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Research Abstracts and Links to Original Sources



CNS Drug Rev 2003 Spring;9(1):21-40

Dehydroepiandrosterone (DHEA) and the Aging Brain: Flipping a Coin in the "Fountain of Youth".

Racchi M, Balduzzi C, Corsini E.

Department of Experimental and Applied Pharmacology, University of Pavia, Viale Taramelli 14, 27100 Pavia, Italy.

The physiological role of dehydroepiandrosterone (DHEA) and its sulphated ester DHEA(S) has been studied for nearly 2 decades and still eludes final clarification. The major interest in DHEA derives from its unique pattern of activity. Its levels exhibit a dramatic age-related decline that supports significant involvement of DHEA(S) in the aging process. Particularly relevant to the aging process is the functional decline that involves memory and cognitive abilities. DHEA is derived mainly from synthesis in the adrenal glands and gonads. It can also be detected in the brain where it is derived from a synthesis that is independent from peripheral steroid sources. For this reason DHEA and other steroid molecules have been named "neurosteroids." Pharmacological studies on animals provided evidence that neurosteroids could be involved in learning and memory processes because they can display memory-enhancing properties in aged rodents. However, human studies have reported contradictory results that so far do not directly support the use of DHEA in aging-related conditions. As such, it is important to remember that plasma levels of DHEA(S) may not reflect levels in the central nervous system (CNS), due to intrinsic ability of the brain to produce neurosteroids. Thus, the importance of neurosteroids in the memory process and in age-related cognitive impairment should not be dismissed. Furthermore, the fact that the compound is sold in most countries as a health food supplement is hampering the rigorous scientific evaluation of its potential. We will describe the effect of neurosteroids, in particular DHEA, on neurochemical mechanism involved in memory and learning. We will focus on a novel effect on a signal transduction mechanism involving a classical "cognitive kinase" such as protein kinase C. The final objective is to provide additional tools to understand the physiological role and therapeutic potentials of neurosteroids in normal and/or pathological aging, such as Alzheimer's disease.


Neuropsychopharmacology 2003 Feb;28(2):379-383

Steroid Synthesis Inhibition with Ketoconazole and its Effect upon the Regulation of the Hypothalamus-Pituitary-Adrenal System in Healthy Humans.

Deuschle M, Lecei O, Stalla GK, Landgraf R, Hamann B, Lederbogen F, Uhr M, Luppa P, Maras A, Colla M, Heuser I.

Steroid synthesis inhibitors are commonly used in the treatment of patients with Cushing's disease, but may also improve psychopathology in hypercortisolemic depressed patients. Since glucocorticoids exert a negative feedback at pituitary and supra-pituitary levels, the inhibition of steroid synthesis may lead to increased expression of corticotropin-releasing hormone (CRH) and arginine vasopressin (AVP). We studied the effect of treatment with 800 mg ketoconazole (3 weeks) upon the concentrations of basal plasma cortisol in the evening, corticosteroid-binding globulin (CBG), dehydroepiandrosterone-sulfate (DHEA-S), and ACTH as well as the concentrations of cortisol, CRH, and AVP in cerebrospinal fluid (CSF) at 8.30 h in 10 healthy, male volunteers. While we found cortisol plasma concentrations to be unchanged, we noted a significant increase in ACTH (post: 45.1+/-43.5; pre: 14.2+/-5.2 pmol/l; F(1,8)=9.78, p<0.02) and CBG concentrations (post: 38.8+/-4.3; pre: 31.9+/-4.2 &mgr;g/l), but DHEA-S plasma concentrations declined (post: 1.75+/-1.83; pre: 2.75+/-2.80 mg/l; F(1,8)=7.9, p<0.03). CRH concentrations in CSF were unchanged after treatment (post: 62.5+/-15.9; pre: 63.7+/-13.9 pg/ml), while there was a trend for AVP concentrations to rise during treatment (post: 2.52+/-1.18; pre: 1.92+/-0.96 pg/ml; paired t=-1.9, p<0.1). Cortisol CSF concentrations declined in the elderly (pre: 52.5+/-23.2; post: 26.7+/-4.6 nmol/l), but not in the young subgroup (pre: 15.6+/-11.3; post: 27.7+/-9.4 nmol/l). We thus conclude that the treatment of healthy controls with steroid-synthesis inhibitors does not lead to a major increase in CRH secretion.Neuropsychopharmacology (2003) 28, 379-383. doi:10.1038/sj.npp.1300044


World J Biol Psychiatry 2001 Jul;2(3):115-43

Stress hormone-related psychopathology: pathophysiological and treatment implications.

Wolkowitz OM, Epel ES, Reus VI.

Department of Psychiatry, University of California, School of Medicine, San Francisco, USA.

Stress is commonly associated with a variety of psychiatric conditions, including major depression, and with chronic medical conditions, including diabetes and insulin resistance. Whether stress causes these conditions is uncertain, but plausible mechanisms exist by which such effects might occur. To the extent stress-induced hormonal alterations (e.g., chronically elevated cortisol levels and lowered dehydroepiandrosterone [DHEA] levels) contribute to psychiatric and medical disease states, manipulations that normalize these hormonal aberrations should prove therapeutic. In this review, we discuss mechanisms by which hormonal imbalance (discussed in the frameworks of "allostatic load" and "anabolic balance") might contribute to illness. We then review certain clinical manifestations of such hormonal imbalances and discuss pharmacological and behavioural treatment strategies aimed at normalizing hormonal output and lessening psychiatric and physical pathology.


World J Biol Psychiatry 2001 Apr;2(2):99-102

Movement disorder, memory, psychiatric symptoms and serum DHEA levels in schizophrenic and schizoaffective patients.

Harris DS, Wolkowitz OM, Reus VI.

Department of Psychiatry, Box CPR-0984, University of California, San Francisco Medical Center, 401 Parnassus Ave., San Francisco, CA 94143-0984, USA.

OBJECTIVE: Reports of low levels of dehydroepiandrosterone (DHEA) or its sulphate (DHEA-S) in some schizophrenic patients and in some persons with poorer motoric and cognitive functioning led us to examine clinical correlates of serum DHEA and DHEA-S levels in schizophrenic patients. METHOD: Ratings of abnormal movements, memory and psychiatric symptoms in 17 medicated chronic schizophrenic or schizoaffective inpatients at a state hospital were correlated with serum DHEA and DHEA-S levels, and their ratios with serum cortisol. RESULTS: Controlling for age, higher DHEA levels and/or higher DHEA/cortisol ratios were significantly correlated with lower symptom ratings on the Brief Psychiatric Rating Scale, better performance on some measures of memory, and lower ratings of parkinsonian symptoms. CONCLUSION: Relatively low DHEA levels or DHEA/cortisol ratios may identify a particularly impaired subgroup of medicated patients with chronic schizophrenia. Potential implications are discussed.


Med Hypotheses 2003 Mar;60(3):391-7

-oxo-DHEA and Raynaud's phenomenon.

Ihler G, Chami-Stemmann H.

Department of Medical Biochemistry and Medical Genetics, Texas A&M College of Medicine, Texas, USA

Patients with Raynaud's phenomenon have abnormal digital vasoconstriction in response to cold. The pathogenesis remains unknown but may involve a local neurovascular defect leading to vasoconstriction. Diagnosis of primary Raynaud's phenomenon is based on typical symptomatology coupled with normal physical examination, normal laboratory studies and lack of observable pathology by nail fold capillaroscopy. Secondary Raynaud's phenomenon is known to occur associated with several connective tissue diseases, vascular injury due to repeated vibrational trauma, and other causes which produce demonstrable vascular and microcirculatory damage. Treatment of Raynaud's symptoms is conservative and aimed at prevention of attacks. Patients are advised to remain warm and, if possible, to live in warm climates. We suggest that an ergogenic (thermogenic) steroid, 7-oxo-DHEA (3-acetoxyandrost-5-ene-7,17-dione), which is available without prescription as the trademarked 7-keto DHEA, may be very helpful in prevention of primary Raynaud's attacks by increasing the basal metabolic rate and inhibiting vasospasm.


Yao Xue Xue Bao 2001 Aug;36(8):576-80

Studies on the anti-tumorpromotion activities of dehydroepiandrosterone and its mechanism of action

[Article in Chinese]

Yang S, Fu ZD, Han R.

Institute of Materia Medica, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing 100050, China.

AIM: To investigate the anti-tumorpromoting activity of dehydroepiandrosterone (DHEA) and its mechanism of action. METHODS: Using croton oil-induced ear edema model and applying confocal laser scanning microscopy, flow cytometry, immuno-fluorescent techniques to investigate the inhibitory effect of DHEA on tumor promotion. RESULTS: DHEA 25 mg.kg-1 was shown to inhibit croton oil induced ear edema in mice by 51%. DHEA at dose of 40 mg.kg-1 and 10 mg.kg-1 exhibited inhibitory effects on croton oil-induced ornithine decarboxylase (ODC) activity by 64% and 53%, respectively. These results revealed that DHEA can block the change of cell cycle and the percentage of S phase was decreased to 17% at concentration of 10(-7) mol.L-1. The increase of[Ca2+]i and pH as well as PKC-activation induced by TPA stimulation were significantly inhibited by DHEA pretreatment. CONCLUSION: The present experiments demonstrate that DHEA appears to be an attractive candidate as an anti-tumorpromotion agent for tumor chemoprevention. The mechanism of its action might be related to its inhibitory effects on ODC activity and Ca(2+)-DG-PKC signal pathway.


Arch Gen Psychiatry 2003 Feb;60(2):133-41

Dehydroepiandrosterone augmentation in the management of negative, depressive, and anxiety symptoms in schizophrenia.

Strous RD, Maayan R, Lapidus R, Stryjer R, Lustig M, Kotler M, Weizman A.

Beer Yaakov Mental Health Center, P.O. Box 1, Beer Yaakov 70350, Israel.

CONTEXT: Negative symptoms of schizophrenia are a prominent feature of the illness, and frequently remain refractory to treatment. Dehydroepiandrosterone (DHEA), along with its sulfated form, DHEA-S, is an important circulating neurosteroid with several vital neurophysiological functions, including the regulation of neuronal excitability and function. OBJECTIVE: Since the administration of DHEA has demonstrated improvement in mood, sense of well-being, interest, activity, and energy in several subpopulations, we investigate the efficacy of DHEA in the management of the negative symptoms of schizophrenia. DESIGN: Thirty DSM-IV-diagnosed schizophrenic patients with prominent negative symptoms (inpatients in a large referral state hospital) were randomized to receive either DHEA or placebo in double-blind fashion, in addition to regular antipsychotic medication, dose-stabilized prior to study entry. The DHEA was titrated up to a dose of 100 mg in divided doses during 6 weeks. RESULTS: Results indicated significant improvement in negative symptoms (P<.001), as well as in depressive (P<.05) and anxiety (P<.001) symptoms in individuals receiving DHEA. This effect was especially noted in women. The improvement in negative symptoms was independent of improvement in depression. No differences were noted on the positive symptom subscale of the Positive and Negative Syndrome Scale (PANSS) or on the total PANSS score as compared with placebo. Subjects receiving DHEA demonstrated a significant increase in DHEA (P<.05) and DHEA-S (P<.01) plasma levels, without changes in cortisol levels. Increases in DHEA and plasma DHEA-S levels were correlated with improvement in negative symptoms (P<.05), but not with improvement in depressive and anxiety symptoms. No obvious adverse effects were experienced by participating subjects. CONCLUSIONS: Our preliminary observations report for the first time in double-blind fashion the efficacy of DHEA augmentation in the management of negative, depressive, and anxiety symptoms of schizophrenia. The findings from this study raise important issues regarding the role of neurosteroids in general, and DHEA in particular, in the ongoing symptomatology and pharmacotherapy of schizophrenia.


Mol Cell Endocrinol 2002 Dec 30;198(1-2):7-14

Androgen biosynthesis from cholesterol to DHEA.

Miller WL.

Department of Pediatrics, University of California, Bldg. MR IV, Room 209, 94142-0978, San Francisco, CA, USA

Androgens and estrogens are made from dehydroepiandrosterone (DHEA), which is made from cholesterol via four steps. First, cholesterol enters the mitochondria with the assistance of the steroidogenic acute regulatory protein (StAR). Mutations in the StAR gene cause congenital lipoid adrenal hyperplasia. Second, within the mitochondria, cholesterol is converted to pregnenolone by the cholesterol side chain cleavage enzyme, P450scc. Third, pregnenolone undergoes 17alpha-hydroxylation by microsomal P450c17. Finally, 17-OH pregnenolone is converted to DHEA by the 17,20 lyase activity of P450c17. The ratio of the 17,20 lyase to 17alpha-hydroxylase activity of P450c17 determines the ratio of C21 to C19 steroids produced. This ratio is regulated post-translationally by at least three factors: the abundance of the electron-donating protein P450 oxidoreductase, the presence of cytochrome b(5), and the serine phosphorylation of P450c17. Study of these and related factors may yield important information about the pathophysiology of adrenarche and the polycystic ovary syndrome (PCOS).


J Rheumatol 2003 Feb;30(2):269-75

Serum Levels of Pregnenolone and 17-hydroxypregnenolone in Patients with Rheumatoid Arthritis and Systemic Lupus Erythematosus: Relation to Other Adrenal Hormones.

Vogl D, Falk W, Dorner M, Scholmerich J, Straub RH.

Department of Internal Medicine I, Laboratory of Neuroendocrinoimmunology, University Medical Center Regensburg, Regensberg, Germany.

