ReviewEstradiol regulation of progesterone synthesis in the brain
Introduction
The brain has always been considered a target for sex steroid hormones produced by peripheral steroidogenic organs, the gonads and the adrenal glands, but it is now well accepted that the brain synthesizes neurosteroids de novo, and converts circulating steroids to neuroactive steroids (Corpechot et al., 1981, Guennoun et al., 1995, Jung-Testas et al., 1989, Jung-Testas et al., 1991, Kohchi et al., 1998, Micevych et al., 2007, Robel and Baulieu, 1995, Sanne and Krueger, 1995, Sinchak et al., 2003, Zwain and Yen, 1999). Regardless of their origin, steroids affect brain function through actions at their cognate receptors, or by affecting receptors whose primary transmitter is not a steroid (e.g., GABA receptors).
As with a number of different signaling molecules, the site of their synthesis has been used to classify them as hormones or neurotransmitters. Similarly, sex steroids of peripheral origin are hormones. They are released into the general circulation to act on distal target sites that have the appropriate receptors, which includes nervous tissue. Neurosteroids are neurotransmitters: they are made in the brain, their synthesis and levels are regulated and they influence neuronal activity by modulating intracellular signaling pathways, channels and transcription.
This awareness of neurosteroid function led Kawato et al. (2003) to classify these compounds as fourth generation (4-G) neurotransmitters. In this schema, first generation transmitters are the small molecular weight messengers (e.g., acetylcholine, glutamate and GABA). Second generation neurotransmitters are catecholamines (e.g., dopamine, serotonin), and third generation neurotransmitters are large family of neuropeptides (e.g., neuropeptide Y (NPY), cholecystokinin (CCK), β-endorphin). Although Kawato et al. (2003) suggest that neurosteroids are the 4-G transmitters, this class of neurotransmitter should include not only neurosteroids (e.g., progesterone, estrogen), but also gaseous transmitters (e.g., nitric oxide, carbon monoxide) and endocannabinoids. The 4-G transmitters employ a volumetric mode of transmission affecting a region of the brain rather than the more classical point to point neurotransmission of the first generation neurotransmitters. Moreover, 4-G neurotransmitters are unique, they are regulated at the level of synthesis unlike other classes of transmitters which are stored and whose release is tightly controlled. Once 4-G neurotransmitters are synthesized—they are rapidly released to affect surrounding cells.
One of the more intriguing questions has been the relationship of peripheral steroids to neurosteroids. Free steroids (i.e., steroids not bound to carrier proteins) are capable of diffusing across the blood–brain barrier to bind both membrane-associated steroid receptors and intracellular receptors. Thus, levels of a particular steroid in the brain are a composite of steroids from the periphery, converted peripheral steroids, and neurosteroids. Additionally, hormonal steroids also regulate the site-specific synthesis of neurosteroid levels (Maguire and Mody, 2007, Micevych et al., 2003) and their cognate receptors (Chappell and Levine, 2000, MacLusky and McEwen, 1978, Soma et al., 2005) that affect neurosteroid levels and function. Such peripheral sex steroid–neurosteroid interactions are the subject of this review, especially as it relates to neuroprogesterone synthesis.
