31 August 2007. Is estrogen neuroprotective? Laboratory studies suggest yes, but epidemiological evidence is mixed. Trumping all, the results of the Women’s Health Study—showing no benefit, but exactly the opposite with an increased risk of dementia in older women on hormone replacement therapy—dealt a body blow to both basic and clinical research on the question (Rapp et al., 2003; Shumaker et al., 2003; also see ARF Live Discussion).
For estrogen, however, evidence is mounting that timing and drug selectivity is everything. The idea that there is a window of opportunity for neuroprotection by the hormone, and that it comes early in menopause, got support this week from two papers showing that women who have their ovaries removed before menopause have a higher risk of cognitive impairment, dementia, and movement disorders later in life. The earlier the women lose their natural supply of estrogen, the higher the risk appears to be. The studies, from Walter Rocca and colleagues at the Mayo Clinic in Rochester, Minnesota, appear in the August 29 online Neurology. Other new papers, from Rhonda Voskuhl at the University of California David Geffen School of Medicine in Los Angeles and Roberta Brinton of the University of Southern California in Los Angeles, build on a growing understanding of the multiple receptors and cellular targets involved in estrogen’s actions. Their studies suggest that activating the right receptors and pathways with selective agonists also is important for harnessing neuroprotective effects of estrogen.
For the epidemiological work, Rocca and colleagues tracked nearly 3,000 women long-term, half of whom had one or both ovaries removed before menopause. Median follow-up was 25 years. Women who lost one or both ovaries before menopause had a 1.5 times increased risk of cognitive impairment or dementia compared to a reference group of women who kept their ovaries. The risk increased to nearly twofold in women who had surgery before age 43. For movement disorders (parkinsonism), the same effects were seen, but were statistically weaker, and need to be confirmed in other studies.
“This study is one of the first to support the hypothesis of a critical age window for the protective effect of estrogen on the brain in humans,” the authors conclude. This fits with a growing appreciation that hormone replacement therapy that strives to really replace what’s missing—using hormone preparations that mimic natural estrogens, and deploying them early in menopause—may be the key to preserving mental capacity and possibly, preventing Alzheimer disease (see recent comment to Hao et al., 2007 on this topic).
One of the roadblocks to harnessing the neuroprotective effects of estrogen is our limited understanding of the complex pathways it activates. Estrogen acts through multiple receptors. In animal models it shows both neuroprotective and anti-inflammatory actions, but the relationship between the two is unclear. In this week’s PNAS online, Voskuhl and colleagues report using selective estrogen receptor agonists to separate the neuroprotective and anti-inflammatory actions in a mouse model of multiple sclerosis. Their results suggest that activation of one type of estrogen receptor (ERα) is both neuroprotective and anti-inflammatory, while another (ERβ) mediates neuroprotection without affecting inflammation. The prospect that treatment with specific ERβ ligands may be neuroprotective has the added advantage such ligands might get around the cancer-causing effects of estrogen, which stem from ERα activation.
Voskuhl’s data highlight the need for selective estrogen analogs, a need that Brinton and coworkers are working to address. In the current Journal of Medicinal Chemistry, Brinton and collaborators from RTI International, a private research institute in Research Triangle Park, North Carolina, introduce a new estrogen receptor ligand that shows neuroprotective effects against glutamate toxicity in cultured rat hippocampal neurons. Their compound also activates pathways related to neuroprotection (ERK2 and Akt kinases, and antiapoptotic proteins) and increases dendritic spine protein levels. The researchers had previously found that an FDA-approved anti-estrogenic compound (ICI 182,780), which antagonizes the ability of estrogen to drive proliferation in reproductive tissues, has estrogen receptor agonist activity in neurons (Zhao et al., 2006). Their new work shows that an analog of this compound, tailored to enhance entry into the brain, keeps its neuroprotective actions.
Selective Estrogen Receptor Modulators (aka SERMs) are a far cry from the concoction commonly used for estrogen replacement therapy, a mixture of conjugated hormones derived from horse urine. Estrogens clearly have neuroprotective and anti-amyloidogenic properties. Perhaps in the future, the ability to tickle the right estrogen receptor with the right ligand in the right place at the right time will unlock the hidden potential of this neuroprotective pathway.—Pat McCaffrey.
Rocca WA, Bower JH, Maraganore DM Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ. Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007 Aug 29; early online publication. Abstract
Rocca WA, Bower JH, Maraganore DM Ahlskog JE, Grossardt BR, de Andrade M, Melton LJ. Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2007 Aug 29; early online publication. Abstract
Tiwari-Woodruff S, Morales LBJ, Lee R, Voskuhl RR. Differential neuroprotective and anti-inflammatory effects of estrogen receptor (ER)α and ERβ ligand treatment. Proc. Natl. Acad. Sci. Early Edition. 2007 Aug 27. Abstract
Zhao L, Jin C, Mao Z, Gopinathan MB, Rehder K, Brinton RD. Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator-a hybrid structure of 17β-estradiol and vitamin e in hippocampal neurons. J Med Chem. 2007 Sep 6;50(18):4471-81. Epub 2007 Aug 14. Abstract