OBJECTIVE: In patients with rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE), low levels of adrenal steroids have been repeatedly demonstrated, but the site of alteration has not been exactly described because measurements of serum pregnenolone and 17-hydroxypregnenolone (17OHPreg) together with other adrenal steroids have never been performed. METHODS: We measured serum levels of adrenal hormones such as pregnenolone, 17OHPreg, dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), progesterone (P), 17-hydroxyprogesterone (17OHP), androstenedione (ASD), and cortisol in 24 healthy controls, 24 patients with RA, and 24 patients with SLE. RESULTS: Serum levels of pregnenolone were similar in RA and SLE patients as compared to healthy controls irrespective of prior prednisolone therapy. In all RA and SLE patients (including those with prior prednisolone treatment), serum levels of all measured hormones except pregnenolone were significantly lower as compared to controls. In RA patients without prior prednisolone treatment, serum levels of 17OHPreg, DHEA, cortisol, and ASD were similar to controls, and serum levels of P, 17OHP, and DHEAS were significantly lower as compared to controls. In SLE patients without prior prednisolone treatment, serum levels of 17OHPreg and cortisol were similar, and serum levels of P, 17OHP, ASD, DHEA, and DHEAS were significantly lower as compared to controls. CONCLUSION: The primary hormone of the adrenal steroid cascade, pregnenolone, is almost normal in RA and SLE irrespective of corticosteroid treatment. In patients with RA, we believe that there is a near normal P450scc reaction and a normal double step P450c17 reaction. In SLE patients, the P450scc reaction also seems normal but the second step of the P450c17 reaction seems to be inhibited. In both diseases, cortisol levels remain relatively stable at the expense of other adrenal hormones. This study revealed distinct changes of steroid pathways that are related to the disease entities.


J Clin Psychopharmacol 2003 Feb;23(1):96-9

Influence of DHEA administration on 24-hour cortisol concentrations.

Kroboth PD, Amico JA, Stone RA, Folan M, Frye RF, Kroboth FJ, Bigos KL, Fabian TJ, Linares AM, Pollock BG, Hakala C.

Pharmacodynamic Research Center, University of Pittsburgh, Pittsburgh, Pennsylvania 15261, USA.

DHEA is marketed and readily available as a daily nutritional supplement to counteract the effects of aging. The effect of DHEA administration on 24-hour plasma cortisol profiles has not been investigated. In this single-blind placebo-controlled crossover study, the effect of DHEA administration on cortisol concentrations was evaluated in healthy older women and men. Once each morning, subjects took either placebo (Days 1 to 7, and 23 to 29) or oral DHEA 200 mg (Days 8 to 22: doses 1 to 15). Twenty-four hour DHEA and cortisol concentrations were measured on Day 1 (placebo), Day 8 (DHEA dose 1), Day 15 (DHEA dose 8), Day 22 (DHEA dose 15), and Day 29 (placebo washout dose 7). DHEA administration resulted in a decrease in plasma cortisol concentrations (mean, peak, and/or AUC) in healthy older women and men. The cortisol-lowering effect of DHEA was more pronounced in women than in men in our study; pairwise differences in concentrations between days showed that relative to Day 1, cortisol was lower on Days 15, 22, and 29 in women (p = 0.0001) and on Day 15 in men (p = 0.002). The mechanism by which DHEA lowers plasma cortisol concentrations merits further investigation.


Exp Gerontol 2003 Jan;38(1-2):35-46

Calorie restriction in rhesus monkeys.

Mattison JA, Lane MA, Roth GS, Ingram DK.

Intramural Research Program, Gerontology Research Center, National Institute on Aging, NIH, 5600 Nathan Shock Drive, 21224, Baltimore, MD, USA

Calorie restriction (CR) extends lifespan and reduces the incidence and age of onset of age-related disease in several animal models. To determine if this nutritional intervention has similar actions in a long-lived primate species, the National Institute on Aging (NIA) initiated a study in 1987 to investigate the effects of a 30% CR in male and female rhesus macaques (Macaca mulatta) of a broad age range. We have observed physiological effects of CR that parallel rodent studies and may be predictive of an increased lifespan. Specifically, results from the NIA study have demonstrated that CR decreases body weight and fat mass, improves glucoregulatory function, decreases blood pressure and blood lipids, and decreases body temperature. Juvenile males exhibited delayed skeletal and sexual maturation. Adult bone mass was not affected by CR in females nor were several reproductive hormones or menstrual cycling. CR attenuated the age-associated decline in both dehydroepiandrosterone (DHEA) and melatonin in males. Although 81% of the monkeys in the study are still alive, preliminary evidence suggests that CR will have beneficial effects on morbidity and mortality. We are now preparing a battery of measures to provide a thorough and relevant analysis of the effectiveness of CR at delaying the onset of age-related disease and maintaining function later into life.


Eur J Endocrinol 2003 Jan;148(1):45-53

During a corticotropin-releasing hormone test in healthy subjects, administration of a beta-adrenergic antagonist induced secretion of cortisol and dehydroepiandrosterone sulfate and inhibited secretion of ACTH.

Kizildere S, Gluck T, Zietz B, Scholmerich J, Straub RH.

Department of Internal Medicine I, University Hospital of Regensburg, 93042 Regensburg, Germany.

OBJECTIVE: In chronic inflammatory diseases, serum levels of dehydroepiandrosterone (DHEA) sulfate (DHEAS) are low. Interestingly, several non-inflammatory diseases display similarly low levels of DHEAS which points to other inhibitory factors such as an activated sympathetic nervous system (SNS) (e.g. in patients with heart failure, fibromyalgia, or cancer cachexia). We aimed to identify the influence of the SNS tone on stimulated adrenal steroid secretion in 16 male and 12 female healthy subjects. METHODS: One group were given oral propranolol 2 h before a corticotropin-releasing hormone (CRH) test, and levels of adrenocorticotropin (ACTH), cortisol, 17-hydroxyprogesterone (17OHP), androstenedione, DHEA, and DHEAS were measured. RESULTS: Propranolol treatment decreased heart rate (by 20%), diastolic blood pressure (by 20%), and plasma ACTH, and increased serum cortisol, serum DHEAS, and the molar ratio of cortisol/17OHP, cortisol/DHEA, and DHEAS/DHEA similarly in female and male subjects. CONCLUSIONS: A beta-adrenergic influence seems to decrease CRH-stimulated cortisol in relation to ACTH and 17OHP, and decreases DHEAS in relation to DHEA. Although other workers have found beta-adrenergic stimulation of steroid secretion in cultured adrenocortical cells, the overall systemic influence of the SNS via beta-adrenoceptors seems to inhibit adrenal steroids under unstimulated and stimulated conditions. Sympathetic hyperactivity may be a common denominator for low levels of DHEAS in inflammatory and non-inflammatory diseases.


Drugs Aging 2003;20(2):85-100

Effect of Reproductive Hormones and Selective Estrogen Receptor Modulators on Mood during Menopause.

Soares CN, Poitras JR, Prouty J.

Harvard Medical School, MGH Center for Women's Mental Health, Boston, Massachusetts, USA.

Periods of intense hormonal fluctuations have been associated with heightened prevalence and exacerbation of underlying psychiatric illness, particularly the occurrence of premenstrual dysphoria, puerperal depression and depressive symptoms during perimenopause. It has been speculated that sex steroids such as estrogens, progestogens, testosterone and dehydroepiandrosterone (DHEA) exert a significant modulation of brain functioning, possibly through interactions with various neurotransmitter systems. It is therefore intuitive that abrupt alterations of these hormones would interfere with mood and behaviour. On the other hand, accumulating data suggest that hormonal interventions may also promote relief or even remission of depressive symptoms, as already demonstrated in studies with patients experiencing postpartum depression and perimenopausal depressive disorders. The extent to which perimenopause, alone, may increase the risk for depression is unclear. However, existing data strongly suggest that some women are particularly vulnerable to developing significant physical and psychological disturbances when entering perimenopause. This article reviews the effect of sex hormones and selective estrogen receptor modulators (SERMs) on mood among peri- and postmenopausal women. There are preliminary, though promising, data on the use of estradiol (particularly transdermal estradiol) to alleviate depression during perimenopause, use of a combination of estrogens and selective serotonin reuptake inhibitors for depression during the postmenopausal period, and the use of testosterone to improve psychological well-being and increase libido among women with induced menopause. Further studies would help to better delineate the usage of hormones as an antidepressant strategy (monotherapy or augmenting treatment) for peri- and postmenopausal women. A brief review of some nonhormonal interventions for the treatment of menopause-related symptoms that may significantly affect a woman's quality of life is also presented. There are some preliminary data suggesting the efficacy of antidepressants for the treatment of hot flushes; existing data on diet supplements and herbal products have shown more mixed results.


Endocr Res 2002 Nov;28(4):637-40

Fibronectin, laminin, and collagen IV interact with ACTH and angiotensin II to dictate specific cell behavior and secretion in human fetal adrenal cells in culture.

Chamoux E, Narcy A, Lehoux JG, Gallo-Payet N.

Service of Endocrinology, Faculty of Medicine, University of Sherbrooke, Sherbrooke (Qc), Canada, J1H 5N4.

Whereas collagen IV is expressed throughout the fetal adrenal gland during the second trimester of human development, fibronectin, and laminin demonstrate a rather mirror-image distribution, with higher expression of fibronectin in the central portion and laminin at the periphery of the gland. In the present study, extracellular matrices were able to modulate the profile of steroid secretion in primary cultures: collagen IV favored cortisol secretion following adrenocorticotropin (ACTH) or angiotensin II (Ang II) stimulation while specific stimulation of the AT2 receptor of Ang II elicited dehydroepiandrostenedione (DHEA) production. These effects were correlated by changes in mRNA levels of 3beta-hydroxysteroid dehydrogenase (3beta-HSD) and cytochrome P450C17. In contrast, fibronectin and laminin decreased cell responsiveness to ACTH in terms of cortisol secretion, but enhanced ACTH-stimulated androgen secretion. Finally, extracellular matrices were able to orchestrate cell behavior: collagen IV and laminin enhanced cell proliferation whereas fibronectin incited cell death. These results indicate that the nature of extracellular matrix coordinates specific steroidogenic pathways and cell turnover in the developing human fetal adrenal gland.


Adolesc Med 2003 Feb;14(1):97-108

Osteopenia and osteoporosis in anorexia nervosa.

Golden NH.

Osteopenia is a frequent and severe complication of anorexia nervosa. Once established, it is difficult to treat and is only partially reversible. Osteoporosis is a preventable disease, and intervention should begin during childhood and adolescence. Optimizing peak bone mass accrual during adolescence is essential, and an episode of anorexia nervosa during adolescence interferes with that process. In anorexia nervosa, results with hormone replacement therapy have been disappointing. Calcium and vitamin D supplementation should be prescribed where necessary. Excessive exercise should be avoided and moderate weight-bearing exercise encouraged. Ongoing research studying newer modalities such as IGF-1, DHEA, and bisphosphonates looks promising. Until more effective treatment regimens become available, the mainstay of treatment remains weight gain, nutritional rehabilitation, and spontaneous resumption of menses.


Nicotine Tob Res 2002 Nov;4(4):451-8

Effects of smoking cessation or reduction on hormone profiles and bone turnover in postmenopausal women.

Oncken C, Prestwood K, Cooney JL, Unson C, Fall P, Kulldorff M, Raisz LG.

Department of Medicine, University of Connecticut Health Center, Farmington, Connecticut, USA.

The purpose of this study was to prospectively evaluate the impact of smoking cessation on hormonal concentrations, sex hormone-binding globulin (SHBG) and markers of bone turnover in postmenopausal women. Sixty-six women who were either users or non-users of estrogen replacement therapy (ERT) were randomly assigned, using a weighted randomization scheme, to smoking cessation (SC) or to smoking cessation after 6 weeks of monitoring (wait-list control group, WLC). We measured hormones [estrone, estradiol, testosterone, parathyroid hormone, dehydroepiandrosterone (DHEA), dehydroepiandrosterone sulfate (DHEAS) and androstenedione] and SHBG, markers of bone turnover [procollagen peptide (PINP), bone alkaline phosphatase (BAP), and osteocalcin (OC), N- and C-terminal collagen cross-links (NTx and CTx)], and cotinine, at baseline and again at 6 weeks in women who reported smoking cessation and in women randomized to the WLC group. Analyses included 20 subjects who quit or significantly reduced their smoking and 18 subjects in the WLC group. After controlling for differences in age and ERT use between groups, we found a significant change in SHBG in the SC vs. the WLC group (-8% vs. +5%, respectively; p = 0.01), and in DHEA (-18% vs. -5%, respectively; p = 0.04), but not in other hormonal concentrations. We also noted a significant change in NTx in the SC vs. WLC group (-5% vs. +56%, respectively, p = 0.01), but not in other markers of bone turnover. Percentage changes in SHBG and NTx were correlated with changes in plasma cotinine (r = 0.48; p = 0.004 and r = 0.36; p = 0.04, respectively). Six weeks of smoking abstinence produces reductions in SHBG and NTx. This may partly explain how smoking contributes to osteoporosis in postmenopausal women.


Drugs 2003;63(2):167-80

Newer drugs for the treatment of lupus nephritis.

Kuiper-Geertsma DG, Derksen RH.

Department of Rheumatology, Isalaklinieken, Zwolle, and Ijsselmeerziekenhuizen, Emmeloord, The Netherlands.

This article first reviews the current treatment of lupus nephritis, with a focus on the most serious forms, that is, the proliferative subtypes. Current standards for treatment have been developed empirically. Corticosteroids form the basis of all regimens. Cyclophosphamide given intravenously for prolonged periods is the current gold standard. Azathioprine can be regarded as an effective drug for maintenance treatment of lupus nephritis. Studies on its efficacy in schedules for remission induction are in progress. It has been learned from studies on 'conventional' immunosuppression that randomised, clinical trials should comprise large numbers of patients and a follow-up of many years to elucidate differences between effective strategies. These requirements are not met by any of the 'new' treatments we discuss in this review. There is only limited experience in patients with lupus nephritis with drugs that are currently used for immunosuppression in other autoimmune diseases, such as methotrexate, cyclosporin and high-dose intravenous gammaglobulins, nor with new immunosuppressive drugs that have been developed for immunosuppression in organ transplantation (mycophenolate mofetil, tacrolimus, fludarabine and cladribine). Hormonal therapy with the weak androgen prasterone (dehydroepiandrosterone; DHEA) has no role in treatment of active lupus nephritis. There are interesting experiences with agents that have evolved from progress in immunobiology and in our understanding of immunological processes. These modalities enable more specific immunosuppression and include monoclonal antibodies directed at immune cells, cytokines and components of the complement system, constructs developed to induce tolerance in pathogenic B cells, and gene therapy. Finally, we review data on autologous bone marrow transplantation in patients with systemic lupus erythematosus. We conclude that some strategies (like mycophenolate mofetil) are good candidates for further investigation in large-scale, prospective, randomised trials with prolonged follow-up (which are almost by definition hard to perform). Most new biological agents still are in a pre-clinical phase.


