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Estradiol Membrane‐Initiated Signaling and Female Reproduction

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ABSTRACT

The discoveries of rapid, membrane‐initiated steroid actions and central nervous system steroidogenesis have changed our understanding of the neuroendocrinology of reproduction. Classical nuclear actions of estradiol and progesterone steroids affecting transcription are essential. However, with the discoveries of membrane‐associated steroid receptors, it is becoming clear that estradiol and progesterone have neurotransmitter‐like actions activating intracellular events. Ultimately, membrane‐initiated actions can influence transcription. Estradiol membrane‐initiated signaling (EMS) modulates female sexual receptivity and estrogen feedback regulating the luteinizing hormone (LH) surge. In the arcuate nucleus, EMS activates a lordosis‐regulating circuit that extends to the medial preoptic nucleus and subsequently to the ventromedial nucleus (VMH)—the output from the limbic and hypothalamic regions. Here, we discuss how EMS leads to an active inhibition of lordosis behavior. To stimulate ovulation, EMS facilitates astrocyte synthesis of progesterone (neuroP) in the hypothalamus. Regulation of GnRH release driving the LH surge is dependent on estradiol‐sensitive kisspeptin (Kiss1) expression in the rostral periventricular nucleus of the third ventricle (RP3V). NeuroP activation of the LH surge depends on Kiss1, but the specifics of signaling have not been well elucidated. RP3V Kiss1 neurons appear to integrate estradiol and progesterone information which feeds back onto GnRH neurons to stimulate the LH surge. In a second population of Kiss1 neurons, estradiol suppresses the surge but maintains tonic LH release, another critical component of the estrous cycle. Together, evidence suggests that regulation of reproduction involves membrane action of steroids, some of which are synthesized in the brain. © 2015 American Physiological Society. Compr Physiol 5:1211‐1222, 2015.

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Figure 1. Figure 1. Female rats were anesthetized with pentobarbital and injection (i.v.) with 100 μCi/100 g body weight of 2,4,6,7,16,17‐[3H]estradiol (specific activity 130 Ci/mmol, New England Nuclear). At 2 h after injection of the isotope, animals were killed, brains removed and cryosectioned (l0 μm) through the medial preoptic nucleus (MPN) and lateral preoptic area (LPOA). Sections were collected under safe‐light conditions and thaw‐mounted onto slides which had been coated with nuclear track emulsion and exposed at −70°C for 28 weeks, then photodeveloped. The MPN contains many cells that concentrate 3H‐estradiol as indicated by the accumulation of silver grains over nuclei (arrow). In the LPOA, some cells have accumulations of silver grains (arrow) but levels are much lower in both the estradiol‐accumulating cells and the surrounding background compared with the MPN. Bar in LPOA is 20 μm and applies to both images. Sections are adapted, with permission, from a study by Akesson TR and Micevych PE ().
Figure 2. Figure 2. The estradiol (E2) induction of sexual receptivity in the female rat is indicated by lordosis behavior. The CNS regulation of this global response to hormonal and sensory input is regulated by a diffuse circuit that extends from the limbic system to the spinal cord. Within this lordosis regulating circuit, E2 acts rapidly through estrogen membrane signaling (EMS) to release neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH), which activates β‐endorphin (β‐END) projection neurons that extend to the medial preoptic nucleus (MPN). The MPN is an important integrative node receiving accessory olfactory and limbic input. β‐END activates μ‐opioid receptors (MOR), producing a transient inhibition of the MPN which is relieved by progesterone in the cycling female. The MPN MOR neurons in turn project to the ventromedial nucleus of the hypothalamus (VMH), the final common output of the hypothalamus. The integrated hypothalamic output is modified by inputs from the periaquaductal gray, and the vestibular complex on its way to the motoneurons mediating lordosis behavior. The EMS that mediates this activation of the circuit requires the transactivation of metabotropic glutamate receptor‐1a (mGluR1a), which leads to the phosphorylation of PKCθ and the release of NPY and activation of the Y1 receptor on β‐END projection cells. The EMS and resulting transient inhibition is necessary for the full expression of lordosis behavior in the rat [adapted, with permission, from ()].
Figure 3. Figure 3. A model showing proposed estradiol (E2) actions on hypothalamic cells. In Kiss1 neurons, E2 acts at both membrane and nuclear estrogen receptors. During diestrus, classical nuclear E2 signaling induces PR expression in kisspeptin (Kiss1) neurons in the RP3V. On proestrus, rising E2 leads to transactivation of mGluR1a in astrocytes, which increases [Ca2+]i leading to stimulation of a kinase cascade resulting in the activation of translocator protein (TSPO) and steroid acute regulatory protein (StAR), which results in an increase of cholesterol import into the mitochondrion—the rate limiting step in steroidogenesis. The resulting pregnenolone (PREG) is converted to progesterone (neuroP) by 3β‐HSD. Simultaneously, E2 activates an ERα‐mGluR1a complex in neurons leading to the expression of Kiss1. Newly synthesized neuroP diffuses out of the astrocytes and activates E2‐induced PR, which have been trafficked to the Kiss1 neuronal membrane. This leads to a series of events culminating in Kiss1 secretion onto GPR54 expressing GnRH neurons. We hypothesize that signaling through the membrane PR involves transactivation of another receptor (indicated by [?]) to stimulate [Ca2+]i, and induce Kiss1 release, activating GnRH neurons and triggering the E2‐induced LH surge from anterior pituitary gonadotrophs.


