], ptrend=0.07). The inverse association between IGF-I levels and risk of invasive EOC was stronger in analyses limited to women aged <55 years at diagnosis (ORT3 vs. T1: 0.74 [0.57-0.96], ptrend=0.03). No associations were observed between pre-diagnostic progesterone, SHBG, placental GH, and AMH with EOC risk overall, or by tumor invasiveness and histology. The longitudinal study showed that hormone concentrations were more strongly correlated between consecutive trimesters of a pregnancy than between the 1st and 3rd trimesters. Further, 3rd trimester hormone concentrations can be estimated from 1st or 2nd trimester measurements. Conclusion: Higher pre-diagnostic androgens, estradiol, and IGF-I are associated with EOC risk, and associations differ by tumor invasiveness and histology.

Sea Turtles are long-lived marine reptiles that have existed for more than 150,000 years. All seven turtle species extant today are characterised as endangered by the World Conservation Union Red List of Threatened Species. This PhD thesis investigates aspects of endocrinology and toxicology in green (Chelonia mydas) (Peninsular Malaysia) and flatback (Natator depressus) (Curtis Island, Queensland, Australia) turtles. This thesis aimed to identify if toxicants have an affect on reproduction and development in marine turtles. A high affinity steroid binding protein showing an affinity for testosterone and oestradiol was identified and described in nesting C. mydas and the thermal profile of sex steroid binding proteins in C. mydas was studied. This is the first study that has investigated sex steroid binding proteins in marine turtles. A sex steroid binding protein was also observed in male and female hatchling C. mydas and the effect of temperature on sex steroid binding proteins was investigated. This new, minor-invasive method of sex identification shows that different sex steroid binding proteins could reflect different hormonal patterns in female and male hatchling C. mydas. The steroid and metabolites profiles in nesting C. mydas (Peninsular Malaysia) and N. depressus (Curtis Island, Queensland) were established. Progesterone levels were the highest followed by testosterone, oestrone and dihydrotestosterone levels. The significant role of oestrone in nesting sea turtles was verified. The elevated concentrations of corticosterone, thyroxine, glucose and triglyceride indicated high metabolic demands placed upon C. mydas and N. depressus during nesting activities. The metabolite profiles and hormone concentrations were investigated to determine whether there was any relationship between hormonal changes during nesting activities in C. mydas and N. depressus. A methodology to measure heavy metal concentrations in the blood and eggs of N. depressus was developed. Moreover, this was the first time that tin compound derivatives have been identified in marine turtles in Australia. A complex heavy metal profile was identified in eggs. It is suggested that eggs may be an important, practical and reliable indicator of environmental contamination in nesting marine turtles. Pesticides were measured in the blood and eggs of N. depressus. Organochlorine and polychlorinated biphenyl concentrations were measured in the blood in N. depressus. Traces of OCs and PCBs were detected in eggs of N. depressus. Furthermore, the effects of heavy metals in developing C. mydas of both sexes are presented. During development, it was investigated whether heavy metal concentrations were affected by age, gender or the different clutch in C. mydas. The effect of a variety of toxicants (i.e. pesticides and heavy metals) on the sex steroid binding protein properties was investigated in nesting C. mydas. This important study identifies mechanisms by which toxicants may exert a physiological effect upon sex steroids (i.e. testosterone and oestradiol) in nesting turtles. The toxicants were studied at a wide range of concentrations. Some toxicants were shown to weaken or abolish the association of the testosterone and/or oestradiol binding proteins in nesting C. mydas. Correlations were observed between heavy metal concentrations found in blood and eggs and steroid and metabolite levels in nesting N. depressus. Zinc which was previously measured in the blood was positively correlated with testosterone concentrations in nesting N. depressus. Chromium which was found in eggs was negatively correlated corticosterone concentrations. Manganese was the only heavy metal (measured in eggs) which was negatively correlated with progesterone and positively correlated with triglyceride concentrations in nesting N. depressus. Finally, a quantified histological method was developed to determine the sex in C. mydas hatchlings by investigating specific histological criteria. A number of “undetermined sex” hatchlings were verified and it is hypothesised that abnormal reproductive development is related to the presence of environmental contaminants previously found in the studied C. mydas population of Peninsular Malaysia.