Review
Progesterone receptors: Form and function in brain

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Abstract

Emerging data indicate that progesterone has multiple non-reproductive functions in the central nervous system to regulate cognition, mood, inflammation, mitochondrial function, neurogenesis and regeneration, myelination and recovery from traumatic brain injury. Progesterone-regulated neural responses are mediated by an array of progesterone receptors (PR) that include the classic nuclear PRA and PRB receptors and splice variants of each, the seven transmembrane domain 7TMPRβ and the membrane-associated 25-Dx PR (PGRMC1). These PRs induce classic regulation of gene expression while also transducing signaling cascades that originate at the cell membrane and ultimately activate transcription factors. Remarkably, PRs are broadly expressed throughout the brain and can be detected in every neural cell type. The distribution of PRs beyond hypothalamic borders, suggests a much broader role of progesterone in regulating neural function. Despite the large body of evidence regarding progesterone regulation of reproductive behaviors and estrogen-inducible responses as well as effects of progesterone metabolite neurosteroids, much remains to be discovered regarding the functional outcomes resulting from activation of the complex array of PRs in brain by gonadally and/or glial derived progesterone. Moreover, the impact of clinically used progestogens and developing selective PR modulators for targeted outcomes in brain is a critical avenue of investigation as the non-reproductive functions of PRs have far-reaching implications for hormone therapy to maintain neurological health and function throughout menopausal aging.

Introduction

It has become increasingly evident that the functions of gonadal steroid hormones, such as progesterone (P4), extend well beyond reproduction. Multiple regions within the central nervous system (CNS) beyond the hypothalamus are targeted by P4, including the hippocampus and cortex. In recent years, both of these extrahypothalamic sites have garnered increasing interest from endocrinologists based on accumulating evidence that P4 has potent and direct neuroprotective and neuroregenerative effects in these brain regions while also regulating estrogen action [20], [44], [91], [94], [102], [127], [135], [172], [182], [201], [202], [214], [231], [232], [243], [244], [246], [295], [299]. The non-reproductive neural effects of P4 have substantial clinical significance, as progestogens are administered in conjunction with estrogens in hormone therapy to counter the proliferative effect of estrogen on the uterine epithelium. Estrogen, 17β-estradiol (E2), acts in concert with progesterone to regulate multiple non-reproductive brain functions, such as cognition and neuroprotection [201], [42], [99], [100], [126], [161], [203], [228], [242], [254], [93]. Perhaps the best-known neural effect of estrogen is its ability to protect neurons against a wide variety of insults including glutamate excitotoxicity, amyloid beta (Aβ), and oxidative stress [201], [202], [42], [99], [100], [126], [161], [228], [242], [254], [39], [38], [64], [253], [292], [306]. On the other hand, the neuroprotective role of P4[42], [99], [100], [126], [161], [228], [242], [101], [162], [156], [98] is just emerging. From a reproductive gonadal hormone perspective, progesterone always acts in concert with E2. However, this is not the case for glial derived progesterone [244], [18] or for current and future therapeutic uses of progesterone [244], [18], [258], [259]. Here, we discuss the non-reproductive neural functions of P4 as well as the possible mechanisms by which P4 achieves these effects, including ‘classical’ progesterone receptor-mediated pathways and alternate ‘non-genomic’ mechanisms.

Section snippets

Progesterone receptors from membrane to nucleus

The classical nuclear progesterone receptor (cPR) was first characterized in the 1970s and since this time, has been localized to many regions of the CNS, including the hippocampus, cortex, hypothalamus, and cerebellum [117], [116], [115], [114], [43], [147], [120], [121], [145], [146]. Like most steroids, P4 exerts its effects by binding and activating specific cellular receptors. According to the common theory of steroid action, P4 effects are mediated by binding to its cognate receptors

Progesterone receptors in the brain: the case for multiple isoforms

Two major isoforms of cPR are known to exist, the full-length B isoform (PRB) and the N-terminal-truncated A isoform (PRA) [55]. Both isoforms are encoded by a single gene (with 8 exons), with translation being initiated from separate start codons (Fig. 1). Like other steroid nuclear receptors, cPR is composed of a variable N-terminal region (encoded by exon 1), a conserved DNA-binding domain (encoded by exons 2 and 3), a variable hinge region (encoded by part of exon 4), and a conserved

Localization of progesterone receptors in the brain

Progesterone receptors are broadly expressed throughout the brain, with no apparent restriction to specific cell types. Nevertheless, PR expression may vary depending on the brain region, cell type, or hormonal status (Fig. 3). Both of the classical PR isoforms (PRA and PRB) are expressed in the hippocampus and frontal cortex of the rat (Fig. 3). PR immunoreactivity is especially high within the bed nucleus of the stria terminalis (BST), in particular the medial division of the medial nucleus

