Clinical Practice & Epidemiology in Mental Health




ISSN: 1745-0179 ― Volume 15, 2019

Dehydroepiandrosterone, Its Sulfate and Cognitive Functions



Karina Junqueira de Menezes1, Clayton Peixoto1, Antonio Egidio Nardi1, Mauro Giovanni Carta2, Sérgio Machado1, André Barciela Veras3, *
1 Laboratory of Panic and Respiration, Institute of Psychiatry, UFRJ (Federal University of Rio de Janeiro), Brazil
2 Department of Public Health, Clinical and Molecular Medicine, University of Cagliari, Cagliari, Italy
3 Dom Bosco Catholic University (UCDB), Laboratory of Panic and Respiration, Institute of Psychiatry, UFRJ, Brazil

Abstract

To present a review of cross-sectional and longitudinal studies that investigate the relationship between the hormones Dehydroepiandrosterone (DHEA) and Dehydroepiandrosterone sulfate (DHEA-S) and cognition. Methods: The cognition items included in this review were global cognitive function, memory, attention, executive function, intelligence, perception and visuospatial ability. A systematic review was proceeded using three databases: PubMed, ISI Web of Science, and PsycINFO. Results: Two thousand fifty five references about cognition and hormones were found; 772 duplicated references were excluded, resulting in 1.283 references to be evaluated. According to exclusion and inclusion criteria, 25 references were selected. A positive correlation between DHEA-S blood levels and global cognition was found in women and men. Other positive correlations between DHEA-S and working memory, attention and verbal fluency were found only in women. The DHEA effect on cognition is limited to one study conducted among young men with high-doses.

Keywords: Attention, Cognition, Dehydroepiandrosterone, Dehydroepiandrosterone Sulfate, Executive Function, Memory, Neuropsychology.


Article Information


Identifiers and Pagination:

Year: 2016
Volume: 12
First Page: 24
Last Page: 37
Publisher Id: CPEMH-12-24
DOI: 10.2174/1745017901612010024

Article History:

Received Date: 20/6/2015
Revision Received Date: 27/9/2015
Acceptance Date: 2/12/2015
Electronic publication date: 29/04/2016
Collection year: 2016

Article Metrics:

CrossRef Citations:
0

Total Statistics:

Full-Text HTML Views: 2630
Abstract HTML Views: 1407
PDF Downloads: 334
ePub Downloads: 240
Total Views/Downloads: 4611

Unique Statistics:

Full-Text HTML Views: 674
Abstract HTML Views: 948
PDF Downloads: 228
ePub Downloads: 150
Total Views/Downloads: 2000
Geographical View

© de Menezes et al.; Licensee Bentham Open.

open-access license: This is an open access articles licensed under the terms of the Creative Commons Attribution-Non-Commercial 4.0 International Public License (CC BY-NC 4.0) (https://creativecommons.org/licenses/by-nc/4.0/legalcode), which permits unrestricted, non-commercial use, distribution and reproduction in any medium, provided that the work is properly cited.


* Address correspondence to this author at the Dom Bosco Catholic University (UCDB), Laboratory of Panic and Respiration, Institute of Psychiatry, UFRJ, Brazil; E-mail: barciela@ibest.com.br





1. INTRODUCTION

Dehydroepiandrosterone (DHEA) and its sulfate (DHEA-S) are two active androgens mainly produced by the adrenal glands. DHEA is the main pro-hormone related to biosynthesis of testosterone and estrogen [1Speroff L, Glass RH, Kase NG. Endocrinologia ginecológica clínica e infertilidade. 5th ed. São Paulo: Manole 1995.-4Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22(3): 185-212.
[http://dx.doi.org/10.1006/frne.2001.0216] [PMID: 11456468]
]. Studies have shown that these hormones are not synthesized just by the gonads and adrenal glands of men and women [1Speroff L, Glass RH, Kase NG. Endocrinologia ginecológica clínica e infertilidade. 5th ed. São Paulo: Manole 1995., 2Wajchenberg BL. Tratado de encdocrinologia clínica. São Paulo: Roca 1992.]. DHEA is also produced in brain regions, being recently considered a neurosteroid [3Wolkowitz OM, Rothschild AJ. Psychoneuroendocrinology: The scientific sasis of clinical practice. Arlington, Virgínia: American Psychiatric Publishing, Inc. 2003.]. Although there is still debate on DHEA receptors in brain, these findings corroborate the evidence that DHEA is not just a pre-hormone from adrenals, but rather a hormone in its own right, and that it modulates a series of biological processes, with a remarkable tropism for the central nervous system [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
].

DHEA-S is a protective anabolic hormone with an important role in maintaining and restoring the human organism. It is known for its antioxidant activity and ability to help in neuronal preservation. DHEA-S is originated in the zona reticularis area of the adrenal cortex in response to adrenocorticotropic hormone (ACTH). As DHEA, has a higher production between 25 and 35 years old and then gradually decrease over time [6Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A. The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Curr Drug Targets 2014; 15(9): 901-14.
[http://dx.doi.org/10.2174/1389450115666140717111116] [PMID: 25039497]
, 7Lennartsson AK, Theorell T, Kushnir MM, Jonsdottir IH. Low levels of dehydroepiandrosterone sulfate in younger burnout patients. PLoS One 2015; 10(10): e0140054.
[http://dx.doi.org/10.1371/journal.pone.0140054] [PMID: 26441131]
]. Sex difference in DHEA-S levels remains unclear, while most studies reported higher levels in men than in women, others studies did not found differences [7Lennartsson AK, Theorell T, Kushnir MM, Jonsdottir IH. Low levels of dehydroepiandrosterone sulfate in younger burnout patients. PLoS One 2015; 10(10): e0140054.
[http://dx.doi.org/10.1371/journal.pone.0140054] [PMID: 26441131]
-9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
].

The effects of DHEA and DHEA-S on cognitive functions have been targeted in all fields [10Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000; 160(14): 2193-8.
[http://dx.doi.org/10.1001/archinte.160.14.2193] [PMID: 10904463]
-12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
]. In a study that assessed the relationship between sex hormones and cognition, it was found that DHEA-S is positively associated with executive function and memory [13Castanho TC, Moreira PS, Portugal-Nunes C, et al. The role of sex and sex-related hormones in cognition, mood and well-being in older men and women. Biol Psychol 2014; 103: 158-66.
[http://dx.doi.org/10.1016/j.biopsycho.2014.08.015] [PMID: 25196100]
]. However, a literature review in the period of time between 1994 and 2013 observed that despite cross-cohort studies point to evidence of relationship between DHEA-S and cognition, RCTs and longitudinal studies were not able to consistently confirm these evidences [14Maggio M, De Vita F, Fisichella A, et al. DHEA and cognitive function in the elderly. J Steroid Biochem Mol Biol 2015; 145: 281-92.
[http://dx.doi.org/10.1016/j.jsbmb.2014.03.014] [PMID: 24794824]
]. Besides, the long term risk-effects remain unclear [15Guyton AC, Hall JE. Tratado de Fisiologia Médica. 10th ed. Rio de Janeiro: Guanabara Koogan 2002., 16Genazzani AR, Pluchino N. DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence. Climacteric 2010; 13(4): 314-6.
[http://dx.doi.org/10.3109/13697137.2010.492496] [PMID: 20540592]
].

Cognitive functions are organized by classes, similar to the operation of a computer. There are input, storage, processing and output classes [17Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008; 33(1): 88-109.
[http://dx.doi.org/10.1038/sj.npp.1301574] [PMID: 17851537]
-21Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. 4th ed. Oxford, Oxfordshire: Oxford University Press 2004.] and each of these functional classes comprises of many discrete activities as perception, memory, attention, executive function and intellectual function [21Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. 4th ed. Oxford, Oxfordshire: Oxford University Press 2004.-23Fuentes D, Malloy-Diniz LF, Camargo CH, Cosenza RM. Neuropsicologia: teoria e prática. Porto Alegre, Rio Grande do Sul: Artmed 2008.]. One way to access the deve-lopment and integrity of cognitive function is through neuropsychology, which is the study of the relationship between brain and behavior [23Fuentes D, Malloy-Diniz LF, Camargo CH, Cosenza RM. Neuropsicologia: teoria e prática. Porto Alegre, Rio Grande do Sul: Artmed 2008., 24Malloy-Diniz LF, Fuentes D, Mattos P, Abreu N. Avaliação Neuropsicológica. São Paulo: Artmed 2010.]. Neuropsychological evaluation is a way of investigating different cognitive functions and their relations with brain function and its neurochemical factors, such as DHEA and DHEA-S.

