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Degeneration of the ovary in middle-aged women results in castrate levels of ovarian steroids and increased gonadotropin secretion from the anterior pituitary gland. Ageing in women is also accompanied by significant changes in energy homeostasis. We have observed alterations in hypothalamic morphology and gene expression in older women, including hypertrophy and increased gene expression of neurokinin B (NKB) neurones, elevated levels of gonadotropin releasing-hormone (GnRH) mRNA and decreased numbers of neurones expressing pro-opiomelanocortin (POMC) mRNA. To determine if loss of ovarian steroids could produce comparable changes in gene expression in young primates, we measured the effects of ovariectomy on NKB, GnRH and POMC gene expression in young cynomolgus monkeys. We also measured serum leptin and body weight to examine the consequences of ovariectomy on energy balance. NKB neurones in the infundibular nucleus of ovariectomized monkeys were larger, more numerous and displayed increased levels of NKB mRNA compared to those of intact controls. Moreover, ovariectomy increased the number of neurones expressing GnRH gene transcripts and elevated serum luteinizing hormone. By contrast, several parameters related to energy balance, including POMC gene expression, serum leptin and body weights, were unchanged by ovariectomy. Thus, the rise in NKB and GnRH gene expression in older women was simulated by ovariectomy in monkeys, but the changes in POMC gene expression and energy balance were not. This study provides strong support for the hypothesis that ovarian failure contributes to the increased NKB and GnRH gene expression observed in postmenopausal women.

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BackgroundIntracranial atherosclerosis is a leading cause of stroke, but little is known about the composition of the intracranial atherosclerotic lesion and how intracranial plaque morphology is related to the risk of stroke. High‐resolution magnetic resonance imaging (HR MRI) has been used in patients with extracranial carotid atherosclerosis as an in vivo tool to identify, with high‐interrater agreement, histologically defined plaque components (i.e., intraplaque hemorrhage, fibrous cap, and lipid core), which have been shown to be predictors of recurrent stroke. With careful imaging the components of atherosclerotic plaque can be visualized in the intracranial arteries using HR MRI, but there are no reports of reproducibility or interrater reliability.Methods/Study designThe Characterization of intracranial atherosclerotic stenosis using high‐resolution MRI (CHIASM) study is a single‐center NIH‐funded prospective observational study, to (1) demonstrate high ‐interrater agreement for identifying intracranial plaque components on HR MRI, (2) determine the frequency of these components in symptomatic versus asymptomatic plaques, and (3) estimate the 1‐year rate of stroke in the territory of high‐risk plaque components. CHIASM will recruit 90 patients with 50–99% intracranial atherosclerosis to undergo HRMRI of the intracranial artery plaque at enrollment and 1‐year follow‐up. Both symptomatic and asymptomatic subjects will be recruited.ConclusionDetermination of good interrater reliability is an important first step in the development of HR MRI as a tool to predict risk in patients with intracranial atherosclerosis. This study will inform the design of future multicenter studies to determine the prevalence and prognosis of intracranial atherosclerotic plaque components. Such studies could lead to new understanding of the pathophysiological mechanisms of cerebral ischemia in patients with atherosclerotic intracranial stenosis, improvements in risk stratification, and potentially to new treatments of this common and serious disease.

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