Current Pharmaceutical Design

ISSN: 1381-6128

Current Pharmaceutical Design
Volume 11, Number 32, 2005

Contents

Biochemical and Clinical Relevance of Hyperuricaemia
Executive Editor: Dimitri P. Mikhailidis
Associate Editor: Stella S. Daskalopoulou


Editorial Pp.4115


Overview of Hyperuricaemia and Gout Pp.4117
D. Masseoud, K. Rott, R. Liu-Bryan and C. Agudelo
[Abstract]


Serum Uric Acid and Risk of Coronary Heart Disease Pp.4125
S.G. Wannamethee
[Abstract]


Dietary Factors and Hyperuricaemia Pp.4133
N. Schlesinger
[Abstract]


Uric Acid and Hypertension Pp.4139
M. Schachter
[Abstract]


Uric Acid and Oxidative Stress Pp.4145
G.K. Glantzounis, E.C. Tsimoyiannis, A.M. Kappas and D.A. Galaris
[Abstract]


Uric Acid and the Kidney: Urate Transport, Stone Disease and Progressive Renal Failure Pp.4153
G. Capasso, Ph. Jaeger, W.G. Robertson and R.J. Unwin
[Abstract]


Effect on Serum Uric Acid Levels of Drugs Prescribed for Indications other than Treating Hyperuricaemia Pp.4161
S.S. Daskalopoulou, V. Tzovaras, D.P. Mikhailidis and M. Elisaf
[Abstract]


Rasburicase: A New Approach for Preventing and/or Treating Tumor Lysis Syndrome Pp.4177
O. Bessmertny, L.M. Robitaille and M.S. Cairo
[Abstract]


General Articles


Raloxifene and Cardiovascular Health: Its Relationship to Lipid and Glucose Metabolism, Hemostatic and Inflammation Factors and Cardiovascular Function in Postmenopausal Women Pp.4187
C.M. Francucci, A. Camilletti and M. Boscaro
[Abstract]


Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa Pp.4207
A. Kranjc, D. Kikelj and L. Peterlin-Masic
[Abstract]


Lifelong Endocrine Fluctuations and Related Cognitive Disorders Pp.4229
M.L. Ancelin and K. Ritchie
[Abstract]




Abstracts

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Editorial

Biochemical and Clinical Relevance of Hyperuricaemia

Hyperuricaemia is a common ‘metabolic disorder’ with several biochemical and clinical implications. Although hyperuricaemia is often asymptomatic, it can be associated with gout, renal calculi and impaired renal function. There is also evidence that elevated serum urate levels may predict an increased risk of vascular events. These topics are considered in this issue of the journal. In addition, current and future treatment options are discussed.

This issue of Current Pharmaceutical Design is dedicated to hyperuricaemia and its treatment. This is a common ‘metabolic disorder’, especially in men. Hyperuricaemia is often asymptomatic, but it can be associated with gout (a common arthropathy), renal calculi and impaired renal function. There is also evidence that elevated serum urate levels may predict an increased risk of vascular events.

Masseoud et al. provide an overview of hyperuricaemia and gout that sets the pace for the whole issue [1]. These authors expertly consider the current treatment of acute gout. Future treatment options, in part guided by a better understanding of pathophysiology, are also discussed.

Wannamethee comprehensively discusses the link between raised circulating urate levels and vascular disease in the general population, among hypertensives and those with coronary heart disease (CHD), stroke, diabetes and heart failure [2]. It is proposed that the influence of urate on CHD is explained by the secondary association with other established risk factors (e.g. hypertension, dyslipidaemia, hyperinsulinaemia, obesity and pre-existing disease). Furthermore, there is evidence that insulin resistance is partially responsible for the hyperuricaemia seen in many patients with the metabolic syndrome, a condition associated with an increased vascular risk [2-5]. All these factors are likely to confound the relationship between urate and vascular risk [2]. Therefore, it is not yet clear whether urate plays a causative role or if it is just a ‘marker’ of vascular risk. Nevertheless, urate may provide useful prognostic information in subjects with hypertension and vascular disease [2].