Considering the recent speculation about the relationship between cognition and DHEA and DHEA-S, this paper aims to review the relationship between DHEA, DHEAS and cognitive functions.

2. METHODS

A systematic search of the literature was proceeded in PubMed, ISI Web of Knowledge and PsycINFO, using the terms: Dehydroepiandrosterone, Dehydroepiandrosterone sulfate, DHEA, DHEAS, cognition, cognitive function, memory, attention, executive function, intelligence, perception, visuospatial ability. All combinations between the first four terms for the specific hormones of this review were crossed with each specified mental function. The last search was proceeded in October 2015 and no time restriction was used. Two thousand and fifty three references were found (PubMed, 1217; The study selection process obeyed the following steps: Database search; exclusion of repeated references; summary analysis; exclusion of articles deemed ineligible after reading the summaries; full analysis of potentially eligible articles; exclusion of articles considered ineligible after complete reading; and the final selection of studies considered suitable to compose this review (Fig. 1).

References analyzed were included if they met the inclusion criteria: 1) report at least one cognitive function assessed by neuropsychological measures and 2) report clinical or community-based studies with populations that had DHEA or DHEA-S levels assessed. The, exclusion criteria were: 1) review papers; 2) studies that included population with genetic syndromes (such as Down syndrome, Turner’s disorder, and Klinefelter’s), severe cognitive impairment (such as schizophrenia, dementia, and epilepsy) and endocrine diseases (such as polycystic ovary syndrome, androgen insensitivity syndrome and others); 3) studies with animals. After abstract analysis, 25 references were selected for this review (Table 1).

Methodology was based on the Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA), which addresses conceptual and practical advances in systematic reviews [25Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097.
[http://dx.doi.org/10.1371/journal.pmed.1000097] [PMID: 19621072]
].

3. RESULTS

3.1. Cognitive Functions Assessed

Despite growing knowledge about the role of DHEA and DHEA-S in the central nervous system, the majority of the research has focused on manifestations of sexual disorders, mood and aging [16Genazzani AR, Pluchino N. DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence. Climacteric 2010; 13(4): 314-6.
[http://dx.doi.org/10.3109/13697137.2010.492496] [PMID: 20540592]
-20Moser U, Wadsak W, Spindelegger C, et al. Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women. Neurosci Lett 2010; 476(3): 161-5.
[http://dx.doi.org/10.1016/j.neulet.2010.04.020] [PMID: 20399839]
] rather than the assessment of the relationship between these hormones and cognitive functions [18Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30(1): 65-91.
[http://dx.doi.org/10.1016/j.yfrne.2008.11.002] [PMID: 19063914]
, 19Charalampopoulos I, Remboutsika E, Margioris AN, Gravanis A. Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol Metab 2008; 19(8): 300-7.
[http://dx.doi.org/10.1016/j.tem.2008.07.004] [PMID: 18771935]
].

In this review, the most evaluated topics were global cognition (n=13 articles) and memory (n=11), followed by attention (n=4), executive function (n=3), intelligence (n=2), perception (n=1) and visuospatial ability (n=1). Several studies evaluated more than one cognitive function.

3.1.1. Global Cognition

Cognitive functions constitute a set of the basic elements of cognition such as: perception, learning, memory, attention, vigilance and reasoning among others [21Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. 4th ed. Oxford, Oxfordshire: Oxford University Press 2004., 26Antunes HK, Santos RF, Cassilhas R, et al. Exercício físico e função cognitiva: uma revisão. Rev Bras Med Esporte 2006; 12(2): 108-14.
[http://dx.doi.org/10.1590/S1517-86922006000200011]
]. Through cognition humans are able to process all information stored in brain [26Antunes HK, Santos RF, Cassilhas R, et al. Exercício físico e função cognitiva: uma revisão. Rev Bras Med Esporte 2006; 12(2): 108-14.
[http://dx.doi.org/10.1590/S1517-86922006000200011]
]. Fourteen articles addressed the relationships between DHEA, DHEA-S and global cognition. Concerning the endogenous levels of DHEA and/or DHEA-S, 12 articles were found.

Fig. (1)

Flowchart of the different phases of the systematic review.



3.1.1.1. Correlations in Both Genders Samples

In a cross-sectional evaluation of healthy elderly subjects (n=313; women, mean age, 77.3±6.4 years; men, mean age, 76.7±5.4 years), the Mini-Mental State Examination (MMSE) was presented and blood samples were collected. The results showed that DHEA had a negative correlation with cognitive function in women (b=-.79, p=.03) [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
].

Two articles from the same research group using the same sample and battery of tests showed: In the first study, 967 elderly Taiwanese were evaluated and blood and urine samples were collected. DHEA-S was positively associated with cognitive function in women [27Glei DA, Goldman N, Weinstein M, Liu IW. Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 2004; 39(3): 321-31.
[http://dx.doi.org/10.1016/j.exger.2003.11.003] [PMID: 15036391]
]. In the second study, these authors compared the results of previous evaluations from the same sample in 836 elderly patients. This time, a positive correlation was found between DHEA-S and cognitive function in 86% of the male sample (r= -0.0016, p <0.001) [28Goldman N, Glei DA. Sex differences in the relationship between DHEAS and health. Exp Gerontol 2007; 42(10): 979-87.
[http://dx.doi.org/10.1016/j.exger.2007.05.005] [PMID: 17604586]
]. Corroborating this last finding, in a study among older elderly Japanese adults (n=208) assessed by the Hasegawa Dementia Scale - Revised, blood levels of DHEA-S were associated with better cognitive function in men [29Fukai S, Akishita M, Yamada S, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009; 9(3): 282-9.
[http://dx.doi.org/10.1111/j.1447-0594.2009.00534.x] [PMID: 19702939]
].

Another study, published into two papers, evaluated 86 elderly people using an extended neuropsychological battery. Both transversal and longitudinal assessments did not show any correlations between hormones and cognition [30Carlson LE, Sherwin BB. Steroid hormones, memory and mood in a healthy elderly population. Psychoneuroendocrinology 1998; 23(6): 583-603.
[http://dx.doi.org/10.1016/S0306-4530(98)00025-0] [PMID: 9802129]
, 31Carlson LE, Sherwin BB. Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women. Neurobiol Aging 1999; 20(3): 315-24.
[http://dx.doi.org/10.1016/S0197-4580(99)00052-4] [PMID: 10588579]
]. Similarly, another study using elderly subjects (n=145) failed to find any correlation between hormonal levels and MMSE scores [32Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
].

3.1.1.2. Correlations in Male Samples

A cross-sectional study of elderly African men (n=124), using the multiple linear regression model, found that higher levels of DHEA-S, measured from blood samples, were associated with higher scores of MMSE (b=.098; p=.008) [9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
]. The other study evaluated 883 men for a period of 31 years period. DHEA-S blood levels were measured, and neuropsychological assessments were performed every two years. The comparison between the first and the last assessments found no statistically significant associations between DHEA-S levels and cognition [10Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000; 160(14): 2193-8.
[http://dx.doi.org/10.1001/archinte.160.14.2193] [PMID: 10904463]
].

3.1.1.3. Correlations in Female Samples

A cross-sectional study of DHEA-S using MMSE compared healthy elderly women (n=103) with a control group of healthy young women (n=25). Significantly (p<0.01) lower concentrations of DHEA-S were observed in women with lower MMSE scores compared to those with higher MMSE scores [33Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
]. Another study aimed to evaluate the association between the decline of blood levels of DHEA-S and cognitive functions over the years. Elderly women (n=394) were assessed using the MMSE and neuropsychological tests at baseline and 4-6 years later. No associations were found between the cognitive performance and DHEA-S [11Yaffe K, Ettinger B, Pressman A, et al. Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatry 1998; 43(9): 694-700.
[http://dx.doi.org/10.1016/S0006-3223(97)00303-X] [PMID: 9583004]
]. Similarly, a study assessing transversal and longitudinal global cognition in 218 Australian post-menopausal women through a composite derived from standardized scores of 17 individual test scores, found no significant relations between levels of DHEA-S and cognitive function [34Chua CK, Henderson VW, Dennerstein L, Ames D, Szoeke C. Dehydroepiandrosterone sulfate and cognition in midlife, post-menopausal women. Neurobiol Aging 2014; 35(7): 1654-5.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.140] [PMID: 24612674]
].

