Sam Gandy Phyllis Wise Dominique Toran-Allerand Kristine Yaffe Rena Li John Breitner Peter Zandi Chris Gregory

You may think the Women’s Health Study has sounded the death knell for estrogen replacement therapy, but actually, the idea is showing new signs of life. A second-generation approach with better compounds may warrant continued investment, and yet, how does one pull that off in the face of a seemingly definitive trial failure? Sam Gandy led a panel discussion featuring Phyllis Wise, Dominique Toran-Allerand, Kristine Yaffe, Rena Li, John Breitner, and Peter Zandi on the dilemmas and opportunities of hormone replacement in the treatment of age-related dementia. Sam Gandy, with John Breitner, Rena Li, Dominique Toran-Allerand, Phyllis Wise, Kristine Yaffe, and Peter Zandi, led this live discussion on 9 March 2006. Readers are invited to submit additional comments by using our Comments form at the bottom of the page.

View Transcript of Live Discussion — Posted 9 March 2006

Background Text

The story of hormone replacement therapy (HRT) in Alzheimer disease treatment is a long and frustrating one. Many epidemiological studies indicate that HRT cuts the risk of developing the disease by half (e.g., Tang et al., 1996, for a meta-analysis see Yaffe et al., 1998). Together with experimental studies suggesting a biological rationale for estrogen’s effects on the aging brain, that epidemiological data led to treatment trials. However, beginning HRT at age 65 proved not to prevent dementia (Shumaker et al., 2004), and treatment of established dementia does not slow its progression (Mulnard et al., 2000). The recently uncovered cardiovascular risks of HRT (Anderson et al., 2004), further added to a constellation of setbacks that has relegated HRT to the "back burner" in much of the Alzheimer universe. Today, newer approaches ranging from vaccines to secretase inhibitors and neuroprotectives are receiving most of the attention.

Even so, one could argue that it is premature to dismiss estrogen replacement just yet. What follows is a snapshot of some of the recent research that should keep the field engaged. For one thing, consider this nagging issue: The epidemiological data (e.g., Zandi et al., 2002) strongly suggests that HRT has its greatest protective benefit when initiated at the time of menopause, not 15 yrs later, which is the only HRT/Alzheimer's protection paradigm to have been tested so far. Hence, estrogen deficiency may join the growing group of health factors that, when present in midlife, increase the risk for dementia later on (e.g., Kivipelto et al., 2005).

The notion that effective prevention must begin in the 40s or 50s in order to delay or prevent dementia 20 to 30 years later presents a staggering challenge for anyone seeking to prove this principle via the gold standard of randomized, placebo-controlled, prospective clinical trials. This hurdle has virtually stopped clinical HRT research dead in its tracks. How can government or industry commit to such a trial in the face of negative reports and adverse effects? The sole investment currently comes from billionaire John Sperling, founder of both the University of Phoenix Online and the Kronos Institute, who privately supports an ongoing 5-year trial of perimenopausal HRT in 720 women for Alzheimer disease prevention. Few data will emerge until this trial (known by the acronym KEEPS, for Kronos Early Estrogen Prevention Study) is complete around the year 2010.

Meanwhile, three new academic studies have associated estrogen or its derivatives with cognitive status and neuropathology. Kristine Yaffe and colleagues at the University of California, San Francisco, studied the cognitive outcome of over 5,000 women in a trial of the selective estrogen receptor modulator (SERM) raloxifene as a treatment for osteoporosis among post-menopausal women (Yaffe et al., 2005). After three years, women taking raloxifene at 120 mg/day had a reduction in risk for either mild cognitive impairment (relative risk = 0.67) or Alzheimer disease (relative risk = 0.52), suggesting that compounds other than estrogen itself may yet prove useful.

Clinical studies on sex hormone deprivation in men are also instructive in considering hormone therapies for neurodegenerative diseases. Androgen deprivation is used to treat prostate cancer because testosterone can drive tumor growth, but the effects of this therapy on cognition are poorly understood. This month in the Journal of Urology, Tomasz Beer of Oregon Health and Science University, Portland, reported a small, 1-month study of prostate cancer patients, in which men on androgen deprivation therapy scored worse on verbal memory tests than did men who also received estradiol patches or a third group who were not on androgen deprivation (J Urol 2006;175:130-135, not in PubMed yet.) And a larger clinical study also focused on cognitive function in estrogen-deficient men. Eeva Salminen and colleagues at the University of Turku, Finland, reported cognitive decline in men with prostate cancer who were undergoing hormone suppression with flutamide and leuprolide (Salminen et al., 2005).

