- Email: [email protected]
The age of dehydroepiandrosterone
of the
six-membered rings, which are the core structure of the quinolones and related classes of gyrase inhibitors (figure). Adjacent carbonyl and carboxyl groups attached to the core are necessary for the anti-gyrase activity of quinolones and are retained in the 2-pyridones. Fluorine and positively charged ring substitutions attached to the core, which are components of the most potent fluoroquinolones, are also components of two
promising 2-pyridones. 2-pyridone compound designated ABT719 (also A-86719.1) is striking for its breadth of spectrum and substantial enhancement of activity against gram-positive bacteria and anaerobes relative to that of ciprofloxacin/ Thus ABT719 showed twenty to forty-fold increased activity in vitro against Staphylococcus aureus (including some methicillin and ciprofloxacin resistant strains), Enterococcus spp (including some vancomycin-resistant strains), Streptococcus pyogenes, and Bacteroides fragilis. ABT719 also retained the strong activity against gramnegative pathogens that is characteristic of current fluoroquinolones.7,9 Again by comparison with ciprofloxacin, ABT719 was two to ten-fold more active against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Like the quinolones, ABT719 is
7
8
9
A
bactericidal.’," In rodents, in-vivo antibacterial activity of ABT719 was shown for various infections-eg, systemic (S aureus,
enterococci), lung (Streptococcus pneumoniae, Haemophilus influenzae, and P aeruginosa), kidney (enterococci), and skin (S aureus, S pyogenes, and mixed organisms). ED 50 values were generally several fold higher when the drug was given orally rather than subcutaneously, so oral bioavailability is incomplete in rodents. 2-pyridones offer promise for development of newer broad-spectrum gyrase inhibitors with activity against some of the more troublesome and resistant gram-positive pathogens. Other fluoroquinolones that show enhanced activity against gram-positive and anaerobic bacteria (eg, levofloxacin, clinafloxacin, grepafloxacin, CP-99,219, and DU6859a) are under development. The next steps in evaluation of these new drugs will be to assess their tolerability and show their clinical efficacy in human beings, bearing in mind that other initially promising members of the quinolone and naphthyridine classes have been halted at various stages of development because of toxicities.’4 David C
Hooper
Infectious Disease Unit, Massachusetts General Hospital, Boston, MA, USA 1 Gellert M, Mizuuchi K, O’Dea M, et al. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci USA 1977; 74: 4772-76. 2 Sugino A, Peebles CL, Kruezer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc Natl Acad Sci USA 1977; 74: 4767-71. 3 Lesher GY, Forelich ED, Gruet MD, et al. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Pharm Chem 1962, 5: 1063-68. 4 Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med 1991; 324: 384-94. 5 Hooper DC, Wolfson JS. Mechanisms of quinolone action and bacterial killing. In: Hooper DC, Wolfson JS, eds. Quinolone antimicrobial agents, 2nd ed. Washington, DC: American Society for Microbiology, 1993: 53-75. 6 Chu DTW, Li Q, Claiborne A, et al. Synthesis and antibacterial activity of A-86719.1 and related 2-pyridones: a novel series of potent
10
11
12
13
14
DNA gyrase inhibitors. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida, 1994: abstr F41. Eliopoulos GM, Wennersten CB, Cole G, et al. In vitro activity of A-86719.1, a novel pyridone antimicrobial. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F43. Flamm RK, Vojtko C, Ramer N, et al. Comparative in vitro activity of A-86719.1, a novel bacterial DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F45. Chin NX, Chu D, Neu HC. In vitro antibacterial activity of A-86719.1, a new class DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F49. Flamm RK, Vojtko C, Ramer N, et al. Characterisation of in vitro activity of A-86719.1, a novel bacterial DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F47. Chin NX, Chu D, Huang HB, Neu HC. A-86719.1, a new class DNA gyrase inhibitor, its time-killing activity, postantibiotic effect and assay condition effect. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F51. Alder JD, Meulbroek JM, Shipkowitz NL, et al. Efficacy of A-86719.1, a novel 2-pyridone gyrase inhibitor, for treatment of systemic, lung and abscess infections in mice and rats. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F53. Meulbroek JA, Oleksijew A, Tanaka SK, Alder JD. Efficacy of A-86719.1, a novel 2-pyridone gyrase inhibitor, for treatment of endocarditis, pyelonephritis and systemic infections caused by enterococci in mice. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F55. Hooper DC, Wolfson JS. Adverse effects. In: Hooper DC, Wolfson JS, eds. Quinolone antimicrobial agents, 2nd ed. Washington, DC: American Society for Microbiology, 1993: 489-512.