What is needed is to assess, in specifically designed interventional trials, whether pharmacologically lowering circulating urate levels results in a reduction in vascular events. Such trials would probably be restricted to patients with established CHD so as to allow for an increased event rate. One problem would be similar to that seen in lipid lowering and hypertension trials – i.e. ‘how low should we go?’. It is possible that lower is not necessarily better, as outlined by Glantzounis et al. in this issue [6]. In fact, at the molecular level there is evidence to support both a causative and protective (e.g. antioxidant) role for urate [1, 5-7].

The link between hyperuricaemia and hypertension is particularly interesting since it is common and possibly aggravated (or improved) by antihypertensive agents (reviewed by Schachter in this issue) [5, 8]. This topic recently received attention because in the Losartan Intervention For Endpoint reduction in hypertension (LIFE) trial, 29% of the benefit from treatment with losartan, when compared with atenolol, was attributed to a fall in serum urate levels [9]. Along these lines, it is of interest that in another study the benefit from diuretic treatment was restricted to the patients who did not show a marked increase in serum urate levels [10].

Renal impairment and CHD may progress in parallel. Therefore, it is of interest that in the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) study we found that aggressive cholesterol lowering with atorvastatin was associated with a fall in both serum creatinine and urate [11, 12]. A statin-associated beneficial effect on renal function was also seen in the much larger Heart Protection Study (HPS) [13].

Renal calculi and impaired renal function may occur in hyperuricaemic patients. This topic is expertly reviewed by Capasso et al. [7]. The novel and as yet unexplained link between hyperuricaemia and the urinary glycoprotein Tamm-Horsfall protein (uromodulin) is also discussed.

Although many patients with elevated urate levels need pharmacological intervention, we must not forget the role of diet (reviewed by Schlesinger in this issue) [4]. Worldwide studies suggest that the incidence of hyperuricaemia and gout may be increasing, probably because of physical inactivity and dietary changes [4]. Controlled weight management, moderation in the consumption of alcohol and “low purine” diets are some of the suggested non-pharmacological beneficial measures [4].

Several drugs can lower circulating urate levels (reviewed by Daskalopoulou et al. in this issue) [8]. This ‘beneficial’ additional effect is relevant since the risk of acute gout varies considerably within a relatively narrow range of urate levels [8]. Such ‘small’ changes may also influence vascular risk. A careful selection of drugs prescribed for other reasons will maximise their beneficial effect in terms of lowering urate levels. This approach could avoid polypharmacy, decrease the occurrence of drug interactions and also improve compliance [8].

Although allopurinol is widely used to treat hyperuricaemia, there is a need for other options to accommodate those who cannot tolerate allopurinol. Patients in special circumstances (e.g. those at a high risk of developing tumour lysis syndrome) may also benefit from a rapid and extensive hypouricaemic effect [1, 14]. Several drugs are being developed to fulfil these needs. Among them, rasburicase (a recombinant urate oxidase) is already available in several countries (see review by Bessmertny et al. in this issue) [14].

Hyperuricaemia deserves attention not only because it is a common problem but also because the consequences can impact on several organs (joints, kidneys and the vasculature).

References

[1] Masseoud D, Rott K, Liu-Bryan R, Agudelo C. Overview of Hyperuricaemia and Gout. Curr Pharm Design 2005; 11(32): 4117-4124.

[2] Wannamethee SG. Serum Uric Acid and Risk of Coronary Heart Disease. Curr Pharm Design 2005; 11(32): 4125-4132.

[3] Daskalopoulou SS, Mikhailidis DP, Elisaf M. Prevention and treatment of the metabolic syndrome. Angiology 2004; 55: 589-612.

[4] Schlesinger N. Dietary Factors and Hyperuricaemia. Curr Pharm Design 2005; 11(32): 4133-4138.

[5] Schachter M. Uric acid, hypertension and dyslipidaemia. Curr Pharm Design 2005; 11(32): 4139-4143.

[6] Glantzounis GK, Tsimoyiannis EC, Kappas AM, Galaris DA. Uric Acid and Oxidative Stress. Curr Pharm Design 2005; 11(32): 4145-4151.

