Postmenopausal Hypertrophy of Neurons Expressing the Estrogen Receptor Gene in the Human Hypothalamus*

Computer microscopy and in situ hybridization were used to investigate neuronal hypertrophy in the infundibular nucleus of postmenopausal women. In the first experiment, hypothalami from premenopausal (n = 3) and postmenopausal (n = 3) women were formalin fixed, paraffin embedded, serially sectioned, and stained with cresyl violet. Soma areas of more than 3500 neurons were digitized using an image-combining computer microscope. The mean cross-sectional area of infundibular neurons in the postmenopausal women was 30% greater than that in premenopausal women, with no change in cell density. The mean cross-sectional area of mammillary neurons was unchanged, indicating that the infundibular neuronal hypertrophy was not an artifact of tissue processing. In the second experiment, hypothalami from premenopausal (n = 3) and postmenopausal (n = 2) women were frozen, serially sectioned, and incubated with a 48-base synthetic cDNA probe complementary to estrogen receptor (ER) mRNA. Adjacent sections were incubated with a cDNA probe complementary to GnRH mRNA. Morphometric analysis revealed that the mean cross-sectional area of infundibular neurons expressing the ER gene in the postmenopausal women was twice as large as the mean area in premenopausal hypothalami. The hypertrophied neurons did not contain GnRH mRNA. Finally, analysis of the infundibular nucleus from an oophorectomized 38-yr-old woman also revealed hypertrophied neurons containing ER mRNA. These data support the hypothesis that hypertrophy of infundibular neurons in postmenopausal women is secondary to loss of the inhibitory feedback of ovarian steroids.