These two studies echo, in men, the connection between cancer, estrogen, and cognition known for aging women, but beyond that, the second one is especially interesting for two reasons. First, flutamide and leuprolide have been previously implicated as potential causes for an elevation in circulating Aβ peptide (Gandy et al., 2001). Second, the North Carolina-based pharmaceutical firm Voyager is currently recruiting people with mild-to-moderate AD into a Phase III trial (known as ALADDIN, for Antigonadotropin Leuprolide in Alzheimer’s Disease Drug INvestigation), of a form of leuprolide acetate, one of the compounds implicated in causing cognitive decline in the Finnish study. Leuprolide reduces luteinizing hormone release from the pituitary gland. Richard Bowen is the founder of Voyager and, with his colleagues, bases this approach on evidence that leuprolide lowers the level of endogenous Aβ in the brains of wildtype mice (Bowen et al., 2004; for more detail, see ARF related conference story). The fact that the Alzheimer literature supports the contradictory possibilities that leuprolide is both pro-amyloidogenic and anti-amyloidogenic illustrates how far we have to go in unraveling the relationship between gonadal hormones and dementia.

A separate study sheds further light on the link between estrogen and amyloid in mice. Last month in PNAS, Rena Li and colleagues at Sun Health Research Institute in Sun City, Arizona, crossed the Novartis APP23 plaque-forming mice with another strain from which the aromatase (Ar) gene had been deleted (Yue et al., 2005.) Aromatase is responsible for converting testosterone to estrogen, so these mice are unable to synthesize any estrogen at all. The APP23 x Ar-/- mice developed cerebral amyloid pathology quite prematurely, with plaque load in the 6-month-old crossed mice dramatically exceeding that exhibited by standard APP23 mice at 12 months of age. Eventually, however, the plaque densities were identical in the wildtype and Ar-/- mice, indicating that estrogen status apparently controlled age of onset. This would be consistent with the notion that estrogen given early might delay or prevent Alzheimer's but have no effect when given late. Studies from the tissues of these mice implicated both excess generation of Aβ by BACE and impaired Aβ clearance as potential explanations for the elevation in Aβ levels in the absence of estrogen.

Furthermore, the molecular biology of estrogen signal transduction continues to surprise. Dominique Toran-Allerand at Columbia University in New York, and Eric Prossnitz at the University of New Mexico have reported advances in characterizing membrane-bound estrogen receptors (ERs; Toran-Allerand et al., 2002, Revankar et al., 2005). Toran-Allerand’s new pathway begins with a non-ERα, non-ERβ protein, dubbed “ER-X”, that is located at the plasma membrane and coupled to MAPK/ERK where it signals through the neuroprotective phosphatidylinositol 3-kinase-Akt pathway. The molecule described by Revankar et al. is quite different: Unexpectedly, their molecule turned out to be an orphan G-protein-coupled receptor localized to the endoplasmic reticulum and playing a role in controlling calcium flux. More recently, Toran-Allerand et al. (2005) have identified the ligand of ER-X as the 17α isomer of estradiol. They hypothesize that it is synthesized not in the gonads but locally in the brain, where they believe it functions independently of the classical hormone/receptor endocrine system. This is a controversial finding. Scientists generally believe the brain does not synthesize estrogen, and 17α-estradiol is held by conventional wisdom to lack neuroactivity and neuroprotective properties. Indeed, this compound is routinely applied to signaling experiments as a competitive inhibitor of signaling across a typical estrogen receptor in order to establish that the signal under study indeed utilizes the standard estrogen receptor, so, heretofore, 17α has served as a negative control.

The continuing discovery of estrogenic pathways suggests that we may still be at the “tip of the iceberg” in elucidating estrogen physiology. Clearly, if we are to understand the pleiotropic actions of estrogens in the brain, in bone, and in other tissues, we must develop a comprehensive knowledge base of all of estrogen’s receptors, as well as their signaling pathways and downstream effectors.