J Endocrinol Invest 2002;25(10 Suppl):29-35

Adrenopause: an imbalance between dehydroepiandrosterone (DHEA) and cortisol secretion.

Valenti G.

University of Parma, Parma, Italy.

Several clinical signs might be related to the decline of DHEA secretion in aged people: sarcopenia, osteopenia, atherosclerosis progression, impairment of cognitive and affective performances, deterioration of immunocompetence are the most significant evidences. In addition, in aged people this clinical condition might be worsened by the concomitant relative glucocorticoid excess which develops in an age related manner. All together, these clinical signs construct the corpus of a syndrome named adrenopause. DHEA replacement therapy might find its indication besides the obvious condition of primary and secondary corticoadrenal insufficiency in those aged patients with typical signs of adrenopause accompanied by magnified decline of DHEA and relative excess of cortisol. Two further indications for aged patients might be represented by those with chronic inflammatory diseases, especially when long term treated with glucocorticoids and those who undergo surgical procedures.


J Endocrinol Invest 2002;25(10 Suppl):24-8

Pituitary function in chronic heart failure in the elderly.

Ceda GP, Dall'Aglio E, Salimbeni I, Rocci A, Mazzoni S, Corradi F, Cattadori E, Visioli S, Banchini A, Ceresini G, Valenti G, Hoffman AR.

Department of Internal Medicine and Biomedical Sciences, Section of Geriatrics, University of Parma, Parma, Italy.

Heart failure is a complex syndrome characterized by the activation of hemodynamic, immunologic and neurohormonal systems, which have beneficial effects in the short run, but will ultimately lead to secondary end-organ damage with worsening of LV remodeling and subsequent cardiac decompensation. A very important role seems to be played by modifications of the pituitary hormone systems. Due to the neurohormonal activation there is an increase in the activity in the renin angiotensin system, in the adrenergic nervous system, and in the cytokine system. In heart failure there is a decrease in many anabolic hormones, such as a decrease of GH and IGF-I, of DHEA/DHEAS with normal or increased F, and a decrease of LH and sex steroids, resulting in an important catabolic drive, capable of contributing to the development of cardiac failure and to sarcopenia and/or cachexia, frequently observed in the advanced stages of the disease. However, these hormone alterations have been described in relatively young patients with chronic heart failure, since the mean age of all the subjects studied was of about 60 yr and none of the studies have specifically addressed this issue in the very old patients, who represent the largest portion of population affected by this pathological condition. The role of hormone replacement therapy needs to be verified in a population of elderly patients with heart failure.


J Endocrinol Invest 2002;25(10 Suppl):2-9

Replacement therapy in the aging male.

Lunenfeld B.

Faculty of Life Sciences, Bar, Ilan University Ramat Gan 52900 Israel.

In the aging male, endocrine changes and decline in endocrine function involve tissue responsiveness as well as reduced secretory output from peripheral glands and alterations in the central mechanism controlling the temporal organization of hormonal release. The latter are likely to be responsible for the dampened circadian hormonal and non-hormonal rhythms. These are in part responsible of the age dependent decrease of the peripheral levels of T, DHEA, the thyroid hormones, GH, IGF-I, and melatonin. These hormonal changes which develop in most men at about the age of 50 are in part responsible for the partial endocrine deficiencies of aging male (PEDAM). In cases of endocrine deficiencies, traditional endocrinology aims at replacing the missing hormone or hormones with substitutes. It has been demonstrated that interventions, such as hormone replacement therapies and use of antioxidant drugs may favorably influence some of the pathological conditions in aging men, by preventing the preventable and delaying the inevitable. A comprehensive medical, psycho-social and life-style history, a physical examination and laboratory testing are essential for the diagnosis and management of PEDAM. Acute, chronic or inter-current diseases must be taken into consideration prior to initiating any hormonal substitution therapy. Hormone substitution should only be performed by physicians with basic knowledge and clinical experience in diagnosis, treatment and monitoring of endocrine deficiencies. In the Era of Evidence Based Medicine, we have to acknowledge that data on hormone replacement therapy (HRT) in the aging male is mostly circumstantial, based on experience in treatment of transitional or chronic endocrine deficiencies in young men due to disease or experiments of nature. However over the past several years, there has been an increasing interest in evaluating whether male HRT might be beneficial for a specific category of older men in preventing or delaying some aspects of ageing, and a number of prospective studies on hormone replacement therapy in the aging male were performed and these are presented in detail.


J Infect Dis 2003 Jan 1;187(1):124-7

Adrenocortical hormones and interleukin patterns in paracoccidioidomycosis.

Leal AM, Magalhaes PK, Martinez R, Moreira AC.

Division of Endocrinology, Department of Internal Medicine, School of Medicine of Ribeirao Preto, University of Sao Paulo, Brazil.

The functional status of adrenocortical hormones and their relationship to the pattern of inflammatory cytokines in paracoccidioidomycosis were investigated in a prospective study. Patients were evaluated before treatment and 1 and 6 months after receiving antifungal therapy. Interleukin (IL)-1beta, IL-6, and tumor necrosis factor-alpha plasma levels, C-reactive protein (CRP) concentrations, and erythrocyte sedimentation rate (ESR) were significantly higher in untreated patients than in control subjects. After 6 months of treatment, levels of the 3 cytokines, CRP concentrations, and the ESR decreased significantly. Both baseline and stimulated adrenocorticotropic hormone and cortisol plasma levels were not different between patients and control subjects. In contrast, adrenal androgen dehydroepiandrosterone sulfate (DHEA-S) plasma levels were significantly lower in patients than in sex- and age-matched control subjects. There was a significant inverse correlation between DHEA-S and IL-6 plasma levels. This finding may be of pathogenetic significance in this disease and in other inflammatory states.


Encephale 2002 Nov-Dec;28(6):563-6

A case report of mania precipitated by use of DHEA

[Article in French]

Vacheron-Trystram MN, Cheref S, Gauillard J, Plas J.

Secteur 13, Service du Docteur Caroli, Hopital Sainte-Anne, 1, rue Cabanis, 75014 Paris.

Dehydroepiandrosterone (DHEA) and its sulfate ester metabolite (DHEA-S) are precursors to testosterone and, to a lesser extent, to estrogen, and, for both sexes, they are produced in the adrenal cortex. They are among the most abundant steroids in the human body, yet their physiological roles remain unknown. DHEA and DHEA-S appear to have diverse biochemical activities, including actions within the central nervous system. So DHEA is produced in the central nervous system as well as the human adrenals and is present in the brain, concentrated in limbic regions, in levels much higher than other steroids. DHEA has been postulated to function as an excitory neuroregulator, antagonizing g-aminobutyric acid transmission. The main characteristic of DHEA is that its level of concentration in plasma varies throughout life, such level being low during the early childhood and after the age of 60 years. Adrenal production and serum concentrations of DHEA are then known to peak between ages 25 and 30 years and thereafter decrease with age, severe illness and chronic stress. The decrease of DHEA over time would appear to be responsible for morbidity related to aging process. Previous reports have found low levels of DHEA in association with physical and with frailty in the elderly (immunosenescence, increased incidence of osteoporosis, atherosclerosis and cancer, decreased cognitive functions and/or well-being). As it has been touted as a fountain of youth and a sexual tonic and promoted for a variety of illnesses associated with aging, DHEA is widely available over all the United States (since 1994) as a dietary supplement. In France, as a result of a massive advertising campaign, DHEA is already the subject of a widespread use and a growing demand although it has not yet been approved by the relevant authorities for sale as drug to the public. In practice, DHEA is prescribed and delivered under the sole responsibility of both doctor and chemist who ascertain the benefit-risk ratio and the quality of the product. DHEA may then be purchased on the internet or in the form of magistral preparations delivered on the basis of such prescription. Accordingly, there is little information or data on efficacy, drug interactions, results of long-term use, abrupt discontinuation or potential adverse effects related to the use of DHEA. We report a case of mania possibly precipitated by the use of high doses of DHEA (150-200 mg/day at the time of presentation) during several weeks in a 68 years old man who had already been hospitalized for an acute mania many years ago. Although, in this case, the patient suffered a bipolar diathesis in the past, oral DHEA may have played a role in the induction of his acute manic episode. Further research is required to assess the mood effects of DHEA, including its potential risk for patients with bipolar disorder.


Arch Med Res 2002 Nov-Dec;33(6):524-30

Relationship of insulin resistance and overweight with cortisol and dehydroepiandrosterone-sulfate levels.

Mino D, Amato D, Cuevas ML, Fonseca ME, Burbano G, Wacher N, Lifshitz A.

Coordinacion de Investigacion Medica, Division de Investigacion Clinica, Mexico City, Mexico.

BACKGROUND: Our objective was to assess the relationship of hormones such as cortisol and dehydroepiandrosterone-sulfate (DHEA-S) with insulin resistance and overweight. METHODS: We designed and conducted a cross-sectional, observational survey consisting of home visits within a previously defined area of Mexico City. The study included 303 apparently healthy volunteers from a middle-class socioeconomic urban community. We measured glucose, cholesterol, triglycerides, insulin, cortisol, and DHEA-S. Insulin resistance (IR) was defined as belonging to the first quartile of fasting glucose/insulin ratio (G/IR) distribution or fourth quartile of IR (HOMA). Overweight was defined as body mass index (BMI) > or =25 kg/m(2). RESULTS: To predict IR in women < or =35 years of age, principal component analysis (PCA) disclosed three components: 1) cholesterol, BMI, and diastolic blood pressure (DBP); 2) cholesterol, triglycerides, and cortisol, and 3) dehydroepiandrosterone-sulfate [DHEA-S]. Solely the latter (DHEA-S) was significantly associated with IR (odds ratio [OR] = 1.80, confidence interval 95% [CI 95%] 1.11-2.91, p = 0.015). For men < or =35 years of age, there were two components: 1) cholesterol, triglycerides, BMI, and DBP, and 2) DHEA-S, cholesterol, and cortisol. Component 1 was significantly associated with IR (OR = 5.65; CI 95% 1.62-19.65, p = 0.006). To predict overweight in women >35 years of age, there were three components, including 1) cholesterol and triglycerides, 2) cortisol, and 3) DHEA-S and G/IR. Component 2 was significantly associated with overweight (OR = 0.38, CI 95% 0.23-0.64, p = 0.000). CONCLUSIONS: In women < or =35 years of age, high DHEA-S levels were associated with insulin resistance, which suggests that in young women DHEA-S exerts anti-estrogenic action, perhaps caused by its competitive binding with the estrogen receptor. Additionally, in women >35 years of age, low cortisol levels were associated with overweight. These associations were not identified for the male subgroup.


Biol Pharm Bull 2002 Dec;25(12):1634-8

Serum concentrations of delta(5)-3beta-hydroxysteroids in type 2 diabetes mellitus.

Tagawa N, Ohta M, Nakamura N, Nakano K, Obayashi H, Kobayashi Y.

Clinical Chemistry Laboratory, Kobe Pharmaceutical University.

We examined the serum concentrations of Delta(5)-3beta-hydroxysteroids, pregnenolone (Preg), 17-hydroxypregnenolone (17-OH-Preg), dehydroepiandrosterone (DHEA), androstenediol (ADIOL) and their sulfates in 30 well controlled (Group I: HbA1c<7.0%) and 15 poorly controlled (Group II: HbA1c>7.1%) type 2 diabetic patients, and 30 normal controls. These patients were treated with diet therapy or anti-diabetic agent. The distribution of gender and age of the subjects were matched between the groups. The serum levels of sulfo-conjugated and unconjugated steroids described above were measured by GC-MS and enzyme immunoassay (EIA), respectively. The serum levels of the entire sulfo-conjugated steroid measured in this study were significantly lower in Groups I and II than in controls. On the other hand, Preg levels in both Groups I and II were significantly higher than those in controls, whereas the serum levels of the downstream unconjugated steroids were not different from controls. To investigate the effect of sulfonylurea (SU) on the serum levels of steroids, the serum concentrations of steroids between the patients who were treated with diet therapy and SU agent were compared in Group I. No significant differences were observed between both groups. These results suggest that (1) since increased Preg levels did not cause any changes in the downstream Delta(5)-3beta-hydroxysteroid levels, the metabolic pathway of Delta(4)-3-ketosteroids may be accelerated in type 2 diabetes; (2) serum steroid levels were not affected by SU treatment; (3) sulfo-conjugated steroid catabolism was altered in type 2 diabetes; (4) the decreased sulfo-conjugated steroids especially ADIOLS may contribute to the alteration of sex steroid levels and onset or exacerbate infectious diseases in diabetes.


Neurobiol Aging 2003 Jan-Feb;24(1):57-65

Oxidative stress-mediated DHEA formation in Alzheimer's disease pathology.

Brown RC, Han Z, Cascio C, Papadopoulos V.

