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.

References:
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

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  1. Comment by Gemma Casadesus, George Perry, Kathryn Bryan, Mark A. Smith

    Estrogen and Alzheimer Disease: Is It Really All in the Timing?
    There is a wealth of evidence, including this latest study, suggesting the involvement of sex steroids in the etiology of Alzheimer disease (AD) (reviewed in Manly et al., 2000; Casadesus et al., 2004; Casadesus et al., 2005) and data indicating a positive effect of hormone replacement therapy (HRT, Henderson et al., 1994; Kawas et al., 1997).

    However, contradicting findings from the Women's Health Initiative Memory Study, reporting negative cognitive effects following HRT in women at an AD-vulnerable age (Henderson et al., 2003; Rapp et al., 2003; Shumaker et al., 2003; Almeida et al., 2006) have caused complete havoc in the estrogen research field and cast serious doubt on the role of sex steroid hormones in age-related cognitive decline, neuronal dysfunction, and AD etiology. One key issue that these seemingly opposing studies lead to is the importance of the timing of estrogen treatment. However, other alternative explanations are equally, if not more, plausible. Indeed, one must not forget that estrogen is part of a hormonal axis and thus does not work alone.

    In this regard, a more encompassing hypothesis for the timing effects of HRT is that degenerating dynamics within the hypothalamic-pituitary-gonadal (HPG)-axis observed during and after the menopausal years, specifically the capacity of estrogen to suppress rising levels of the gonadotropin luteinizing hormone (LH), is a key element in AD-related cognitive/neuronal function decline. In support of this, estrogen-feedback on LH secretion (Lloyd et al., 1994) and GnRH gene expression (Park et al., 1990) is decreased during aging. Estrogen also becomes increasingly less effective at modulating LH expression and biosynthesis the later HRT is started after ovariectomy (OVX, King et al., 1987). These later findings parallel those for cognitive decline after menopause and OVX, such that HRT begun a long interval after menopause or OVX fails to rescue cognitive/neuronal function associated with these events (reviewed in Gibbs, 2000; Sherwin, 2005; Daniel et al., 2006). Also of note is the fact that LH receptors are present in the highest levels in the hippocampus (Lei et al., 1993), a major cognition center; ICV treatment with hCG has behavior modulatory effects (Lukacs et al., 1995). Aged transgenic AD mice (Tg 2576) treated with leuprolide acetate, a GnRH agonist that depletes levels of gonadotropins and sex steroids via the internalization of the GnRH receptor, showed sustained cognitive function compared to non-treated animals (Casadesus et al., 2006). In clinical trials, luprolide acetate appears to also benefit patients with AD (see publications list of sponsoring company).

    Timing certainly plays a role, but a question that is also worth asking is whether estrogen is the single bright star that it has been reputed to be until now or simply one of the stars of a well-organized team (Webber et al., 2005).

    View all comments by Kathryn Bryan

References

Webinar Citations

  1. Not Dead Yet: Estrogen Deserves Another Chance

Paper Citations

  1. . Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2663-72. PubMed.
  2. . Estrogen plus progestin and the incidence of dementia and mild cognitive impairment in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA. 2003 May 28;289(20):2651-62. PubMed.
  3. . Interactive effects of age and estrogen on cognition and pyramidal neurons in monkey prefrontal cortex. Proc Natl Acad Sci U S A. 2007 Jul 3;104(27):11465-70. PubMed.
  4. . Estrogenic agonist activity of ICI 182,780 (Faslodex) in hippocampal neurons: implications for basic science understanding of estrogen signaling and development of estrogen modulators with a dual therapeutic profile. J Pharmacol Exp Ther. 2006 Dec;319(3):1124-32. PubMed.
  5. . Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007 Sep 11;69(11):1074-83. PubMed.
  6. . Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008 Jan 15;70(3):200-9. PubMed.
  7. . Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. PubMed.
  8. . Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons. J Med Chem. 2007 Sep 6;50(18):4471-81. PubMed.

Further Reading

Papers

  1. . Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998 Apr;4(4):447-51. PubMed.
  2. . Androgens regulate the development of neuropathology in a triple transgenic mouse model of Alzheimer's disease. J Neurosci. 2006 Dec 20;26(51):13384-9. PubMed.
  3. . Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007 Sep 11;69(11):1074-83. PubMed.
  4. . Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008 Jan 15;70(3):200-9. PubMed.
  5. . Conjugated equine estrogens and incidence of probable dementia and mild cognitive impairment in postmenopausal women: Women's Health Initiative Memory Study. JAMA. 2004 Jun 23;291(24) PubMed.
  6. . Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons. J Med Chem. 2007 Sep 6;50(18):4471-81. PubMed.
  7. . Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. PubMed.

Primary Papers

  1. . Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology. 2007 Sep 11;69(11):1074-83. PubMed.
  2. . Increased risk of parkinsonism in women who underwent oophorectomy before menopause. Neurology. 2008 Jan 15;70(3):200-9. PubMed.
  3. . Design, synthesis, and estrogenic activity of a novel estrogen receptor modulator--a hybrid structure of 17beta-estradiol and vitamin E in hippocampal neurons. J Med Chem. 2007 Sep 6;50(18):4471-81. PubMed.
  4. . Differential neuroprotective and antiinflammatory effects of estrogen receptor (ER)alpha and ERbeta ligand treatment. Proc Natl Acad Sci U S A. 2007 Sep 11;104(37):14813-8. PubMed.