Midlife lifestyle factors, including estrogen, are gaining more and more attention (see the "Maintain Your Brain" campaign by the Alzheimer’s Association). We must develop strategies for evaluating these factors rigorously so that we can strengthen their scientific underpinning and justify the inclusion of lifestyle factor management in practice parameters developed by the major professional associations (see related ARF Live Discussion). As other SERMs are developed, the industrial sector will perform more studies such as that of Yaffe et al., in which cognitive decline is either a primary or secondary endpoint. KEEPS may well be a watershed study, either reinvigorating the notion that HRT might prevent AD or else excluding a role for HRT once and for all.

I suggest the following questions for discussion:

• How can midlife risk factors, including estrogen decline, be tested short of financing large prospective trials?
• What sorts of less-expensive pilot trials could give useful information?
• Do we know enough about brain-specific estrogen signaling to devise more specific SERMs?
• What targets other than the gonadal hormones themselves are attractive?
• While KEEPS is ongoing, what animal and cell-based studies could provide the necessary research base for next-generation therapies?
• Which resources could be mined to obtain comprehensive data about human estrogen ligands, receptors, and pathways?
• Should the AD field shrug off the discouraging findings of the Women’s Health Study results and keep investigating estrogen pathways? Early cytokine and NMDA receptor antagonist trials failed, yet these molecules still hold promise. Or better to cut losses and focus on new approaches altogether?

Bowen RL, Verdile G, Liu T, Parlow AF, Perry G, Smith MA, Martins RN, Atwood CS. Luteinizing hormone, a reproductive regulator that modulates the processing of amyloid-beta precursor protein and amyloid-beta deposition. J Biol Chem. 2004 May 7;279(19):20539-45. Abstract

Gandy S, Almeida OP, Fonte J, Lim D, Waterrus A, Spry N, Flicker L, Martins RN. Chemical andropause and amyloid-beta peptide. JAMA. 2001 May 2;285(17):2195-6. Abstract

Kivipelto M, Ngandu T, Fratiglioni L, Viitanen M, Kareholt I, Winblad B, Helkala EL, Tuomilehto J, Soininen H, Nissinen A. Obesity and vascular risk factors at midlife and the risk of dementia and Alzheimer disease. Arch Neurol. 2005 Oct;62(10):1556-60. Abstract

Mulnard RA, Cotman CW, Kawas C, van Dyck CH, Sano M, Doody R, Koss E, Pfeiffer E, Jin S, Gamst A, Grundman M, Thomas R, Thal LJ. Estrogen replacement therapy for treatment of mild to moderate Alzheimer disease: a randomized controlled trial. Alzheimer's Disease Cooperative Study. JAMA. 2000 Feb 23;283(8):1007-15. Erratum in: JAMA 2000 Nov 22-29;284(20):2597. Abstract

Revankar CM, Cimino DF, Sklar LA, Arterburn JB, Prossnitz ER. A transmembrane intracellular estrogen receptor mediates rapid cell signaling. Science. 2005 Mar 11;307(5715):1625-30. Abstract

Salminen EK, Portin RI, Koskinen AI, Helenius HY, Nurmi MJ. Estradiol and cognition during androgen deprivation in men with prostate carcinoma. Cancer. 2005 Apr 1;103(7):1381-7. Abstract

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. Abstract

Tang MX, Jacobs D, Stern Y, Marder K, Schofield P, Gurland B, Andrews H, Mayeux R. Effect of oestrogen during menopause on risk and age at onset of Alzheimer's disease. Lancet. 1996 Aug 17;348(9025):429-32. Abstract

Toran-Allerand CD, Guan X, MacLusky NJ, Horvath TL, Diano S, Singh M, Connolly ES Jr, Nethrapalli IS, Tinnikov AA. ER-X: a novel, plasma membrane-associated, putative estrogen receptor that is regulated during development and after ischemic brain injury. J Neurosci. 2002 Oct 1;22(19):8391-401. Abstract

Toran-Allerand CD, Tinnikov AA, Singh RJ, Nethrapalli IS. 17alpha-estradiol: A brain active estrogen? Endocrinology. 2005. Sep;146(9):3843-50, doi:10.1210/en.2004-1616. Abstract

