Findings released from recent pivotal clinical trials on hormone therapy (HT) benefits and risks have stimulated a growing trend towards lower doses and earlier discontinuation of HT for menopausal women. Yet, there is little knowledge regarding women's personal experiences with the resultant earlier and possibly abrupt withdrawal of HT. The purpose of this study was to explore postmenopausal women's vasomotor symptom experiences after discontinuing HT. The data for this study was collected from menopausal women who discontinued HT. The study questionnaire was created through an extensive review of the literature as well as an expert panel review. The questionnaire was also piloted with a small group of women prior to its use in this study. Data analysis consisted of descriptive analysis with means and standard deviations and/or frequency distributions with percentages for demographic data, health behaviors, factors influencing HT decisions, use of CAM and perceived efficacy. Chi-square analysis, Spearman Rho correlation, and logistic regression analysis were conducted for contextual factors and vasomotor symptom experiences. A McNemar test was performed to assess within group differences for vasomotor symptoms experiences pre and post HT. Questionnaires were received from 563 menopausal women throughout the United States. This study revealed that 80% of participants experienced vasomotor symptoms after discontinuing HT. The most common predictors which accounted for only 13% of variance in the occurrence of vasomotor symptoms were younger age, type of menopause and the occurrence of vasomotor symptoms prior to initiation of HT. Of the 563 women participating in the study, less than half reported the use of CAM to treat reemerging vasomotor symptoms. For the most part, less than half of the women felt their treatment choices were helpful in relieving their reemerging vasomotor symptoms Because a woman's experience of menopause can be highly individualized, an adaptation of Bronfenbrenner's ecological theory was used guide this exploratory study. The study findings supported the usefulness of the adaptation of Bronfenbrenner's ecological theory as a model through which to view the vasomotor experiences of menopausal women who have discontinued HT. / text

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Indiana University-Purdue University Indianapolis (IUPUI) / Menopausal symptoms, primarily hot flashes, are a pressing clinical problem for both naturally menopausal women and breast and ovarian cancer patients, with a high societal and personal cost. Hot flashes are poorly understood, and animal modeling has been scarce, which has substantially hindered the development of non-hormonal treatments. An emerging factor in the hot flash experience is the role of anxiety and stress-related stimuli, which have repeatedly been shown to influence the bother, frequency, and severity of hot flashes. Causal relationships are difficult to determine in a clinical setting, and the use of animal models offers the ability to elucidate causality and mechanisms. The first part of this work details the development and validation of novel animal models of hot flashes using clinically relevant triggers (i.e., compounds or stimuli that cause hot flashes in clinical settings), which also increase anxiety symptoms. These studies revealed that these triggers elicited strong (7-9 °C) and rapid hot flash-associated increases in tail skin temperature in rats. In a surgical ovariectomy rat model of menopause, which typically exhibit anxiety-like behavior, hot flash provocation revealed an ovariectomy-dependent vulnerability, which was attenuated by estrogen replacement in tested models. An examination of the neural circuitry in response to the most robust flushing compound revealed increased cellular activity in key thermoregulatory and emotionally relevant areas. The orexin neuropeptide system was hyperactive and presented as a novel target; pretreatment with selective and dual orexin receptor antagonists significantly diminished or eliminated, respectively, the response to a hot flash provocation in ovariectomized rats. The insertion/deletion polymorphism of the serotonin transporter has been linked to increased anxiety-associated traits in humans, and subsequent studies prolonged hot flashes in SERT+/- rats, which also caused hot flashes in highly symptomatic women. These studies indicate the orexin system may be a novel non-hormonal treatment target, and future studies will determine the therapeutic importance of orexin receptor antagonists for menopausal symptoms.