Figure 1. Female rats were anesthetized with pentobarbital and injection (i.v.) with 100 μCi/100 g body weight of 2,4,6,7,16,17‐[3H]estradiol (specific activity 130 Ci/mmol, New England Nuclear). At 2 h after injection of the isotope, animals were killed, brains removed and cryosectioned (l0 μm) through the medial preoptic nucleus (MPN) and lateral preoptic area (LPOA). Sections were collected under safe‐light conditions and thaw‐mounted onto slides which had been coated with nuclear track emulsion and exposed at −70°C for 28 weeks, then photodeveloped. The MPN contains many cells that concentrate 3H‐estradiol as indicated by the accumulation of silver grains over nuclei (arrow). In the LPOA, some cells have accumulations of silver grains (arrow) but levels are much lower in both the estradiol‐accumulating cells and the surrounding background compared with the MPN. Bar in LPOA is 20 μm and applies to both images. Sections are adapted, with permission, from a study by Akesson TR and Micevych PE ().


Figure 2. The estradiol (E2) induction of sexual receptivity in the female rat is indicated by lordosis behavior. The CNS regulation of this global response to hormonal and sensory input is regulated by a diffuse circuit that extends from the limbic system to the spinal cord. Within this lordosis regulating circuit, E2 acts rapidly through estrogen membrane signaling (EMS) to release neuropeptide Y (NPY) in the arcuate nucleus of the hypothalamus (ARH), which activates β‐endorphin (β‐END) projection neurons that extend to the medial preoptic nucleus (MPN). The MPN is an important integrative node receiving accessory olfactory and limbic input. β‐END activates μ‐opioid receptors (MOR), producing a transient inhibition of the MPN which is relieved by progesterone in the cycling female. The MPN MOR neurons in turn project to the ventromedial nucleus of the hypothalamus (VMH), the final common output of the hypothalamus. The integrated hypothalamic output is modified by inputs from the periaquaductal gray, and the vestibular complex on its way to the motoneurons mediating lordosis behavior. The EMS that mediates this activation of the circuit requires the transactivation of metabotropic glutamate receptor‐1a (mGluR1a), which leads to the phosphorylation of PKCθ and the release of NPY and activation of the Y1 receptor on β‐END projection cells. The EMS and resulting transient inhibition is necessary for the full expression of lordosis behavior in the rat [adapted, with permission, from ()].


Figure 3. A model showing proposed estradiol (E2) actions on hypothalamic cells. In Kiss1 neurons, E2 acts at both membrane and nuclear estrogen receptors. During diestrus, classical nuclear E2 signaling induces PR expression in kisspeptin (Kiss1) neurons in the RP3V. On proestrus, rising E2 leads to transactivation of mGluR1a in astrocytes, which increases [Ca2+]i leading to stimulation of a kinase cascade resulting in the activation of translocator protein (TSPO) and steroid acute regulatory protein (StAR), which results in an increase of cholesterol import into the mitochondrion—the rate limiting step in steroidogenesis. The resulting pregnenolone (PREG) is converted to progesterone (neuroP) by 3β‐HSD. Simultaneously, E2 activates an ERα‐mGluR1a complex in neurons leading to the expression of Kiss1. Newly synthesized neuroP diffuses out of the astrocytes and activates E2‐induced PR, which have been trafficked to the Kiss1 neuronal membrane. This leads to a series of events culminating in Kiss1 secretion onto GPR54 expressing GnRH neurons. We hypothesize that signaling through the membrane PR involves transactivation of another receptor (indicated by [?]) to stimulate [Ca2+]i, and induce Kiss1 release, activating GnRH neurons and triggering the E2‐induced LH surge from anterior pituitary gonadotrophs.
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Paul E Micevych, Angela May Wong, Melinda Anne Mittelman‐Smith. Estradiol Membrane‐Initiated Signaling and Female Reproduction. Compr Physiol 2015, 5: 1211-1222. doi: 10.1002/cphy.c140056