The age of
dehydroepiandrosterone
Why have dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), hormones dismissed for years as "weak androgens", lately attracted media attention? DHEAS, generated in the liver from the parent adrenal steroid DHEA, circulates in the blood of man and other primates in relatively huge quantities (about 10 times that of cortisol). However, unlike cortisol, blood DHEA(S) concentrations peak at about 20 years, declining thereafter remorselessly and profoundly so that by 60 years they are one-third or less of those in young adults.’ Recent interest has been spurred by clinical data linking the decrease in DHEA(S) with agerelated illnesses such as ischaemic heart disease (in men at least),z changes in the amount or distribution of body fat,3 onset of non-insulin-dependent diabetes, and some forms of cancer/ Moreover, there are considerable individual differences in the rate of DHEA(S) decline, which may be partly under hereditary control.I Nearly all the clinical facets of this story rest on correlation-eg, the relation between individual or group differences in frequency of myocardial infarction with those in concentrations of DHEA(S). A serious drawback with some of these studies is that DHEA(S) also decreases during illness, as has been observed in rheumatoid arthritis and major depressive disorder as well as during other forms of stress.5,6 We therefore need to separate the effects of age or individuality from those of either acute or chronic ill health. Long-term prospective studies (in which DHEA[S] concentrations at an earlier age are used to predict subsequent health) go some way towards separating these confounding factors. The intriguing conclusions are that the downward trajectory of DHEA(S) may indicate individual differences in ageing
1193
or
lifespan, and either foretell
or
DHEA administration for adequate periods, and critical importance of using cross-disciplinary outcome measures. Does DHEA(S) therapy retard, or even reverse, any of the age-dependent processes in which it has been implicated? Do specific somatic or mental illnesses accentuate or initiate age-related processes? Satisfactory evidence for rational therapy will not be obtained easily or quickly-ageing is not a simple unitary process-but the possibility that DHEA might alleviate some of the problems of ageing, or improve the treatment or complications of intercurrent illnesses, opens new and
initiate age-related
studying
illness.
the
Experimental work supports a protective role for DHEA(S) in some pathological processes. DHEA reduced the development of vascular stenosis in heterotopic heart transplants,’ and stimulated the production of cytokines in mice.8 There is some experimental evidence for an anticarcinogenic effect of DHEAS.’ Oral administration of DHEA reduced food intake and body weight in genetically obese rats.9 DHEA(S) also has effects on the brain. In common with other neurosteroids, DHEA(S) acts directly on neural membranes either to increase or to antagonise the effects of glutamate or gamma-aminobutyric acid." By contrast, conventional steroids such as cortisol act via cytoplasmic as DNA receptors transcriptional regulators. enhances some forms of Experimentally, DHEA(S) and reduces memory, aggression." Attempts to show correlations between DHEA(S) concentrations and memory in normal ageing human beings or those with Alzheimer’s disease have not proved unsuccessful.’2" A negative correlation has been found between aggression and DHEAS in adolescent girls,’4 but a positive one between DHEA and "dominance" in middle-aged men." Both the immunological and neural effects of DHEA(S) may also be due to its powerful antiglucocorticoid action," the precise nature of which is still unclear. Low DHEA(S) may thus accentuate the immunosuppressive effects of raised corticoids (eg, during stress or trauma). Increased cortisol can induce brain damage in animals," and -may amplify that caused by other neurotoxic events both experimentally and clinically (eg, following a stroke).18 Low DHEA(S) in the ageing brain might therefore predispose to damage, or allow endogenous normal concentrations of cortisol to act as neurotoxic agents. Does the age-dependent decline in DHEA(S) have medical significance? If so, there would be a case for therapeutic regulation of DHEA(S) during advancing years. Two reports describe administration of DHEA (50 mg daily, which reproduces blood levels of early adulthood) to middle-aged and older people. In one" (limited to immune studies) there was pronounced stimulation of natural killer lymphocyte activity (thus confirming experimental conclusions). In the other" DHEA