The Interdisciplinary Program in Neuroscience, Georgetown University Medical Center, 3900 Reservoir Road NW, 20007, Washington, DC, USA

An alternative pathway for dehydroepiandrosterone (DHEA) synthesis has been suggested by treating rat and human brain cells with ferrous sulfate and beta-amyloid (Abeta). To determine if this pathway exists in human brain, levels of DHEA in hippocampus, hypothalamus and frontal cortex from Alzheimer's disease (AD) patients and age-matched controls were measured. DHEA is significantly higher in AD brain than control, and was highest in AD hippocampi. Cytochrome P450 17alpha-hydroxylase, responsible for peripheral DHEA synthesis, is not present in hippocampus. DHEA levels in AD cerebrospinal fluid (CSF) were significantly higher than age-matched controls. AD serum DHEA levels are lower than CSF, and not significantly different from controls. Treatment of control hippocampus, hypothalamus and serum with FeSO(4) increases DHEA, suggesting that levels of precursor are higher in control that in AD brain. This suggests that (i) an alternative precursor is present in control brain, (ii) AD brain DHEA is formed by oxidative stress metabolism of precursor, and (iii) CSF DHEA levels and serum DHEA formation in response to FeSO(4) may serve as an indicator of AD pathology.


Endocrinology 2003 Jan;144(1):253-9

Dehydroepiandrosterone down-regulates the expression of peroxisome proliferator-activated receptor gamma in adipocytes.

Kajita K, Ishizuka T, Mune T, Miura A, Ishizawa M, Kanoh Y, Kawai Y, Natsume Y, Yasuda K.

The Third Department of Internal Medicine, Gifu University School of Medicine, Tsukasa-machi 40, Gifu 500-8705, Japan.

Dehydroepiandrosterone (DHEA) is expected to have a weight-reducing effect. In this study, we evaluated the effect of DHEA on genetically obese Otsuka Long Evans Fatty rats (OLETF) compared with Long-Evans Tokushima rats (LETO) as control. Feeding with 0.4% DHEA-containing food for 2 wk reduced the weight of sc, epididymal, and perirenal adipose tissue in association with decreased plasma leptin levels in OLETF. Adipose tissue from OLETF showed increased expression of peroxisome proliferator-activated receptor gamma (PPARgamma) protein, which was prevented by DHEA treatment. Further, we examined the effect of DHEA on PPARgamma in primary cultured adipocytes and monolayer adipocytes differentiated from rat preadipocytes. PPARgamma protein level was decreased in a time- and concentration-dependent manner, and DHEA significantly reduced mRNA levels of PPARgamma, adipocyte lipid-binding protein, and sterol regulatory element-binding protein, but not CCAAT/enhancer binding protein alpha. DHEA-sulfate also reduced the PPARgamma protein, but dexamethasone, testosterone, or androstenedione did not alter its expression. In addition, treatment with DHEA for 5 d reduced the triglyceride content in monolayer adipocytes. These results suggest that DHEA down-regulates adiposity through the reduction of PPARgamma in adipocytes.


FEBS Lett 2002 Dec 18;532(3):373-8

In vivo activation of the constitutive androstane receptor beta (CARbeta) by treatment with dehydroepiandrosterone (DHEA) or DHEA sulfate (DHEA-S).

Fujita A, Furutama D, Tanaka T, Sakai R, Koyama A, Hanafusa T, Mitsuhashi T, Ohsawa N.

Aino Institute for Aging Research, 3-9-25, Ohta, Ibaraki, 567-0018, Osaka, Japan.

We investigated whether dehydroepiandrosterone (DHEA) or DHEA-sulfate (S) affected the activities of nuclear receptors, with special reference to constitutive androstane receptor beta (CARbeta). Administration of DHEA or DHEA-S enhanced the DNA binding of hepatic nuclear extracts to responsive elements for the retinoic acid receptor, the retinoic acid receptor beta 2 and the peroxisome proliferator activated receptor. The bound complexes were shown to be the CARbeta-RXR heterodimer by antibody-supershift assays. The expression of a target gene of CARbeta, Cyp2b10, was increased in liver by DHEA or DHEA-S treatment, suggesting that DHEA or DHEA-S actually activated CARbeta in vivo. It was suggested that the metabolic conversion of DHEA, DHEA-S to CARbeta ligands could occur in vivo and the metabolites could regulate the expression of CARbeta target gene expression. Our results provide new insights into the in vivo relationship between DHEA/DHEA-S and CARbeta activation.


J Endocrinol 2002 Dec;175(3):779-92

Modulation of the peroxisomal gene expression pattern by dehydroepiandrosterone and vitamin D: therapeutic implications.

Depreter M, Vandesompele J, Espeel M, Speleman F, Roels F.

Department of Human Anatomy, Embryology, Histology and Medical Physics, Ghent University, Godshuizenlaan 4, B-9000 Ghent, Belgium.

Peroxisomes are ubiquitous organelles required for several metabolic functions. Their dysfunction is responsible for a group of human inherited disorders. In the search for endogenous factors regulating the peroxisomal compartment in normal liver, we treated female rats with dehydroepiandrosterone (DHEA) and 25-hydroxycholecalciferol for 1 and 6 days. Relative transcription levels of 39 selected genes were evaluated by real-time quantitative RT-PCR analysis. Catalase (peroxisomal marker)-specific activity was assayed in total liver homogenate and peroxisomes were visualized by catalase localization. DHEA induced peroxisome proliferation and raised catalase specific activity. Expression levels of 16 (of which 11 were peroxisomal) genes were altered. Pex 11, acyl-CoA oxidase,l - andd -multifunctional enzyme, thiolase 1, phytanoyl-CoA hydroxylase, 70 kDa peroxisomal membrane protein and very long chain acyl-CoA synthetase were upregulated, three others were downregulated. Vitamin D caused downregulation of six genes. Administration of vitamin D to peroxisomal disorder patients may be contraindicated. The adrenocortical hormone DHEA is a potential natural regulator of the peroxisomal compartment. Its therapeutic use in X-linked adrenoleukodystrophy, some other beta-oxidation defects and classical Refsum should be considered.


Proteins 2003 Jan 1;50(1):135-43

Analysis of the binding energies of testosterone, 5alpha-dihydrotestosterone, androstenedione and dehydroepiandrosterone sulfate with an antitestosterone antibody.

Nordman N, Valjakka J, Perakyla M.

Department of Chemistry, University of Kuopio, Kuopio, Finland.

Molecular dynamics simulations and molecular mechanics-Poisson-Boltzmann surface area (MM-PBSA) free energy calculations were used to study the binding of testosterone (TES), 5alpha-dihydrotestosterone (5ADHT), androstenedione (AND), and dehydroepiandrosterone sulfate (DHEAS) to the monoclonal antitestosterone antibody 3-C(4)F(5). The relative binding free energy of TES and AND was also calculated with free energy perturbation (FEP) simulations. The antibody 3-C(4)F(5) has a relatively high affinity (3 x 10(8) M(-1)) and on overall good binding profile for testosterone but its cross-reactivity with DHEAS has been the main reason for the failure to use this antibody in clinical immunoassays. The relative binding free energies obtained with the MM-PBSA method were 1.5 kcal/mol for 5ADHT, 3.8 kcal/mol for AND, and 4.3 kcal/mol for DHEAS, as compared to TES. When a water molecule of the ligand binding site, observed in the antibody-TES crystal structure, was explicitly included in MM-PBSA calculations, the relative binding energies were 3.4, 4.9, and 5.4 kcal/mol for 5ADHT, AND, and DHEAS, respectively. The calculated numbers are in correct order but larger than the corresponding experimental energies of 1.3, 1.5, and 2.6 kcal/mol, respectively. The fact that the MM-PBSA method reproduced the relative binding free energies of DHEAS, a steroid having a negatively charged sulfate group, and the neutrally charged TES, 5ADHT, and AND in satisfactory agreement with experiment shows the robustness of the method in predicting relative binding affinities. The 800-ps FEP simulations predicted that the antibody 3-C(4)F(5) binds TES 1.3 kcal/mol tighter than AND. Computational mutagenesis of selected amino acid residues of the ligand binding site revealed that the lower affinities of AND and DHEAS as compared to TES are due to a combined effect of several residues, each contributing a small fraction to the tighter binding of TES. An exception to this is Tyr99H, whose mutation to Ala lowered the binding of DHEAS 0.7 kcal/mol more than the binding of TES. This is probably due to the hydrogen bonding interaction formed between the OH group of Tyr99H and the sulfate group of DHEAS. Computational mutagensis data also showed that the affinity of the steroids to the antitestosterone antibody 3-C(4)F(5) would be enhanced if Trp47H were repositioned so that it would make more extensive contacts with the bound ligands. In addition, the binding of steroids to antitestosterone, antiprogesterone, and antiestradiol antibodies is discussed.


Psychother Psychosom 2003 Jan-Feb;72(1):49-58

A longitudinal study of hormonal reactions accompanying life events in recently resettled refugees.

Sondergaard HP, Theorell T.

National Swedish Institute for Psychosocial Factors and Health, Stockholm, Sweden.

Background: Refugees constitute a growing section of the general population in many countries. It is therefore important to study which factors in everyday life are important to recently resettled refugees after they have been granted residence. Methods: Life events from a checklist, as well as categories derived from written responses to open-ended questions were analysed (repeated-measures ANOVA). Changes over time in mean serum/plasma concentrations of cortisol, thyroxine, prolactin, and dehydroepiandrosterone sulphate (DHEA-S) were compared in subjects with and without the reported events. Results: Distress in significant others (close friends or first-degree relatives) and a perception of excessive demands in everyday life were associated with increases in serum cortisol. Events associated with decreased levels of prolactin were typically situations of strain in relation to authorities or individuals to which the subjects were in a position of dependency. DHEA-S changed in opposite directions in post-traumatic stress disorder (PTSD) and non-PTSD subjects. DHEA-S also changed with positive events. Conclusions: Distress in significant others and a too demanding everyday life lead to significant changes in the stress-responsive hormones cortisol, prolactin and DHEA-S. Since DHEA-S behaves differently in PTSD, this condition is a potential confounder in studies of DHEA-S with an unknown proportion of PTSD among participants.


Clin Exp Rheumatol 2002 Nov-Dec;20(6 Suppl 28):S52-9

No alterations of serum levels of adrenal and gonadal hormones in patients with ankylosing spondylitis.

Straub RH, Struharova S, Scholmerich J, Harle P.

Department of Internal Medicine I, University Hospital Regensburg, Germany.

Ankylosing spondylitis (AS) is a chronic inflammatory disease with a marked preponderance of affected males compared to females of approximately 6 to 1. During the last two decades, this circumstance stimulated several research groups to investigate serum levels of gonadal and adrenal sex hormones. From available results of cross-sectional studies, there seems to be no particular defect in secretion or production of adrenal, gonadal, and pituitary hormones. This is in striking contrast to diseases such as rheumatoid arthritis and other chronic inflammatory diseases. In the latter diseases, low serum levels of dehydroepiandrosterone (DHEA), DHEA sulphate (DHEAS), and testosterone have been described in an advanced chronic disease stage, whereas estrogen serum levels remain normal. Although AS is an inflammatory disease with signs of systemic inflammation such as elevated erythrocyte sedimentation rate or increased circulating proinflammatory cytokines, serum levels of adrenal and gonadal androgens are normal. It is unclear whether this can be considered as unexpected. It may be that inflammation does not reach the pituitary, adrenal, and gonadal glands or does not alter the aromatase complex in peripheral tissue. Furthermore, the inflammation-induced changes may be subtle so that only specific endocrine examination of these axes may reveal signs of alterations. In conclusion, current data on sex steroid hormones provide no straightforward explanation for the male predominance in AS. At the moment, there is no rationale to treat AS patients with sex steroid hormones.


FEBS Lett 2002 Dec 4;532(1-2):153-8

Synergistic effect of retinoic acid and dehydroepiandrosterone on differentiation of human neuroblastoma cells.

Silvagno F, Guarnieri V, Capizzi A, Pescarmona GP.

Dipartimento di Genetica, Biologia e Biochimica, Facolta' di Medicina e Chirurgia, Universita' di Torino, Sezione di Biochimica, Via Santena 5 bis, 10126 Turin, Italy.

Retinoic acid (RA) affects many cell types by either promoting their survival or inducing their differentiation. Dehydroepiandrosterone (DHEA), a precursor for both androgenic and estrogenic steroids and abundantly produced by brain, is known as an inhibitor of cell proliferation. Differentiation of a human neuroblastoma cell line (SK-N-BE) was evaluated measuring growth rate, motility, neurite extension and GAP-43 expression. We report that DHEA enhances the differentiating effect of RA on neuroblastoma cells via a signalling that is not RA receptor-mediated. Instead, we show a differential expression of matrix metalloproteinases: RA enhances the activity of MMP-2, whereas MMP-9 expression is up-regulated by DHEA. The concerted modulation of these proteinases may support the neurite outgrowth observed after co-treatment with the two drugs.


Rev Med Interne 2002 Oct;23(10):819-27

Relation between physical activity, muscle function and IGF-1, testosterone and DHEAS concentrations in the elderly

[Article in French]

Bonnefoy M, Patricot MC, Lacour JR, Rahmani A, Berthouze S, Kostka T.

Service de medecine geriatrique, centre hospitalier Lyon-Sud, 69495 Pierre-Benite, France.

