Thesis (M.A.)--University of North Carolina at Wilmington, 2004. / Includes bibliographical references (leaves : [109]-111).

published_or_final_version / Medical Sciences / Master / Master of Medical Sciences

Sex differences exist in the progression of heart disease, as premenopausal women are protected from developing severe hypertension, aortic stenosis, myocardial infarction and hypertrophic cardiomyopathies. The susceptibility and progression of cardiovascular disease increases in post-menopausal women. This is at least partially underlined by a pronounced decrease in circulating estrogen levels. Estradiol (E2), the most abundant estrogen in premenopausal women, is known to be cardioprotective. Recently, AMP-activated protein kinase (AMPK) has emerged as a prominent player in the development of cardiac hypertrophy and heart failure. AMPK is central to the energetic metabolism of the cell and is activated in response to energy deprivation. E2 has been shown to activate AMPK, by yet an unknown mechanism. The first part of this dissertation focuses on describing the molecular mechanism behind this AMPK activation. We found that E2 activates AMPK through a non- genomic pathway and involves direct interaction of classical estrogen receptors (ERα and ERβ) with the α-catalytic subunit of AMPK. These receptors also associate with the upstream kinase LKB1, which is required for E2-dependent activation of AMPK. Furthermore, the two estrogen receptors play opposite roles, where ERα increases AMPK activation, and ERβ acts as a repressor, inhibiting AMPK phosphorylation. To translate our findings to heart disease, the next step was to determine the effect of ovarian failure, underlined by E2 loss, on AMPK signaling during the progression of cardiac hypertrophy. We hypothesized that ovarian failure decreases cardiac AMPK signaling, translating in worsening of hypertrophy. We found that the status of cardiac AMPK signaling depends on the nature of the hypertrophic stimulus and the timing of ovarian failure in relation to the onset of hypertrophy. Furthermore, we did not detect any differences in the development of cardiac hypertrophy between wild type mice and mice in ovarian failure, which most likely occur down the line. In summary we described a novel mechanism of AMPK activation by the hormone E2. We also explored the effect of estrogen loss on cardiac AMPK activity, and found that it is dependent on factors such as the pathological state of the heart and timing of the intervention. These findings add to our understanding of the molecular mechanisms behind sex differences in energy handling and in the future could be translated into better therapeutics for the treatment of cardiac pathologies.

The place of estrogen in women's health remains controversial. Premenopausal women have a lower prevalence of cardiovascular disease (CVD) than men and in observational studies hormone replacement therapy (HRT) decreases CVD in postmenopausal women. However, prospective randomized trials of secondary and primary prevention have failed to substantiate an overall protective effect from HRT and have even shown some harm. To explain this paradox it is necessary to better understand the effects of estrogen on the vascular wall. Estrogen rapidly mediates the activation of eNOS and increases the production of nitric oxide (NO), an important factor for endothelial health. In ovariectomized rats estrogen reduces production of superoxide (O2-) by NAD(P)H oxidase. The decreased function is associated with a decrease in the p47phox component of NAD(P)H oxidase and its interaction with the multicomponent enzyme. In these rats estrogen did not alter eNOS expression and bioavailability of NO, which is in contrast to its acute effects. This highlights the difference between chronic and acute studies. The decrease in O2-production suggests the intracellular signaling. / Estrogen has antiapoptotic effects. Oxidized low-density lipoprotein (oxLDL) and the inflammatory cytokine TNFalpha increased apoptosis which is associated with atherosclerosis. In human umbilical vein endothelial cells (HUVEC), estrogen decreased the extent of TNFalpha and oxLDL induced apoptosis as indicated by the expression of cleaved caspase-3 and FACS assay. Estrogen also preserves the antiapoptotic mitochondrial Bcl-2 and Bcl-xL proteins. / Estrogen has angiogenic properties that can help a healthy endothelium respond to injury. However, estrogen increases the angiogenesis caused by TNFalpha and this could lead to revascularization in the plaques of women with advanced disease. / Overall the balance between the positive and negative aspects of the effects of estrogen on the vascular wall could explain the paradoxical response in older women.