Conclusion 1. The results of the research partly supported hypothesis 1a. There was a significant reduction in both endothelium-dependent arterial relaxation following a surgical menopause. The results of the research partly supported hypothesis 1b. There was a significant reduction in endothelium-dependent arterial relaxation but no significant effect on endothelium-independent arterial relaxation. / Conclusion 2. The results of the research partly supported hypothesis 2a. The addition of unopposed oestrogen significantly improved endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research supported hypothesis 2b. The addition of oestradiol combined with progestogen (norethisterone acetate) reversed the reduction in arterial relaxation caused by a surgical menopause. The results of the research partly supported hypothesis 2c. The addition of tibolone reversed the reduction endothelium-dependent but not endothelium-independent arterial relaxation. The results of the research partly supported hypothesis 2d. The addition of oestradiol combined with a progestogen (norethisterone acetate) reversed the reduction in endothelium-dependent but not endothelium-independent arterial relaxation. / Conclusion 3. The results of the research partly supported hypothesis 3a. Endothelium-dependent arterial relaxation but no endothelium-independent arterial relaxation was improved after the addition of menopausal hormone therapy using oestrogen combined with a progestogen in a continuous manner. The results of the research did not support hypothesis 3b. Neither endothelium-dependent arterial relaxation nor the endothelium-independent arterial relaxation was improved by cyclical menopausal HT. / Conclusion 4. The results of the research did not support hypothesis 4. The addition of menopausal hormone therapy using combined oestrogen with progestogen did not improve arterial relaxation in postmenopausal women with established coronary heart disease. / Hypothesis 2. This hypothesis examined three different types of commonly used menopausal HT. That unopposed oestrogen (2a), oestrogen combined with a progestogen (2b and 2d) or a synthetic steriod that has oestrogenic, progestogenic as well as androgenic activity (tibolone, 2c), reverse the reduction in arterial relaxation following menopause in Hong Kong Chinese women. / Hypothesis 3. That menopausal hormone therapy using oestrogen combined with progestogen given in either continuous (3a) or cyclical (3b) regimens improves arterial relaxation in postmenopausal Hong Kong Chinese women. / Hypothesis 4. That menopausal hormone therapy using combined oestrogen with progestogen improves arterial relaxation in postmenopausal Hong Kong Chinese women with established coronary heart disease. / Menopausal HT can in general at least partially reverse changes in arterial relaxation in postmenopausal women. Different types of menopausal HT exhibit different effects on arterial relaxation. In healthy vessels, menopause HT mainly reverses the endothelium-dependent vascular effect, but it remains unclear how menopausal HT affects the endothelium-independent vascular effect. However, with established coronary heart disease, menopausal HT cannot reverse the changes in vascular reactivity. / Summary. Menopause results in a reduction in arterial relaxation. However, GnRHa temporarily induced menopause in young women, the endothelium-independent vasodilatation was not impaired. This difference can be partly explained by the difference in age as vascular reactivity is age dependent. Secondly, GnRHa works with an initial phase of increase in oestrogen production resulting in a shorter duration of hypo-oestrogenism resulting in the lack of impairment on endothelium-independent vasodilatation. / This thesis tested the following hypotheses: Hypothesis 1. That vascular reactivity decreases after the menopause as shown in premenopausal Hong Kong Chinese women with either a surgical (1a) or a medically induced (1b) menopause. / This thesis will examine the effects of menopause and menopausal HT on arterial reactivity which is an indirect measurement of vascular function. Previous studies have shown that oestrogen is a potent coronary artery vasodilator, and this effect may be mediated via both endothelium-dependent and endothelium-independent mechanisms. One method of assessing vascular reactivity is to use ultrasound measurement of changes in brachial artery diameter in response to certain stimuli. Using this technique, changes in both endothelium-dependent and endothelium-independent vasodilatation can be measured. Increased rather than decreased arterial relaxation after stimulus can be viewed as a favourable response. / Yim, So-fan. / Adviser: C. J. Haines. / Source: Dissertation Abstracts International, Volume: 68-09, Section: B, page: 5873. / Thesis (M.D.)--Chinese University of Hong Kong, 2006. / Includes bibliographical references (p. 159-194). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Electronic reproduction. [Ann Arbor, MI] : ProQuest Information and Learning, [200-] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / School code: 1307.