OBJECTIVE: Lower amounts of circulating anabolic hormones are thought to accelerate the age related decline in muscle mass and function. Replacement therapies are promising interventions but there are problems with these therapies. Thus alternative strategies should be developed. The age related changes in hormonal status may be probably influenced by exercise. The purpose of this study was: a) to confirm with other methods, more adapted for elderly people, the results of a previous study that has shown relationship between physical activity (PA) and quadriceps muscle function with dehydroepiandrosterone sulphate (DHEAS), insulin like growth factor-1 (IGF-1). Quadriceps muscle power (Pmax) is measured in this new work with a recently developed leg extensor machine and, b) to complete the results of the first study examining simultaneously the relationship between PA, Pmax and cardiorespiratory fitness (VO2max) with DHEAS, IGF-1 and testosterone in a group of healthy elderly people. METHODS: Fifty independent, community dwelling elderly subjects (25 mens and 25 womens) aged from 66 to 84 volunteered to participate in the study. PA was evaluated by the questionnaire and expressed using two activity indices: mean habitual daily energy expenditure (MHDEE) and the daily energy expenditure corresponding to leisure time sports activities (Sports Activity). Pmax and optimal shortening velocity (vopt) were measured on a Ergopower dynamometer. The Pmax was expressed relative to body mass, Pmax/kg (W kg-1), and relative to the mass of the two quadriceps muscles, Pmax/Quadr (W.kgQuadr-1). VO2max has been measured during a maximal treadmill exercise. RESULTS: In women, IGF-1 correlated significantly with MHDEE (r = 0.54, P = 0.004), Pmax/kg (r = 0.54, P = 0.004) and Pmax/Quadr (r = 0.46, P = 0.02), whereas DHEAS with MHDEE (r = 0.54, P = 0.004), Sports Activity (r = 0.65, P < 0.001), VO2max (r = 0.46, P = 0.02), Pmax/kg (r = 0.46, P = 0.02) and Pmax/Quadr (r = 0.55, P = 0.004). No such correlation was found in men. CONCLUSION: These findings confirm that in healthy elderly women physical activity, cardiorespiratory fitness and quadriceps muscle function are similarly related to levels of circulating DHEAS and IGF-1 suggesting a favourable influence of exercise on anabolic hormonal production in the elderly.


Arthritis Rheum 2002 Nov;46(11):2924-7

Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebo-controlled trial.

Chang DM, Lan JL, Lin HY, Luo SF.

Tri-Service General Hospital, National Defense Medical Center, Taipei, Taiwan, Republic of China.

OBJECTIVE: To evaluate the efficacy and tolerability of dehydroepiandrosterone (DHEA) at a dosage of 200 mg/day in adult women with active systemic lupus erythematosus (SLE). METHODS: In a multicenter randomized, double-blind, placebo-controlled trial, 120 adult women with active SLE received oral DHEA (200 mg/day; n = 61) or placebo (n = 59) for 24 weeks. The primary end point was the mean change from baseline in the Systemic Lupus Activity Measure (SLAM) score at 24 weeks of therapy. Secondary end points included time to first flare, change in SLE Disease Activity Index (SLEDAI) score, and physician's and patient's global assessment scores at week 24. RESULTS: The two groups were well balanced for baseline characteristics. Mean reductions in SLAM scores from baseline were similar and were not statistically significantly different between treatment groups (DHEA -2.6 +/- 3.4 versus placebo -2.0 +/- 3.8, mean +/- SD). The number of patients with flares was decreased by 16% in the DHEA group (18.3% of DHEA-treated patients versus 33.9% of placebo-treated patients; P = 0.044, based on time to first flare). The mean change in the patient's global assessment was statistically significant between the two groups (DHEA -5.5 versus placebo 5.4; P = 0.005). The number of patients with serious adverse events, most of which were related to SLE flare, was significantly lower in DHEA-treated patients compared with placebo-treated patients (P = 0.010). Expected hormonal effects, including increased testosterone levels and increased incidence of acne, were observed. No life-threatening reactions or serious safety issues were identified during this study. CONCLUSION: The overall results confirm that DHEA treatment was well-tolerated, significantly reduced the number of SLE flares, and improved patient's global assessment of disease activity.


Mech Ageing Dev 2002 Sep;123(11):1477-86

Changes in peripheral blood lymphocyte subsets in elderly subjects are associated with an impaired function of the hypothalamic-pituitary-adrenal axis.

Martinez-Taboada V, Bartolome MJ, Amado JA, Blanco R, Garcia-Unzueta MT, Rodriguez-Valverde V, Lopez-Hoyos M.

Services of Rheumatology, Immunology, and Endocrinology, Santander, Spain.

A growing body of evidence indicates that ageing brings a progressive disruption in the immune and endocrine systems. However, very few reports have correlated the changes in the immune system with the endocrine function in the elderly. The aim of the present study was to investigate the changes occurring in the peripheral blood lymphocyte subpopulations with age and correlate them with the hypothalamic-pituitary-adrenal (HPA) function. We determined the peripheral blood lymphocyte phenotype and the T cell receptor usage by flow cytometry analysis. The HPA function was evaluated by the basal serum levels of adrenal steroids and the response to stimulation with a low-dose ACTH. In the elderly, we observed a decrease of major T subsets together with an increase of NK cells and activated T cells. With regard to the HPA function, the most significant decline was found in dehydroepiandrosterone (DHEA) and dehydroepiandrosterone-sulphate (DHEAS). A close correlation between immune changes with ageing and DHEA response to ACTH stimulation was found. The present study showed an inverse correlation of lymphocyte changes with the plasma levels of steroids, especially DHEA and its metabolite, DHEAS. This association was not found for other steroids and points for the possibility of using DHEA to correct the immunological decline associated with ageing.


MMW Fortschr Med 2002 Sep 26;144(39):24-7

Hormonal "rejuvenation". Warning your patients from false claims!

[Article in German]

Bruckel J.

Abt. f. Innere Medizin, Bereich Endokrinologie und Diabetes, Krankenhaus Wangen, Oberschwaben-Klinik GmbH.

No intervention, including drugs and hormones, has been proven to slow or even reverse aging. Such promises, as well as the term "anti-aging medicine", are misleading. On the other hand, remarkable progress has been made in the prevention and treatment of age-related diseases. The use of hormones constitutes a potentially new option in the prevention and treatment of age-related diseases, but is not an established therapy. The status of scientific evidence for the treatment of seniors with growth hormone, melatonin, DHEA or testosterone is critically reviewed.


Synapse 2003 Jan;47(1):10-4

Dehydroepiandrosterone (DHEA) such as 17beta-estradiol prevents MPTP-induced dopamine depletion in mice.

D'Astous M, Morissette M, Tanguay B, Callier S, Di Paolo T.

Molecular Endocrinology and Oncology Research Center, Laval University Medical Center (CHUL), Quebec, Qc, G1V 4G2, and Faculty of Pharmacy, Laval University, Quebec, Qc, G1K 7P4, Canada.

Previous work from our laboratory has shown prevention of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced striatal dopamine (DA) depletion in mice by 17beta-estradiol, progesterone, and raloxifene. Dehydroepiandrosterone (DHEA), a neurosteroid, was shown to have neuroprotective activities in various paradigms of neuronal death but its effect in vivo in mice on MPTP toxicity has not been reported. We investigated the effects of 17beta-estradiol (2 microg/day) and DHEA (3 mg/day) for 5 days before and after an acute treatment of four MPTP (10 mg/kg) injections in male C57Bl/6 mice. Striatal DA concentrations and its metabolites dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA) were measured by HPLC. MPTP mice that received 17beta-estradiol or DHEA had striatal DA, DOPAC, and HVA concentrations comparable to intact animals and higher than striatal DA, DOPAC, and HVA levels in saline-MPTP-treated mice. MPTP treatment led to an increase of striatal DA turnover (assessed with the HVA/DA ratio); DHEA and 17beta-estradiol prevented this increase. 17beta-Estradiol did not affect striatal DA and metabolites concentrations in intact mice in this paradigm. Furthermore, in the substantia nigra DHEA and 17beta-estradiol prevented the MPTP-induced dopamine transporter and tyrosine hydroxylase mRNA decreases measured by in situ hybridization. Therefore, DHEA such as 17beta-estradiol is active in preventing the catecholamine-depleting effect of MPTP and our results suggest that this involves neuroprotection of DA neurons.


Neuroscience 2002;115(2):415-24

Dehydroepiandrosterone and alpha-estradiol limit the functional alterations of rat brain mitochondria submitted to different experimental stresses.

Morin C, Zini R, Simon N, Tillement JP.

Departement de Pharmacologie, Faculte de Medecine de Paris XII, 8 rue du General Sarrail, F-94010 Creteil, France.

The effects of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEA-S), alpha-estradiol and beta-estradiol on the main functions of purified rat brain mitochondria were investigated in basal conditions and after being submitted to various stresses including anoxia-reoxygenation, uncoupling and apoptosis. In basal conditions, DHEA (1 microM) and alpha-estradiol (1 microM) inhibited the respiratory control ratio (RCR) from 3.1 to 2.3 (25%). After anoxia-reoxygenation, DHEA (1 microM) and alpha-estradiol (1 microM) reversed significantly (P<0.01) the RCR decrease from 1.4 to 2.0 (21.5%) by restoring the state 4. This effect was observed when DHEA was added either before anoxia or before reoxygenation and when alpha-estradiol was added before anoxia. The mitochondrial membranes damaged after the anoxia-reoxygenation were 70 and 50%, respectively, protected by DHEA and alpha-estradiol at 1 microM. They also limited by about 50%, the cytochrome c release induced by the anoxia-reoxygenation. The oxygen consumption of mitochondria in presence of NADH (130 microM) and cytochrome c (5 microM) was significantly inhibited by DHEA and alpha-estradiol with high EC(50) of 30 and 22 pM, respectively. At 1 microM, they also inhibited the 10 microM carbonyl cyanide m-chlorophenylhydrazone-induced uncoupling to about 35% whereas beta-estradiol only decreased it to 9%.Our results indicated that DHEA and alpha-estradiol partly preserved the mitochondrial functions altered by an anoxia-reoxygenation with a concentration-dependent effect. The mechanism involved was independent of the classical genomic effect of steroids, the antioxidant properties but implicated a direct action on the mitochondrial membranes.


Psychopharmacology (Berl) 2003 Jan;165(2):97-110

Neurosteroids in depression: a review.

Van Broekhoven F, Verkes RJ.

Department of Psychiatry, Unit for Clinical Psychopharmacology and Neuropsychiatry, University Medical Centre Nijmegen, P.O. Box 9101, 6500 HB Nijmegen, The Netherlands,

RATIONALE. A deregulation in concentrations of the neurosteroids (allo)pregnanolone and 3alpha,5alpha-tetrahydrodeoxycorticosterone (3alpha,5alpha-TH DOC) has been found in depressed patients. These levels normalize following treatment with selective serotonin reuptake inhibitors (SSRIs). Furthermore, administration of the neurosteroid dehydroepiandrosterone (DHEA) to depressed patients is associated with an improvement in the symptoms of depression. OBJECTIVE. The aim of the present review is to clarify the mechanisms whereby neurosteroids, particularly allopregnanolone and DHEA, are involved in depression and to discuss the effect of SSRIs on allopregnanolone concentration. METHODS. Literature on preclinical and clinical research has been analyzed in relation to the pathophysiology of depression. RESULTS. Decreased plasma and cerebrospinal fluid concentrations of allopregnanolone in depressed patients increase to normal levels following effective psychopharmacological treatment. This might either be a physiological aspect of improvement in the symptoms of depression or a pharmacologically induced alteration. Several findings support the hypothesis of an antidepressant effect of allopregnanolone. These include an antidepressant effect demonstrated in an animal model of depression and a suppressing effect on corticotropin-releasing hormone (CRH) and arginine-vasopressin (AVP) gene expression. SSRIs increase levels of allopregnanolone, but this effect is not confined to this class of drugs alone. The beneficial effect of DHEA administration in depressed patients might result from its sigma 1 receptor-mediated enhancement of noradrenaline and serotonin neurotransmission, antiglucocorticoid effects, and cognition enhancing effects. CONCLUSIONS. Indirect genomic (allopregnanolone) and non-genomic (allopregnanolone and DHEA) mechanisms are involved in the neurosteroidogenic pathophysiology of depression. Clinical studies in homogeneous groups of non-pharmacologically treated depressed patients are required to elucidate this relationship further.


J Clin Endocrinol Metab 2002 Nov;87(11):5138-43

Neurosteroid quantification in human brain regions: comparison between Alzheimer's and nondemented patients.

Weill-Engerer S, David JP, Sazdovitch V, Liere P, Eychenne B, Pianos A, Schumacher M, Delacourte A, Baulieu EE, Akwa Y.

INSERM U-488, Steroides et Systeme Nerveux, 80 rue du General Leclerc, 54276 Le Kremlin-Bicetre, France.

Some neurosteroids have been shown to display beneficial effects on neuroprotection in rodents. To investigate the physiopathological significance of neurosteroids in Alzheimer's disease (AD), we compared the concentrations of pregnenolone, pregnenolone sulfate (PREGS), dehydroepiandrosterone, dehydroepiandrosterone sulfate (DHEAS), progesterone, and allopregnanolone, measured by gas chromatography-mass spectrometry, in individual brain regions of AD patients and aged nondemented controls, including hippocampus, amygdala, frontal cortex, striatum, hypothalamus, and cerebellum. A general trend toward decreased levels of all steroids was observed in all AD patients' brain regions compared with controls: PREGS and DHEAS were significantly lower in the striatum and cerebellum, and DHEAS was also significantly reduced in the hypothalamus. A significant negative correlation was found between the levels of cortical beta-amyloid peptides and those of PREGS in the striatum and cerebellum and between the levels of phosphorylated tau proteins and DHEAS in the hypothalamus. This study provides reference values for steroid concentrations determined by gas chromatography-mass spectrometry in various regions of the aged human brain. High levels of key proteins implicated in the formation of plaques and neurofibrillary tangles were correlated with decreased brain levels of PREGS and DHEAS, suggesting a possible neuroprotective role of these neurosteroids in AD.


J Clin Endocrinol Metab 2002 Nov;87(11):5038-43

Pubertal and gender-related changes in the sympathoadrenal system in healthy children.

Weise M, Eisenhofer G, Merke DP.

Developmental Endocrinology Branch, National Institute of Child Health and Human Development/NIH, Building 10, 10 Center Drive, Bethesda, MD 20892-1932, USA.

