Hypertrophy and increased kisspeptin gene expression in the hypothalamic infundibular nucleus of postmenopausal women and ovariectomized monkeys.
BACKGROUND
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 whether menopause is accompanied by changes in hypothalamic kisspeptin neurons.


OBJECTIVE
Our objective was to map the location of neurons expressing kisspeptin gene (KiSS-1) transcripts in the human hypothalamus and determine whether menopause is associated with changes in the size and gene expression of kisspeptin neurons. In monkeys, our objective was to evaluate the effects of ovariectomy and hormone replacement on neurons expressing KiSS-1 mRNA in the infundibular nucleus.


METHODS
Hypothalamic tissues were collected at autopsy from eight premenopausal and nine postmenopausal women and from 42 young cynomolgus monkeys in various endocrine states.


METHODS
We used hybridization histochemistry, quantitative autoradiography, and computer-assisted microscopy.


RESULTS
Examination of human 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 and the number of labeled cells and autoradiographic grains per neuron. 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.
Rometo
Adonna M
AM
Department of Pathology, University of Arizona College of Medicine, 1501 North Campbell Avenue, Tucson, Arizona 85724, USA.
Krajewski
Sally J
SJ
Voytko
Mary Lou
ML
Rance
Naomi E
NE
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D001111:Arcuate Nucleus of Hypothalamus / Q000166:cytology / Q000502:physiology; D015914:Estrogen Replacement Therapy; D004967:Estrogens / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D025461:Feedback, Physiological / Q000187:drug effects / Q000502:physiology; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology; D006801:Humans; D006984:Hypertrophy; D059648:Kisspeptins; D008252:Macaca fascicularis; D008875:Middle Aged; D009474:Neurons / Q000502:physiology; D010052:Ovariectomy; D010904:Pituitary Gland, Posterior / Q000166:cytology / Q000502:physiology*; D017698:Postmenopause / Q000502:physiology*; D011374:Progesterone / Q000494:pharmacology / Q000627:therapeutic use; D012333:RNA, Messenger / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*
D004967:Estrogens; C106628:KISS1 protein, human; D059648:Kisspeptins; D012333:RNA, Messenger; D025521:Tumor Suppressor Proteins; D011374:Progesterone