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      The negative feedback actions of progesterone on gonadotropinreleasing hormone secretion are transduced by the classical progesterone receptor

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      Proceedings of the National Academy of Sciences

      Proceedings of the National Academy of Sciences

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          GABA(A) receptor alpha4 subunit suppression prevents withdrawal properties of an endogenous steroid.

          The hormone progesterone is readily converted to 3alpha-OH-5alpha-pregnan-20-one (3alpha,5alpha-THP) in the brains of males and females. In the brain, 3alpha,5alpha-THP acts like a sedative, decreasing anxiety and reducing seizure activity, by enhancing the function of GABA (gamma-aminobutyric acid), the brain's major inhibitory neurotransmitter. Symptoms of premenstrual syndrome (PMS), such as anxiety and seizure susceptibility, are associated with sharp declines in circulating levels of progesterone and, consequently, of levels of 3alpha,5alpha-THP in the brain. Abrupt discontinuation of use of sedatives such as benzodiazepines and ethanol can also produce PMS-like withdrawal symptoms. Here we report a progesterone-withdrawal paradigm, designed to mimic PMS and post-partum syndrome in a rat model. In this model, withdrawal of progesterone leads to increased seizure susceptibility and insensitivity to benzodiazepine sedatives through an effect on gene transcription. Specifically, this effect was due to reduced levels of 3alpha,5alpha-THP which enhance transcription of the gene encoding the alpha4 subunit of the GABA(A) receptor. We also find that increased susceptibility to seizure after progesferone withdrawal is due to a sixfold decrease in the decay time for GABA currents and consequent decreased inhibitory function. Blockade of the alpha4 gene transcript prevents these withdrawal properties. PMS symptoms may therefore be attributable, in part, to alterations in expression of GABA(A) receptor subunits as a result of progesterone withdrawal.
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            Pulsatile secretion of luteinizing hormone: differential suppression by ovarian steroids.

            In sheep, physiological levels of estradiol and progesterone each suppress the pulses of LH characteristics of tonic LH secretion, but do so by completely different mechanisms. Estradiol treatment decreases LH pulse amplitude but not frequency and also inhibits the height of the LH peak resulting from the administration of gonadotropin-releasing hormone (GnRH). In contrast, progesterone decreases the frequency of LH pulses without reducing their amplitude or the response to exogenous GnRH. This suggests that progesterone suppresses tonic LH secretion by acting in the brain to decrease the frequency of GnRH pulses, while estradiol may suppress the response of the pituitary to GnRH and thereby decrease LH pulse amplitude.
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              Progesterone modulation of pulsatile luteinizing hormone secretion in normal women.

              Recent studies show that the frequency and amplitude of pulsatile LH secretion change during the normal human menstrual cycle; however, the neuroendocrine mechanisms underlying these changes are poorly understood. To assess the role of progesterone (P) in regulating LH secretion patterns, we treated normal women (n = 5) with im P in oil during the follicular phase of their cycle and compared LH pulse frequency, amplitude, and mean plasma level during treatment to those in normal cycling women. Normal women were studied five times in five menstrual cycles. Each study lasted 24 h, with a sampling interval of 20 min. The cycle phases studied were early follicular (twice), late follicular (LF), midluteal, and LF with P therapy to simulate luteal phase plasma P levels. LH pulse frequency was slower (P less than or equal to 0.001) in the midluteal phase than in either the early follicular phase or LF, and furthermore, P, administered in the normal follicular phase, slowed LH pulse frequency, augmented pulse amplitude, and reduced mean plasma LH levels compared to those in untreated women studied at the same cycle phase (P less than or equal to 0.02). We infer that P secretion by the ovary mediates the change in the LH secretory pattern during the luteal phase of the normal menstrual cycle, and that at least part of this effect is mediated by the central nervous system.
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                Author and article information

                Journal
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                Proceedings of the National Academy of Sciences
                0027-8424
                1091-6490
                September 01 1998
                September 01 1998
                : 95
                : 18
                : 10978-10983
                Article
                10.1073/pnas.95.18.10978
                © 1998
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