A critical amount of body fat is necessary for the initiation of puberty, and leptin, an adipocyte-derived hormone, is necessary for pubertal development. The sympathoadrenal system modulates body fat stores and leptin secretion and interacts with adrenocortical androgen production, suggesting a possible role in sexual maturation. We studied sympathetic nerve and adrenomedullary activity at rest in 80 healthy children (ages, 5-17 yr; 37 boys and 43 girls) in relation to age, pubertal stage, gender, physical activity, body mass index, and serum levels of sex steroids, dehydroepiandrosterone sulfate, cortisol, leptin, and insulin. Plasma concentrations of the adrenomedullary hormone, epinephrine (E), and its metabolite metanephrine (MN), decreased significantly with advancing puberty and were higher in boys than in girls. E and MN correlated significantly and inversely with dehydroepiandrosterone sulfate, estradiol, testosterone, leptin, and insulin. Plasma norepinephrine, which is primarily derived from sympathetic nerve endings, increased significantly with advancing puberty and increasing testosterone levels in boys. Stepwise multiple regression analysis revealed that E was best predicted by pubertal stage and leptin, and MN by estradiol and leptin. Our data suggest that sympathoadrenal hormones may play a role in the complex process of sexual maturation. Further studies are needed to investigate a possible modulatory role of the adrenal medulla in the body weight-related timing of adrenarche and/or gonadarche.


J Clin Endocrinol Metab 2002 Nov;87(11):4935-41

Effects of oral dehydroepiandrosterone on bone density in young women with anorexia nervosa: a randomized trial.

Gordon CM, Grace E, Emans SJ, Feldman HA, Goodman E, Becker KA, Rosen CJ, Gundberg CM, LeBoff MS.

Division of Adolescent/Young Adult Medicine, Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA.

Young women with anorexia nervosa (AN) have subnormal levels of dehydroepiandrosterone (DHEA) and estrogen that may be mechanistically linked to the bone loss seen in this disease. The purpose of this study was to compare the effects of a 1-yr course of oral DHEA treatment vs. conventional hormonal replacement therapy (HRT) in young women with AN. Sixty-one young women were randomly assigned to receive oral DHEA (50 mg/d) or HRT (20 micro g ethinyl estradiol/0.1 mg levonorgestrel). Anthropometric, nutrition, and exercise data were acquired every 3 months, and bone mineral density (BMD) and body composition were measured by dual energy x-ray absorptiometry (DXA) every 6 months over 1 yr. Serum samples were obtained for measurements of hormones, proresorptive cytokines, and bone formation markers, and urine was collected for determinations of bone resorption markers at each visit. In initial analyses, total hip BMD increased significantly and similarly (+1.7%) in both groups. Hip BMD increases were positively correlated with increases in IGF-I (r = 0.44; P = 0.030) and the bone formation marker, bone-specific alkaline phosphatase increased significantly only in the DHEA treatment group (P = 0.003). However, both groups gained significant amounts of weight over the year of therapy, and after controlling for weight gain, no treatment effect was detectable. There was no significant change in lumbar BMD in either group. Both bone formation markers, bone-specific alkaline phosphatase and osteocalcin, increased transiently at 6-9 months in those subjects receiving DHEA compared with the estrogen-treated group (P < 0.05). Both DHEA and HRT significantly reduced levels of the bone resorption markers, urinary N-telopeptides (P < 0.05). There was a positive correlation between changes in IGF-I and changes in weight, body fat determined by DXA, and estradiol for both groups. In addition, patients receiving DHEA exhibited improvement on three validated psychological instruments (Eating Attitudes Test, Anorexia Nervosa Subtest, and Spielberger Anxiety Inventory). Both DHEA and HRT had similar effects on hip and spinal BMD. Over the year of treatment, maintenance of both hip and spinal BMD was seen, but there was no significant increase after accounting for weight gain. Compared with HRT, DHEA appeared to have anabolic effects, evidenced by the positive correlation between increases in hip DXA measurements and IGF-I and significant increases in bone formation markers. Both therapies significantly decreased bone resorption. Replicating results from studies of the elderly, DHEA resulted in improvements in specific psychological parameters in these young women.


Fertil Steril 2002 Nov;78(5):1001-4

Use of dexamethasone and clomiphene citrate in the treatment of clomiphene citrate-resistant patients with polycystic ovary syndrome and normal dehydroepiandrosterone sulfate levels: a prospective, double-blind, placebo-controlled trial.

Parsanezhad ME, Alborzi S, Motazedian S, Omrani G.

Division of Infertility, Department of Obstetrics and Gynecology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran.

OBJECTIVE: To evaluate the effects of short-course administration of dexamethasone (DEX) combined with clomiphene citrate (CC) in CC-resistant patients with polycystic ovary syndrome (PCOS) and normal DHEAS levels. DESIGN: Prospective, double-blind, placebo-controlled, randomized study. SETTING: Referral university hospitals. PATIENT(S): Two hundred thirty women with PCOS and normal DHEAS who failed to ovulate after a routine protocol of CC. INTERVENTION(S): The treatment group received 200 mg of CC from day 5 to day 9 and 2 mg of DEX from day 5 to day 14 of the menstrual cycle. The control group received the same protocol of CC combined with placebo. MAIN OUTCOME MEASURE(S): Follicular development, hormonal status, ovulation rate, pregnancy rate. RESULT(S): Mean follicular diameters were 18.4124 +/- 2.4314 mm and 13.8585 +/- 2.0722 mm for the treatment and control groups, respectively. Eighty-eight percent of the treatment group and 20% of the control group had evidence of ovulation. The difference in the cumulative pregnancy rate in the treatment and control groups was statistically significant. CONCLUSION(S): Hormonal levels, follicular development, and cumulative pregnancy rates improved with the addition of DEX to CC in CC-resistant patients with PCOS and normal DHEAS. This regimen is recommended before any gonadotropin therapy or surgical intervention.


Shock 2002 Nov;18(5):445-9

Dehydroepiandrosterone (DHEA) modulates the activity and the expression of lymphocyte subpopulations induced by cecal ligation and puncture.

van Griensven M, Dahlweid FM, Giannoudis PV, Wittwer T, Bottcher F, Breddin M, Pape HC.

Department of Trauma Surgery, Hannover Medical School, Germany.

Dehydroepiandrosterone (DHEA) exerts a variety of positive effects on the immunologic alterations after trauma and sepsis. We therefore measured the therapeutic efficacy of DHEA after cecal ligation and puncture (CLP) on the expression of lymphocyte subpopulations and on the delayed type hypersensitivity (DTH) reaction. Male NMRI-mice were randomly assigned to four different treatment groups. Treatment consisted of DHEA or saline (S) administration after CLP or laparotomy only. Flow cytometry was performed (CD4+, CD8+, and CD56 lymphocytes) after 96 hours. DTH-reaction, activity and mortality rate were documented. The CLP-induced reduction in activity and survival (mortality: 34/40) was significantly (p < 0.03) less sustained in CLP-DHEA (mortality: 22/40). The DTH-ratio (before vs. after secondary challenge) was significantly lowered in CLP-S (1.01 +/- 0.15) compared to CLP-DHEA (1.35 +/- 0.1) after 48 hours (p < 0.01). CLP-DHEA (22.2 +/- 7.9%) was associated with a statistically significant less sustained increase of CD56+ cells (p < 0.01) compared with CLP-S (49.0 +/- 6.9%). DHEA-treatment after CLP was associated with less reduction in the CD8+ T-lymphocyte subsets (p < 0.01 vs. all other groups). DHEA treatment after CLP was associated with fewer alterations in the changes of CD8+ and CD56, cells, and the DTH reaction compared with animals submitted to CLP without any treatment. This difference was associated with improved outcome (reactivity, mortality). These results suggest a modulation at specific immune reactions by DHEA treatment.


Am J Physiol Endocrinol Metab 2003 Feb;284(2):E390-8

Characterization and identification of steroid sulfate transporters of human placenta.

Ugele B, St-Pierre MV, Pihusch M, Bahn A, Hantschmann P.

I. Frauenklinik Innenstadt and Medizinische Klinik II Grosshadern, Klinikum der Universitat Munchen, D-80337 Munich, Germany.

Human trophoblasts depend on the supply of external precursors, such as dehydroepiandrosterone-3-sulfate (DHEA-S) and 16 alpha-OH-DHEA-S, for synthesis of estrogens. The aim of the present study was to characterize the uptake of DHEA-S by isolated mononucleated trophoblasts (MT) and to identify the involved transporter polypeptides. The kinetic analysis of DHEA-(35)S uptake by MT revealed a saturable uptake mechanism (K(m) = 26 microM, V(max) = 428 pmol x mg protein(-1) x min(-1)), which was superimposed by a nonsaturable uptake mechanism (diffusion constant = 1.2 microl x mg protein(-1) x min(-1)). Uptake of [(3)H]DHEA-S by MT was Na(+) dependent and inhibited by sulfobromophthalein (BSP), steroid sulfates, and probenecid, but not by steroid glucuronides, unconjugated steroids, conjugated bile acids, ouabain, p-aminohippurate (PAH), and bumetanide. MT took up [(35)S]BSP, [(3)H]estrone-sulfate, but not (3)H-labeled ouabain, estradiol-17beta-glucuronide, taurocholate, and PAH. RT-PCR revealed that the organic anion-transporting polypeptides OATP-B, -D, -E, and the organic anion transporter OAT-4 are highly expressed, and that OATP-A, -C, -8, OAT-3, and Na(+)-taurocholate cotransporting polypeptide (NTCP) are not or are only lowly expressed in term placental tissue and freshly isolated and cultured trophoblasts. Immunohistochemistry of first- and third-trimester placenta detected OAT-4 on cytotrophoblast membranes and at the basal surface of the syncytiotrophoblast. Our results indicate that uptake of steroid sulfates by isolated MT is mediated by OATP-B and OAT-4 and suggest a physiological role of both carrier proteins in placental uptake of fetal-derived steroid sulfates.


Eur J Clin Invest 2002 Oct;32(10):775-84

Longitudinal evolution of HIV-1-associated lipodystrophy is correlated to serum cortisol:DHEA ratio and IFN-alpha.

Christeff N, De Truchis P, Melchior JC, Perronne C, Gougeon ML.

Institut Pasteur, Hopital Raymond Poincare, Garches, CHU Bichat Claude Bernard, Paris Cedex, France.

BACKGROUND: We have previously shown that lipid alterations in HIV-1-associated lipodystrophy (LD) are correlated with decreased serum dehydroepiandosterone (DHEA) and increased cortisol:DHEA ratio and IFN-alpha levels. OBJECTIVE: To evaluate in a longitudinal study whether steroid and cytokine modifications are associated with the evolution of physical changes and lipid alterations associated with LD. METHODS: Thirty-four HIV-1-positive men were followed during 32.5 +/- 4.0 months and tested at four time-points. The patients were subdivided into five groups according to physical changes and anthropometric measurements: LD-negative, initially LD-negative becoming LD-positive, LD-positive unchanged, aggravated or improved. Serum lipids, apolipoproteins, adrenal steroids and cytokines were measured and compared with baseline values. RESULTS: (1) LD aggravation is associated with persistent elevated lipids, a decrease in serum DHEA, an increase in cortisol:DHEA ratio and persistent high levels of IFN-alpha. (2) LD improvement is associated with normalization of serum lipids, an increase in serum DHEA leading to normalization in cortisol:DHEA ratio, and normalization of IFN-alpha levels. (3) In LD-positive men evolution of VLDL cholesterol is negatively correlated with DHEA (r = -0.56, P < 0.01) and positively with cortisol:DHEA ratio (r = 0.62, P < 0.004) and with IFN-alpha (r = 0.57, P < 0.01). (4) The switch to LD is associated with a decrease in serum DHEA. (5) Patients who remained LD-negative maintained normal lipids, elevated cortisol and DHEA, and normal cortisol:DHEA ratio and normal levels of IFN-alpha. CONCLUSIONS: This study indicates that cortisol:DHEA ratio and serum IFN-alpha levels are closely associated with clinical evolution and atherogenic lipid alterations in LD.


Metabolism 2002 Nov;51(11):1458-62

Low circulating estradiol and adrenal androgens concentrations in men on glucocorticoids: a potential contributory factor in steroid-induced osteoporosis.

Hampson G, Bhargava N, Cheung J, Vaja S, Seed PT, Fogelman I.

Department of Chemical Pathology, St Thomas' Hospital, London, UK.

Reductions in circulating estradiol concentrations could be implicated in the pathogenesis of steroid-induced osteoporosis (SIOP) in men. We assessed serum estradiol and adrenal androgens (dehydroepiandrosterone sulfate [DHEAS] and androstenedione) in 77 men (group A: idiopathic osteoporosis [IOP], n = 38, aged [mean +/- SD] 57.7 +/- 12.1 years; group B: SIOP, n = 39, aged 55.3 +/- 13.1 years). We also studied the relationship between bone mineral density (BMD) and serum estradiol in the group of men with SIOP. In group B, we observed a higher prevalence of low serum testosterone concentrations (<9.0 nmol/L) (P =.0052), which was significantly correlated with steroid dosage (r = -0.42, P =.0089) and estradiol concentrations (r = 0.42, P =.012). There was a significant positive association between BMD at the lumbar spine and serum estradiol (P =.004) in the men with SIOP (group B). A high proportion of subjects had low serum estradiol concentrations (<48 pmol/L) in both groups (group A: 44.7 %, group B: 36 %). Serum adrenal androgens concentrations were also significantly suppressed in group B (serum androstenedione-group A: 4.99 +/- 1.8; Group B: 2.1 +/- 1.6 nmol/L; P =.0001). Serum DHEAS was undetectable in 59% of patients in group B versus 6% in group A (P =.001). Reductions in androstenedione also correlated with steroid dosage (r = -0.35, P =.01). In conclusion, the data show that adrenal androgens synthesis is markedly suppressed in men with SIOP. The clinical relevance of this finding remains to be determined. This study also shows a positive association between serum estradiol and BMD and a high prevalence of low serum estradiol in men with SIOP. Low serum estradiol may contribute to bone loss in men with SIOP.


Int J Sports Med 2002 Oct;23(7):510-5

Cortisol, DHEA, Performance and Training in Elite Swimmers.

Chatard JC, Atlaoui D, Lac G, Duclos M, Hooper S, Mackinnon L.

Laboratoire de Physiologie, GIP Exercice, Faculte de Medecine Jean Monnet, Saint-Etienne, France.

