Raloxifene analog LY 117018 effects on central and peripheral β-endorphin

Genazzani, Ar; Bernardi, F; Stomati, Massimo; Rubino, S; Giardina, L; Luisi, Stefano; Monteleone, P.; Genazzani, A. R.; Luisi, M; Petraglia, Felice

doi:10.3109/09513599909167563

Cited by 29 publications

(22 citation statements)

References 30 publications

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“…We suggest that the increase of bendorphin tone, observed by Genazzani et al (17) in rats, but above all by Florio et al (18) in postmenopausal raloxifene-treated women, could reduce PRL synthesis and secretion. On the contrary, the increase of opiatergic tone could exert a minor role on gonadotropin secretion, because of the prevalent stimulatory effect of hypoestrogenemia.…”

Section: Discussionmentioning

confidence: 46%

“…In premenopausal women, Baker et al (9) showed that raloxifene increases serum FSH and E2 levels, and reduces PRL concentrations by 10 -35% of basal values. Studies performed in ovariectomized rats which had not undergone estrogen replacement therapy suggested that raloxifene can play an estrogen-like action on neuroendocrine opiatergic pathways, increasing b-endorphin concentrations in the anterior and neurointermediate pituitary lobe and in the hypothalamus (17). These data were recently confirmed also in postmenopausal women, in whom the administration of raloxifene 60 mg/day significantly increased circulating b-endorphin levels after 3 and 6 months of treatment (18).…”

Section: Discussionmentioning

confidence: 87%

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Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

Lasco

Cannavò²,

Gaudio³

et al. 2002

European Journal of Endocrinology

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Objective: To evaluate the effects of a 6 month administration of raloxifene hydrochloride, a selective estrogen receptor modulator which was recently approved for the prevention of osteoporosis, on serum gonadotropin and prolactin (PRL) levels and on TRH-stimulated PRL responsiveness in postmenopausal women who have not undergone estrogen replacement therapy. Design and methods: Sixteen healthy postmenopausal women were divided into two groups on the basis of their bone status, evaluated by dual energy X-ray absorptiometry at the lumbar level. Eight women (chronological age 52:4^4:1 (S.D.) years, menopausal age 42:4^3:9 years), in whom T-score L2 -L4 was less than 2 2.5 S.D., were treated with raloxifene (60 mg p.o.) administered daily for 6 months (group 1), while the other eight women (chronological age 52:6^2:5 years, menopausal age 42:13 :6 years), in whom the T-score L2 -L4 ranged between 21 and 22.5 S.D., were used as a control group (group 2). Serum PRL, FSH, LH and 17b-estradiol (E2) levels were evaluated at baseline and after 3 and 6 months of treatment. In all subjects, PRL responsiveness to TRH (200 mg i.v.) administration was evaluated at baseline and at the end of the study. Results: At baseline, mean PRL, LH and FSH levels were not significantly different in the two groups (PRL 133:6^21:7 vs 136:7^28:1 mIU=l (NS), LH 25:1^6:8 vs 24:4^6:7 mIU=ml (NS), FSH 74:42 5:0 vs 71:1^24:1 mIU=ml (NS), in group 1 and group 2 respectively). No significant variations in serum FSH and LH values, in either group, or in serum PRL levels in group 2, were observed at the 3 and 6 month examinations. On the contrary, serum PRL values decreased significantly in group 1 after 3 months ð100:1^47:7 mIU=l; P , 0:05Þ and 6 months ð81:5^30:2 mIU=l; P , 0:001Þ: At baseline, no significant differences were observed in the TRH-stimulated serum PRL peak between the groups (1015:4^30:5 vs 1030:2^25:7 mIU=l in group 1 and in group 2 respectively), while it decreased significantly at the 6 month examination in group 1 ð770:5^47:4 mIU=l; P , 0:001Þ and it was significantly lower than in group 2 ð1068:1^301:8 mIU=l; P ¼ 0:02Þ: Serum E2 was not detected at baseline and at each examination, in all patients. Conclusions: The decrease of PRL values induced by long-term raloxifene administration in postmenopausal women could be explained by a direct antiestrogenic effect of raloxifene on lactotrope cells or by the recently suggested increase of opiatergic tone on the hypothalamic -pituitary region.

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Section: Discussionmentioning

confidence: 46%

Section: Discussionmentioning

confidence: 87%

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

Lasco

Cannavò²,

Gaudio³

et al. 2002

European Journal of Endocrinology

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“…Interesting data have recently been reported concerning the effects of the raloxifene analog LY-117018 on β-endorphin content in various rat organs [35]. This compound has been shown to act on central and peripheral β-endorphin levels via an estrogen-like mechanism in OVX rats, thus increasing β-endorphin levels in pituitary, hypothalamus, and plasma.…”

Section: Discussionmentioning

confidence: 99%

“…This compound has been shown to act on central and peripheral β-endorphin levels via an estrogen-like mechanism in OVX rats, thus increasing β-endorphin levels in pituitary, hypothalamus, and plasma. On the contrary, LY-117018 shows a clear antiestrogenic effect on β-endorphin levels both in fertile animals and in OVX rats treated with 17β-E2 [35]. These data suggest that LY-117018 has a different influence on the opioidergic pathways, depending upon the presence or absence of endogenous or exogenous estradiol.…”

Section: Discussionmentioning

confidence: 99%

Effects of Estradiol and Raloxifene Analog on Brain, Adrenal and Serum Allopregnanolone Content in Fertile and Ovariectomized Female Rats

