We have been able to examine directly the effects of acute hypogonadism and individual gonadal steroid replacement in both men and women on the following measures: mood and behavior, cognitive test performance, neuroendocrine serotonergic system function (mCPP pharmacologic challenges and DASB brain imaging), regional cerebral blood flow as measured by both O15 PET scans and bold signal with fMRI, HPA axis function (DEX/CRH testing), and CSF measures.? ? Findings to date: 1) the development of clinically significant mood symptoms and loss of sexual interest in approximately 10% and 30%, respectively of hypogonadal men and women despite the presence of hot flushes in 90-100% of these subjects; 2) the prediction of greater declines in sexual functioning during hypogonadism in both men and women by baseline (higher) sexual function but not hormone levels; 3)the correlation between CSF measures of the neurosteroid androsterone but not testosterone and sexual function in men during both hypogonadism and testosterone replacement; 4) the elimination in hypogonadal women of both cognition-activated (N-Back task) regional cerebral blood flow (O15 PET scans) in the dorsolateral prefrontal cortex and the reciprocal functional connectivity between the left hippocampal formation and the contralateral dorsolateral prefrontal cortex compared to either estradiol or progesterone replacement; 5) the absence of significant effects of hypogonadism, or ovarian steroid replacement on spatial reference memory as measured by the virtual Morris water maze; 6) increased resting regional cerebral blood flow (rCBF) in the left lateral orbitofrontal cortex, left dorsomedial prefrontal cortex, left posterior hippocampus, and regions of left and right cingulate gyrus and right hypothalamus during hypogonadism; 7) increased rCBF in the medial gyri, subgenual cingulate cortex, and orbitofrontal cortex, during estradiol replacement compared with hypogonadism; 8) increased rCBF in the left anterior hippocampus, ventromedial orbitofrontal cortex, and right frontal cortex during progesterone replacement compared with hypogonadism; and 9) increased cognition-activated (mental rotation task) rCBF during estradiol replacement.
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