Evidence for an estrogen-like action of raloxifene upon the hypothalamic-pituitary unit: raloxifene inhibits luteinizing hormone secretion and stimulates prolactin secretion in ovariectomized female rats L. Pinilla, L.C. Gonzalez, M. Tena-Sempere, E. Aguilar * Department of Cell Biology, Physiology and Immunology. University of Co ´rdoba School of Medicine. Co ´rdoba, Spain Received 15 June 2001; received in revised form 12 July 2001; accepted 12 July 2001 Abstract Selective estrogen receptor modulators (SERMs) constitute a new family of drugs with growing interest in the management of estrogen-associated pathology. Raloxifene is a SERM that is used to treat and prevent osteoporosis in postmenopausal women. The actions of raloxifene on bone, breast, uterus and serum cholesterol have been widely analyzed, but very few studies have been carried out to evaluate whether raloxifene has an estrogenic activity upon the hypothalamic-pituitary axis in the rat. For this purpose, adult female rats were ovariectomized or sham ovariectomized. One week later, the rats were implanted with intracardiac canullae and 24 h after injected daily with raloxifene (500 mg/ rat/day) or vehicle for 5 days. One hour after the last injection, blood samples were obtained at 5 min intervals for a 3 h. period (10:00–13:00 h). Our results indicate that raloxifene inhibits the pulsatile nature of the post-ovariectomy hyperse- cretion of luteinizing hormone (LH) and increases prolactin (PRL) secretion in ovariectomized animals. These effects are suggestive of an estrogenic activity of raloxifene on LH and PRL secretion in ovariectomized females. q 2001 Published by Elsevier Science Ireland Ltd. Keywords: Raloxifene; Selective estrogen receptor modulators; luteinizing hormone; Rats Raloxifene is a non-steroidal selective estrogen receptor modulator developed as a therapeutic agent for menopausal osteoporosis [9]. Interestingly, raloxifene blocks the effects of estrogen in some tissues, such as the breast, while it mimics estrogen action on bone and blood lipid levels [2,6,10,29]. The endocrine (extraneural) regulation of luteinizing hormone (LH) and PRL secretion in females appears to be mainly carried out by estrogen action [8], but at the present the effects of raloxifene on the hypothalamic-pituitary axis have not been extensively evaluated. Raloxifene injected to female rats prevented the effects of estradiol on serum LH levels [19], but stimulated PRL secretion and inhibited folli- cle stimulating hormone (FSH) release [3]. In human volun- teers, raloxifene blunted the effects of estrogen on different anterior pituitary hormones such PRL, and FSH [7]. These data reveal a compound estrogenic/antiestrogenic action of raloxifene in the control of anterior pituitary secretion depending on the experimental approach used. Recently, we have demonstrated that raloxifene injected to neonatal female and male rats induced permanent changes in repro- ductive physiology similar to those induced by estradiol [23]. To further explore the action of raloxifene upon reproduc- tive axis, the present study was undertaken to examine in adult female rats the effects of raloxifene on the pulsatile nature of the post ovariectomy hypersecretion of LH. In addi- tion, the actions of raloxifene upon pulsatile nature of the PRL secretion was also analyzed in this experimental setting. Adult cyclic Wistar rats weighing 250 ^ 20 g were kept under controlled conditions of light (12:12 h light/darkness, light on at 07:00 h) and temperature (228C), with free access to pelleted food (Pacsa Sanders, Seville, Spain) and tap water. Ovariectomy or sham-ovariectomy were performed after light ether anesthesia. One week after, all rats were implanted with intracardiac canullae under sodium pento- barbital (50 mg/Kg) anesthesia. After surgery, the animals were placed directly in isolation test chambers for 6 days. Twenty-four hours after cannulation, the animals were intra- peritoneally injected for 5 days with vehicle or 500 mg/day Neuroscience Letters 311 (2001) 149–152 0304-3940/01/$ - see front matter q 2001 Published by Elsevier Science Ireland Ltd. PII: S0304-3940(01)02104-8 www.elsevier.com/locate/neulet * Corresponding author. Fax: 134-57-218288. E-mail address: fi1agbee@uco.es (E. Aguilar).