3.1.1.4. Intervention Studies

In the first paper, MMSE was used for evaluation and 1 mg of dexamethasone was administered for 1 year and 9 months to elderly men and women (n=189). DHEA-S blood levels were measured before and after this medication and no statistically significant relationships were found between the hormone levels and cognitive impairment [33Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
]. The longitudinal study, in which only postmenopausal women (n=20) received DHEA supplementation (25 mg) for 6 months, showed different results. A battery of tests was administered at the beginning (T1) and at the end (T2) of the treatment period. DHEA, DHEA-S and cortisol levels from blood samples were also measured. DHEA-S and the cortisol/DHEA ratios appeared to be negatively correlated with cognition before and after supplementation [36Parsons TD, Kratz KM, Thompson E, Stanczyk FZ, Buckwalter JG. Dhea supplementation and cognition in postmenopausal women. Int J Neurosci 2006; 116(2): 141-55.
[http://dx.doi.org/10.1080/00207450500341506] [PMID: 16393880]
].

Although some studies have shown a positive correlation between DHEA and cognition, others have shown negative correlations, indicating that these relations are not yet clear. Two cross-sectional studies revealed a positive correlation between the DHEA-S levels and global cognition in women, whereby the first study used a battery of neuropsychological tests [27Glei DA, Goldman N, Weinstein M, Liu IW. Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 2004; 39(3): 321-31.
[http://dx.doi.org/10.1016/j.exger.2003.11.003] [PMID: 15036391]
] and the second study used MMSE [33Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
]. The cross-sectional study using MMSE showed a negative correlation between DHEA and cognition in women [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
]. In the male population, 3 studies showed a positive correlation with DHEA-S among older men [9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
, 28Goldman N, Glei DA. Sex differences in the relationship between DHEAS and health. Exp Gerontol 2007; 42(10): 979-87.
[http://dx.doi.org/10.1016/j.exger.2007.05.005] [PMID: 17604586]
, 29Fukai S, Akishita M, Yamada S, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009; 9(3): 282-9.
[http://dx.doi.org/10.1111/j.1447-0594.2009.00534.x] [PMID: 19702939]
]. Seven studies failed to observe any connection between hormonal levels and cognition [10Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000; 160(14): 2193-8.
[http://dx.doi.org/10.1001/archinte.160.14.2193] [PMID: 10904463]
, 11Yaffe K, Ettinger B, Pressman A, et al. Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatry 1998; 43(9): 694-700.
[http://dx.doi.org/10.1016/S0006-3223(97)00303-X] [PMID: 9583004]
, 30Carlson LE, Sherwin BB. Steroid hormones, memory and mood in a healthy elderly population. Psychoneuroendocrinology 1998; 23(6): 583-603.
[http://dx.doi.org/10.1016/S0306-4530(98)00025-0] [PMID: 9802129]
-32Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
, 34Chua CK, Henderson VW, Dennerstein L, Ames D, Szoeke C. Dehydroepiandrosterone sulfate and cognition in midlife, post-menopausal women. Neurobiol Aging 2014; 35(7): 1654-5.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.140] [PMID: 24612674]
, 35Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83(10): 3487-92.
[http://dx.doi.org/10.1210/jcem.83.10.5164] [PMID: 9768651]
] and one identified negative correlations in women [36Parsons TD, Kratz KM, Thompson E, Stanczyk FZ, Buckwalter JG. Dhea supplementation and cognition in postmenopausal women. Int J Neurosci 2006; 116(2): 141-55.
[http://dx.doi.org/10.1080/00207450500341506] [PMID: 16393880]
].

3.1.2. Memory

Memory is a function that gives meaning to time, maintains one’s identity and ensures learning [23Fuentes D, Malloy-Diniz LF, Camargo CH, Cosenza RM. Neuropsicologia: teoria e prática. Porto Alegre, Rio Grande do Sul: Artmed 2008.]. The complex process of memory requires a number of successive stages and it cannot be construed as a solitary system. Memory can be divided into working memory, declarative memory, procedural memory, short-term memory, long-term memory, and others [37Luria AR. Fundamentos de Neuropsicologia. São Paulo: Ed. da Universidade Federal de São Paulo 1981., 38Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004.]. In this sample, 11 articles included have addressed memory. Four articles focusing on the endogenous levels of DHEA or DHEA-S and 7 articles are on DHEA supplementation.

3.1.2.1. Correlations in Both Genders Samples

The first cross-sectional study, using a sample of healthy elderly adults (n=313) assessed by memory components of the MMSE, showed that episodic declarative memory was negatively correlated with DHEA blood levels in women [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
]. Another cross-sectional study, only with women (n=295 between the ages of 21 and 77 years), suggested a positive relationship between DHEA-S levels and working memory [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
].

3.1.2.2. Correlations in Male Samples

One study was performed in 25 elderly men to assess long-term verbal memory. No correlation was found with DHEA-S blood levels in men [40Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
]. Similarly, a survey of 981 elderly men showed no correlation between DHEA-S or DHEA blood levels and working memory [12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
].

3.1.2.3. Intervention Studies

Three of these studies were conducted using only male subjects. The first study evaluated 46 men. They received 50 mg DHEA daily for 13 weeks followed by placebo for 13 weeks, or the reverse. Salivary cortisol and DHEA levels were measured and cognition was assessed using Word List Memory and Object Location Memory. No significant effects of DHEA were observed in any of the trial outcomes, providing no support for benefits of DHEA supplementation for episodic declarative memory, despite the significant increase of DHEA levels after treatment [41van Niekerk JK, Huppert FA, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001; 26(6): 591-612.
[http://dx.doi.org/10.1016/S0306-4530(01)00014-2] [PMID: 11403980]
]. Similarly, 17 elderly men on placebo or DHEA (50 mg/day) for 2 weeks (double blind) did not enhance their declarative and visual memory [42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
]. However, the last study showed that DHEA supplementation can influence on memory aspects. The sample composed of young men (n=24) had the episodic memory assessed after daily DHEA supplementation (300 mg for 7 days). Significant effects when compared to the placebo group were found [43Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
].

Studies comprising only of women showed different results. The first study, conducted among postmenopausal women (n=6), demonstrated that DHEA supplementation influenced memory. This sample was treated with 50 mg of DHEA daily for 4 weeks and showed negative effects of androgens on recognition memory. Recognition memory was observed to be negatively correlated to the level of ANDRO factor [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
]. The second longitudinal study, using a daily dose of 50 mg of DHEA for 4 weeks, did not lead to short-term memory improvements in postmenopausal women (n=48) [45Merritt P, Stangl B, Hirshman E, Verbalis J. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Res 2012; 1483: 54-62.
[http://dx.doi.org/10.1016/j.brainres.2012.09.015] [PMID: 22985672]
].

Two other studies comprised of men and women. Divided into control and treatment groups, 111 men and 118 women (mean age 68.7±7.9) received 50 mg of DHEA or placebo for one year. These groups were assessed using the Word List Memory and Word List Recall tests. No difference was found between groups in terms of changes in declarative memory [46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
]. Another study with 40 elderly men and women also found no effect on memory after DHEA supplementation [47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
].