increased insulin growth factor 1 concentrations (which themselves decline with age); this observation suggests one mechanism whereby low concentrations of DHEA(S) may be associated with obesity or diabetes in later life. Changes in blood lipoproteins were minor. There was a remarkable increase in feelings of "wellbeing" in about 70% of the subjects, although exactly how this was defined or measured is unclear. There are no adequate studies of cognitive function in man during DHEA therapy. Enough is known or suspected to warrant investigation of DHEA(S) as an effective, worthwhile, and relatively risk-free replacement therapy in advancing age. This can only be done by a controlled prospective trial of DHEA treatment; no amount of correlational evidence, however carefully collected, is enough. Organisers of such trials will need to be aware of the problems of subject selection (and controls), the effects on DHEA(S) of extraneous factors such as illness or smoking, the necessity of
1194
exciting avenues. J Herbert Department of Anatomy and University of Cambridge, UK 1
MRC
Cambridge Centre for Brain Repair,
Vogelman JH, Andres R, Baldwin H. Longlongitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992; 75: 1002-04. Barrett-Connor E, Edelstein SL. A prospective study of dehydroepiandrosterone sulfate and cognitive function in an older population. J Am Geriat Soc 1994; 42: 420-23. Williams DP, Boyden TW, Pamenter RW, Lohman TG, Coing SB. Relationship of body fat percentage and fat distribution with dehydroepiandrosterone sulfate in premenstrual females. J Clin Endocrinol Metab 1993; 77: 80-85. Ebeling P, Kiovisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994; 343: 1479-81. Goodyer IM, Herbert J, Altham PME, Pearson J, Secher SM, Shiers HM. Adrenal secretion during major depression in 8 to 16 year olds: altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation. Psychol Med (in press). Hedman M, Nilsson E, Torre B de la. Low blood and synovial fluid levels of sulpho-conjugated steroids in rheumatoid arthritis. Clin Exp Rheumatol 1992; 10: 25-30. Eich DM, Nestier JE, Johnson DE, et al. Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation. Circulation 1993; Orentreich N, Brind JL,
term
2
3
4
5
6
7
87: 261-69.
8
Daynes RA, Dudley DJ, Araneo BA. Regulation of murine lymphokine production in vivo, II: dehydroepiandrosterone is a natural enhancer of interleukin II synthesis by helper T cells. Eur J Immunol 1990; 20:
793-802. Abadie JM, Wright B, Correa G, Browne ES, Porter JR, Svec F. Effect of dehydroepiandrosterone on neurotransmitter levels and appetite regulation of the obese Zucker rat. Diabetes 1993; 42: 662-69. 10 Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor: mechanisms of action and physiological significance. Progr Neurobiol 1992; 38: 379-95. 1 1 Schlegel ML, Spetz JF, Robel P, Haug M. Studies on the effects of dehydroepiandrosterone and its metabolites on attack by castrated mice on intruders. Physiol Behav 1985; 34: 867-70. 12 Schneider LS, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer’s disease. Biol Psychiatry 1992; 34: 867-70. 13 Barrett-Connor E, Khaw K-T, Yen SSC. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986; 315: 1519-24. 14 Brooks-Gunn J, Warren MP. Biologic and social contributions to negative affect in young adolescent girls. Child Devel 1989; 60: 40-55. 15 Gray A, Jackson DN, McKinlay JB. The relation between dominance, anger, and hormones in normally aging men: results from the Massachusetts male aging study. Psychosomatic Med 1991; 53: 375-85. 16 Blauer KL, Poth M, Rogers WM, Bernton EW. Dehydroepiandrosterone antagonises the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 1991; 129: 3174-79. 17 Sapolsky RM. Stress, the aging brain, and the mechanisms of neuron death. Cambridge, MA: MIT Press, 1992. 18 Murros K, Fogelholm R, Kettunen S, Vuorela A-L. Serum cortisol and outcome of ischemic brain infarction. J Neurol Sci 1993; 116: 12-17. 19 Casson PR, Andersen RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993; 169: 1536-39. 20 Morales AJ, Nolan JJ, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78: 1360-67. 9
six-membered rings, which are the core structure of the quinolones and related classes of gyrase inhibitors (figure). Adjacent carbonyl and carboxyl groups attached to the core are necessary for the anti-gyrase activity of quinolones and are retained in the 2-pyridones. Fluorine and positively charged ring substitutions attached to the core, which are components of the most potent fluoroquinolones, are also components of two