published_or_final_version / abstract / Medicine / Master / Master of Philosophy

The purpose of this research was to examine some of the factors which may affect body composition of postmenopausal women. The effect of estrogen, physical activity, diet and lifestyle were examined in 9 women receiving estrogen replacement therapy and 11 women not using this drug. For 3 consecutive days, the subjects collected 24-hour urine samples and recorded their dietary intake. Body fat was estimated by obesity indices based on height and weight and a regression equation based on abdominal skinfold, abdominal circumference and bideltoid diameter (Young, 1964). Lean body mass (LBM) was estimated from urinary excretion of creatinine (Forbes & Bruining, 1976). Physical activity and lifestyle were assessed by a self-administered questionnaire. Age, height, physical activity, diet and lifestyle were similar for the two groups. Estrogen users were heavier than non-users (p < 0.05) and as a group had a higher prevalence of obesity. Percent body fat and LBM also tended to be higher in the estrogen users than in the non-estrogen users. The weight difference between the two groups was already present at age 25 years and persisted through the subsequent 30-year period. All 20 subjects maintained their weight between ages 25 and 35 years, thereafter, increasing in weight significantly (p < 0.05) by decade through age 55 years. For all 20 subjects no correlation was found between energy intake and any measure of obesity or body fatness. Obesity was unrelated to energy consumption. Physical activity did not correlate significantly with any estimate of body composition. Energy intake showed an inverse correlation with hours spent watching television (r = -0.82, p < 0.002). Nutrient intake for most women was adequate; however, calcium intake in women not receiving estrogen replacement therapy may be insufficient. / Graduation date: 1987

Menopause is associated with disorders such as osteoporosis and ovarian cancer. It is unclear whether the postmenopausal ovary retains steroidogenic capacity and how it can impact the development of these disorders. The present studies used the VCD-treated follicle-depleted mouse model of menopause to test the hypothesis that residual ovarian tissue retains steroidogenic capacity following ovarian failure and, thus, affects the development of these disorders. Microarray technology was used to evaluate gene expression in residual ovarian tissue of follicle-depleted mice compared to that in ovaries from cycling animals. Among the genes identified were those encoding proteins for synthesis of androgens. Steroidogenic capacity of residual ovarian tissue was further evaluated by determining the expression of genes and proteins involved in ovarian steroidogenesis, and by measuring levels of circulating and rostenedione and gonadotropins. Follicle-depleted ovaries were enriched in mRNAs for androgenic enzymes, receptors involved in the internalization of cholesterol, and luteinizing hormone receptor. Increased circulating levels of FSH and LH and detectable and rostenedione were measured throughout the study. Protein for 3β-hydroxysteroid dehydrogenase, 17α- hydroxylase/17,20-lyase and luteinizing hormone receptor was detected in follicledepleted ovaries by Western blot analysis and localized by immunofluorescence staining. The contribution of retaining residual ovarian tissue to accelerated bone loss following ovarian failure was evaluated by comparing bone mineral density from young and aged VCD-treated mice to that in age-matched ovariectomized (OVX) animals. Retaining residual ovarian tissue resulted in protection against accelerated bone loss in young but not aged VCD-treated mice. Whether residual ovarian tissue is more susceptible to development of ovarian neoplasms compared to ovaries from cycling animals was addressed by combining the VCD-treated mouse with the DMBA model of ovarian carcinogenesis. VCD-treated follicle-depleted mice that received DMBA developed Sertoli-Leydig cell tumors while no tumors were observed in cycling animals. Residual ovarian tissue following ovarian failure appears to have a protective effect against loss of bone integrity, but a detrimental effect on development of ovarian neoplasms. Findings from these studies: provided evidence of a physiological role for residual ovarian tissue following ovarian failure, and furthered the use of the VCD-treated mouse as a relevant model for menopause and associated disorders.