Results regarding memory demonstrated a correlation between working memory and DHEA-S in women in just one cross-sectional study [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
]. One longitudinal study, which focused on DHEA supplementation, demonstrated a negative correlation between DHEA and recognition memory in women [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
], whereas other studies failed to demonstrate the effects of hormonal supplementation on working memory and episodic declarative memory [45Merritt P, Stangl B, Hirshman E, Verbalis J. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Res 2012; 1483: 54-62.
[http://dx.doi.org/10.1016/j.brainres.2012.09.015] [PMID: 22985672]
-47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
]. In men, the majority of studies showed no relationship between DHEA or DHEA-S and all types of memory functions [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
, 12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
, 40Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
-42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
, 46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
, 47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
]. The only study that demonstrated a correlation between DHEA and memory was a longitudinal study, which used a higher DHEA dose supplementation (300 mg for 7 days) in young males [43Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
]. All other studies that failed to demonstrate effects were conducted with a 50 mg daily dose [41van Niekerk JK, Huppert FA, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001; 26(6): 591-612.
[http://dx.doi.org/10.1016/S0306-4530(01)00014-2] [PMID: 11403980]
, 42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
, 44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
-47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
].

3.1.3. Attention

Among the articles included in this review, 4 articles evaluated attention. Attention is a cognitive function defined as the ability to target and select information, inside and outside of the body, to maintain vigilance and organize behavior and mental processes [37Luria AR. Fundamentos de Neuropsicologia. São Paulo: Ed. da Universidade Federal de São Paulo 1981., 38Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004.]. It is also defined as the direction of consciousness or a state of mental concentration about a specific object [49Dalgalarrondo P. Psicopatologia e semiologia dos transtornos mentais. 2nd ed. Porto Alegre: Artmed 2008.]. Attention is considered a multifaceted system and some authors subdivide it in focused attention; selective attention; response selection and executive control; and sustained attention [22Miotto EC, Lucia MC. Scaff M Neuropsicologia e as Interfaces com as neurociências. São Paulo: Casa do Psicólogo 2007., 38Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004., 49Dalgalarrondo P. Psicopatologia e semiologia dos transtornos mentais. 2nd ed. Porto Alegre: Artmed 2008.].

3.1.3.1. Correlations in Female Samples

One cross-sectional study that assessed attention in women (n=295; age range, 21-77 years) found that DHEA-S blood levels are positively correlated with attention [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
]. Another cross-sectional study conducted in elderly men (n=981) showed no correlations with DHEA or DHEA-S [12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
].

3.1.3.2. Intervention Studies

A longitudinal study of postmenopausal women (n=6) identified a negative relationship between the variable ANDROfactor and attention [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
]. The longitudinal study conducted on 40 elderly subjects from both genders found no significant effect of 50 mg DHEA for two weeks on attention [47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
].

Again, a positive correlation was found only in a cross-sectional study with women [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
] ,but not in the cross-sectional study with men [12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
]. Longitudinal studies with DHEA replacement showed no effects on either men and women [47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
] or even a negative relationship between androgens and attention [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
].

3.1.4. Executive Function

Executive function is a set of skills that allows individuals to perform and control operations and to regulate information in the brain. Executive function can be divided into working memory, planning, problem solving, decision making, inhibitory control, fluency, cognitive flexibility, categorization, and others [23Fuentes D, Malloy-Diniz LF, Camargo CH, Cosenza RM. Neuropsicologia: teoria e prática. Porto Alegre, Rio Grande do Sul: Artmed 2008., 38Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004.]. The assessment of executive function was performed in 3 studies; one study reporting endogenous levels and 2 studies reporting DHEA supplementation.

3.1.4.1. Correlations in Female Samples

The cross-sectional study of a sample of 295 women (age range, 21-77 years) used the Controlled Oral Word Association Test (FAS) to assess verbal fluency, which is an executive function. Higher DHEA-S blood levels corresponded with higher FAS scores, indicating a positive correlation between verbal fluency and DHEA-S [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
].

3.1.4.2. Intervention Studies

Two longitudinal studies [46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
, 47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
] with mixed populations did not find any relationship between DHEA supplementation and an improvement of the executive functions. In the first study, 110 men and 115 women (mean age, 68.7±7.9 years) were divided into treatment and placebo groups. The treatment group received 50 mg of DHEA for one year [46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
]. In the second study, 25 elderly men and 15 elderly women received two weeks of 50 mg of DHEA. Analyses showed no significant correlations [47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
].

The types of executive function studied in the articles were verbal fluency, categorization and cognitive flexibility. As observed in other cognitive functions, the cross-sectional study showed a correlation between DHEA-S and verbal fluency in women [39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
], whereas the two longitudinal studies, showed no improvement on categorization or cognitive flexibility with DHEA administration [46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
, 47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
].

3.1.5. Intelligence

Intelligence is a broad and widely used concept, but so far there is no definitive concept about it. However, we can define it as the ability to identify and solve new problems and find the best possible solution, it is the outcome of the individual's intellectual skills [49Dalgalarrondo P. Psicopatologia e semiologia dos transtornos mentais. 2nd ed. Porto Alegre: Artmed 2008.], but not includes only skills and abilities, and also includes how the brain works to process the information it receives [38Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004.]. Two studies investigated the relationship between DHEA, DHEA-S and intelligence, measuring the endogenous levels of hormones [40Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
, 48Azurmendi A, Braza F, Sorozabal A, et al. Cognitive abilities, androgen levels, and body mass index in 5-year-old children. Horm Behav 2005; 48(2): 187-95.
[http://dx.doi.org/10.1016/j.yhbeh.2005.03.003] [PMID: 15878571]
].

The first study was conducted in 25 elderly men and evaluated crystallized intelligence, which is not sensitive to aging, and fluid intelligence, which is sensitive to aging. The results showed that DHEA-S blood levels were neither correlated with crystallized intelligence nor with fluid intelligence [40Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
]. The other study was conducted in children (n=60 boys and 69 girls; mean age=5 years 11 months) using the Kaufman Brief Intelligence Test and a negative correlation was found (r = −0.121, P < 0.05.) [42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
].

3.1.6. Perception and Visuospatial Ability

Perception is a complex and active process in which one examines and formulates a hypothesis about the present [37Luria AR. Fundamentos de Neuropsicologia. São Paulo: Ed. da Universidade Federal de São Paulo 1981.]. The perception can also be described as the awareness of sensory stimuli, external objects or facts of different complexity degrees [49Dalgalarrondo P. Psicopatologia e semiologia dos transtornos mentais. 2nd ed. Porto Alegre: Artmed 2008.]. Visuospatial ability is a broad construct and involves the ability to produce, record, recall and work with images and visual sensations via global processing [50Schelini PW. Teoria das inteligências fluida e cristalizada: início e evolução. Estud Psicol 2006; 11: 323-32.]. Some of the specific skills involved in visuospatial ability are: visualization, spatial relationships, closing speed, closing flexibility, visual memory and spatial rummage [51Gomes CM, Borges OR. Psychometric proprieties of visual-spatial ability tests kit. Psico-USF 2009; 14(1): 19-34.
[http://dx.doi.org/10.1590/S1413-82712009000100004]
].

One study was found for each of these cognitive functions. For the first function, a longitudinal study conducted among postmenopausal women (n=6) assessed the relationship between visual perception and DHEA after treatment with 50 mg of DHEA daily for 4 weeks. The results of the Perceptual Identification Test showed that androgen hormones were negatively correlated with perception (r=-.28) [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
]. The second study, a cross-sectional one, explored visuospatial ability and the endogenous levels of DHEA and DHEA-S. It was conducted in older adults (n=981; mean age, 62.66 years) using the Relation Figural Test. Results showed no relationship between visuospatial ability and blood levels of DHEA-S or DHEA [12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
]

Table 1

Summary of the studies included in this review.




4. DISCUSSION

To discuss the relationship between DHEA, DHEA-S and cognitive function in populations of regular development, it is important to analyze all methodologic differences observed. Methodology design will be discussed in three levels: (1) type of study (with endogenous or exogenous hormones); (2) populations characteristics; (3) instruments used.

Regarding the type of study, some studies focused on endogenous levels whereas others focused on DHEA supplementation. No other review compiled studies with endogenous levels. In this review it was observed that studies that focused on endogenous DHEA-S levels showed a positive correlation with global cognition in women and men and a positive correlation with working memory, attention and verbal fluency (executive function) in women [9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
, 27Glei DA, Goldman N, Weinstein M, Liu IW. Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 2004; 39(3): 321-31.
[http://dx.doi.org/10.1016/j.exger.2003.11.003] [PMID: 15036391]
-29Fukai S, Akishita M, Yamada S, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009; 9(3): 282-9.
[http://dx.doi.org/10.1111/j.1447-0594.2009.00534.x] [PMID: 19702939]
, 33Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
, 39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
].