Section snippets
Model of estrogen positive feedback
In a cycling rat, steroidogenesis in ovarian follicles is stimulated by gonadotropins released from the pituitary gland. As the cycle advances the levels of circulating estradiol increase until they peak on the afternoon of proestrus. This spike of estradiol signals the process of estrogen positive feedback that stimulates the surge release of gonadotropin releasing hormone that triggers the of surge release of LH from the pituitary. In the ovary, LH induces ovulation and the luteinization of
Regulation of neurosteroidogenesis
Steroids are derived from cholesterol. There are two sources of cholesterol for steroidogenesis: the lipoproteins in the circulation and from de novo synthesis in the individual cells (Freeman, 1987). However, circulating cholesterol cannot cross the blood–brain barrier, and cholesterol is produced de novo in the brain (reviewed in Bjorkhem and Meaney, 2004) Almost all brain cholesterol is unesterified, and comprises a structural component of myelin sheaths (oligodendrocytes) and the plasma
Menopause
A consequence of the loss of neuroprogesterone synthesis may be reproductive senescence in which estrogen positive feedback is attenuated and then lost (Micevych et al., 2008b). One of the first signs of reproductive aging is a reduction in the magnitude of the LH surge (Cooper et al., 1980, Nass et al., 1984, Wise, 1982), which is followed by irregular estrous cycles suggesting impaired estrogen positive feedback. Eventually, the rat becomes acyclic, exhibiting a cornified vaginal cytology—a
Summary
In addition to its role as a hormone, progesterone made in the nervous system, neuroprogesterone, may be one of a family of 4-G neurotransmitters that are regulated at the level of their synthesis. They diffuse and activate cognate receptors to influence neuronal activity and function. Neuroprogesterone and its metabolites also have the ability to activate different receptors expanding their role as neuroactive compounds. Neuroprogesterone has been implicated in a variety of tropic and
Acknowledgements
We appreciate the contributions of our collaborators Drs. Dewing, Chaban, Kuo and Bondar. The research was supported by NIH grant HD042635.
References (82)
- et al.
Differential effects of calcium on progesterone production in small and large bovine luteal cells
J. Steroid Biochem.
(1990) - et al.
Phosphorylation of steroidogenic acute regulatory protein (StAR) modulates its steroidogenic activity
J. Biol. Chem.
(1997) - et al.
Estradiol inhibits atp-induced intracellular calcium concentration increase in dorsal root ganglia neurons
Neuroscience
(2003) Cyclic AMP mediated modification of cholesterol traffic in Leydig tumor cells
J. Biol. Chem.
(1987)- et al.
A key enzyme in the biosynthesis of neurosteroids, 3 beta-hydroxysteroid dehydrogenase/delta 5-delta 4-isomerase (3 beta-HSD), is expressed in rat brain
Brain Res. Mol. Brain Res.
(1995) - et al.
Estrogen-inducible progesterone receptor in primary cultures of rat glial cells
Exp. Cell Res.
(1991) - et al.
Unveiling the mechanism of action and regulation of the steroidogenic acute regulatory protein
Mol. Cell. Endocrinol.
(1998) - et al.
Brain neurosteroids are 4th generation neuromessengers in the brain: cell biophysical analysis of steroid signal transduction
Adv. Biophys.
(2003) - et al.
Age- and region-specific expressions of the messenger RNAs encoding for steroidogenic enzymes p450scc, P450c17 and 3beta-HSD in the postnatal rat brain
Brain Res.
(1998) - et al.
The endogenous benzodiazepine receptor ligand ODN increases cytosolic calcium in cultured rat astrocytes
Brain Res. Mol. Brain Res.
(1996)
Interaction between ovarian and adrenal steroids in the regulation of gonadotropin secretion
J. Steroid Biochem. Mol. Biol.
Neuroendocrine mechanisms underlying the control of gonadotropin secretion by steroids
Steroids
Neuroprogesterone: key to estrogen positive feedback?
Brain Res. Rev.
Site-specific decrease of progesterone receptor mRNA expression in the hypothalamus of middle-aged persistently estrus rats
Brain Res.
Peripheral benzodiazepine receptor in cholesterol transport and steroidogenesis
Steroids
Targeted disruption of the peripheral-type benzodiazepine receptor gene inhibits steroidogenesis in the R2C Leydig tumor cell line
J. Biol. Chem.
Control of bovine placental progestin synthesis: calcium dependent steroidogenesis is modulated at the site of the cholesterol side chain cleavage enzyme
J. Steroid Biochem.
Role of the steroidogenic acute regulatory protein (StAR) in steroidogenesis
Biochem. Pharmacol.
Novel mechanisms of estrogen action in the brain: new players in an old story
Front. Neuroendocrinol.