promising 2-pyridones. 2-pyridone compound designated ABT719 (also A-86719.1) is striking for its breadth of spectrum and substantial enhancement of activity against gram-positive bacteria and anaerobes relative to that of ciprofloxacin/ Thus ABT719 showed twenty to forty-fold increased activity in vitro against Staphylococcus aureus (including some methicillin and ciprofloxacin resistant strains), Enterococcus spp (including some vancomycin-resistant strains), Streptococcus pyogenes, and Bacteroides fragilis. ABT719 also retained the strong activity against gramnegative pathogens that is characteristic of current fluoroquinolones.7,9 Again by comparison with ciprofloxacin, ABT719 was two to ten-fold more active against Escherichia coli, Klebsiella pneumoniae, and Pseudomonas aeruginosa. Like the quinolones, ABT719 is
7
8
9
A
bactericidal.’," In rodents, in-vivo antibacterial activity of ABT719 was shown for various infections-eg, systemic (S aureus,
enterococci), lung (Streptococcus pneumoniae, Haemophilus influenzae, and P aeruginosa), kidney (enterococci), and skin (S aureus, S pyogenes, and mixed organisms). ED 50 values were generally several fold higher when the drug was given orally rather than subcutaneously, so oral bioavailability is incomplete in rodents. 2-pyridones offer promise for development of newer broad-spectrum gyrase inhibitors with activity against some of the more troublesome and resistant gram-positive pathogens. Other fluoroquinolones that show enhanced activity against gram-positive and anaerobic bacteria (eg, levofloxacin, clinafloxacin, grepafloxacin, CP-99,219, and DU6859a) are under development. The next steps in evaluation of these new drugs will be to assess their tolerability and show their clinical efficacy in human beings, bearing in mind that other initially promising members of the quinolone and naphthyridine classes have been halted at various stages of development because of toxicities.’4 David C
Hooper
Infectious Disease Unit, Massachusetts General Hospital, Boston, MA, USA 1 Gellert M, Mizuuchi K, O’Dea M, et al. Nalidixic acid resistance: a second genetic character involved in DNA gyrase activity. Proc Natl Acad Sci USA 1977; 74: 4772-76. 2 Sugino A, Peebles CL, Kruezer KN, Cozzarelli NR. Mechanism of action of nalidixic acid: purification of Escherichia coli nalA gene product and its relationship to DNA gyrase and a novel nicking-closing enzyme. Proc Natl Acad Sci USA 1977; 74: 4767-71. 3 Lesher GY, Forelich ED, Gruet MD, et al. 1,8-Naphthyridine derivatives. A new class of chemotherapeutic agents. J Med Pharm Chem 1962, 5: 1063-68. 4 Hooper DC, Wolfson JS. Fluoroquinolone antimicrobial agents. N Engl J Med 1991; 324: 384-94. 5 Hooper DC, Wolfson JS. Mechanisms of quinolone action and bacterial killing. In: Hooper DC, Wolfson JS, eds. Quinolone antimicrobial agents, 2nd ed. Washington, DC: American Society for Microbiology, 1993: 53-75. 6 Chu DTW, Li Q, Claiborne A, et al. Synthesis and antibacterial activity of A-86719.1 and related 2-pyridones: a novel series of potent
10
11
12
13
14
DNA gyrase inhibitors. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy. Orlando, Florida, 1994: abstr F41. Eliopoulos GM, Wennersten CB, Cole G, et al. In vitro activity of A-86719.1, a novel pyridone antimicrobial. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F43. Flamm RK, Vojtko C, Ramer N, et al. Comparative in vitro activity of A-86719.1, a novel bacterial DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F45. Chin NX, Chu D, Neu HC. In vitro antibacterial activity of A-86719.1, a new class DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F49. Flamm RK, Vojtko C, Ramer N, et al. Characterisation of in vitro activity of A-86719.1, a novel bacterial DNA gyrase inhibitor. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F47. Chin NX, Chu D, Huang HB, Neu HC. A-86719.1, a new class DNA gyrase inhibitor, its time-killing activity, postantibiotic effect and assay condition effect. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F51. Alder JD, Meulbroek JM, Shipkowitz NL, et al. Efficacy of A-86719.1, a novel 2-pyridone gyrase inhibitor, for treatment of systemic, lung and abscess infections in mice and rats. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F53. Meulbroek JA, Oleksijew A, Tanaka SK, Alder JD. Efficacy of A-86719.1, a novel 2-pyridone gyrase inhibitor, for treatment of endocarditis, pyelonephritis and systemic infections caused by enterococci in mice. 34th Interscience Conference on Antimicrobial Agents and Chemotherapy, Orlando, Florida, 1994: abstr F55. Hooper DC, Wolfson JS. Adverse effects. In: Hooper DC, Wolfson JS, eds. Quinolone antimicrobial agents, 2nd ed. Washington, DC: American Society for Microbiology, 1993: 489-512.