We speculate that the neuropsychiatric and cognitive effects of DHEA and DHEA-S are modulated by ɣ-aminobutyric acid-A receptor antagonistic effects, N-Methyl-D-aspartic acid and σ-receptor potentiation effects. These hormones increases regional serotonin and dopamine activity in the brain, hippocampal primed burst potentiation and cholinergic function, anti glucocorticoid activity, inhibition of production of proinflammatory factors and bioavailability of insulin-like growth factor I [17Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008; 33(1): 88-109.
[http://dx.doi.org/10.1038/sj.npp.1301574] [PMID: 17851537]
-20Moser U, Wadsak W, Spindelegger C, et al. Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women. Neurosci Lett 2010; 476(3): 161-5.
[http://dx.doi.org/10.1016/j.neulet.2010.04.020] [PMID: 20399839]
, 52Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct 2012; 19: 8-61.
[http://dx.doi.org/10.1186/1744-9081-8-61]
, 53Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G. Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder. J Clin Psychopharmacol 2006; 26(4): 379-84.
[http://dx.doi.org/10.1097/01.jcp.0000229483.52955.ec] [PMID: 16855455]
]. These findings can bring greater evidence for the repercussion of DHEA-S in global cognition, working memory, attention and verbal fluency verified in this review.

However, studies with DHEA replacement failed to improve such cognitive functions [35Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83(10): 3487-92.
[http://dx.doi.org/10.1210/jcem.83.10.5164] [PMID: 9768651]
, 41van Niekerk JK, Huppert FA, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001; 26(6): 591-612.
[http://dx.doi.org/10.1016/S0306-4530(01)00014-2] [PMID: 11403980]
, 42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
, 45Merritt P, Stangl B, Hirshman E, Verbalis J. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Res 2012; 1483: 54-62.
[http://dx.doi.org/10.1016/j.brainres.2012.09.015] [PMID: 22985672]
, 47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
] or even worsened their performance (negatively correlated) [36Parsons TD, Kratz KM, Thompson E, Stanczyk FZ, Buckwalter JG. Dhea supplementation and cognition in postmenopausal women. Int J Neurosci 2006; 116(2): 141-55.
[http://dx.doi.org/10.1080/00207450500341506] [PMID: 16393880]
, 44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
]. This finding corroborates other reviews about DHEA replacement. There were four previous reviews on DHEA supplementation [54 Goel RM, Cappola AR. Dehydroepiandrosterone sulfate and postmenopausal women. Curr Opin Endocrinol Diabetes Obes 2011; 18(3): 171-6.
[http://dx.doi.org/10.1097/MED.0b013e3283461818] [PMID: 21478748]
- 57Huppert FA, Van Niekerk JK. WITHDRAWN: Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev 2006; 18(2): CD000304.
[PMID: 17636627]
]. They showed that DHEA supplementation does not affect cognition in unimpaired people. In this review, just one of the longitudinal study with DHEA supplementation showed a positive influence on memory. However, this study comprised of young male population and a 300 mg dosage for supplementation [43Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
], whereas other studies cited in this present review and studies cited in the previous reviews focused on elderly people using a 25 mg or a 50 mg dosage. This comparison highlights the necessity of using higher doses to achieve positive effects on cognition. However, the safety of this treatment is controversial and the risk of side effects may increase at higher doses [16Genazzani AR, Pluchino N. DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence. Climacteric 2010; 13(4): 314-6.
[http://dx.doi.org/10.3109/13697137.2010.492496] [PMID: 20540592]
, 57Huppert FA, Van Niekerk JK. WITHDRAWN: Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev 2006; 18(2): CD000304.
[PMID: 17636627]
], although it is noteworthy that the side effects associated with DHEA use are described by literature as mild [6Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A. The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Curr Drug Targets 2014; 15(9): 901-14.
[http://dx.doi.org/10.2174/1389450115666140717111116] [PMID: 25039497]
].

The second category of analyses clarifies additional data. Studies’ designs were different in many points, such as age and the number of subjects. In the only study that proved the influence of DHEA supplementation on memory [43Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
], the population comprised of young men. DHEA and DHEA-S concentrations peak at approximately 20 years-old and decay over time [4Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22(3): 185-212.
[http://dx.doi.org/10.1006/frne.2001.0216] [PMID: 11456468]
-6Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A. The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Curr Drug Targets 2014; 15(9): 901-14.
[http://dx.doi.org/10.2174/1389450115666140717111116] [PMID: 25039497]
, 9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
-12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
, 15Guyton AC, Hall JE. Tratado de Fisiologia Médica. 10th ed. Rio de Janeiro: Guanabara Koogan 2002.]; thus, young men have higher endogenous levels of these hormones before treatment. The other studies that did not demonstrate differences in global cognition after DHEA supplementation were all conducted on with elderly people. This finding also corroborates a previously study [56Sorwell KG, Urbanski HF. Dehydroepiandrosterone and age-related cognitive decline. Age (Dordr) 2010; 32(1): 61-7.
[http://dx.doi.org/10.1007/s11357-009-9113-4] [PMID: 19711196]
] which suggested that age related changes of human DHEA metabolic pathways may contribute to the relative inefficacy of DHEA replacement therapy.

In another article [10Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000; 160(14): 2193-8.
[http://dx.doi.org/10.1001/archinte.160.14.2193] [PMID: 10904463]
], a cross-sectional study showed no relationship between cognition and DHEA-S in both genders. Participants’ ages ranged from 22 years to 91 years and this variation might have affected the outcome because of the differences in hormone levels in the young and elderly. This factor can explain why this finding contradicts other cross-sectional studies that demonstrate a positive correlation between DHEA-S and global cognition in both gender and memory in women.

An analysis of the characteristic of the sample in articles that did not show any correlation between endogenous hormone levels and global cognition included those with a mixed population (men and women) [30Carlson LE, Sherwin BB. Steroid hormones, memory and mood in a healthy elderly population. Psychoneuroendocrinology 1998; 23(6): 583-603.
[http://dx.doi.org/10.1016/S0306-4530(98)00025-0] [PMID: 9802129]
-32Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
].

Regarding these differences observed in these studies, it is important to discuss gender differences in the effects of DHEA and its sulfate on memory, attention and executive function. Results that showed higher influences on memory, attention and executive function were all studies constituted of elderly women. Several authors explained this difference based on the dynamics of aging and metabolism in men and women: men have a higher exposure to gonadal hormones, which may have physical, mental and emotional implications [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
]. DHEA, despite being the primary pro-hormone, is still present in lower levels in women [4Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22(3): 185-212.
[http://dx.doi.org/10.1006/frne.2001.0216] [PMID: 11456468]
]. In menopause, DHEA becomes the primary source of sex hormones in women; however, at this period, DHEA levels have declined by approximately 60%. In postmenopausal women, these levels may become undetectable in several cases. Because no other significant source of those hormones is available after menopause, low DHEA levels are associated with the majority of medical problems observed in postmenopausal women. In men, DHEA levels reach only 40% between the ages of 65 years and 75 years, and men continue to receive a nearly constant supplementation of sex hormones from the testis throughout life, which can minimize the consequences of the DHEA deficit [58Labrie F. DHEA, important source of sex steroids in men and even more in women. Prog Brain Res 2010; 182: 97-148.
[http://dx.doi.org/10.1016/S0079-6123(10)82004-7] [PMID: 20541662]
-61Wolkowitz OM, Reus VI, Roberts E, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry 1997; 41(3): 311-8.
[http://dx.doi.org/10.1016/S0006-3223(96)00043-1] [PMID: 9024954]
]. These findings call the attention for the longer exposure and higher concentrations to these hormones in men, which may explain the differences between genders in this review.

