Review
Estradiol regulation of progesterone synthesis in the brain

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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-α 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.

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.

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