Biochemical diversity of cAMP-dependent transcription of steroid hydroxylase genes in the adrenal cortex
J. Biol. Chem.
Definition of estrogen receptor pathway critical for estrogen positive feedback to gonadotropin-releasing hormone neurons and fertility
Neuron
Immunoreactivity for diazepam binding inhibitor in Gomori-positive astrocytes
Regul. Pept.
Brain cholesterol: long secret life behind a barrier
Arterioscler. Thromb. Vasc. Biol.
Estradiol activates group I and II metabotropic glutamate receptor signaling, leading to opposing influences on cAMP response element-binding protein
J. Neurosci.
Acute changes in the estrous cycle following ovariectomy in the golden hamster
Neuroendocrinology
Activity of the pituitary–adrenocortical system and thyroid gland during the oestrous cycle of the rat
J. Endocrinol.
A membrane estrogen receptor mediates intracellular calcium release in astrocytes
Endocrinology
Stimulation of gonadotropin-releasing hormone surges by estrogen. I. Role of hypothalamic progesterone receptors
Endocrinology
Characterization of the LH surge in middle-aged female rats
Biol. Reprod.
Characterization and measurement of dehydroepiandrosterone sulfate in rat brain
Proc. Natl. Acad. Sci. U.S.A.
Neurosteroids: 3 alpha-hydroxy-5 alpha-pregnan-20-one and its precursors in the brain, plasma, and steroidogenic glands of male and female rats
Endocrinology
Attenuation of preovulatory gonadotrophin surges by epostane: a new inhibitor of 3 beta-hydroxysteroid dehydrogenase
J. Endocrinol.
Dose dependent effects of progesterone on the facilitation and inhibition of spontaneous gonadotropin surges in estrogen treated ovariectomized rats
Biol. Reprod.
Membrane estrogen receptor-alpha interactions with metabotropic glutamate receptor 1a modulate female sexual receptivity in rats
J. Neurosci.
Effect of antibodies to 17beta-estradiol and progesterone on the estrous cycle of the rat
Endocrinology
Estrogen-induced activation of Erk-1 and Erk-2 requires the G protein-coupled receptor homolog, GPR30, and occurs via trans-activation of the epidermal growth factor receptor through release of HB-EGF
Mol. Endocrinol.
Estrogen action via the G protein-coupled receptor, GPR30: stimulation of adenylyl cyclase and cAMP-mediated attenuation of the epidermal growth factor receptor-to-MAPK signaling axis
Mol. Endocrinol.
The life cycle of the steroidogenic acute regulatory (StAR) protein: from transcription through proteolysis
Endocr. Res.
Extranuclear steroid receptors: nature and actions
Endocr. Rev.
Midcycle administration of a progesterone synthesis inhibitor prevents ovulation in primates
Proc. Natl. Acad. Sci. U.S.A.
Cited by (91)
Neurosteroids and the mesocorticolimbic system
2023, Neuroscience and Biobehavioral ReviewsThe importance of translationally evaluating steroid hormone contributions to substance use
2023, Frontiers in NeuroendocrinologyThe effect of estrogen and progesterone on melanin-concentrating hormone producing-neurons in brain areas related to reproductive behavior in lactating dams
2023, Journal of Chemical NeuroanatomyCitation Excerpt :The absence of effect of progesterone alone injection was observed in the present study. Since the synthesis of progesterone receptor requires estradiol action (Basurto et al., 2018; Micevych and Sinchak, 2008), our hypothesis is that progesterone activity requires the presence of estradiol, so in ovariectomized female rats injected only with progesterone, the priming effect of estradiol is lacking. Peripherally, the MCH concentration in the bloodstream was also affected by estrogen injection in lactating rats, as demonstrated by our results.
Estradiol and progesterone in female reward-learning, addiction, and therapeutic interventions
2023, Frontiers in NeuroendocrinologyHormone-based models for comparing menstrual cycle and hormonal contraceptive effects on human resting-state functional connectivity
2022, Frontiers in Neuroendocrinology