Other methodological factors that may contribute to the discrepancy are the different assessment materials. Different tests were used to evaluate memory, for example, some of them assessing just working memory [12Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
, 39Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
] or immediate auditory memory [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
, 40Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
, 45Merritt P, Stangl B, Hirshman E, Verbalis J. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Res 2012; 1483: 54-62.
[http://dx.doi.org/10.1016/j.brainres.2012.09.015] [PMID: 22985672]
, 46Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
], visual memory [43Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
], recognition memory [44Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
]. Others used a set of tests to evaluate memory as a whole [41van Niekerk JK, Huppert FA, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001; 26(6): 591-612.
[http://dx.doi.org/10.1016/S0306-4530(01)00014-2] [PMID: 11403980]
, 42Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
, 47Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
]. Maybe because of these methodological discrepancies, it was possible to observe the influence of DHEA-S just in women’s working memory.

Even across studies that used the same test, results can be biased due to the sensitivity of the test. In category Global Cognition, six articles evaluated global cognitive function using the MMSE [5Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
, 9Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
, 11Yaffe K, Ettinger B, Pressman A, et al. Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatry 1998; 43(9): 694-700.
[http://dx.doi.org/10.1016/S0006-3223(97)00303-X] [PMID: 9583004]
, 32Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
, 33Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
, 35Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83(10): 3487-92.
[http://dx.doi.org/10.1210/jcem.83.10.5164] [PMID: 9768651]
], which is a screening test that may not detect mild manifestations of cognitive dysfunction. Screening tests are widely used but are less sensitive to mild impairment [21Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. 4th ed. Oxford, Oxfordshire: Oxford University Press 2004.]. Of these studies, four [11Yaffe K, Ettinger B, Pressman A, et al. Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatry 1998; 43(9): 694-700.
[http://dx.doi.org/10.1016/S0006-3223(97)00303-X] [PMID: 9583004]
, 30Carlson LE, Sherwin BB. Steroid hormones, memory and mood in a healthy elderly population. Psychoneuroendocrinology 1998; 23(6): 583-603.
[http://dx.doi.org/10.1016/S0306-4530(98)00025-0] [PMID: 9802129]
, 32Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
, 35Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83(10): 3487-92.
[http://dx.doi.org/10.1210/jcem.83.10.5164] [PMID: 9768651]
] did not demonstrate any correlation between DHEA-S and memory. It could have happened because the tests were not sensitive enough to memory dysfunctions.

CONCLUSION

The analysis of the studies’ design clarified data and showed a positive correlation between DHEA-S and global cognition in women and men, and positive correlations with working memory, attention and verbal fluency in women only. Studies with DHEA supplementation did not improve cognitive functions or worsened the performance of such functions. The only study in which DHEA supplementation was successful was conducted among young men and with higher doses of DHEA (300 mg). The use of higher doses in elderly populations should be considered in future studies because of the age-related changes in DHEA metabolism. Therefore, before the use of DHEA supplementation for cognition in clinical practice, more studies are necessary to ensure the safety of the procedure.

CONFLICT OF INTEREST

The authors confirm that this article content has no conflict of interest.

ACKNOWLEDGEMENTS

Declared none.