[7] Capasso G, Jaeger Ph, Robertson WG, Unwin RJ. Uric Acid and the Kidney: Urate Transport, Stone Disease and Progressive Renal Failure. Curr Pharm Design 2005; 11(32): 4153-4159.

[8] Daskalopoulou SS, Tzovaras V, Mikhailidis DP, Elisaf M. Effect on serum uric acid levels of drugs prescribed for indications other than treating hyperuricaemia. Curr Pharm Design 2005; 11(32): 4161-4175.

[9] Hoieggen A, Alderman MH, Kjeldsen SE, Julius S, Devereux RB, De Faire U, et al. LIFE Study Group. The impact of serum uric acid on cardiovascular outcomes in the LIFE study. Kidney Int 2004; 65: 1041-9.

[10] Franse LV, Pahor M, Bari M, Shorr RI, Wan JY, Somes GW, et al. Serum uric acid, diuretic treatment and risk of cardiovascular events in the systolic hypertension in the Elderly Program (SHEP). J Hypertens 2000; 18: 1149-54.

[11] Athyros VG, Mikhailidis DP, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. for the GREACE Collaborative Group. The effect of statins versus untreated dyslipidaemia on renal function in patients with coronary heart disease. J Clin Pathol 2004; 57: 728-34.

[12] Athyros VG, Elisaf M, Papageorgiou AA, Symeonidis AN, Pehlivanidis AN, Bouloukos VI, et al. for the GREACE Collaborative Group. Effect of statins versus untreated dyslipidemia on serum uric acid levels in patients with coronary heart disease. A subgroup analysis of the GREek Atorvastatin and Coronary-heart-disease Evaluation (GREACE) Study. Am J Kidney Dis 2004; 43: 589-99.

[13] MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 5963 people with diabetes: a randomized placebo-controlled trial. Lancet 2003; 361: 2005-16

[14] Bessmertny O, Robitaille LM, Cairo MS. Rasburicase: a New Approach for Preventing and/or Treating Tumor Lysis Syndrome. Curr Pharm Design 2005; 11(32): 4177-4185.

S.S. Daskalopoulou MSc DIC MD FASA
D.P. Mikhailidis MD FASA FFPM FRCPath FRCP
Department Clinical Biochemistry
(Vascular Disease Prevention Clinics)
Royal Free Hospital, Royal Free and
University College Medical School
(University of London), Pond Street
London NW3 2QG, UK

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Overview of Hyperuricaemia and Gout
D. Masseoud, K. Rott, R. Liu-Bryan and C. Agudelo

in most mammals purine degradation ultimately leads to the formation of allantoin. Humans lack the enzyme uricase, which catalyzes the conversion of uric acid to allantoin. The resulting higher level of uric acid has been hypothesized to play a role as an antioxidant. Hyperuricaemia is usually an asymptomatic condition which is hypothesized to play a role in cardiovascular disease and hypertension. Some hyperuricaemic individuals develop gout, an inflammatory arthritis caused by the deposition of monosodium urate crystals in joints. Over time, acute intermittent gouty arthritis can develop into a chronic condition with deposits of monosodium urate (MSU) crystals in joints and as tophi. The mechanisms by which MSU crystals lead to an acute inflammatory arthritis are under investigation and current knowledge is reviewed here. Treatment of gout includes management of acute flares with anti-inflammatory medications such as non-steroidal anti-inflammatory drugs or corticosteroids and long term management with urate-lowering therapy when indicated. Future directions in the treatment of gout, in part guided by a better understanding of pathophysiology, are discussed.