Genazzani¹,

Bernardi²,

Stomati³

et al. 2000

Neuroendocrinology

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Allopregnanolone is a neuroactive steroid synthesized in rat gonads, adrenal cortex, and central nervous system. It has been suggested that sex steroid hormones might influence allopregnanolone concentrations but no clear data have ever been reported. The aim of the present study was to investigate the effects of administration of 17β-estradiol (17β-E2), the raloxifene analog LY-117018 or their combination on allopregnanolone levels in fertile and ovariectomized (OVX) rats. Thirteen groups of 12 Wistar female rats each received either 17β-E2 (0.1 or 1 µg/day) or LY-117018 (25, 250, and 1,250 µg/day), or 17β-E2 1 µg/day plus LY-117018: 25, 250, and 1,250 µg/day for 14 days. The rats were then sacrificed and allopregnanolone content was assessed in the hypothalamus, hippocampus, pituitary, adrenals, and serum. Ovariectomy determined a significant decrease in allopregnanolone content in the hypothalamus, hippocampus, pituitary, and serum, while increasing it in the adrenals (p < 0.01). In OVX rats, the administration of either 17β-E2 or LY- 117018 restored ovariectomy-induced allopregnanolone changes. The administration of LY-117018 in addition to 17β-E2 to OVX animals suppressed the increase in allopregnanolone levels determined by 17β-E2 in the hippocampus, hypothalamus, and pituitary, but not in the adrenals and serum. In fertile rats, the administration of LY-117018 reproduced the effects of ovariectomy. This study shows that the raloxifene analog LY-117018 has an estrogen-like action on the central nervous system of OVX rats when administered alone, while it acts as an antiestrogen in the presence of 17β-E2, both in OVX animals treated with 17β-E2 and in fertile rats. A different effect was observed in the adrenal glands. The mechanism of action of this compound has still to be clarified.

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“…Moreover, tamoxifen was also shown to block the effect of estradiol on dendritic spines of hippocampal neurons (Murphy and Segal 1996). The raloxifene analogue LY117018 has an estrogen-like action on neuroendocrine opiatergic pathways when administered alone in ovariectomized rats, whereas it exerts an anti-estrogenic effect in fertile or ovariectomized rats treated with 17␤-estradiol (Genazzani et al 1999).…”

Section: Nmda Receptors Mrna Levelsmentioning

confidence: 99%

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

Cyr

Thibault

Morissette

et al. 2001

Neuropsychopharmacology

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Hormonal specificity of modulation of N-methyl-D-aspartate (NMDA) receptors was investigated by comparing the effects of estradiol with tamoxifen or raloxifene, which display different responses in breast, bone, and uterus. Two weeks ovariectomy in rats decreasedIt has been shown that the female sex steroid estradiol exerts profound effects on neuronal differentiation during development (Toran-Allerand et al. 1983) and recently, accumulating evidence support also a modulatory role of estrogens in the normal maintenance of brain function during aging (Simpkins et al. 1994). Beneficial effects of estradiol in mood disorders (i.e., depression, pre-menstrual syndrome, post-natal depression), as well as mental diseases, such as schizophrenia and Gille de la Tourette's syndrome, have been reported (Di Paolo 1994;Fink et al. 1998). Moreover, a beneficial role of estradiol in neurodegenerative disFrom the Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, (CHUL), and Faculty of Pharmacy, Laval University, Sainte-Foy, Quebec, Canada, G1V 4G2.Address correspondence to: Dr. Thérèse Di Paolo, Oncology and Molecular Endocrinology Research Center, Laval University Medical Center, CHUQ, 2705, Laurier Boulevard, Sainte-Foy, Quebec, Canada G1V 4G2.Received July 5, 2000; revised December 20, 2000; accepted January 3, 2001. N EUROPSYCHOPHARMACOLOGY 2001 -VOL . 25 , NO . 2 SERMs Modulate NMDA Receptors 243 eases, such as Alzheimer has been recently suggested (Tang et al. 1996;Henderson 1997;Inestrosa et al. 1998). However, the mechanisms by which these effects of estrogens are yet to be fully characterized. N-methyl-D-aspartate (NMDA) receptors, a subtype of ionotropic glutamate receptor, have been implicated, as mediators, in some effects of estradiol on morphological plasticity and related physiological and cognitive processes in the brain (Moriyoshi et al. 1991). However, only few studies have directly investigated the role of estradiol in regulating NMDA receptors in rat and, in addition, these studies have focused on the effects of estradiol on hippocampal NMDA receptors (Woolley and McEwen 1992;Gazzaley et al. 1996;Woolley et al. 1997). We have recently investigated the effects of estradiol on the NMDA receptors agonist sites in brain regions implicated in mental disorders, such as frontal cortex, striatum, and nucleus accumbens (Cyr et al. 2000a). Our experiments showed that ovariectomy, as well as estradiol have regional specific effects since, for example, ovariectomy decreases NMDA receptor specific binding in hippocampal CA1 and dentate gyrus regions, whereas it has no effect in frontal cortex. In contrast, estradiol increases NMDA specific binding in the hippocampal CA1 and the dentate gyrus, but it decreases this binding in the frontal cortex (Cyr et al. 2000a).The present study sought to determine whether changes observed previously at the protein level after hormonal withdrawal due to ovariectomy or after estradiol treatment reflect changes at the level of gene transcription...

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Raloxifene analog LY 117018 effects on central and peripheral β-endorphin

Cited by 29 publications

References 30 publications

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

Effects of long-lasting raloxifene treatment on serum prolactin and gonadotropin levels in postmenopausal women

Effects of Estradiol and Raloxifene Analog on Brain, Adrenal and Serum Allopregnanolone Content in Fertile and Ovariectomized Female Rats

Estrogen-like Activity of Tamoxifen and Raloxifene on NMDA Receptor Binding and Expression of its Subunits in Rat Brain

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