REFERENCES

[1] Speroff L, Glass RH, Kase NG. Endocrinologia ginecológica clínica e infertilidade. 5th ed. São Paulo: Manole 1995.
[2] Wajchenberg BL. Tratado de encdocrinologia clínica. São Paulo: Roca 1992.
[3] Wolkowitz OM, Rothschild AJ. Psychoneuroendocrinology: The scientific sasis of clinical practice. Arlington, Virgínia: American Psychiatric Publishing, Inc. 2003.
[4] Labrie F, Luu-The V, Labrie C, Simard J. DHEA and its transformation into androgens and estrogens in peripheral target tissues: intracrinology. Front Neuroendocrinol 2001; 22(3): 185-212.
[http://dx.doi.org/10.1006/frne.2001.0216] [PMID: 11456468]
[5] Rueda Alfaro S, Serra-Prat M, Palomera E, et al. mataró aging study group. Hormonal determinants of depression and cognitive function in independently-living elders. Endocrinol Nutr 2008; 55(9): 396-401.
[http://dx.doi.org/10.1016/S1575-0922(08)75076-9] [PMID: 22974452]
[6] Peixoto C, Devicari Cheda JN, Nardi AE, Veras AB, Cardoso A. The effects of dehydroepiandrosterone (DHEA) in the treatment of depression and depressive symptoms in other psychiatric and medical illnesses: a systematic review. Curr Drug Targets 2014; 15(9): 901-14.
[http://dx.doi.org/10.2174/1389450115666140717111116] [PMID: 25039497]
[7] Lennartsson AK, Theorell T, Kushnir MM, Jonsdottir IH. Low levels of dehydroepiandrosterone sulfate in younger burnout patients. PLoS One 2015; 10(10): e0140054.
[http://dx.doi.org/10.1371/journal.pone.0140054] [PMID: 26441131]
[8] Ghisleni C, Bollmann S, Biason-Lauber A, et al. Effects of steroid hormones on sex differences in cerebral perfusion. PLoS One 2015; 10(9): e0135827.
[http://dx.doi.org/10.1371/journal.pone.0135827] [PMID: 26356576]
[9] Haren MT, Banks WA, Perry Iii HM, et al. Predictors of serum testosterone and DHEAS in African-American men. Int J Androl 2008; 31(1): 50-9.
[PMID: 18190426]
[10] Moffat SD, Zonderman AB, Harman SM, Blackman MR, Kawas C, Resnick SM. The relationship between longitudinal declines in dehydroepiandrosterone sulfate concentrations and cognitive performance in older men. Arch Intern Med 2000; 160(14): 2193-8.
[http://dx.doi.org/10.1001/archinte.160.14.2193] [PMID: 10904463]
[11] Yaffe K, Ettinger B, Pressman A, et al. Neuropsychiatric function and dehydroepiandrosterone sulfate in elderly women: a prospective study. Biol Psychiatry 1998; 43(9): 694-700.
[http://dx.doi.org/10.1016/S0006-3223(97)00303-X] [PMID: 9583004]
[12] Fonda SJ, Bertrand R, O’Donnell A, Longcope C, McKinlay JB. Age, hormones, and cognitive functioning among middle-aged and elderly men: cross-sectional evidence from the Massachusetts Male Aging Study. J Gerontol A Biol Sci Med Sci 2005; 60(3): 385-90.
[http://dx.doi.org/10.1093/gerona/60.3.385] [PMID: 15860479]
[13] Castanho TC, Moreira PS, Portugal-Nunes C, et al. The role of sex and sex-related hormones in cognition, mood and well-being in older men and women. Biol Psychol 2014; 103: 158-66.
[http://dx.doi.org/10.1016/j.biopsycho.2014.08.015] [PMID: 25196100]
[14] Maggio M, De Vita F, Fisichella A, et al. DHEA and cognitive function in the elderly. J Steroid Biochem Mol Biol 2015; 145: 281-92.
[http://dx.doi.org/10.1016/j.jsbmb.2014.03.014] [PMID: 24794824]
[15] Guyton AC, Hall JE. Tratado de Fisiologia Médica. 10th ed. Rio de Janeiro: Guanabara Koogan 2002.
[16] Genazzani AR, Pluchino N. DHEA therapy in postmenopausal women: the need to move forward beyond the lack of evidence. Climacteric 2010; 13(4): 314-6.
[http://dx.doi.org/10.3109/13697137.2010.492496] [PMID: 20540592]
[17] Pittenger C, Duman RS. Stress, depression, and neuroplasticity: a convergence of mechanisms. Neuropsychopharmacology 2008; 33(1): 88-109.
[http://dx.doi.org/10.1038/sj.npp.1301574] [PMID: 17851537]
[18] Maninger N, Wolkowitz OM, Reus VI, Epel ES, Mellon SH. Neurobiological and neuropsychiatric effects of dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEAS). Front Neuroendocrinol 2009; 30(1): 65-91.
[http://dx.doi.org/10.1016/j.yfrne.2008.11.002] [PMID: 19063914]
[19] Charalampopoulos I, Remboutsika E, Margioris AN, Gravanis A. Neurosteroids as modulators of neurogenesis and neuronal survival. Trends Endocrinol Metab 2008; 19(8): 300-7.
[http://dx.doi.org/10.1016/j.tem.2008.07.004] [PMID: 18771935]
[20] Moser U, Wadsak W, Spindelegger C, et al. Hypothalamic serotonin-1A receptor binding measured by PET predicts the plasma level of dehydroepiandrosterone sulfate in healthy women. Neurosci Lett 2010; 476(3): 161-5.
[http://dx.doi.org/10.1016/j.neulet.2010.04.020] [PMID: 20399839]
[21] Lezak MD, Howieson DB, Loring DW. Neuropsychological assessment. 4th ed. Oxford, Oxfordshire: Oxford University Press 2004.
[22] Miotto EC, Lucia MC. Scaff M Neuropsicologia e as Interfaces com as neurociências. São Paulo: Casa do Psicólogo 2007.
[23] Fuentes D, Malloy-Diniz LF, Camargo CH, Cosenza RM. Neuropsicologia: teoria e prática. Porto Alegre, Rio Grande do Sul: Artmed 2008.
[24] Malloy-Diniz LF, Fuentes D, Mattos P, Abreu N. Avaliação Neuropsicológica. São Paulo: Artmed 2010.
[25] Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 2009; 6(7): e1000097.
[http://dx.doi.org/10.1371/journal.pmed.1000097] [PMID: 19621072]
[26] Antunes HK, Santos RF, Cassilhas R, et al. Exercício físico e função cognitiva: uma revisão. Rev Bras Med Esporte 2006; 12(2): 108-14.
[http://dx.doi.org/10.1590/S1517-86922006000200011]
[27] Glei DA, Goldman N, Weinstein M, Liu IW. Dehydroepiandrosterone sulfate (DHEAS) and health: does the relationship differ by sex? Exp Gerontol 2004; 39(3): 321-31.
[http://dx.doi.org/10.1016/j.exger.2003.11.003] [PMID: 15036391]
[28] Goldman N, Glei DA. Sex differences in the relationship between DHEAS and health. Exp Gerontol 2007; 42(10): 979-87.
[http://dx.doi.org/10.1016/j.exger.2007.05.005] [PMID: 17604586]
[29] Fukai S, Akishita M, Yamada S, et al. Association of plasma sex hormone levels with functional decline in elderly men and women. Geriatr Gerontol Int 2009; 9(3): 282-9.
[http://dx.doi.org/10.1111/j.1447-0594.2009.00534.x] [PMID: 19702939]
[30] Carlson LE, Sherwin BB. Steroid hormones, memory and mood in a healthy elderly population. Psychoneuroendocrinology 1998; 23(6): 583-603.
[http://dx.doi.org/10.1016/S0306-4530(98)00025-0] [PMID: 9802129]
[31] Carlson LE, Sherwin BB. Relationships among cortisol (CRT), dehydroepiandrosterone-sulfate (DHEAS), and memory in a longitudinal study of healthy elderly men and women. Neurobiol Aging 1999; 20(3): 315-24.
[http://dx.doi.org/10.1016/S0197-4580(99)00052-4] [PMID: 10588579]
[32] Arai H, Takech H, Wada T, et al. Usefulness of measuring serum markers in addition to comprehensive geriatric assessment for cognitive impairment and depressive mood in the elderly. Geriatr Gerontol Int 2006; 6: 7-14.
[http://dx.doi.org/10.1111/j.1447-0594.2006.00327.x]
[33] Kedziora-Kornatowska K, Beszczyńska-Oleś R, Kornatowski T, Szadujkis-Szadurski L. The analysis of dehydroepiandrosterone sulphate concentration in elderly age women depending on coexisting disease states. Adv Med Sci 2007; 52(Suppl. 1): 126-30.
[PMID: 18229649]
[34] Chua CK, Henderson VW, Dennerstein L, Ames D, Szoeke C. Dehydroepiandrosterone sulfate and cognition in midlife, post-menopausal women. Neurobiol Aging 2014; 35(7): 1654-5.
[http://dx.doi.org/10.1016/j.neurobiolaging.2014.01.140] [PMID: 24612674]
[35] Kalmijn S, Launer LJ, Stolk RP, et al. A prospective study on cortisol, dehydroepiandrosterone sulfate, and cognitive function in the elderly. J Clin Endocrinol Metab 1998; 83(10): 3487-92.
[http://dx.doi.org/10.1210/jcem.83.10.5164] [PMID: 9768651]
[36] Parsons TD, Kratz KM, Thompson E, Stanczyk FZ, Buckwalter JG. Dhea supplementation and cognition in postmenopausal women. Int J Neurosci 2006; 116(2): 141-55.
[http://dx.doi.org/10.1080/00207450500341506] [PMID: 16393880]
[37] Luria AR. Fundamentos de Neuropsicologia. São Paulo: Ed. da Universidade Federal de São Paulo 1981.
[38] Andrade VM, dos Santos FH, Bueno OF. Neuropsicologia Hoje. São Paulo: Artes Médicas 2004.
[39] Davis SR, Shah SM, McKenzie DP, Kulkarni J, Davison SL, Bell RJ. Dehydroepiandrosterone sulfate levels are associated with more favorable cognitive function in women. J Clin Endocrinol Metab 2008; 93(3): 801-8.
[http://dx.doi.org/10.1210/jc.2007-2128] [PMID: 18073302]
[40] Aleman A, de Vries WR, Koppeschaar HP, et al. Relationship between circulating levels of sex hormones and insulin-like growth factor-1 and fluid intelligence in older men. Exp Aging Res 2001; 27(3): 283-91.
[http://dx.doi.org/10.1080/036107301300208718] [PMID: 11441649]
[41] van Niekerk JK, Huppert FA, Herbert J. Salivary cortisol and DHEA: association with measures of cognition and well-being in normal older men, and effects of three months of DHEA supplementation. Psychoneuroendocrinology 2001; 26(6): 591-612.
[http://dx.doi.org/10.1016/S0306-4530(01)00014-2] [PMID: 11403980]
[42] Wolf OT, Naumann E, Hellhammer DH, Kirschbaum C. Effects of dehydroepiandrosterone replacement in elderly men on event-related potentials, memory, and well-being. J Gerontol A Biol Sci Med Sci 1998; 53(5): M385-90.
[http://dx.doi.org/10.1093/gerona/53A.5.M385] [PMID: 9754145]
[43] Alhaj HA, Massey AE, McAllister-Williams RH. Effects of DHEA administration on episodic memory, cortisol and mood in healthy young men: a double-blind, placebo-controlled study. Psychopharmacology (Berl) 2006; 188(4): 541-51.
[http://dx.doi.org/10.1007/s00213-005-0136-y] [PMID: 16231168]
[44] Hirshman E, Merritt P, Wang CC, et al. Evidence that androgenic and estrogenic metabolites contribute to the effects of dehydroepiandrosterone on cognition in postmenopausal women. Horm Behav 2004; 45(2): 144-55.
[http://dx.doi.org/10.1016/j.yhbeh.2003.09.008] [PMID: 15019802]
[45] Merritt P, Stangl B, Hirshman E, Verbalis J. Administration of dehydroepiandrosterone (DHEA) increases serum levels of androgens and estrogens but does not enhance short-term memory in post-menopausal women. Brain Res 2012; 1483: 54-62.
[http://dx.doi.org/10.1016/j.brainres.2012.09.015] [PMID: 22985672]
[46] Kritz-Silverstein D, von Mühlen D, Laughlin GA, Bettencourt R. Effects of dehydroepiandrosterone supplementation on cognitive function and quality of life: the DHEA and Well-Ness (DAWN) Trial. J Am Geriatr Soc 2008; 56(7): 1292-8.
[http://dx.doi.org/10.1111/j.1532-5415.2008.01768.x] [PMID: 18482290]
[47] Wolf OT, Neumann O, Hellhammer DH, et al. Effects of a two-week physiological dehydroepiandrosterone substitution on cognitive performance and well-being in healthy elderly women and men. J Clin Endocrinol Metab 1997; 82(7): 2363-7.
[PMID: 9215320]
[48] Azurmendi A, Braza F, Sorozabal A, et al. Cognitive abilities, androgen levels, and body mass index in 5-year-old children. Horm Behav 2005; 48(2): 187-95.
[http://dx.doi.org/10.1016/j.yhbeh.2005.03.003] [PMID: 15878571]
[49] Dalgalarrondo P. Psicopatologia e semiologia dos transtornos mentais. 2nd ed. Porto Alegre: Artmed 2008.
[50] Schelini PW. Teoria das inteligências fluida e cristalizada: início e evolução. Estud Psicol 2006; 11: 323-32.
[51] Gomes CM, Borges OR. Psychometric proprieties of visual-spatial ability tests kit. Psico-USF 2009; 14(1): 19-34.
[http://dx.doi.org/10.1590/S1413-82712009000100004]
[52] Carta MG, Bhat KM, Preti A. GABAergic neuroactive steroids: a new frontier in bipolar disorders? Behav Brain Funct 2012; 19: 8-61.
[http://dx.doi.org/10.1186/1744-9081-8-61]
[53] Hardoy MC, Serra M, Carta MG, Contu P, Pisu MG, Biggio G. Increased neuroactive steroid concentrations in women with bipolar disorder or major depressive disorder. J Clin Psychopharmacol 2006; 26(4): 379-84.
[http://dx.doi.org/10.1097/01.jcp.0000229483.52955.ec] [PMID: 16855455]
[54] Goel RM, Cappola AR. Dehydroepiandrosterone sulfate and postmenopausal women. Curr Opin Endocrinol Diabetes Obes 2011; 18(3): 171-6.
[http://dx.doi.org/10.1097/MED.0b013e3283461818] [PMID: 21478748]
[55] Davis SR, Panjari M, Stanczyk FZ. Clinical review: DHEA replacement for postmenopausal women. J Clin Endocrinol Metab 2011; 96(6): 1642-53.
[http://dx.doi.org/10.1210/jc.2010-2888] [PMID: 21411558]
[56] Sorwell KG, Urbanski HF. Dehydroepiandrosterone and age-related cognitive decline. Age (Dordr) 2010; 32(1): 61-7.
[http://dx.doi.org/10.1007/s11357-009-9113-4] [PMID: 19711196]
[57] Huppert FA, Van Niekerk JK. WITHDRAWN: Dehydroepiandrosterone (DHEA) supplementation for cognitive function. Cochrane Database Syst Rev 2006; 18(2): CD000304.
[PMID: 17636627]
[58] Labrie F. DHEA, important source of sex steroids in men and even more in women. Prog Brain Res 2010; 182: 97-148.
[http://dx.doi.org/10.1016/S0079-6123(10)82004-7] [PMID: 20541662]
[59] Orentreich N, Brind JL, Rizer RL, Vogelman JH. Age changes and sex differences in serum dehydroepiandrosterone sulfate concentrations throughout adulthood. J Clin Endocrinol Metab 1984; 59(3): 551-5.
[http://dx.doi.org/10.1210/jcem-59-3-551] [PMID: 6235241]
[60] Heinz A, Weingartner H, George D, Hommer D, Wolkowitz OM, Linnoila M. Severity of depression in abstinent alcoholics is associated with monoamine metabolites and dehydroepiandrosterone-sulfate concentrations. Psychiatry Res 1999; 89(2): 97-106.
[http://dx.doi.org/10.1016/S0165-1781(99)00099-2] [PMID: 10646828]
[61] Wolkowitz OM, Reus VI, Roberts E, et al. Dehydroepiandrosterone (DHEA) treatment of depression. Biol Psychiatry 1997; 41(3): 311-8.
[http://dx.doi.org/10.1016/S0006-3223(96)00043-1] [PMID: 9024954]

