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Background: Sex hormone-binding globulin (SHBG) is a 94-kDa homodimer that binds steroids and is made in the hypothalamus. We have demonstrated that infusions of SHBG into the hypothalami of rats increase their female sexual receptivity except when SHBG is coupled to dihydrotestosterone (DHT) suggesting that SHBG has an active function in behavioral neuroendocrinology. Methods: This study examines the possibility that SHBG is internalized by neuronal and/or non-neuronal brain cells as one possible mode of action using in vitro and in vivo techniques. Results: First, analysis of the uptake of radiolabeled SHBG (¹²⁵I-SHBG) found ¹²⁵I-SHBG uptake in HT22 hippocampal cells stably transfected with cDNA for ERβ (HT22-ERβ). The addition of DHT to ¹²⁵I-SHBG significantly inhibited ¹²⁵I-SHBG uptake in HT22-ERβ cells but not in HT22-ERα or HT22 wild-type cells. SHBG internalization was specific as it did not occur in either the human neuroblastoma cell line SK-N-SH or the glioma cell line C6. Second, SHBG was labeled with a fluor (Alexa-555^TM), and infused into the lateral cerebroventricles of ovariectomized rats. Optimal SHBG uptake was seen 10 min after these infusions. SHBG uptake was seen in specific parts of the choroid plexus and periventricular cells as well as into cells in the paraventricular nucleus, the medial forebrain bundle, and the habenula. Conclusions: These studies suggest that SHBG is internalized by brain cells, which may be affected by the presence of ERβ. The gonadal steroids have numerous effects in brain and the discovery that the steroid-binding protein SHBG is taken up into neurons and brain cells may demand a change in thinking about how steroids are delivered to brain cells to affect neurophysiology.

Ten years ago, only one estradiol receptor was known to mediate the actions of estradiol in the body. Then estradiol receptor beta (ERb) was discovered, and we thought that these two receptors mediated all of the effects of estradiol. We now know, however, that this is only part of the story to understand rapid steroid actions. This review and this entire volume will discuss the emerging roles that binding globulins play on the stage of steroid actions.Selye found anesthetic effects of steroids very early on [1] that were later confirmed to be due to an action of progestin metabolites directly on GABA A receptors [2, 3]. In the 1960s, Towle and Sze [4] demonstrated steroid binding to plasma membranes. In the 1970s and 80s, Szego's laboratory performed a series of fascinating studies in which they discovered that estradiol affects uterine cell physiology within seconds [5 -10]. Based on that work, she concluded that steroids act at membrane receptors as well as on nuclear response elements, with the former being a more rapid mode of action. She further contended that mem-

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