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Serum Uric Acid and Risk of Coronary Heart Disease
S.G. Wannamethee

Many large epidemiological studies confirmed a positive association between raised serum uric acid (SUA) levels and risk of coronary heart disease (CHD) or cardiovascular disease (CVD) in the general population, among hypertensive patients and those with established CHD, stroke, diabetes and heart failure. There is much controversy concerning the role of SUA as an independent risk factor for CHD as SUA is related to many of the established risk factors for cardiovascular disease including hypertension, dyslipidaemia, obesity and pre-existing disease. The epidemiological evidence suggests that SUA is an independent predictor of CVD in subjects with hypertension and established vascular disease but not in healthy subjects. This evidence suggests that the influence of SUA on CHD is explained by the secondary association of SUA with other established etiological risk factors (hypertension, dyslipidaemia, hyperinsulinaemia, obesity and pre-existing disease). There is no evidence so far to indicate that lowering SUA levels with drug treatment has a beneficial effect on CVD outcome.

In summary, there is little support for an independent causal role for SUA in the development of CHD. However, SUA may provide useful prognostic information in subjects with hypertension and vascular disease.


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Dietary Factors and Hyperuricaemia
N. Schlesinger

The connection of gout and hyperuricaemia with gluttony, overindulgence in food and alcohol and obesity dates from ancient times. Studies from different parts of the world suggest that the incidence and severity of hyperuricaemia and gout may be increasing.

Uric acid (urate) is the end product of purine degradation. Although most uric acid is derived from the metabolism of endogenous purine, eating foods rich in purines contributes to the total pool of uric acid.

Sustained hyperuricaemia is a risk factor for acute gouty arthritis, chronic tophaceous gout, renal stones and possibly cardiovascular events and mortality. Before starting lifelong urate-lowering drug therapy, it is important to identify and treat underlying disorders that may be contributing to hyperuricaemia. It is relevant to recognize the strong association of the insulin resistance syndrome (IRS) (abdominal obesity, dyslipidaemia, hypertension, raised serum insulin levels and glucose intolerance) with hyperuricaemia.

Consumption of meat, seafood and alcoholic beverages in moderation and attention to food portion size is important. Moderation in the consumption of not only beer but also other forms of alcohol is essential. In the obese, controlled weight management has the potential to lower serum urate in a quantitatively similar way to relatively unpalatable "low purine" diets. Non-fat milk and low-fat yogurt have a variety of health benefits and dairy products may have clinically meaningful antihyperuricaemic effects. In addition, fruits, such as cherries and high intakes of vegetable protein diet may reduce serum urate levels.


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Uric Acid and Hypertension
M. Schachter

Increased levels of uric acid are associated with cardiovascular disease and the metabolic syndrome. They may predict clinical outcomes and also the onset of hypertension, though it is less clear that hyperuricaemia can be regarded as an independent risk factor given its clustering with other well-recognised factors. Uric acid may increase as a result of pathophysiological processes such as impaired renal sodium handling but may also contribute to renal and vascular damage, particularly endothelial dysfunction. It is notable that the synthesis of uric acid may be associated with the generation of reactive oxygen species if the enzyme xanthine oxidorectase is converted to the oxidase, as may occur in ischaemia. It has been suggested that uric acid may play a role in the pathogenesis of early-onset hypertension but evidence for this is limited. There is also very limited data to suggest that in some circumstances lowering uric acid can lower blood pressure. In the metabolic syndrome, the presence of elevated uric acid concentrations is closely associated with raised triglyceride levels, for reasons that have not been clearly defined. It remains to be seen whether uric acid could or should be considered a specific therapeutic target in cardiovascular disease and especially in hypertension and if so what should be the optimal pharmacological approach to lowering serum urate levels.


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Uric Acid and Oxidative Stress
G.K. Glantzounis, E.C. Tsimoyiannis, A.M. Kappas and D.A. Galaris

Uric acid is the final product of purine metabolism in humans. The final two reactions of its production catalyzing the conversion of hypoxanthine to xanthine and the latter to uric acid are catalysed by the enzyme xanthine oxidoreductase, which may attain two inter-convertible forms, namely xanthine dehydrogenase or xanthine oxidase. The latter uses molecular oxygen as electron acceptor and generates superoxide anion and other reactive oxygen products. The role of uric acid in conditions associated with oxidative stress is not entirely clear. Evidence mainly based on epidemiological studies suggests that increased serum levels of uric acid are a risk factor for cardiovascular disease where oxidative stress plays an important pathophysiological role. Also, allopurinol, a xanthine oxidoreductase inhibitor that lowers serum levels of uric acid exerts protective effects in situations associated with oxidative stress (e.g. ischaemia-reperfusion injury, cardiovascular disease). However, there is increasing experimental and clinical evidence showing that uric acid has an important role in vivo as an antioxidant.