The age of
dehydroepiandrosterone
Why have dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulphate (DHEAS), hormones dismissed for years as "weak androgens", lately attracted media attention? DHEAS, generated in the liver from the parent adrenal steroid DHEA, circulates in the blood of man and other primates in relatively huge quantities (about 10 times that of cortisol). However, unlike cortisol, blood DHEA(S) concentrations peak at about 20 years, declining thereafter remorselessly and profoundly so that by 60 years they are one-third or less of those in young adults.’ Recent interest has been spurred by clinical data linking the decrease in DHEA(S) with agerelated illnesses such as ischaemic heart disease (in men at least),z changes in the amount or distribution of body fat,3 onset of non-insulin-dependent diabetes, and some forms of cancer/ Moreover, there are considerable individual differences in the rate of DHEA(S) decline, which may be partly under hereditary control.I Nearly all the clinical facets of this story rest on correlation-eg, the relation between individual or group differences in frequency of myocardial infarction with those in concentrations of DHEA(S). A serious drawback with some of these studies is that DHEA(S) also decreases during illness, as has been observed in rheumatoid arthritis and major depressive disorder as well as during other forms of stress.5,6 We therefore need to separate the effects of age or individuality from those of either acute or chronic ill health. Long-term prospective studies (in which DHEA[S] concentrations at an earlier age are used to predict subsequent health) go some way towards separating these confounding factors. The intriguing conclusions are that the downward trajectory of DHEA(S) may indicate individual differences in ageing
1193
or
lifespan, and either foretell
or
DHEA administration for adequate periods, and critical importance of using cross-disciplinary outcome measures. Does DHEA(S) therapy retard, or even reverse, any of the age-dependent processes in which it has been implicated? Do specific somatic or mental illnesses accentuate or initiate age-related processes? Satisfactory evidence for rational therapy will not be obtained easily or quickly-ageing is not a simple unitary process-but the possibility that DHEA might alleviate some of the problems of ageing, or improve the treatment or complications of intercurrent illnesses, opens new and
initiate age-related
studying
illness.
the
Experimental work supports a protective role for DHEA(S) in some pathological processes. DHEA reduced the development of vascular stenosis in heterotopic heart transplants,’ and stimulated the production of cytokines in mice.8 There is some experimental evidence for an anticarcinogenic effect of DHEAS.’ Oral administration of DHEA reduced food intake and body weight in genetically obese rats.9 DHEA(S) also has effects on the brain. In common with other neurosteroids, DHEA(S) acts directly on neural membranes either to increase or to antagonise the effects of glutamate or gamma-aminobutyric acid." By contrast, conventional steroids such as cortisol act via cytoplasmic as DNA receptors transcriptional regulators. enhances some forms of Experimentally, DHEA(S) and reduces memory, aggression." Attempts to show correlations between DHEA(S) concentrations and memory in normal ageing human beings or those with Alzheimer’s disease have not proved unsuccessful.’2" A negative correlation has been found between aggression and DHEAS in adolescent girls,’4 but a positive one between DHEA and "dominance" in middle-aged men." Both the immunological and neural effects of DHEA(S) may also be due to its powerful antiglucocorticoid action," the precise nature of which is still unclear. Low DHEA(S) may thus accentuate the immunosuppressive effects of raised corticoids (eg, during stress or trauma). Increased cortisol can induce brain damage in animals," and -may amplify that caused by other neurotoxic events both experimentally and clinically (eg, following a stroke).18 Low DHEA(S) in the ageing brain might therefore predispose to damage, or allow endogenous normal concentrations of cortisol to act as neurotoxic agents. Does the age-dependent decline in DHEA(S) have medical significance? If so, there would be a case for therapeutic regulation of DHEA(S) during advancing years. Two reports describe administration of DHEA (50 mg daily, which reproduces blood levels of early adulthood) to middle-aged and older people. In one" (limited to immune studies) there was pronounced stimulation of natural killer lymphocyte activity (thus confirming experimental conclusions). In the other" DHEA increased insulin growth factor 1 concentrations (which themselves decline with age); this observation suggests one mechanism whereby low concentrations of DHEA(S) may be associated with obesity or diabetes in later life. Changes in blood lipoproteins were minor. There was a remarkable increase in feelings of "wellbeing" in about 70% of the subjects, although exactly how this was defined or measured is unclear. There are no adequate studies of cognitive function in man during DHEA therapy. Enough is known or suspected to warrant investigation of DHEA(S) as an effective, worthwhile, and relatively risk-free replacement therapy in advancing age. This can only be done by a controlled prospective trial of DHEA treatment; no amount of correlational evidence, however carefully collected, is enough. Organisers of such trials will need to be aware of the problems of subject selection (and controls), the effects on DHEA(S) of extraneous factors such as illness or smoking, the necessity of
1194
exciting avenues. J Herbert Department of Anatomy and University of Cambridge, UK 1
MRC
Cambridge Centre for Brain Repair,
Vogelman JH, Andres R, Baldwin H. Longlongitudinal measurements of plasma dehydroepiandrosterone sulfate in normal men. J Clin Endocrinol Metab 1992; 75: 1002-04. Barrett-Connor E, Edelstein SL. A prospective study of dehydroepiandrosterone sulfate and cognitive function in an older population. J Am Geriat Soc 1994; 42: 420-23. Williams DP, Boyden TW, Pamenter RW, Lohman TG, Coing SB. Relationship of body fat percentage and fat distribution with dehydroepiandrosterone sulfate in premenstrual females. J Clin Endocrinol Metab 1993; 77: 80-85. Ebeling P, Kiovisto VA. Physiological importance of dehydroepiandrosterone. Lancet 1994; 343: 1479-81. Goodyer IM, Herbert J, Altham PME, Pearson J, Secher SM, Shiers HM. Adrenal secretion during major depression in 8 to 16 year olds: altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation. Psychol Med (in press). Hedman M, Nilsson E, Torre B de la. Low blood and synovial fluid levels of sulpho-conjugated steroids in rheumatoid arthritis. Clin Exp Rheumatol 1992; 10: 25-30. Eich DM, Nestier JE, Johnson DE, et al. Inhibition of accelerated coronary atherosclerosis with dehydroepiandrosterone in the heterotopic rabbit model of cardiac transplantation. Circulation 1993; Orentreich N, Brind JL,
term
2
3
4
5
6
7
87: 261-69.
8
Daynes RA, Dudley DJ, Araneo BA. Regulation of murine lymphokine production in vivo, II: dehydroepiandrosterone is a natural enhancer of interleukin II synthesis by helper T cells. Eur J Immunol 1990; 20:
793-802. Abadie JM, Wright B, Correa G, Browne ES, Porter JR, Svec F. Effect of dehydroepiandrosterone on neurotransmitter levels and appetite regulation of the obese Zucker rat. Diabetes 1993; 42: 662-69. 10 Majewska MD. Neurosteroids: endogenous bimodal modulators of the GABAA receptor: mechanisms of action and physiological significance. Progr Neurobiol 1992; 38: 379-95. 1 1 Schlegel ML, Spetz JF, Robel P, Haug M. Studies on the effects of dehydroepiandrosterone and its metabolites on attack by castrated mice on intruders. Physiol Behav 1985; 34: 867-70. 12 Schneider LS, Hinsey M, Lyness S. Plasma dehydroepiandrosterone sulfate in Alzheimer’s disease. Biol Psychiatry 1992; 34: 867-70. 13 Barrett-Connor E, Khaw K-T, Yen SSC. A prospective study of dehydroepiandrosterone sulfate, mortality, and cardiovascular disease. N Engl J Med 1986; 315: 1519-24. 14 Brooks-Gunn J, Warren MP. Biologic and social contributions to negative affect in young adolescent girls. Child Devel 1989; 60: 40-55. 15 Gray A, Jackson DN, McKinlay JB. The relation between dominance, anger, and hormones in normally aging men: results from the Massachusetts male aging study. Psychosomatic Med 1991; 53: 375-85. 16 Blauer KL, Poth M, Rogers WM, Bernton EW. Dehydroepiandrosterone antagonises the suppressive effects of dexamethasone on lymphocyte proliferation. Endocrinology 1991; 129: 3174-79. 17 Sapolsky RM. Stress, the aging brain, and the mechanisms of neuron death. Cambridge, MA: MIT Press, 1992. 18 Murros K, Fogelholm R, Kettunen S, Vuorela A-L. Serum cortisol and outcome of ischemic brain infarction. J Neurol Sci 1993; 116: 12-17. 19 Casson PR, Andersen RN, Herrod HG, et al. Oral dehydroepiandrosterone in physiologic doses modulates immune function in postmenopausal women. Am J Obstet Gynecol 1993; 169: 1536-39. 20 Morales AJ, Nolan JJ, Nelson JC, Yen SSC. Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age. J Clin Endocrinol Metab 1994; 78: 1360-67. 9