Estrogen and Neuroprotection: A Matter of Time?

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

Comments

  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).

    References:

    Almeida OP, Lautenschlager NT, Vasikaran S, Leedman P, Gelavis A, Flicker L. A 20-week randomized controlled trial of estradiol replacement therapy for women aged 70 years and older: effect on mood, cognition and quality of life. Neurobiol Aging. 2006 Jan;27(1):141-9. PubMed.

    Casadesus G, Atwood CS, Zhu X, Hartzler AW, Webber KM, Perry G, Bowen RL, Smith MA. Evidence for the role of gonadotropin hormones in the development of Alzheimer disease. Cell Mol Life Sci. 2005 Feb;62(3):293-8. PubMed.

    Casadesus G, Webber KM, Atwood CS, Pappolla MA, Perry G, Bowen RL, Smith MA. Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta. 2006 Apr;1762(4):447-52. PubMed.

    Casadesus G, Zhu X, Atwood CS, Webber KM, Perry G, Bowen RL, Smith MA. Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease. Curr Drug Targets CNS Neurol Disord. 2004 Aug;3(4):281-5. PubMed.

    Daniel JM, Hulst JL, Berbling JL. Estradiol replacement enhances working memory in middle-aged rats when initiated immediately after ovariectomy but not after a long-term period of ovarian hormone deprivation. Endocrinology. 2006 Jan;147(1):607-14. PubMed.

    Gibbs RB. Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging. 2000 Jan-Feb;21(1):107-16. PubMed.

    Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L. Estrogen exposures and memory at midlife: a population-based study of women. Neurology. 2003 Apr 22;60(8):1369-71. PubMed.

    Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG. Estrogen replacement therapy in older women. Comparisons between Alzheimer's disease cases and nondemented control subjects. Arch Neurol. 1994 Sep;51(9):896-900. PubMed.

    Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle DD, Metter E. A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology. 1997 Jun;48(6):1517-21. PubMed.

    King JC, Anthony EL, Damassa DA, Elkind-Hirsch KE. Morphological evidence that luteinizing hormone-releasing hormone neurons participate in the suppression by estradiol of pituitary luteinizing hormone secretion in ovariectomized rats. Neuroendocrinology. 1987 Jan;45(1):1-13. PubMed.

    Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES. Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology. 1993 May;132(5):2262-70. PubMed.

    Lloyd JM, Hoffman GE, Wise PM. Decline in immediate early gene expression in gonadotropin-releasing hormone neurons during proestrus in regularly cycling, middle-aged rats. Endocrinology. 1994 Apr;134(4):1800-5. PubMed.

    Lukacs H, Hiatt ES, Lei ZM, Rao CV. Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav. 1995 Mar;29(1):42-58. PubMed.

    Manly JJ, Merchant CA, Jacobs DM, Small SA, Bell K, Ferin M, Mayeux R. Endogenous estrogen levels and Alzheimer's disease among postmenopausal women. Neurology. 2000 Feb 22;54(4):833-7. PubMed.

    Park OK, Gugneja S, Mayo KE. Gonadotropin-releasing hormone gene expression during the rat estrous cycle: effects of pentobarbital and ovarian steroids. Endocrinology. 1990 Jul;127(1):365-72. PubMed.

    Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D, . 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.

    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 Sep 11;69(11):1074-83. PubMed.

    Sherwin BB. Estrogen and memory in women: how can we reconcile the findings?. Horm Behav. 2005 Mar;47(3):371-5. PubMed.

    Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, . 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.

    Webber KM, Casadesus G, Marlatt MW, Perry G, Hamlin CR, Atwood CS, Bowen RL, Smith MA. Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis. Ann N Y Acad Sci. 2005 Jun;1052:201-9. PubMed.

    View all comments by Kathryn Bryan

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References

Webinar Citations

  1. Not Dead Yet: Estrogen Deserves Another Chance

Paper Citations

  1. Rapp SR, Espeland MA, Shumaker SA, Henderson VW, Brunner RL, Manson JE, Gass ML, Stefanick ML, Lane DS, Hays J, Johnson KC, Coker LH, Dailey M, Bowen D, . 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. Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J, . 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. Hao J, Rapp PR, Janssen WG, Lou W, Lasley BL, Hof PR, Morrison JH. 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. Zhao L, O'Neill K, Brinton RD. 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.

Further Reading

Papers

  1. Xu H, Gouras GK, Greenfield JP, Vincent B, Naslund J, Mazzarelli L, Fried G, Jovanovic JN, Seeger M, Relkin NR, Liao F, Checler F, Buxbaum JD, Chait BT, Thinakaran G, Sisodia SS, Wang R, Greengard P, Gandy S. Estrogen reduces neuronal generation of Alzheimer beta-amyloid peptides. Nat Med. 1998 Apr;4(4):447-51. PubMed.
  2. Rosario ER, Carroll JC, Oddo S, Laferla FM, Pike CJ. 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. Shumaker SA, Legault C, Kuller L, Rapp SR, Thal L, Lane DS, Fillit H, Stefanick ML, Hendrix SL, Lewis CE, Masaki K, Coker LH, Women's Health Initiative Memory Study. 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):2947-58. PubMed.

Primary Papers

  1. 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 Sep 11;69(11):1074-83. PubMed.
  2. 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. 2008 Jan 15;70(3):200-9. PubMed.
  3. 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 17beta-estradiol and vitamin E in hippocampal neurons. J Med Chem. 2007 Sep 6;50(18):4471-81. PubMed.
  4. Tiwari-Woodruff S, Morales LB, Lee R, Voskuhl RR. 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.

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