This review presents the current evidence regarding the antioxidant role of uric acid and suggests that it has an important role as an oxidative stress marker and a potential therapeutic role as an antioxidant. Further well designed clinical studies are needed to clarify the potential use of uric acid (or uric acid precursors) in diseases associated with oxidative stress.


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Uric Acid and the Kidney: Urate Transport, Stone Disease and Progressive Renal Failure
G. Capasso, Ph. Jaeger, W.G. Robertson and R.J. Unwin

In this brief review and update, we try to cover recent developments in our understanding of uric acid transport by the kidney, the contribution of uric acid to renal stone disease, its potential role in progressive renal failure and, most recently, the novel and as yet unexplained link between the urinary glycoprotein Tamm-Horsfall protein (uromodulin) and hyperuricaemia and two inherited forms of renal disease with chronic renal failure.


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Effect on Serum Uric Acid Levels of Drugs Prescribed for Indications other than Treating Hyperuricaemia
S.S. Daskalopoulou, V. Tzovaras, D.P. Mikhailidis and M. Elisaf

Beyond allopurinol and the well-established uricosuric drugs, several other agents can decrease serum uric acid (SUA) levels, such as losartan, fenofibrate and some non-steroidal anti-inflammatory drugs (NSAIDs). Some of these drugs increase renal urate excretion.

Hyperuricaemia and gout are common problems (at least 1% of Western men are affected by gout). Raised SUA levels increase the incidence of acute gout and renal calculi. Hyperuricaemia may also predict an increased risk of vascular events. Therefore, lowering SUA levels is of clinical relevance.

In this review we consider the effect on SUA levels of drugs that are prescribed for indications other than treating hyperuricaemia. These drugs may obviate the need for specific treatment (e.g. allopurinol) aimed at lowering SUA levels. Furthermore, because hyperuricaemic patients may already be on several drugs (e.g. due to associated dyslipidaemia, hypertension and/or arthritis) compliance may be improved by avoiding additional medication. The potential for adverse effects associated with polypharmacy would also be decreased.


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Rasburicase: A New Approach for Preventing and/or Treating Tumor Lysis Syndrome
O. Bessmertny, L.M. Robitaille and M.S. Cairo

Tumor lysis syndrome (TLS) is an oncologic emergency requiring prompt attention to the management of potentially life-threatening metabolic derangements. Hyperuricaemia is one of the prominent features of TLS which, if not adequately prevented or treated, may lead to renal failure, requiring dialysis. Conventional management of hyperuricaemia involved the use of aggressive hydration, urinary alkalinization and allopurinol. Despite these measures, as many as 14.1% of high-risk patients may still develop renal failure. With the advent of newer agents such as rasburicase, the paradigm of TLS management has shifted towards risk stratification and the use of rasburicase in conjunction with hydration in patients at high risk for TLS. The advantage of rasburicase over allopurinol is its rapid onset of action, lack of need for urine alkalinization, which may worsen hyperphosphataemia and a satisfactory safety profile. Overall, rasburicase offers a safe and more effective alternative to allopurinol in patients at highest risk for TLS. Some of the unanswered questions requiring further investigation with regard to rasburicase use include the optimal number of doses needed, optimal dose based on uric acid levels and tumor burden, dosing in obese patients and maximum dose.


General Articles


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Raloxifene and Cardiovascular Health: Its Relationship to Lipid and Glucose Metabolism, Hemostatic and Inflammation Factors and Cardiovascular Function in Postmenopausal Women
C.M. Francucci, A. Camilletti and M. Boscaro

CHD is one of the most common serious chronic conditions in postmenopausal women and leads to extremely high risk for recurrent myocardial infarction and death. On the basis of the currently available randomized clinical-trial results the role of conventional HRT for treatment and prevention of CHD is rapidly evolving from presumed benefit to proven harm, at least in some categories of women yet to define. For this reason there has been a particular interest in potential clinical uses of selective estrogen receptor modulators (SERMs).

