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Recent basic and clinical advances have consolidated the concept of tissue-selective estrogens, i.e. molecules that express different degrees of partial agonist, full agonist or antagonist activity in different tissues or cells. Delta8,9-Dehydroestrone sulfate (delta8,9-DHES) is a conjugated estrogen and a component of conjugated equine estrogens (CEE). It is metabolized in the human in at least a 1:1 ratio to its 17beta form, 17beta-delta8,9-DHES. To evaluate its activity in different clinical and biochemical parameters, a clinical research study was conducted with delta8,9-DHES and estrone sulfate as a comparator in postmenopausal women. Delta8,9-DHES was given orally at a daily dose of 0.125 mg for 12 weeks in a group of 10 women. Two additional groups of women received either estrone sulfate alone (1.25 mg/day) or the combination of delta8,9-DHES and estrone sulfate at the previously specified doses. A significant and consistent suppression of hot flushes (number, severity, and total score) was observed with delta8,9-DHES, reaching more than 95% suppression in all parameters of vasomotor symptoms. This level of activity was equal to that obtained with the much higher dose of estrone sulfate, and it was sustained for the duration of the treatment period (12 weeks). Measurements of a bone resorption marker, i.e. urinary excretion of N-telopeptide, demonstrated that delta8,9-DHES at 8 weeks produced a degree of suppression (40%) similar to that observed with the higher dose of estrone sulfate. Gonadotropin secretion (FSH and LH) was significantly suppressed in women receiving delta8,9-DHES, similar to that observed with estrone sulfate alone or with the combination of the two. Other parameters, such as total cholesterol, low density lipoprotein cholesterol and high density lipoprotein cholesterol were not modified significantly, whereas serum globulins (sex hormone-binding globulin and corticosteroid-binding globulin) showed only marginal increases after delta8,9-DHES administration. Taken together with preclinical data, it is found that delta8,9-DHES is an active estrogen with a distinct pharmacological profile that results in significant clinical activity in vasomotor, neuroendocrine (gonadotropin and PRL) and bone preservation parameters, whereas displaying little or no efficacy, at the dose tested, on other peripheral parameters normally affected by estrogens. Collectively, this information supports the concept that delta8,9-DHES is an integral component of CEE, with distinct tissue selectivity contributing to the CEE's overall clinical activity, and places this estrogen as a distinct member of a novel class of centrally active molecules with unique peripheral tissue selectivity.

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We have investigated the role of protein kinase C (PK-C) in luteinizing hormone-releasing hormone (LHRH)-induced testosterone secretion from purified rat Leydig cells (70-80-day old Sprague-Dawley rats) by pretreating the cells in vitro with 200 mM phorbol 12,13-dibutyrate (PDBu) (a known procedure to down-modulate this enzyme in most cell types) and 1 muM [D-Ala6,Des-Gly10]-LHRH ethylamide, an LHRH agonist (LHRH-A). Following pretreatment we measured PK-C activity and secretion of testosterone in response to subsequent challenges with the PK-C activator PDBu (20-2000 nM) and with LHRH (0.001-1.0 muM) and the Ca(2+)-mobilizing secretagogue A23187 (0.1-100 microM) in the same cell preparation. PDBu and LHRH-A pretreatments caused a reduction in testosterone secretion in response to subsequent exposure to PDBu or LHRH. Both pretreatments decreased PK-C activity in crude and purified extracts of the same cells. The magnitude of reduction of the secretory response was greater than that of enzyme activity for both PDBu and LHRH-A pretreatment (68.9% reduction of testosterone secretion vs 54.7% reduction of PK-C activity in PDBu-pretreated cells and 78.6% reduction of testosterone production vs 36.6% reduction of PK-C activity in LHRH-A-pretreated cells). The effect of phorbol ester pretreatment on PDBu- or LHRH-stimulated testosterone secretion and PK-C activity was specific (no measurable effect with 4 alpha-PDBu, an inactive phorbol ester). While PDBu and LHRH-A pretreatment reduced Leydig cell responsiveness to PDBu or LHRH, the secretion of testosterone in response to the Ca2+ -mobilizing secretagogue A23187 was similar in PDBu- and LHRH-A-pretreated and in control (non-pretreated) cells. We conclude that down-modulation of protein kinase C by prolonged exposure of Leydig cells to phorbol esters or LHRH-A results in decreased PK-C activity and testosterone secretion. These results provide the first evidence that pretreatment with LHRH-A, which does not enter the cell, can affect the steroidogenesis and PK-C activity responses to PDBu (the intracellular ligand of PK-C).

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1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

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1. The present review discusses the proposed roles of the amino acids glutamate and GABA in the central regulation of luteinizing hormone-releasing hormone (LHRH) and in luteinizing hormone (LH) secretion. 2. Descriptions of the mechanisms of action of these neurotransmitters have focused on two diencephalic areas, namely, the preoptic-anterior hypothalamic area where the cell bodies of LHRH neurons are located, and the medial basal hypothalamus which contains the nerve endings of the LHRH system. Increasing endogenous GABA concentration by drugs, GABA agonists, or blockade of glutamatergic neurotransmission by selective antagonists in rats and non-human primates prevents ovulation and pulsatile LH release, and blunts the LH surges induced by estrogen or an estrogen-progesterone combination. In contrast, glutamate and different glutamate agonists such as NMDA, AMPA and kainate, can increase LHRH/LH secretion. 3. The simultaneous enhancement of glutamatergic activity and a decrease of GABAergic tone may positively influence the maturation of the pituitary-gonadal system in rats and non-human primates. Administration of glutamate receptor agonists has been shown to significantly advance the onset of puberty. Conversely, glutamate antagonists or increased endogenous GABA levels may delay the onset of puberty. The physiological regulation of LHRH/LH secretion may thus involve a GABA-glutamate interaction and a cooperative action of the various types of ionotropic glutamate receptors. 4. The inhibitory actions of GABA on LH release and ovulation may be exerted at the level of afferent nerve terminals that regulate LHRH secretion. A likely candidate is noradrenaline, as suggested by the synaptic connections between noradrenergic nerve terminals and GABAergic interneurons in the preoptic area. Recent experiments have provided complementary evidence for the physiological balance between inhibitory and excitatory transmission resulting in modulation of the action of noradrenaline to evoke LHRH release.

