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Review
. 2008 Aug 13;290(1-2):44-50.
doi: 10.1016/j.mce.2008.04.016. Epub 2008 May 3.

Estradiol Regulation of Progesterone Synthesis in the Brain

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Free PMC article
Review

Estradiol Regulation of Progesterone Synthesis in the Brain

Paul Micevych et al. Mol Cell Endocrinol. .
Free PMC article

Abstract

Steroidogenesis is now recognized as a global phenomenon in the brain, but how it is regulated and its relationship to circulating steroids of peripheral origin have remained more elusive issues. Neurosteroids, steroids synthesized de novo in nervous tissue, have a large range of actions in the brain, but it is only recently that the role of neuroprogesterone in the regulation of arguably the quintessential steroid-dependent neural activity, regulation of the reproduction has been appreciated. Circuits involved in controlling the LH surge and sexual behaviors were thought to be influenced by estradiol and progesterone synthesized in the ovary and perhaps the adrenal. It is now apparent that estradiol of ovarian origin regulates the synthesis of neuroprogesterone, and it is the locally produced neuroprogesterone that is involved in the initiation of the LH surge and subsequent ovulation. In this model, estradiol induces the transcription of progesterone receptors while stimulating synthesis of neuroprogesterone. Although the complete signaling cascade has not been elucidated, many of the features have been characterized. The synthesis of neuroprogesterone occurs primarily in astrocytes and requires the interaction of membrane-associated estrogen receptor-alpha with metabotropic glutamate receptor-1a. This G protein-coupled receptor activates a phospholipase C that in turn increases inositol trisphosphate (IP3) levels mediating the release of intracellular stores of Ca2+ via an IP3 receptor gated Ca2+ channel. The large increase in free cytoplasmic Ca2+ ([Ca2+]i) stimulates the synthesis of progesterone, which can then diffuse out of the astrocyte and activate estradiol-induced progesterone receptors in local neurons to trigger the neural cascade to produce the LH surge. Thus, it is a cooperative action of astrocytes and neurons that is needed for estrogen positive feedback and stimulation of the LH surge.

Figures

Figure 1
Figure 1
Blocking neuroprogesterone synthesis alters the pattern of estrous cycles in gonadally intact rats. The four day rat estrous cycle is diagrammatically presented. Each day of the cycle is indicated on the ordinate: D1 = diestrous day 1, D2 = diestrous day 2, P = proestrus and E=estrus. Neuroprogesterone synthesis was blocked by infusion of a P450scc inhibitor, aminoglutethimide (AGT), into the third ventricle (3V) via an implanted cannula. All animals treated with DMSO (5%, vehicle n = 14; data not shown) had normal 4 day estrous cycles as determined by vaginal cytology. In contrast, 11/14 AGT treated rats (0800 hrs on proestrus, indicated by the arrow) had disrupted estrous cycles with delayed onset of estrous as determined by vaginal cytology.
Figure 2
Figure 2
The rapid release of Ca2+ from internal stores by thapsigargin (Thp) induces neuroprogesterone synthesis in post-pubertal female hypothalamic astrocyte cultures. Astrocytes were treated with Thp or Thp (10−7 M) with 10−6 M estradiol (E2/Thp) for one hour. Media was collected and replaced with either estradiol-free DMEM/F12 (DMEM Post Thp) or 10−6 M estradiol (E2 48hrs Post Thp). The neuroprogesterone concentration was significantly higher following treatment with E2 (48 hrs), or Thp or Thp+E2 (1 hr). Following an hour of Thp, treatment with either DMEM or E2 for 48 hours did not statistically increase the concentration of neuroprogesterone. Data are mean ± SEM (n = 4). * Represent values significantly different (p < 0.05) compared to the control media, DMEM + DMSO (DMSO) (Micevych et al., 2007).
Figure 3
Figure 3
Effect of mGluR1a antagonist, LY 367385, on the estradiol-induced [Ca2+]i flux in post-pubertal hypothalamic astrocytes. LY367385 inhibited the estradiol (E2) stimulated release of Ca2+ from internal stores. Astrocytes were stimulated with E2 and then washed for 7 min. prior to the second E2 stimulation, LY367385 was added. * Significantly different compared with E2 stimulation alone (p<0.05, Student’s t-test).
Figure 4
Figure 4
Estradiol did not induce neuroprogesterone synthesis in reproductively senescent, 9 month old Long-Evans female rats exhibiting continuous cornified vaginal smears) for 30 days (indicating they were in constant estrous (CE)). CE rats were ovx/adx and subsequently subcutaneously injected with estradiol (50 µg EB) or the safflower oil vehicle. Brain tissue was examined for neuroprogesterone 45 hr after EB. Unlike young animals, estradiol treatment had no effect on hypothalamic, progesterone levels (2 way ANOVA (2,23), F = 2.237, p = 0.15) or serum levels (t-test df = 6, t = 1.34, p = 0.23 (Fig 4).Values are means ± SEM of at least 9 animals per group. Abbreviations: CRB: cerebellum; HYPO: hypothalamus; CTX: cortex.

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