SERMs are a class of compounds that can act as estrogen receptor (ER) agonists in some domains (bone and lipids) and acting as ER antagonists in others (breast and uterus). Raloxifene hydrochloride is an antiestrogen that is currently approved only to treat osteoporosis in postmenopausal women. Because of its effects on lipids and other biomarkers of cardiovascular risk, there is great interest in determining whether it may benefit the cardiovascular system. The great major-ity of data on cardiovascular effects of raloxifene concern effects on lipids and markers of thrombosis and inflammation.

The purpose of this review is to summarize the best available evidence concerning raloxifene and cardiovascular disease focusing some areas known to be important risk factors for cardiovascular diseases: lipids and lipoproteins, glucose metabolism, hemostatic factors, markers of inflammation and cardiovascular function.


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Recent Advances in the Discovery of Tissue Factor/Factor VIIa Inhibitors and Dual Inhibitors of Factor VIIa/Factor Xa
A. Kranjc, D. Kikelj and L. Peterlin-Masic

The search for an ideal anticoagulant has spanned decades and has taken several approaches to the identification of novel target molecules for preventing and treating thrombosis. In the group of anticoagulants acting through direct inhibition of coagulation factors, most research has focused on thrombin and factor Xa inhibitors. Attention has been drawn most recently to factor VIIa as a promising anticoagulation target, because of its role in complex with tissue factor, in initiating the coagulation cascade following blood vessel damage. Several reports suggest that inhibitors of the tissue factor/factor VIIa complex prevent thrombosis with a lower bleeding risk than other types of inhibitors. Accordingly, there is increasing interest in the generation of potent and selective small-molecule factor VIIa inhibitors that can be safely administered once or twice daily in an oral formulation with no need for routine coagulation monitoring.

The emphasis of this review will be placed on recent advances in the development of the small-molecule inhibitors of factor VIIa complexed with tissue factor. The role of factor VIIa and tissue factor as initiators of the coagulation cascade following blood vessel damage is described, along with the structure of the active site of factor VIIa.


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Lifelong Endocrine Fluctuations and Related Cognitive Disorders
M.L. Ancelin and K. Ritchie

The aim of this review is to examine the relationship between endocrine fluctuation and cognitive functioning. A plethora of in vitro and in vivo studies has demonstrated the neuroprotective role of estrogens and their impact on the neurotransmitter systems implicated in cognition. Recent hormonal replacement therapy (HRT) trials in non-demented post-menopausal women suggest a temporary positive effect (notably on verbal memory), and four recent meta-analyses converge to suggest a possible protective effect in relation to Alzheimer’s disease (reducing risk by 29 to 44%). However, data from the only large randomised controlled trial published to date, the Women's Health Initiative Memory Study, did not confirm these observations and have even suggested an increase in dementia risk for women using HRT compared to controls. Several methodological differences between observation studies and controlled trials with regard to patient group, type, timing and duration of HRT, cognitive measures and analyses, are discussed to explain these discrepancies. The association between hormonal serum level and cognitive functioning remains controversial suggesting high inter-individual vulnerability in risk. Moreover, research on the impact of endocrine functioning on cognition during the female reproductive cycle suggests life-long fluctuations in vulnerability. Etiological models taking into account the interaction of clinical, reproductive, and menstrual events throughout life may provide a more valid approach in understanding the effects of steroids on the brain and in determining sub-groups at heightened risk. Cognitive disorders in the elderly are more likely be related to cumulated lifelong exposure to steroids, rather than to a specific exposure to a given steroid. Multifactorial models based on an exhaustive view of all hormonal events throughout reproductive life together with other risk factors (notably genetic risk factors related to estrogen receptor polymorphisms) should be explored to clarify the role of hormonal risk factors, or protective factors for cognitive dysfunction and dementia.