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 (2006) 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 27, 141-149. Abstract
Casadesus G, Atwood CS, Zhu X, Hartzler AW, Webber KM, Perry G, Bowen RL, Smith MA (2005) Evidence for the role of gonadotropin hormones in the development of Alzheimer disease. Cell Mol Life Sci 62, 293-298. Abstract
Casadesus G, Webber KM, Atwood CS, Pappolla MA, Perry G, Bowen RL, Smith MA (2006) Luteinizing hormone modulates cognition and amyloid-beta deposition in Alzheimer APP transgenic mice. Biochim Biophys Acta 1762, 447-452. Abstract
Casadesus G, Zhu X, Atwood CS, Webber KM, Perry G, Bowen RL, Smith MA (2004) Beyond estrogen: targeting gonadotropin hormones in the treatment of Alzheimer's disease. Curr Drug Targets CNS Neurol Disord 3, 281-285. Abstract
Daniel JM, Hulst JL, Berbling JL (2006) 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 147, 607-614. Abstract
Gibbs RB (2000) Long-term treatment with estrogen and progesterone enhances acquisition of a spatial memory task by ovariectomized aged rats. Neurobiol Aging 21, 107-116. Abstract
Henderson VW, Guthrie JR, Dudley EC, Burger HG, Dennerstein L (2003) Estrogen exposures and memory at midlife: a population-based study of women. Neurology 60, 1369-1371. Abstract
Henderson VW, Paganini-Hill A, Emanuel CK, Dunn ME, Buckwalter JG (1994) Estrogen replacement therapy in older women. Comparisons between Alzheimer's disease cases and nondemented control subjects. Arch Neurol 51, 896-900. Abstract
Kawas C, Resnick S, Morrison A, Brookmeyer R, Corrada M, Zonderman A, Bacal C, Lingle DD, Metter E (1997) A prospective study of estrogen replacement therapy and the risk of developing Alzheimer's disease: the Baltimore Longitudinal Study of Aging. Neurology 48, 1517-1521. Abstract
King JC, Anthony EL, Damassa DA, Elkind-Hirsch KE (1987) Morphological evidence that luteinizing hormone-releasing hormone neurons participate in the suppression by estradiol of pituitary luteinizing hormone secretion in ovariectomized rats. Neuroendocrinology 45, 1-13. Abstract
Lei ZM, Rao CV, Kornyei JL, Licht P, Hiatt ES (1993) Novel expression of human chorionic gonadotropin/luteinizing hormone receptor gene in brain. Endocrinology 132, 2262-2270. Abstract
Lloyd JM, Hoffman GE, Wise PM (1994) Decline in immediate early gene expression in gonadotropin-releasing hormone neurons during proestrus in regularly cycling, middle-aged rats. Endocrinology 134, 1800-1805. Abstract
Lukacs H, Hiatt ES, Lei ZM, Rao CV (1995) Peripheral and intracerebroventricular administration of human chorionic gonadotropin alters several hippocampus-associated behaviors in cycling female rats. Horm Behav 29, 42-58. Abstract
Manly JJ, Merchant CA, Jacobs DM, Small SA, Bell K, Ferin M, Mayeux R (2000) Endogenous estrogen levels and Alzheimer's disease among postmenopausal women. Neurology 54, 833-837. Abstract
Park OK, Gugneja S, Mayo KE (1990) Gonadotropin-releasing hormone gene expression during the rat estrous cycle: effects of pentobarbital and ovarian steroids. Endocrinology 127, 365-372. Abstract
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 (2003) Effect of estrogen plus progestin on global cognitive function in postmenopausal women: the Women's Health Initiative Memory Study: a randomized controlled trial. JAMA 289, 2663-2672. Abstract
Rocca WA, Bower JH, Maraganore DM, Ahlskog JE, Grossardt BR, de Andrade M, Melton Iii LJ (2007) Increased risk of cognitive impairment or dementia in women who underwent oophorectomy before menopause. Neurology in press. Abstract
Sherwin BB (2005) Estrogen and memory in women: how can we reconcile the findings? Horm Behav 47, 371-375. Abstract
Shumaker SA, Legault C, Rapp SR, Thal L, Wallace RB, Ockene JK, Hendrix SL, Jones BN, 3rd, Assaf AR, Jackson RD, Kotchen JM, Wassertheil-Smoller S, Wactawski-Wende J (2003) 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 289, 2651-2662. Abstract
Webber KM, Casadesus G, Marlatt MW, Perry G, Hamlin CR, Atwood CS, Bowen RL, Smith MA (2005) Estrogen bows to a new master: the role of gonadotropins in Alzheimer pathogenesis. Ann N Y Acad Sci 1052, 201-209. Abstract
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