Salivary cortisol (C) and DHEA concentrations were measured in 9 elite swimmers (4 female and 5male) over a 37-week period, 5 to 12 times per swimmer, before 68 competitions. For female and male swimmers, no significant relationship was found between C, DHEA and performance. For the whole group, C was negatively correlated with week number of training (r = -0.31, p < 0.01). The incorporation of the cumulated distance swum as a second variable in the regression increased r to 0.56 (p < 0.01). The higher the cumulated distance swum, the higher C. No significant relationship was found between DHEA and distance swum. For individual swimmers, 3 of 4 females showed a significant negative relationship between C and cumulated dry-land training. No equivalent relationship was found for DHEA. The 2 males practicing dry-land training showed a significant and negative relationship between DHEA and cumulated dry-land training. No equivalent relationship was found for C. Thus, C and DHEA were not good predictors of swimming performance. C for individual females, and DHEA for individual males were considered useful markers for dry-land training stress.


Horm Res 2002;58(5):215-22

Increased adrenal androgen levels in patients with prader-willi syndrome are associated with insulin, igf-I, and leptin, but not with measures of obesity.

L'Allemand D, Eiholzer U, Rousson V, Girard J, Blum W, Torresani T, Gasser T.

Foundation Growth Puberty Adolescence, Zurich, Switzerland.

Background/Aim: Since hyperandrogenism in simple obesity is assumed to arise from hyperinsulinism and/or increased insulin-like growth factor I (IGF-I) or leptin levels, we examined how in patients with Prader-Willi syndrome (PWS), the most frequent form of syndromal obesity, the accelerated adrenarche can be explained despite hypothalamic-pituitary insufficiency with low levels of insulin and IGF-I. Methods: In 23 children with PWS and a mean age of 5.6 years, height, weight, fat mass, fasting insulin concentration, insulin resistance (by HOMA-R; see text), and leptin and IGF-I levels were determined to test whether they explain the variance of the levels of dehydroepiandrosterone (DHEA) and its sulfate (DHEAS), of androstenedione, and of cortisol before and during 42 months of therapy with growth hormone. Results: The baseline DHEAS, DHEA, and androstenedione concentrations were increased as compared with age-related reference values, whereas the cortisol level was always normal. During growth hormone treatment, the DHEA concentration further rose, and the cortisol level decreased significantly. The insulin and IGF-I concentrations were low before therapy, while fat mass and leptin level were elevated. The hormonal covariates provided alone or together between 24 and 60% of the explanation for the variance of adrenal androgen levels, but the anthropometric variables did not correlate with them. Conclusions: In children with PWS, elevated androgen levels correlate with hormones that are usually associated with adiposity. However, the lack of direct correlations between disturbed body composition and androgen levels as well as the increased sensitivity to insulin and IGF-I are abnormalities specific to PWS, potentially caused by the underlying hypothalamic defect.


Steroids 2002 Nov;67(12):967-77

Steroid and sterol 7-hydroxylation: ancient pathways.

Lathe R.

Division of Biomedical Sciences, University of Edinburgh, George Square, EH9 9XD, Edinburgh, UK

B-ring hydroxylation is a major metabolic pathway for cholesterols and some steroids. In liver, 7alpha-hydroxylation of cholesterols, mediated by CYP7A and CYP39A1, is the rate-limiting step of bile acid synthesis and metabolic elimination. In brain and other tissues, both sterols and some steroids including dehydroepiandrosterone (DHEA) are prominently 7alpha-hydroxylated by CYP7B. The function of extra-hepatic steroid and sterol 7-hydroxylation is unknown. Nevertheless, 7-oxygenated cholesterols are potent regulators of cell proliferation and apoptosis; 7-oxygenated derivatives of DHEA, pregnenolone, and androstenediol can have major effects in the brain and in the immune system. The receptor targets involved remain obscure. It is argued that B-ring modification predated steroid evolution: non-enzymatic oxidation of membrane sterols primarily results in 7-oxygenation. Such molecules may have provided early growth and stress signals; a relic may be found in hydroxylation at the symmetrical 11-position of glucocorticoids. Early receptor targets probably included intracellular sterol sites, some modern steroids may continue to act at these targets. 7-Hydroxylation of DHEA may reflect conservation of an early signaling pathway.


Crit Care. 2002; 6 (5): 434–438

Decreased levels of dehydroepiandrosterone sulphate in severe critical illness: a sign of exhausted adrenal reserve?

Beishuizen A, Thijs LG, Vermes I.

Department of Intensive Care, VU University Medical Center, Amsterdam, The Netherlands.

INTRODUCTION: Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are pleiotropic adrenal hormones with immunostimulating and antiglucocorticoid effects. The present study was conducted to evaluate the time course of DHEAS levels in critically ill patients and to study their association with the hypothalamic-pituitary-adrenal axis. MATERIALS AND METHOD: This was a prospective observational clinical and laboratory study, including 30 patients with septic shock, eight patients with multiple trauma, and 40 age- and sex-matched control patients. We took serial measurements of blood concentrations of DHEAS, cortisol, tumour necrosis factor-alpha and IL-6, and of adrenocorticotrophic hormone immunoreactivity over 14 days or until discharge/death. RESULTS: On admission, DHEAS was extremely low in septic shock (1.2 +/- 0.8 mol/l) in comparison with multiple trauma patients (2.4 +/- 0.5 micromol/l; P < 0.05) and control patients (4.2 +/- 1.8; P < 0.01). DHEAS had a significant (P < 0.01) negative correlation with age, IL-6 and Acute Physiology and Chronic Health Evaluation II scores in both patient groups. Only during the acute phase did DHEAS negatively correlate with dopamine. Nonsurvivors of septic shock (n = 11) had lower DHEAS levels (0.4 +/- 0.3 micromol/l) than did survivors (1.7 +/- 1.1 micromol/l; P < 0.01). The time course of DHEAS exhibited a persistent depletion during follow up, whereas cortisol levels were increased at all time points. CONCLUSION: We identified extremely low DHEAS levels in septic shock and, to a lesser degree, in multiple trauma patients as compared with those of age- and sex-matched control patients. There appeared to be a dissociation between DHEAS (decreased) and cortisol (increased) levels, which changed only slightly over time. Nonsurvivors of sepsis and patients with relative adrenal insufficiency had the lowest DHEAS values, suggesting that DHEAS might be a prognostic marker and a sign of exhausted adrenal reserve in critical illness.

Introduction

Dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are the most abundant steroids secreted by the adrenal cortex [1]. The concentration of DHEA in the blood oscillates in parallel with cortisol, in response to levels of adrenocorticotrophic hormone (ACTH), but without feedback control at the hypothalamic–pituitary level.

The physiological role and biological actions of DHEA(S) are not well known but studies in humans suggest a positive impact on sense of well-being [2], and DHEA has recently been recognized as a potent modulator of the immune response [1]. DHEA improved host defences by restoring immune cell function and reversed susceptibility to infection [3].

Serum DHEA(S) concentration was low in patients with primary adrenal insufficiency, and short-term oral DHEA replacement improved the clinical condition of these patients [2,4]. Functional or relative adrenal insufficiency frequently occurs in critically ill patients, with possible fatal consequences, although diagnostic criteria for this entity still pose problems [5]. We hypothesize that the serum DHEAS level has utility as a diagnostic tool and a prognostic marker in such patients. Furthermore, low serum concentrations of DHEAS might be a more sensitive marker of hypothalamic–pituitary–adrenal (HPA) hypofunction than is glucocorticoid secretion.

The present study was conducted to evaluate the time course of DHEAS levels (an immunostimulator) as compared with those of cortisol (an immunosuppressor), ACTH (an inducer of DHEAS) and cytokines (stimulators of the HPA axis) in patients with critical illness and in age- and sex-matched control patients.

Discussion

We found a clear dissociation between high blood levels of cortisol and extremely low levels of DHEAS in critically ill patients in both the acute and prolonged phases. Parker and coworkers [7] demonstrated such a divergence in adrenal steroid secretion; in that study serum cortisol was increased in adult men with burn injuries, whereas serum DHEAS was reduced. Luppa and coworkers [8] studied serum androgens in a large group of critically ill patients and also found markedly decreased DHEAS levels in both males and females, mainly in those patients with a prolonged clinical course. These data indicate a shift in adrenal steroid synthesis away from mineralocorticoids and androgens and toward excessive cortisol production. The dissociation between blood levels of cortisol and DHEAS appears to be a contradiction because both hormones are synthesized and secreted mainly by the adrenal cortex. However, DHEAS is produced mainly in the zona reticularis of the adrenal cortex, possibly indicating that a differential alteration in the cortical zone is responsible for DHEAS deficiency during severe critical illness.

The sustained hypercortisolism, as opposed to the marked DHEAS depletion, during severe critical illness could theoretically result in an imbalance between immunosuppressive and immunostimulatory pathways, and may therefore play a role in susceptibility to infectious complications [1].

Interestingly, we found the lowest DHEAS and the highest cortisol levels in nonsurvivors and the most severely ill patients, indicating that the DHEAS : cortisol ratio might be a prognostic indicator for outcome of critical illness, in particular septic shock. Interpretation of cortisol levels measured in seriously ill patients is difficult. Serum cortisol levels that are regarded as high in control individuals may be inappropriately low in patients who are severely ill. We recently showed that functional or relative adrenal insufficiency can be present in critically ill patients despite 'high' initial serum cortisol levels [5]. By using the low-dose ACTH stimulation test and Thorn test, we demonstrated the relative lack of adrenocortical response to extra stimulation by ACTH in some critically ill patients, because their HPA axis is already maximally stimulated. In the present study the low-dose ACTH test identified four patients out of eight with a clinical suspicion for relative adrenal insufficiency. These patients had very low serum concentrations of DHEAS, which may also be a sign of limited adrenocortical reserve arising during the course of critical illness [6].

In both septic and trauma patients we found a similar degree of stimulation of the HPA axis; however, patients with septic shock were more severely ill than were patients with multiple trauma, as reflected by their APACHE II scores, and TNF-a and IL-6 levels. One could argue that this also indicates a state of exhausted adrenal reserve.

We found a relation between dopamine use and DHEAS levels, but only during the acute phase. Therefore, acute depletion of DHEAS might reflect the liberal use of dopamine [9]. In addition, we found a negative correlation between IL-6 and DHEAS during the acute phase. In healthy persons, serum IL-6 correlated inversely with DHEAS, and DHEA administration led to inhibition of IL-6 secretion from monocytes, indicating a functional link between DHEAS and IL-6 [10]. IL-6 can act synergistically with ACTH on the adrenal glands to release cortisol [11]. Therefore, IL-6 may be an important regulator of DHEAS in (acute) critical illness. However, the dopamine dosage and IL-6 levels decreased significantly over time whereas DHEAS concentrations remained low, suggesting different mechanisms for the prolonged DHEAS depletion during critical illness.

We found a negative correlation between age and DHEAS concentrations. DHEAS concentrations exhibit a biphasic time course following the onset of adrenarche, reaching a peak between the ages 20 and 30 years, and with the greatest decline occurring by age 50–60 years [12,13]. This dramatic age-related reduction might be caused by a specific defect in the desmolase activity in the reticular zone of the adrenal gland. Most of patients studied here, including control patients, were aged approximately 50–60 years.

In conclusion, we found extremely low DHEAS levels in virtually all critically ill patients, in both septic shock and multiple trauma. DHEAS depletion was associated with a worse outcome and represents a prognostic marker. Acute depletion of DHEAS is probably related to the use of dopamine and high IL-6 levels. The prolonged depletion of DHEAS might reflect an exhausted adrenal adaptation. Whether DHEA should be administered in DHEAS-deficient states remains to be elucidated. However, theoretically, beneficial effects on immunity, susceptibility for infections and well-being may be expected.


J Neurochem 2002 Nov;83(3):713-26

Characterization of the dehydroepiandrosterone (DHEA) metabolism via oxysterol 7alpha-hydroxylase and 17-ketosteroid reductase activity in the human brain.

Steckelbroeck S, Watzka M, Lutjohann D, Makiola P, Nassen A, Hans VH, Clusmann H, Reissinger A, Ludwig M, Siekmann L, Klingmuller D.

Department of Clinical Biochemistry, University of Bonn, Sigmund-Freud-Strasse 25, D-53105 Bonn, Germany.

Dehydroepiandrosterone and its sulphate are important factors for vitality, development and functions of the CNS. They were found to be subjects to a series of enzyme-mediated conversions within the rodent CNS. In the present study, we were able to demonstrate for the first time that membrane-associated dehydroepiandrosterone 7alpha-hydroxylase activity occurs within the human brain. The cytochrome P450 enzyme demonstrated a sharp pH optimum between 7.5 and 8.0 and a mean KM value of 5.4 micro m, corresponding with the presence of the oxysterol 7alpha-hydroxylase CYP7B1. Real-time RT-PCR analysis verified high levels of CYP7B1 mRNA expression in the human CNS. The additionally observed conversion of dehydroepiandrosterone via cytosolic 17beta-hydroxysteroid dehydrogenase activity could be ascribed to the activity of an enzyme with a broad pH optimum and an undetectably high KM value. Subsequent experiments with cerebral neocortex and subcortical white matter specimens revealed that 7alpha-hydroxylase activity is significantly higher in the cerebral neocortex than in the subcortical white matter (p < 0.0005), whereas in the subcortical white matter, 17beta-hydroxysteroid dehydrogenase activity is significantly higher than in the cerebral neocortex (p < 0.0005). No sex differences were observed. In conclusion, the high levels of CYP7B1 mRNA in brain tissue as well as in a variety of other tissues in combination with the ubiquitous presence of 7alpha-hydroxylase activity in the human temporal lobe led us to assume a neuroprotective function of the enzyme such as regulation of the immune response or counteracting the deleterious effects of neurotoxic glucocorticoids, rather than a distinct brain specific function such as neurostimulation or neuromodulation.