Yaffe K, Sawaya G, Lieberburg I, Grady D. Estrogen therapy in postmenopausal women: effects on cognitive function and dementia. JAMA. 1998 Mar 4;279(9):688-95. Abstract

Yaffe K, Krueger K, Cummings SR, Blackwell T, Henderson VW, Sarkar S, Ensrud K, Grady D. Effect of raloxifene on prevention of dementia and cognitive impairment in older women: the Multiple Outcomes of Raloxifene Evaluation (MORE) randomized trial. Am J Psychiatry. 2005 Apr;162(4):683-90. Abstract

Yue X, Lu M, Lancaster T, Cao P, Honda S-I, Staufenbiel M, Shen Y, Li R. Brain estrogen deficiency accelerates Aβ plaque formation in an Alzheimer's animal model. Proc Natl Acad Sci U S A. 2005 Dec 27 ; 102(52):19198-203. Abstract

Zandi PP, Carlson MC, Plassman BL, Welsh-Bohmer KA, Mayer LS, Steffens DC, Breitner JC; Cache County Memory Study Investigators. Hormone replacement therapy and incidence of Alzheimer disease in older women: the Cache County Study. JAMA. 2002 Nov 6;288(17):2123-9. Abstract

	Comments on Live Discussion
	Comment by:  Eef Hogervorst (Disclosure)
	Submitted 3 February 2006  |  Permalink	Posted 3 February 2006
	On the basis of our own clinical trial, and the literature reviews and meta-analyses that we have carried out, I think that estrogens, both estradiol and conjugated equine estrogens, may improve cognition, but only for a limited period of 2-3 months, after which effects plateau and then may even reverse (after >1 year). Effects seem to be strongest in women with menopausal symptoms and on verbal memory functions. However, several studies (which held up in the rigorous Cochrane meta-analyses that I did in collaboration with Kristine Yaffe and Felicia Huppert) have also found effects in women with dementia, effects which again could not be maintained for longer than 2-3 months. This indicates that the "window of opportunity theory" may not necessarily be true. It may well be that the short-lived effects of estrogens are due to treatment regimen effects. Dr. Farook Al Azzawi and I would like to collaborate with other clinical centers to set up a controlled trial to test our alternative regimens in a long-term treatment trial (2 years). References: Hogervorst, E. The short-lived effect of HRT on cognition function (2006) In N Rasgon. Estrogen's effects on brain function. What's next? Hogervorst E, Yaffe K, Richards M, Huppert F. Hormone replacement therapy to maintain cognitive function in women with dementia. Cochrane Database Syst Rev. 2002;(3):CD003799. Review. Abstract Hogervorst E, Yaffe K, Richards M, Huppert F. Hormone replacement therapy for cognitive function in postmenopausal women. Cochrane Database Syst Rev. 2002;(3):CD003122. Review. Abstract Hogervorst E, Smith AD. The interaction of serum folate and estradiol levels in Alzheimer's disease. Neuro Endocrinol Lett. 2002 Apr;23(2):155-60. Abstract Hogervorst E, Bandelow S, Moffat SD. Increasing testosterone levels and effects on cognitive functions in elderly men and women: a review. Curr Drug Targets CNS Neurol Disord. 2005 Oct;4(5):531-40. Abstract Hogervorst E, De Jager C, Budge M, Smith AD. Serum levels of estradiol and testosterone and performance in different cognitive domains in healthy elderly men and women. Psychoneuroendocrinology. 2004 Apr;29(3):405-21. Abstract Hogervorst E, Williams J, Combrinck M, David Smith A. Measuring serum oestradiol in women with Alzheimer's disease: the importance of the sensitivity of the assay method. Eur J Endocrinol. 2003 Jan;148(1):67-72. Abstract Hogervorst E, Lehmann DJ, Warden DR, McBroom J, Smith AD. Apolipoprotein E epsilon4 and testosterone interact in the risk of Alzheimer's disease in men. Int J Geriatr Psychiatry. 2002 Oct;17(10):938-40. Abstract Hogervorst E, Williams J, Budge M, Riedel W, Jolles J. The nature of the effect of female gonadal hormone replacement therapy on cognitive function in post-menopausal women: a meta-analysis. Neuroscience. 2000;101(3):485-512. Abstract View all comments by Eef Hogervorst

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