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      The Luteinizing Hormone Surge Is Preceded by an Estrogen-Induced Increase of Hypothalamic Progesterone in Ovariectomized and Adrenalectomized Rats

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          As circulating estrogen levels rise on the afternoon of proestrus, they stimulate the hypothalamo-pituitary axis. This estrogen positive feedback is pivotal to stimulate the luteinizing hormone (LH) surge required for ovulation and luteinization of ovarian follicles. In addition to estrogen, pre-LH surge progesterone is critical for an LH surge as was demonstrated by blocking progesterone synthesis. In ovariectomized (OVX) rats treated with trilostane, a blocker of the enzyme 3β-hydroxysteroid dehydrogenase (3β-HSD) that catalyzes the conversion of pregnenolone to progesterone, estrogen did not induce an LH surge. Further, estrogen induced an LH surge in OVX and adrenalectomized (ADX) rats, indicating that the source of progesterone was neither the ovary nor adrenal gland. This estrogen-only LH surge was inhibited by pretreatment with trilostane, indicating that although the adrenal gland and ovary were not necessary for positive feedback, progesterone synthesis was critical for estrogen-induced positive feedback in an OVX/ADX rat. This suggested that the LH surge is dependent on the pre-LH surge synthesis of progesterone. Estrogen-induced progesterone receptors in the hypothalamus are vital for the LH surge, so a potential location for progesterone synthesis is the hypothalamus. OVX/ADX female rats were treated with 17β-estradiol (50 µg) and progesterone levels were assayed by RIA. Progesterone levels were elevated in hypothalamic tissue following estrogen treatment. No increases in tissue progesterone levels were found in parietal cortex, cerebellum, medulla, pituitary or plasma. Additionally, male rats that do not have an estrogen positive feedback-induced LH surge were examined. Castrated/ADX male rats had no increase in hypothalamic progesterone levels after estrogen treatment. Together, these data strongly suggest that estrogen enhances neuroprogesterone synthesis in the hypothalamus that is involved in the positive feedback regulating the LH surge.

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          Most cited references 11

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          Neurosteroid biosynthesis: genes for adrenal steroidogenic enzymes are expressed in the brain.

          To determine if neurosteroids (steroids synthesized in the brain) are produced by enzymes found in steroidogenic tissues, we determined if mRNA for five steroidogenic enzymes could be detected in brain tissues or cultured cells. We detected mRNAs for adrenodoxin, P450scc (cholesterol side-chain cleavage enzyme) and P450c11 beta (11 beta-hydroxylase) but not for P450c17 (17 alpha-hydroxylase/17,20 lyase) or P450c11AS (aldosterone synthase) in rat brains and cultures of rat glial cells. P450scc mRNA abundance in brain or primary glial cultures was approximately 0.01% of that found in the adrenal, but more P450scc mRNA was detected in C6 glial cells. Both P450scc and P450c11 beta mRNAs were most abundant in the cortex, but there were region-specific differences for both mRNAs, and sex-specific differences for P450c11 beta mRNA. P450scc mRNA was equally abundant in mixed glial cultures containing both astrocytes and oligodendrocytes as in astrocyte-enriched cultures, and P450scc immunoreactivity co-localized with GFAP immunoreactivity in cultured astrocytes. P450c11 beta mRNA was not detected in the mixed primary glial cultures for the C6 glioma cell line that synthesize P450scc mRNA, suggesting that glial cells do not synthesize P450c11 beta mRNA. Thus some of the same enzymes involved in steroidogenesis in classic endocrine tissues are found in a cell-specific and region-specific fashion in the brain. Neurosteroids may be derivatives of known classic steroids, and/or may function through non-classic steroid hormone receptors, such as GABAA, N-methyl-D-aspartate, and corticosterone receptors.
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            Trilostane, an orally active inhibitor of steroid biosynthesis.

            Trilostane is a competitive inhibitor of 3beta-hydroxysteroid dehydrogenase. In vitro, the drug inhibits conversion of pregnenolone to progesterone but does not alter conversion of cholesterol to pregnenolone nor progesterone to corticoid hormones. When given orally to rats, trilostane inhibits corticosterone and aldosterone production and elevates circulating levels of pregnenolone at doses lower than those that produce adrenal hypertrophy or inhibit gonadal steroidogenesis.
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              Demonstration of steroid hormone receptors and steroid action in primary cultures of rat glial cells.

              Primary cultures of rat glial cells were established from newborn rat forebrains. A mixed population of oligodendrocytes and astrocytes was obtained, as confirmed by indirect immunofluorescence staining with specific markers for each cell type. Receptors were measured 3 weeks after primary culture in glial cells cultured in the presence or not of 50 nM estradiol and we have identified progesterone, glucocorticoid, estrogen, and androgen receptors (PR, GR, ER and AR), but only PR was inducible by the estrogen treatment. This estrogen-induction of PR was more dramatic in glial cells derived from female offsprings than from males, as measured by binding studies and by immunohistochemical techniques with the KC 146 anti-PR monoclonal antibody. The antiestrogen tamoxifen inhibited the estrogen induction, but had no effect by itself on PR concentration. Specific binding sites for PR, GR, ER and AR were measured by whole cell assays after labeling cells with, respectively, [3H]R5020, [3H]dexamethasone, [3H]OH-tamoxifen or [3H]R1881. PR and GR were also analyzed by ultracentrifugation and after exposure of cells to agonists, both receptors were recovered from cytosol as a 9S form, and from the nuclear high-salt, tungstate ions-containing fraction as a 4-6S form. In contrast, when the antiprogestin- and antiglucocorticosteroid RU486 was used as a ligand, a non-activated 8.5S receptor complex was found for both receptors in this nuclear fraction. The 8.5S complex of the GR was further analyzed in the presence of specific antibodies and, in addition to GR, the presence of the heat shock protein hsp90 and of a 59 kDa protein was found. During primary culture, the effects of progesterone (P) and estradiol (E2) were tested on glial cell multiplication, morphology and differentiation. Cell growth was inhibited by P and stimulated by E2. Both hormones induced dramatic morphologic changes in oligodendrocytes and astrocytes and increased synthesis of the myelin basic protein in oligodendrocytes and of the glial fibrillary acidic protein in astrocytes.

                Author and article information

                S. Karger AG
                July 2003
                18 July 2003
                : 78
                : 1
                : 29-35
                aDepartment of Neurobiology and bDepartment of OB/GYN, David Geffen School of Medicine at UCLA, Laboratory of Neuroendocrinology, Brain Research Institute, University of California, and cDepartment of Biology and Microbiology, California State University, Los Angeles, Calif., USA
                71703 Neuroendocrinology 2003;78:29–35
                © 2003 S. Karger AG, Basel

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                Page count
                Figures: 2, References: 66, Pages: 7
                Reproductive Neuroendocrinology


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