Clin Endocrinol (Oxf) 2002 Nov;57(5):677-83

Dehydroepiandrosterone, 17alpha-hydroxyprogesterone and aldosterone responses to the low-dose (1 micro g) ACTH test in subjects with preclinical adrenal autoimmunity.

Laureti S, Candeloro P, Aglietti MC, Giordano R, Arvat E, Ghigo E, Santeusanio F, Falorni A.

Department of Internal Medicine and Endocrine and Metabolic Sciences, University of Perugia, Italy.

OBJECTIVE: The appearance of 21-hydroxylase autoantibodies (21OHAbs) identifies subjects with preclinical adrenal insufficiency. In 21OHAb-positive subjects, the adrenocortical function is best evaluated by peak cortisol (F) levels after the low-dose (1 micro g) ACTH stimulation test (LDT). No information is currently available on the correlation between F and other adrenocortical hormone responses to the LDT in subjects with an ongoing autoimmune adrenal process. In this study, we tested the hypothesis that the dehydroepiandrosterone (DHEA), 17alpha-hydroxyprogesterone (17OHP) and aldosterone (A) responses to the LDT are consensual to that of F during the preclinical phase of autoimmune adrenal insufficiency. DESIGN AND PATIENTS: We studied 12 subjects positive for 21OHAb, in the absence of clinical signs of adrenal insufficiency. On the basis of peak F levels after the LDT, and according to the lower level of normal observed in 15 healthy volunteers (510.4 nmol/l), patients were subdivided into two groups: group A, n = 6 subjects with normal F response; and group B, n = 6 subjects with impaired F response. Results were expressed as absolute delta increase (Delta) between peak and basal levels. RESULTS: DeltaF was significantly higher in group A (314.5 +/- 115.8 nmol/l) than in group B (151.7 +/- 88.2 nmol/l) (P = 0.041). DeltaDHEA and Delta17OHP were also significantly higher in group A (17.0 +/- 13.5 nmol/l and 6.1 +/- 4.4 nmol/l, respectively) than in group B (0.69 +/- 2.25 nmol/l and 1.9 +/- 1.7 nmol/l, respectively) (P = 0.002 and P = 0.041). The difference in DeltaA between the two groups did not reach statistical significance (group A 321.8 +/- 272.0 pmol/l vs. group B 157.0 +/- 154.0 pmol/l). DeltaDHEA, Delta17OHP and DeltaA tended to correlate positively with DeltaF (P = 0.039, P = 0.039 and P = 0.044, respectively), but the correlations did not reach significance after correction of the P-value. CONCLUSIONS: Our study demonstrates a high concordance between F and DHEA, 17OHP and A responses to the LDT in subjects with preclinical adrenal autoimmunity, thus strengthening the concept that the LDT is an accurate test to identify early adrenal dysfunction.


Scand J Clin Lab Invest 2002;62(5):361-8

Diurnal rhythm and effects of oral contraceptives on serum dehydroepiandrosterone sulfate (DHEAS) are related to alterations in serum albumin rather than to changes in adrenocortical steroid secretion.

Carlstrom K, Karlsson R, Von Schoultz B.

Department of Obstetrics and Gynecology, Clinical Research Center, Karolinska Institutet, Huddinge University Hospital, Sweden.

Dehydroepiandrosterone sulfate (DHEAS), which is of almost exclusive adrenal origin, is important for the androgen status in women and prepubertal children, and DHEAS assays are used in the investigation of hyperandrogenism. There are conflicting reports concerning a diurnal variation in serum DHEAS. Although of adrenocortical origin, serum DHEAS levels are decreased by oral contraceptives (OCs). DHEAS is strongly bound to serum albumin and has a very low metabolic clearance rate. The present study was performed in order to investigate whether a diurnal variation in serum DHEAS exists and, if so, whether this diurnal variation and the decreased DHEAS levels following OC use are related to alterations in adrenocortical steroids or to changes in serum albumin. Serum concentrations of DHEAS, dehydroepiandrosterone (DHEA), cortisol and albumin were determined in blood samples taken every half hour over a 24-h period in 10 healthy women before and during use of combined OCs. Significant and frequently synchronous diurnal variations in serum DHEAS and albumin were found before as well as during OC use. These variations were not synchronous with the diurnal variation in DHEA. OCs significantly decreased serum DHEAS and albumin levels. A multiple regression analysis showed changes in albumin to be the most decisive factor for the diurnal variation as and for OC-induced changes in DHEAS. Changes in serum DHEAS during the day and following OC use are related to alterations in its main binding protein, serum albumin, rather than to changes in adrenocortical steroid secretion.


J Pediatr Endocrinol Metab 2002 Sep-Oct;15(8):1173-81

Precocious puberty: clinical and endocrine profile and factors indicating neurogenic precocity in Indian children.

Bajpai A, Sharma J, Kabra M, Kumar Gupta A, Menon PS.

Department of Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New Delhi.

The objective of this study was to evaluate the clinical and endocrine profile of patients with precocious puberty followed up in a tertiary care hospital. Records of 140 patients (114 girls, 26 boys) with precocious puberty were reviewed. Clinical features including age of onset, stage of pubertal development, presenting symptoms, features suggestive of CNS involvement and family history were analyzed. Endocrine investigations included basal and GnRH-stimulated levels of LH and FSH as well as 17OHP, DHEA, hCG and thyroid profile. Abdominal and pelvic ultrasonography and CNS imaging were correlated with clinical features. Girls outnumbered boys in this series (4.4:1). Neurogenic central isosexual precocious puberty (CIPP) was more common in boys (10 out of 18, 55.6%) than girls (16 out of 77, 20.8%). The most common cause of neurogenic CIPP was hypothalamic hamartoma present in five girls and four boys. Other causes of neurogenic CIPP included neurotuberculosis, pituitary adenoma, hydrocephalus, post radiotherapy, CNS tumors and malformations. Peripheral precocious puberty (PPP) was secondary to adrenal causes in boys and ovarian cysts in girls. Benign variants of precocious puberty, such as premature thelarche and premature adrenarche, were present in 23 and six girls, respectively. Hypothyroidism was present in four girls and McCune-Albright syndrome in one girl. Girls with neurogenic CIPP had a lower age of onset as compared to idiopathic CIPP (3.6 +/- 2.7 years vs 5.4 +/- 2.5 years, p = 0.014). The lowest age of onset was seen in girls with hypothalamic hamartoma (1.6 +/- 0.9 years). Forty-seven girls with CIPP (seven neurogenic and 40 idiopathic) presented after the age of 6 years. Features of CNS involvement, in the form of seizures, mental retardation, raised intracranial tension or focal neurological deficits, were present in seven girls (43.8%) and four boys (40%), and gelastic seizures were present in three children. Girls with CIPP had greater bone age advancement (3.4 +/- 1.5 years) and negative height standard deviation for bone age (-2.7 +/- 1.5) than those with PPP (1.9 +/- 1.6 years and -1.3 +/- 1.3) and premature thelarche (0.4 +/- 0.4 years and -0.8 +/- 0.8). Patients with neurogenic CIPP had significantly higher levels of baseline and GnRH-stimulated levels of LH and FSH and LH:FSH ratio than those with idiopathic CIPP. Occurrence of neurogenic CIPP in seven girls with an age of onset after 6 years emphasizes the need for CNS imaging in these girls contrary to the current recommendations. The fact that 65.6% cases of idiopathic CIPP presented after the age of 6 years raises the possibility that these patients may be physiological variants of normal puberty. Pointers to neurogenic CIPP included early age of onset in girls, clinical features of CNS involvement, and elevated basal and stimulated LH levels and LH:FSH ratio.


Int J Cancer 2002 Nov 10;102(2):172-8

Relationship between serum hormone concentrations, reproductive history, alcohol consumption and genetic polymorphisms in pre-menopausal women.

Garcia-Closas M, Herbstman J, Schiffman M, Glass A, Dorgan JF.

Division of Cancer Epidemiology and Genetics, National Cancer Institute/NIH, 6120 Executive Boulevard, Bethesda, MD 20852-7234, USA.

Reproductive characteristics, alcohol intake and polymorphisms in genes encoding sex-steroid metabolizing enzymes might influence the risk of hormone-related cancers by changing circulating concentrations of sex hormones. The relationship between these factors and serum concentrations of estradiol, progesterone, androstenedione, testosterone and DHEA was evaluated in a cross-sectional study of 218 pre-menopausal women from Kaiser Permanente Health Plan in Portland, Oregon. Risk factor information was obtained from questionnaires and hormone serum concentrations were determined by radioimmunoassays. Genotypes for CYP11A 5'UTR(tttta)n, CYP17 5'-UTR -34 T>C, CYP19 IVS4(ttta)n, CYP1B1 (L432V and S453N) and COMT (V158M) were determined from genomic DNA samples. Increasing number of full-term pregnancies was associated with a significant decrease in late-follicular progesterone levels (p-trend = 0.03). Increasing alcohol consumption was associated with higher estradiol levels averaged through the menstrual cycle (p-trend = 0.009) and higher progesterone levels during luteal phase (p-trend = 0.04). Androstenedione and testosterone levels were higher among light to moderate drinkers compared to non-drinkers, although we only observe a significant trend with increasing levels of alcohol consumption for androstenedione. Women heterozygous or homozygous for the CYP1B1 L432V or the S453N polymorphisms had increased luteal estradiol levels (p-value = 0.04 for L432V and 0.04 for S453N). None of the other factors evaluated was significantly associated with serum concentration of hormones. In conclusion, results from this cross-sectional study of pre-menopausal women provide support for an association between light to moderate alcohol intake and elevated levels of estrogen and androgen levels. Our data suggest that circulating levels of progesterone might be related to parity and alcohol consumption, however the biological plausibility of the observed associations is unclear. We found little support for an influence of the evaluated genetic polymorphisms in the steroid synthesis and metabolism pathway on serum hormone levels, except for a possible effect of the CYP1B1 L432V and S453N polymorphisms on serum estradiol levels.


J Cell Physiol 2002 Nov;193(2):208-18

Polarized glucose transporters and mRNA expression properties in newly developed rat syncytiotrophoblast cell lines, TR-TBTs.

Kitano T, Iizasa H, Terasaki T, Asashima T, Matsunaga N, Utoguchi N, Watanabe Y, Obinata M, Ueda M, Nakashima E.

Department of Pharmaceutics, Kyoritsu College of Pharmacy, Tokyo, Japan.

In this study, we have established new syncytiotrophoblast cell lines (TR-TBTs) from the recently developed transgenic rat harboring temperature-sensitive simian virus 40 large T-antigen gene (Tg-rat). Four conditionally immortalized syncytiotrophoblast cell lines (TR-TBT 18d-1 approximately 4) were obtained from pregnant Tg-rats at gestational day 18. These cell lines had a syncytium-like morphology, could be prepared as monolayers, expressed cytokeratins and rat syncytiotrophoblast markers, and exhibited apical or basal GLUT1 localizations and apical GLUT3 localizations. TR-TBTs express large T-antigen and grow well at 33 degrees C with a doubling time of about 30 h. TR-TBTs have processes for the uptake of dehydroepiandrosteron-3-sulfate (DHEAS) and these are predominantly located on the basal side, and this is the first report of an in vitro model of blood placental barrier (BPB) able to incorporate DHEAS. Therefore, TR-TBTs are an appropriate in vitro model for investigating carrier-mediated transport functions at the BPB. Moreover, TR-TBTs express betaine/GABA transporter (GAT-2/BGT-1), concentrative nucleoside transporter 2 (CNT2), equilibrative nucleoside transporter 1 (ENT1), and ENT2 and the expression of these transporters has been reported in blood-brain barrier (BBB). Thus, the expression patterns of nucleoside and neurotransmitter transporters examined are quite similar in both the BPB and BBB.


Psychoneuroendocrinology 2002 Nov;27(8):907

Basal plasma hormone levels in depressed perimenopausal women.

Schmidt P, Murphy J, Haq N, Danaceau M, St Clair L.

NIMH, Building 10, Room 3N-238, 10 Center Drive MSC 1276, 20892-1276, Bethesda, MD, USA

BACKGROUND: An association between abnormal changes in reproductive endocrine function during the perimenopause and the onset of depression in some women has been suggested but remains controversial.METHODS: We examined basal plasma hormone levels in two samples of women with well characterized, first onset depression (major or minor) during the perimenopause and matched comparison groups of asymptomatic women. Results were compared by analysis of variance.RESULTS: No significant diagnosis-related differences were observed in plasma hormone measures of the following: follicle stimulating hormone (FSH), luteinizing hormone (LH), estradiol (E2), estrone (E1), total (T) or free testosterone (FT), or the E2/LH ratio. We did identify significantly lower morning plasma dehydroepiandrosterone (DHEA) and its sulphated metabolite DHEA-S (but not cortisol) levels in the depressed women compared to the non-depressed comparison group. Women with hot flushes (regardless of the presence of depression) were significantly older than women without flushes, had significantly higher plasma levels of FT, LH and FSH, and had significantly lower E2/LH ratios.CONCLUSIONS: Women with first onset depression during the perimenopause are not distinguished from controls on the basis of basal hormone measures of ovarian estrogens, testosterone, or gonadotropins. However, perimenopause-related changes in E2 may interact with low levels of DHEA in some women to increase their vulnerability to develop depression. In contrast to perimenopause-related vasomotor symptoms, depression during the perimenopause is not associated with a simple hormone deficiency state. The relatively low levels of E2 and E1 in the depressed women may have met statistical significance in a much larger and homogenous sample.


J Microbiol Immunol Infect 2002 Sep;35(3):199-202

Dehydroepiandrosterone (DHEA) attenuates allergic airway inflammation in Dermatophagoides farinae-sensitized mice.

Yu CK, Liu YH, Chen CL.

Department of Microbiology and Immunology, College of Medicine, National Cheng Kung University, Tainan, Taiwan, ROC.

Dehydroepiandrosterone or DHEA, an androgen abundant in circulation, has important immunomodulating effects. In this study the therapeutic effect of dehydroepiandrosterone on established allergic inflammati