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Submitted on March 12, 2007
Accepted on April 30, 2007
Departments of Pathology, Cell Biology and Anatomy, Neurology and the Evelyn F. McKnight Brain Institute, University of Arizona College of Medicine, Tucson, Arizona, 85724; Department of Pathology, Section of Comparative Medicine, Wake Forest University School of Medicine, Winston-Salem, North Carolina, 27157
* To whom correspondence should be addressed. E-mail: nrance{at}email.arizona.edu.
Context: Human menopause is characterized by ovarian failure, gonadotropin hypersecretion and neuronal hypertrophy in the hypothalamic infundibular (arcuate) nucleus. Recent studies have demonstrated a critical role for kisspeptins in reproductive regulation but it is not known if menopause is accompanied by changes in hypothalamic kisspeptin neurons.
Objectives:
Human: To map the location of neurons expressing kisspeptin gene (KiSS-1) transcripts in the human hypothalamus and determine if menopause is associated with changes in the size and gene expression of kisspeptin neurons.
Monkey: To evaluate the effects of ovariectomy and hormone replacement on neurons expressing KiSS-1 mRNA in the infundibular nucleus of young, cynomolgus monkeys.
Subjects: Hypothalamic tissues were collected at autopsy from 8 premenopausal and 9 postmenopausal women and from 42 young, cynomolgus monkeys in various endocrine states.
Methods: Hybridization histochemistry, quantitative autoradiography and computer-assisted microscopy.
Results:
Human: Examination of hypothalamic sections revealed that KiSS-1 neurons were located predominantly in the infundibular nucleus. In the infundibular nucleus of postmenopausal women, there was a significant increase in the size of neurons expressing KiSS-1 mRNA, the number of labeled cells and autoradiographic grains/neuron.
Monkey: Similar to postmenopausal women, ovariectomy induced neuronal hypertrophy and increased KiSS-1 gene expression in the monkey infundibular nucleus. Conversely, in ovariectomized monkeys, estrogen replacement markedly reduced KiSS-1 gene expression.
Conclusions: The cynomolgus monkey experiments provide strong evidence that the increase in KiSS-1 neuronal size and gene expression in postmenopausal women is secondary to ovarian failure. These studies suggest that kisspeptin neurons regulate estrogen negative feedback in the human.
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