Endorsements



"Open access will revolutionize 21st century knowledge work and accelerate the diffusion of ideas and evidence that support just in time learning and the evolution of thinking in a number of disciplines."


Daniel Pesut
(Indiana University School of Nursing, USA)

"It is important that students and researchers from all over the world can have easy access to relevant, high-standard and timely scientific information. This is exactly what Open Access Journals provide and this is the reason why I support this endeavor."


Jacques Descotes
(Centre Antipoison-Centre de Pharmacovigilance, France)

"Publishing research articles is the key for future scientific progress. Open Access publishing is therefore of utmost importance for wider dissemination of information, and will help serving the best interest of the scientific community."


Patrice Talaga
(UCB S.A., Belgium)

"Open access journals are a novel concept in the medical literature. They offer accessible information to a wide variety of individuals, including physicians, medical students, clinical investigators, and the general public. They are an outstanding source of medical and scientific information."


Jeffrey M. Weinberg
(St. Luke's-Roosevelt Hospital Center, USA)

"Open access journals are extremely useful for graduate students, investigators and all other interested persons to read important scientific articles and subscribe scientific journals. Indeed, the research articles span a wide range of area and of high quality. This is specially a must for researchers belonging to institutions with limited library facility and funding to subscribe scientific journals."


Debomoy K. Lahiri
(Indiana University School of Medicine, USA)

"Open access journals represent a major break-through in publishing. They provide easy access to the latest research on a wide variety of issues. Relevant and timely articles are made available in a fraction of the time taken by more conventional publishers. Articles are of uniformly high quality and written by the world's leading authorities."


Robert Looney
(Naval Postgraduate School, USA)

"Open access journals have transformed the way scientific data is published and disseminated: particularly, whilst ensuring a high quality standard and transparency in the editorial process, they have increased the access to the scientific literature by those researchers that have limited library support or that are working on small budgets."


Richard Reithinger
(Westat, USA)

"Not only do open access journals greatly improve the access to high quality information for scientists in the developing world, it also provides extra exposure for our papers."


J. Ferwerda
(University of Oxford, UK)

"Open Access 'Chemistry' Journals allow the dissemination of knowledge at your finger tips without paying for the scientific content."


Sean L. Kitson
(Almac Sciences, Northern Ireland)

"In principle, all scientific journals should have open access, as should be science itself. Open access journals are very helpful for students, researchers and the general public including people from institutions which do not have library or cannot afford to subscribe scientific journals. The articles are high standard and cover a wide area."


Hubert Wolterbeek
(Delft University of Technology, The Netherlands)

"The widest possible diffusion of information is critical for the advancement of science. In this perspective, open access journals are instrumental in fostering researches and achievements."


Alessandro Laviano
(Sapienza - University of Rome, Italy)

"Open access journals are very useful for all scientists as they can have quick information in the different fields of science."


Philippe Hernigou
(Paris University, France)

"There are many scientists who can not afford the rather expensive subscriptions to scientific journals. Open access journals offer a good alternative for free access to good quality scientific information."


Fidel Toldrá
(Instituto de Agroquimica y Tecnologia de Alimentos, Spain)

"Open access journals have become a fundamental tool for students, researchers, patients and the general public. Many people from institutions which do not have library or cannot afford to subscribe scientific journals benefit of them on a daily basis. The articles are among the best and cover most scientific areas."


M. Bendandi
(University Clinic of Navarre, Spain)

"These journals provide researchers with a platform for rapid, open access scientific communication. The articles are of high quality and broad scope."


Peter Chiba
(University of Vienna, Austria)

"Open access journals are probably one of the most important contributions to promote and diffuse science worldwide."


Jaime Sampaio
(University of Trás-os-Montes e Alto Douro, Portugal)

"Open access journals make up a new and rather revolutionary way to scientific publication. This option opens several quite interesting possibilities to disseminate openly and freely new knowledge and even to facilitate interpersonal communication among scientists."


Eduardo A. Castro
(INIFTA, Argentina)

"Open access journals are freely available online throughout the world, for you to read, download, copy, distribute, and use. The articles published in the open access journals are high quality and cover a wide range of fields."


Kenji Hashimoto
(Chiba University, Japan)

"Open Access journals offer an innovative and efficient way of publication for academics and professionals in a wide range of disciplines. The papers published are of high quality after rigorous peer review and they are Indexed in: major international databases. I read Open Access journals to keep abreast of the recent development in my field of study."


Daniel Shek
(Chinese University of Hong Kong, Hong Kong)

"It is a modern trend for publishers to establish open access journals. Researchers, faculty members, and students will be greatly benefited by the new journals of Bentham Science Publishers Ltd. in this category."


Jih Ru Hwu
(National Central University, Taiwan)


Browse Contents




Webmaster Contact: info@benthamopen.net
Copyright © 2019 Bentham Open