Mechanisms of progesterone action

Progesterone produces multiple effects in the brain through three principle mechanisms: regulation of gene expression, modulation of neurotransmitter systems, and activation of signaling cascades. Classification of the determinant pathways and identification of the specific receptors mediating activation of each of these pathways would be expected to uncover new targets and enable development of improved therapeutic strategies. The effects of P4 are historically thought to be mediated by PRA or

Neuroprotective actions of progesterone and progestin in the CNS

P4 has established neuroprotective actions that likely involve several different mechanisms. Anxiolytic effects are one way by which P4 can reduce neural injury. Diverse stimuli including kainate [25], pilocarpine [275], and pentylenetetrazole [143] elicit stereotypic seizure behaviors and within several hours to a few days, significant neuronal loss in select brain regions such as the hippocampus. In these paradigms, P4 treatment attenuates not only seizure behaviors ([131], Rhodes, 2004

Progesterone regulation of memory and neuronal excitability

After more than three decades of research, it is now well established that the ovarian hormone, E2, exerts a wide variety of effects on neural structures and function, particularly within the hippocampus [191], [298], [296]. Electrophysiological studies have shown that E2 enhances hippocampal CA1 synaptic transmission and plasticity by increasing NMDA and AMPA receptor activity, which results in neuronal excitation [268], [75], [293], [294]. While the above studies have focused exclusively on

Progesterone regulation of glial cell function and response

Progesterone regulates responses in each of the major glial cell types, astrocytes, microglia, oligodendrocytes and Schwann cells. During the estrous cycle astrocyte size varies with CA1 astrocytes shrinking immediately before increases in spine density [153]. Astrocytes also decrease in size in the rostral preoptic location of gonadotropin-releasing hormone cell bodies [45]. Astrocyte size is strongly associated with the expression of glial fibrillary acidic protein (GFAP), which varies during

Progesterone regulation of meiosis and mitosis

During development of both vertebrates and invertebrates, P4 promotes meiosis to generate germ cells [19], [47], [240]. P4 induced re-entry into the cell cycle at mediated by a membrane-bound PR [19], [17], [21], [270], [123].

P4 promotion of meiosis is mediated by a rise in intracellular Ca2+[24], [196], [286]. In Xenopus oocytes, P4 induces the resumption of meiosis (maturation) through a non-genomic mechanism involving inhibition of adenylyl cyclase and reduction of intracellular cAMP.

Progesterone and estrogen regulation of neurogenesis and neural progenitor proliferation

As in the uterus [56], [105], P4 regulation of mitosis of neural progenitors in brain has a complex profile. Tanapat et al. have shown that ovariectomized rats treated with a high level of E2 have enhanced hippocampal cell proliferation, whereas subsequent exposure to P4 resulted in blockade of the E2-induced enhancement of cell proliferation [266]. In contrast to P4 regulation of E2-induced neurogenesis in vivo, we have demonstrated that P4 alone enhances cell proliferation in vitro[284]. More

Progesterone and regulation Alzheimer’s disease pathology

A key hypothesis linking P4 to AD posits that P4 acts as an endogenous regulator of β-amyloid (Aβ) metabolism. According to the widely but not universally embraced ‘amyloid cascade hypothesis,’ AD pathogenesis is triggered by any of a number of events that have the final common endpoint of increasing the pool of soluble Aβ [125], [124], [255]. In turn, elevated soluble Aβ leads to the formation of an array of soluble oligomeric, minimally soluble aggregated, and eventually insoluble fibrillar

Progestogens, progestins and metabolism

Many progestogens are used therapeutically among these, P4 is the only naturally occurring progestogen (see Table 1). The remainder, which are synthetic, are referred to as progestins (see Table 1) [257]. Progestins are classified on the basis of their chemical structure, since the structures of these molecules vary widely. Progestins can be divided into those related in chemical structure to P4 and those related chemically to testosterone. The classification scheme and the names of progestins

Progestogen metabolism

With the exception of P4, little is known about the metabolism of most progestogens. Baulieu first discovered that P4 is converted to neuroactive metabolites in the brain [20], [243], [242]. This has now been well established by many laboratories and documented in multiple species including the rodent and human. Neurosteroids such as APα are synthesized in the central and peripheral nervous system, primarily by myelinating glial cells, but also by astrocytes and several neuron types [243], [193]

Progesterone and PRs: translational and therapeutic challenges

Relative to estrogen neurobiology, the non-reproductive neural functions of P4 and the basic genomic, signaling and cell biology of these processes are just emerging. Progesterone and its neuroactive metabolites can promote the viability of neurons and function of glial cells within both the central and peripheral nervous system. While there is a substantial body of evidence regarding the pleiotrophic actions of P4[244], much remains to be determined regarding the specific PR required and the

Acknowledgments

Development of this work was supported by the National Institute of Aging P01AG026572 on Progesterone in Brain Aging and Alzheimer’s Disease to R.D.B.

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