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Epinephrine (EPI) has been described to stimulate the hypothalamic-pituitary-adrenal axis. However, whether central EPI neuronal systems play a major physiological role in the regulation of ACTH secretion and whether that role is primarily stimulatory or inhibitory in nature is still controversial. The present study addressed these questions using different inhibitors of phenylethanolamine-N-methyltransferase (PNMT), which were either active peripherally or were both peripherally and centrally active. Male rats received either vehicle or a PNMT inhibitor at various times before further experimental procedures. A large decrease in hypothalamic EPI levels was observed in rats given central PNMT inhibitors, whereas these treatments did not affect hypothalamic norepinephrine (NE) levels. Plasma EPI, but not NE, was decreased to similar levels after treatment with peripheral or central PNMT inhibitors. Basal plasma ACTH decreased slightly during the 12 h after central PNMT inhibition. Central, but not peripheral, inhibition of PNMT significantly decreased the plasma ACTH response to ether vapor stress at 5 and 15 min. This effect was seen 3 or 12 h after PNMT inhibition. The suppression of the stress response was not due to a change in responsiveness of the pituitary to CRF. The hypothalamic content of CRF was significantly decreased 9 and 12 h after inhibition of central PNMT. Blockade of the stress response actually preceded the changes in CRF levels. The content of arginine vasopressin, another potent ACTH secretagogue, was not affected 3, 6, 9, or 12 h after that treatment. The effect on CRF was not observed in rats treated with the peripheral PNMT inhibitor, nor was it caused by manipulation and stress of the animals 12 h before death. The dat demonstrate that central inhibition of PNMT, which produces a selective decrease in hypothalamic EPI levels, blunts the response of plasma ACTH to ether vapor stress, and at later times also causes a selective decrease in CRF content. Furthermore, the altered ACTH response to ether stress is not due to a change in responsiveness of the pituitary to CRF or to an alteration in arginine vasopressin levels. Thus, an endogenous EPI neuronal system appears to stimulate CRF neurons responsible for the increase in ACTH after ether vapor stress.

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In order to examine the cellular mechanisms by which estradiol (E2) exerts its acute negative feedback upon luteinizing hormone (LH) secretion, a temporal correlation was made among serum LH concentrations, pituitary responsiveness to luteinizing hormone-releasing hormone (LHRH), and the translocation of E2 to nuclear (NER) receptors of the pituitary (PIT), preoptic hypothalamic area (POA), and the caudal hypothalamic area (HYP). Rats on diestrous day 1 were ovariectomized (OVX) and killed 10 days later. LH and LHRH were measured by RIA. NER was measured by an exchange assay. Serum LH increased 10-12-fold 10 days following OVX as compared to diestrous controls. The injection of estradiol benzoate (Eb, 20 microgram in corn oil/rat, sc) did not affect LH concentrations at 30 min but decreased serum LH at both 60 and 180 min following its administration. Pituitary responsiveness to LHRH (measured as the increase in LH 10 min after iv injections of 100 ng LHRH/rat) was not altered at 60 min but was significantly decreased 180 min following Eb injection. Thus, serum LH decreased prior to a detectable alteration in pituitary responsiveness to LHRH. Translocation of E2 receptors to NER of the HYP and PIT began 60 min following Eb injection and was maximal at 180 min. In contrast, translocation of E2 receptors in the POA was maximal at 60 min, and had recovered to control values 180 min following Eb administration.(ABSTRACT TRUNCATED AT 250 WORDS)

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PIP: Previously, it was shown that intact or castrated female rats which were pretreated with estradiol for 48-72 hours had an increased sensitivity to exogenous LH-Releasing Hormone (LRF). The findings indicated a biphasic effect of estrogen on the pituitary responsiveness to LRH, probably dependent upon the time of exposure of the pituitary to the steroid. A series of experiments were performed in which pituitary sensitivity to LRF was tested at various times after estradiol treatment in ovariectomized mice. Sensitivity to LRF was significantly decreased 3 hours after estradiol treatment. No difference in anterior pituitary sensitivity to LRF was found between control and experimental groups in 6 hours. 9 hours after treatment, there was a clear increase in response; and in animals treated for 24 hours, there was an even higher response. It has been suggested that progesterone may also alter pituitary sensitivity to LRF, but this was not shown to be true in ovariectomized rats. The biphasic effect of estradiol on pituitary sensitivity to LRF suggests that the changes in sensitivity may play a role during the normal estrous cycle. The time of exposure of the anterior pituitary to estradiol rather than the dose is the important factor in determining the inhibitory or facilitatory response to LRF.^ieng

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