Elsevier

Hormones and Behavior

Volume 63, Issue 2, February 2013, Pages 284-290
Hormones and Behavior

Review
Progesterone and neuroprotection

https://doi.org/10.1016/j.yhbeh.2012.06.003Get rights and content

Abstract

This article is part of a Special Issue "Hormones & Neurotrauma".

Numerous studies aimed at identifying the role of estrogen on the brain have used the ovariectomized rodent as the experimental model. And while estrogen intervention in these animals has, at least partially, restored cholinergic, neurotrophin and cognitive deficits seen in the ovariectomized animal, it is worth considering that the removal of the ovaries results in the loss of not only circulating estrogen but of circulating progesterone as well. As such, the various deficits associated with ovariectomy may be attributed to the loss of progesterone as well. Similarly, one must also consider the fact that the human menopause results in the precipitous decline of not just circulating estrogens, but in circulating progesterone as well and as such, the increased risk for diseases such as Alzheimer's disease during the postmenopausal period could also be contributed by this loss of progesterone. In fact, progesterone has been shown to exert neuroprotective effects, both in cell models, animal models and in humans. Here, we review the evidence that supports the neuroprotective effects of progesterone and discuss the various mechanisms that are thought to mediate these protective effects. We also discuss the receptor pharmacology of progesterone's neuroprotective effects and present a conceptual model of progesterone action that supports the complementary effects of membrane-associated and classical intracellular progesterone receptors. In addition, we discuss fundamental differences in the neurobiology of progesterone and the clinically used, synthetic progestin, medroxyprogesterone acetate that may offer an explanation for the negative findings of the combined estrogen/progestin arm of the Women's Health Initiative-Memory Study (WHIMS) and suggest that the type of progestin used may dictate the outcome of either pre-clinical or clinical studies that addresses brain function.

Highlights

► Reviews the current state of knowledge on progesterone-induced neuroprotection. ► Reviews the receptor pharmacology associated with progesterone-induced protection. ► Reviews the signaling mechanisms that mediate progesterone-induced protection. ► Defines key differences in the neurobiology of progesterone and MPA.

Section snippets

The biology of progesterone

Progesterone, the natural progestin, is a major gonadal hormone that is synthesized primarily by the ovary in the female, and the testes and adrenal cortex in the male. While progesterone levels are generally higher in the female, it is worth noting that levels of progesterone during the female follicular phase of the menstrual cycle are similar to those seen in males (Strauss and Barbieri, 2004), and thus, may be equally important in males. The “classical” mechanism by which progesterone

Progesterone-induced neuroprotection

Progesterone has been reported to exert protective effects in a variety of experimental models that mimic certain pathogenic aspects of brain dysfunction seen with advanced age- or age-related neurodegenerative diseases such as Alzheimer's disease. For example, physiologically relevant concentrations of progesterone have been shown to significantly attenuate oxidative injury resulting from glutamate (Kaur et al., 2007, Nilsen and Brinton, 2002a, Nilsen and Brinton, 2002b, Nilsen and Brinton,

Mechanisms underlying progesterone's protective effects

Numerous mechanisms of action likely underlie the protective effects of progesterone. The classical genomic mechanism of progesterone action, for example, may be involved in the regulation of neurotrophin expression (Kaur et al., 2007), which in turn, could promote cell survival. Alternatively, progesterone may act through novel receptor systems, such as the membrane PR or the sigma receptor (another putative receptor for progesterone), to activate certain signal transduction pathways, which in

Progesterone and cognitive function

When considering the ovariectomized animal, it is important to recognize that this surgical intervention results in the loss of not just estradiol, but of progesterone as well. As such, the cognitive deficits we and others have observed following ovariectomy may have been contributed by the loss of circulating progesterone as well. And though numerous studies, including those from our laboratory, have clearly described the neuroprotective effects of progesterone against a wide array of insults

Receptor pharmacology of progesterone's protective effects

It is clear that the classical, intracellular/nuclear PR certainly plays an important role in mediating the effects of progesterone. For example, our laboratory has determined that the ability of progesterone to increase the expression (mRNA and protein levels) of brain-derived neurotrophic factor (BDNF), a key mediator of progesterone's protective effects, requires the classical PR (Jodhka et al., 2009). Further, Cai et al. (2008) have implicated the classical/intracellular PR in the

Why the type of progestin matters

It is estimated that by 2010, the population of women between the ages of 45 and 64 will reach approximately 42 million (U.S. Census Bureau. Projected population of the United States, by Age and Sex: 200 to 2050. www.census.gov/ipc/www/usinterimproj/ Internet release date: March 18, 2004). Among the health-related changes and decisions these women will need to consider include whether or not to consider the use of hormone therapy for not just the management of menopausal symptoms, but

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