Naomi E. Rance, MD, PhD

The focus of my laboratory is the study of hormonal regulation of neuronal morphology and gene expression in the human brain. Specifically, we are examining changes that occur in the hypothalami in postmenopausal women. Menopause is characterized by a complete loss of ovarian estrogen secretion and a secondary rise in plasma levels of luteinizing hormone. We have observed an associated hypertrophy of neurons in the hypothalamic control region for reproduction. Our working hypothesis is that postmenopausal neuronal hypertrophy is secondary to the loss of the inhibitory feedback of ovarian steroids and is not simply a non-specific effect due to aging per se. Our finding of estrogen receptor mRNA in the hypertrophied nuerons is strong support for this hypothesis. We have also used in situ hybridization and computer microscopy to demonstrate that the enlarged neurons contain neurokinin B and substance P gene transcripts. Remarkably, the expression of these genes is markedly increased in the hypothalami of postmenopausal women. More recently, we have found that the increase in gene expression in postmenopausal women is duplicated by removal of the ovaries of rats. These studies provide evidence that the changes we have observed in postmenopausal women are due to ovarian withdrawal and not simply a nonspecific effect of aging. What is the function of the hypertrophied nuerons? We think they might be participating in the hypothalamic circuitry medicating estrogen negative feedback on gonadotropin secretion.

 

Menopause occurs within such a well-defined system and has consistent and dramatic changes in plasma hormones, endocrine organs and a readily identified loss of function. Therefore, we have the rare opportunity of studying human brains to answer basic biological questions.