Rapid increases in plasma androgens are generally associated with short-term aggressive challenges in many breeding vertebrates. However, some animals such as song sparrows (Melospiza melodia) are aggressive year-round, even during the non-breeding season, when gonads are regressed and systemic testosterone (T) levels are non-detectable. In contrast, levels of the prohormone dehydroepiandrosterone (DHEA) are elevated year-round in the plasma and brain. The local conversion of brain DHEA to potent androgens may be critical in regulating non-breeding aggression. 3β-hydroxysteroid dehydrogenase/Δ4-Δ5 isomerase (3β-HSD) catalyzes DHEA conversion to androstenedione (AE) and the cofactor NAD⁺ assists in this transformation. In this thesis, I asked whether brain 3β-HSD activity is regulated by social encounters in seasonally breeding male songbirds. In Experiment 1, I looked at the long-term seasonal regulation of brain 3β-HSD activity. 3β-HSD activity was highest in the non-breeding season compared to the breeding season and molt. In Experiment 2, I hypothesized that brain 3β-HSD activity is rapidly regulated by short-term social encounters during the non-breeding season. A 30 min social challenge increased aggressive behavior. Without exogenous NAD⁺, there was ~355% increase in 3β-HSD activity in the caudal telencephalon and ~615% increase in the medial central telencephalon compared to controls (p<0.05). With exogenous NAD⁺, there was no effect of social challenge on 3β-HSD activity. These data suggest that endogenous cofactors play a critical role in the neuroendocrine response to social challenges. The increase in brain DHEA conversion to AE during social challenges may be a mechanism to rapidly increase local androgens in the non-breeding season, when there are many costs of systemic T.

This dissertation project investigated fluctuations in estradiol and testosterone across the human menstrual cycle. During the part of the cycle when women are most fertile, women show stronger preferences for men with more masculine faces, and these preference changes may be related to changes in hormone levels during ovulation. The present study investigated preferences changes among women for higher testosterone men over the menstrual cycle as estradiol and testosterone in those women fluctuated. 32 women participated in this 5-week long study tracking their estradiol and testosterone levels and preferences for masculine men. Women with higher levels of estradiol preferred men who had higher levels of testosterone than women who had lower levels of estradiol. During ovulation, women were more like to find high testosterone men more attractive than other parts of the menstrual cycle. In addition to ratings of men, several other psychological tests were administered and examined for changes as a function of state and trait levels of hormones.

Ovarian steroid hormones are known to produce several different effects in the brain. In addition to their role in gonadotropin release, ovulation and sexual behaviour they also seem to affect mood and emotions, as shown in women with the premenstrual tension syndrome. Some steroids have the ability to affect brain excitability. Estradiol decreases the electroshock threshold while progesterone acts as an anti-convulsant and anaesthetic in both animals and humans. Several earlier studies have shown a specific uptake of several steroids in the animal brain but only a few recent studies have established the presence of steroids in the human brain. In the present studies, the dissections of rat and human brains were carried out macroscopically and areas that are considered to be related to steroid effects were chosen. Steroid concentrations were measured by radioimmunoassay after extraction and separation with celite chromatography. The accuracy and specificity of these methods were estimated. In the animal studies, immature female rats were treated with Pregnant Mare's Serum Gonadotropin (PMSG) to induce simultaneous ovulations. Concentrations of estradiol and progesterone were measured in seven brain areas pre- and postovulatory. The highest concentration of estradiol, pre- and postovulatory, was found in the hypothalamus and differences between the two cycle phases were detected in most brain areas. The preovulatory concentrations of progesterone were low and the highest postovulatory concentration was found in the cerebral cortex. In one study, the rats were injected with pharmacological doses of progesterone to induce "anaesthesia". High uptake of progesterone was found and a regional variation in the formation of 5&lt;*-pregnane-3,20-dione in the brain with the highest ratio in the medulla oblongata. Concentrations of progesterone, 5a-pregnane-3*20-dione, estradiol and testosterone were determined in 17 brain areas of fertile compared to postmenopausal women. All steroids displayed regional differences in brain concentrations. Higher concentrations of estradiol and progesterone were found in the fertile compared to the postmenopausal women. In summary, these studies show that the concentrations of ovarian steroids in the brain are different at different endocrine states in both rats and humans and that there are regional differences in brain steroid distribution. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 1987, härtill 5 uppsastser</p> / digitalisering@umu