Kidney disease is a major complication of diabetes and accounts for one-third of all diabetes-related deaths. Estrogen is considered protective against cardiovascular and non-diabetic renal disease, however it is unclear if this protection extends to diabetes and diabetic kidney disease.To address these questions, we have used a new model of menopause in which repeated daily injections of 4-vinylcyclohexene (VCD) induces gradual ovarian failure in mice. Unlike with ovariectomy, the VCD model preserves the gradual transition into ovarian failure (OF) (modeling perimenopause). Also, following OF, the residual ovarian tissue is retained and secretes androgens, similar to the androgen production by postmenopausal human ovaries.The VCD model of menopause was combined with the streptozotocin (STZ) model of type 1 diabetes, and the development of diabetes and diabetic kidney damage were studied over the subsequent 6 weeks. We observed that blood glucose levels are higher in post-OF diabetic mice compared to cycling diabetic and peri-OF diabetic mice. Renal cell proliferation, an early marker of kidney damage, is increased in post-OF diabetic mice compared to cycling diabetic mice, as measured by expression of proliferating cell nuclear antigen. We also demonstrate that expression of α-smooth muscle actin is increased in post-OF diabetic mice compared to cycling diabetic mice. Five weeks after STZ injection, post-OF diabetic mice had higher rates of urine albumin excretion than cycling diabetic mice.Using real-time PCR, we identified changes in expression between post-OF diabetic and cycling diabetic mice of genes which have previously been associated with diabetic kidney damage. We also show that some of these changes occur in peri-OF diabetic mice as well. Using microarray, we identified 119 new genes which are regulated by the combination of ovarian failure and diabetes in the mouse kidney.These data support our hypothesis that the changes in hormones which occur during the transition into ovarian failure exacerbate the development and progression of diabetic kidney damage in mice. These data also highlight the utility and importance of the VCD model of menopause in the study of diabetic kidney damage.

Up to 80% of menopausal women suffer from hot flushes, consisting of a coordinated activation of heat loss mechanisms (sweating, cutaneous vasodilatation, etc.). Ovarian steroid withdrawal also leads to hypersecretion of gonadotropins (LH and FSH) and changes in body fat distribution. Because gonadotropin release, thermoregulation, and energy balance are hierarchically controlled by the hypothalamus, it is likely that changes in response to estrogen withdrawal are occurring at the level of the hypothalamus. The infundibular (arcuate) nucleus of the hypothalamus contains an estrogen-sensitive population of cells that co-express kisspeptin, neurokin B (NKB), and dynorphin ("KNDy neurons"). KNDy neurons have been proposed to be a site of estrogen negative feedback on gonadotropin release in multiple species because they are estrogen sensitive and respond to estrogen withdrawal with somatic hypertrophy and significant changes in gene expression. Because KNDy neurons project to known thermoregulatory centers in the hypothalamus (such as the median preoptic nucleus, MnPO), we also hypothesized that changes in thermoregulation were also a due to changes in KNDy neurons. Ovariectomized (OVX) rats also show disorders of thermoregulation, increased serum LH and FSH, and altered weight gain. Furthermore, OVX rats exhibit KNDy gene expression changes similar to changes seen in the human, making this model ideal to study the effects of estrogen withdrawal. We used a novel neurotoxin conjugate NK₃-SAP to ablate KNDy neurons in OVX female rats. We then observed core and tail skin temperatures, serum gonadotropin levels, and weight changes before and after replacement with 17β-estradiol. Next, we ablated NK3R-expressing neurons in the MnPO and monitored the thermoregulatory axis. Rats with KNDy-ablation did not exhibit the rise in LH and profound weight gain associated with ovariectomy. Furthermore, KNDy-ablated animals did not exhibit the chronic vasodilatation observed in OVX rats, providing the first evidence that KNDy neurons play a role in vasomotion. Rats with NK₃R cell-specific MnPO lesions also exhibited decreased activation of heat loss effectors. Together, these data demonstrate an important role for arcuate KNDy neurons in estrogen modulation of LH release and body weight, and demonstrate that NKB signaling is critical for activation of heat dissipation effectors.

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