Background: During the past 5 decades, hormone replacement therapy (HRT) has been used, and appreciated for its beneficial effects, by millions of women in their menopause. As treatment for climacteric symptoms, estrogen is outstanding, and effects on hot flushes, vaginal dryness, and insomnia have been widely documented. The increased risks of venous thrombosis and breast cancer, however, restrict the use of estrogen. Estrogen treatment in women with a remaining uterus includes a progestin, added to protect the endometrium from hyperplasia and malignancies. The long-standing clinical impression, that progestin addition negatively influences mood, has been discussed in previous studies. Mood deterioration is, however, not mortal, although mood is important to the wellbeing and daily functioning of women treated with hormones. Studies of the mental side effects of HRT add to our understanding of steroid effects in the brain. Aims and methods: In our studies, we aimed to establish to what extent negative side effects cause women to discontinue HRT, and find out which drug compounds lead to mood deterioration. The questions asked were whether the type and dose of progestin and the estrogen dose during the progestin addition influence the mood and physical symptoms during sequential HRT. Compliance with HRT and reasons for discontinuing the therapy were evaluated in a retrospective longitudinal follow-up study. Treatment effects were studied in three randomized, double-blind, cross-over trials. During continuous estrogen treatment, effects of sequential addition of a progestin were studied by comparing two different progestins, medroxyprogesterone acetate (MPA) andnorethisterone acetate (NETA), comparing different doses of the same progestin, MPA, and comparing two doses of estrogen during addition of the same dose of MPA. The main outcome measure was the daily rating on mood and physical symptoms kept by the participants throughout the studies. The clinical trials were carried out at three gynecological centers in northern Sweden. Results and conclusions: Besides fear of cancer and a wish to determine whether climacteric symptoms had meanwhile disappeared, negative side effects was the most common reason or discontinuing HRT. Tension in the breasts, weight gain, a depressed mood, abdominal bloating, and irritability were the most important side effects seen both in women who continued HRT and in women who had discontinued the therapy. In our clinical trials, we showed that addition of a progestin to estrogen treatment induces cyclic mood swings characterized by tension, irritability, and depression, as well as increased breast tension, bloatedness, and hot flushes. Women with a history of premenstrual syndrome (PMS) appeared to be more sensitive to the progestin addition and responded with lower mood scores compared with women without previous PMS. In our studies, MPA provoked depressed mood to a lesser extent than did NETA. Surprisingly, the higher dose of MPA (20 mg) enhanced the mood, compared with 10 mg, when added to estrogen treatment. In women continuously treated with 3 mg estradiol, mood and physical symptoms worsened during the progestin addition, as compared with treatment with 2 mg estradiol. The negative side effects seen during sequential HRT have much in common with symptoms seen in the premenstrual dysphoric disorder (PMDD), which is a psychoneuroendocrine disorder with psychiatric expression. Explanations for treatment effects on mood are likely to be found in drug interactions with neurotransmitter systems of the brain. / <p>Diss. (sammanfattning) Umeå : Umeå universitet, 2003</p> / digitalisering@umu

Tests were conducted for 71 pesticides in weekly bulk (wet + dry) deposition samples collected from May 25 to September 21 over two years at two sites in the City of Winnipeg, Canada. Twenty-one pesticides and their metabolites were detected in this study and 99% of samples collected contained mixtures of two or more pesticides. Malathion and glyphosate were the largest contributors to bulk deposition in 2010 and 2011, respectively. A second study examined the mineralization of 2,4-D and 17β-estradiol using a novel in-field soil microcosm study and a series of laboratory experiments under different temperature incubations. Results indicated that temperature fluctuations do not greatly affect the amount or rate of mineralization relative to the traditionally constant laboratory incubations of 20°C; however long-term freezing of soil reduced potential mineralization over time. This research advances scientific knowledge of agri-chemical fate and provides data for strengthening current environmental policy analysis in Canada.

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