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Inhibition of 3'azido-3'deoxythymidine-resistant HIV-1 infection by dehydroepiandrosterone in vitro

BIOCHEM. BIOPHYS. RES. COMMUN. (USA), 1994, 201/3 (1424-1432)

Human immunodeficiency virus type 1 (HIV-1) isolated from patients with acquired immunodeficiency syndrome (AIDS) shows resistance to 3'azido-3' deoxythymidine (AZT) after one or two years of treatment. AZT also has significant toxic side effects, further limiting its use in the therapy of HIV-1-infected individuals. Dehydroepiandrosterone (DHEA) has been shown to have a broad spectrum of biological functions, to be bioavailable orally and to be relatively nontoxic. Epidemiological studies provide evidence that reduced serum levels of DHEA are related to the progression of AIDS in HIV-1 infection. DHEA has also been shown to inhibit HIV-1 replication in vitro and block HIV-1 reactivation from chronically infected cell lines. However, there have been no reports on the ability of DHEA to inhibit the replication of AZT-resistant strains of HIV-1. We investigated whether DHEA treatment could inhibit replication of AZT-resistant strains of HIV-1. Addition of DHEA to MT-2 cell cultures infected with either AZT-sensitive or AZT-resistant isolates of HIV-1 resulted in dose-dependent inhibition of HIV-1-induced cytopathic effect and suppression of HIV-1 replication as measured by accumulation of reverse transcriptase activity. At a concentration as low as 50 microM, DHEA reduced AZT-resistant HIV-1 replication over 50 percent as measured by cytopathic effect and accumulation of reverse transcriptase activity. This study provides evidence that DHEA can inhibit the replication of AZT-resistant as well as wild-type HIV-1. Since the main targets for DHEA are metabolic and cellular signaling pathways leading to HIV-1 replication- activation, DHEA should be effective against multidrug-resistant strains of HIV-1. Combined with recently discovered immunoregulatory properties, the finding that DHEA is able to inhibit replication of both wild-type and AZT- resistant HIV-1 suggests that in vivo DHEA may have a much broader spectrum of action than originally anticipated.

Inhibition of HIV-1 latency reactivation by dehydroepiandrosterone (DHEA) and an analog of DHEA

AIDS RES. HUM. RETROVIRUSES (USA), 1993, 9/8 (747-754)

The initial infection with human immunodeficiency virus type 1 (HIV-1) in most individuals usually results in the establishment of a latent or chronic infection before eventual progression toward acquired immunodeficiency syndrome. HIV-1 can also establish a latent or persistent infection in some T cell lines that show minimal constitutive virus expression. However, activation of the T cell lines leading to enhanced HIV-1 replication can be induced by antigens, mitogens, and cytokines (tumor necrosis factor alpha (TNF- alpha), interleukin 1, and interleukin-2). Various gene products from other viruses (HTLV-1, HSV, EBV, CMV, HBV, and HHV-6) can also enhance HIV-1 long terminal repeat (LTR)-driven reporter gene activity. On the basis of these observations, it has been proposed that reactivation of latent HIV-1 harbored in chronically infected T lymphocytes, monocytes, or macrophages plays an important role in the pathogenesis of AIDS. So far, there are no drugs or therapy available that can provide protection against HIV-1 latency reactivation. ACH-2, derived from a human T cell line (CEM), is chronically infected with HIV-1, with low levels of constitutive virus expression. ACH-2 can be converted to productive infection by stimulation of the cells with 12- O-tetradecanoylphorbol-13-acetate (TPA), mitogen or cytokines (TNF-alpha), or infection with HSV. Therefore the ACH-2 cell line is a good candidate for studying the effects of drugs on HIV-1 activation. Previously, we have reported that DHEA and synthetic analogs of DHEA can be modest inhibitors of HIV-1 IIIB replication in phytohemagglutinin-stimulated peripheral blood lymphocyte cultures. Here we report that DHEA and a synthetic analog of DHEA, 8354, can also reduce HIV-1 latency reactivation in the ACH-2 cell line. The inhibitory effect is not due to cytotoxicity of these drugs. Treatment with DHEA or 8354 resulted in downregulation of HIV-1 latency reactivation in a TPA- or TNF-alpha-stimulated ACH-2 cell line as measured by syncytium formation and accumulation of reverse transcriptase activity. The mechanisms of inhibition are not clear, but evidence suggests that reduction of NF-kappaB activation plays a role.

Evidence for changes in adrenal and testicular steroids during HIV infection

J. ACQUIRED IMMUNE DEFIC. SYNDR. (USA), 1992, 5/8 (841-846)

The serum levels of cortisol, progesterone, 17alpha-hydroxyprogesterone, dehydroepiandrosterone (DHEA), DHEA sulfate, androstenedione (Delta4), testosterone (T), estrone, and estradiol of HIV + men and HIV - men were determined by radioimmunoassay. The cortisol, 17alpha-hydroxyprogesterone, and estrone levels of all HIV + subjects were 35-55% (p < 0.01), 25-90% (p < 0.01), and 30-50% (p < 0.01) higher, respectively, than those of controls. Androgen levels were very high in Centers for Disease Control (CDC) groups II and III of HIV infection (DHEA, 85%, p < 0.01; Delta4, 60%, p < 0.01; T, 30%, p < 0.05), but much lower in group IVC1 and IVC2. The estradiol levels were significantly elevated only in group IVD (50%, p < 0.01) and group IVC2 (25%, NS). These results indicate that serum hormone levels are correlated with HIV infection group. The changes in steroid hormone concentrations during the development of HIV infection may have important implications for the immune response of patients. The high cortisol and estrone levels of all groups, the elevated androgen levels in asymptomatic groups, and the low androgens in AIDS patients may form part of the complex network of immunomodulatory factors.

Dehydroepiandrosterone as predictor for progression to AIDS in asymptomatic human immunodeficiency virus-infected men

J. INFECT. DIS. (USA), 1992, 165/3 (413-418)

The steroid hormone dehydroepiandrosterone (DHEA) has been reported to protect against certain viral infections in animal models and to be a modest inhibitor of human immunodeficiency virus type 1 (HIV-1) infection in vitro. Serum DHEA levels were determined in 41 asymptomatic HIV-1-seropositive subjects, who progressed to AIDS within 5 years after entering a cohort study, in 41 HIV-1-seropositive controls, who remained asymptomatic, and in 41 HIV-1-seronegative controls. At entry, DHEA levels were higher in the seronegative group (median, 13.3 nmol/l) than in either the seropositive nonprogressors (median, 9.2 nmol/l; P = .01) or the progressors (median, 7.2 nmol/l; P < .001). DHEA levels in the progressors similar5 months before the diagnosis of AIDS were lower than the levels in the nonprogressors after the same follow-up (median, 5.6 vs. 8.8 nmol/l; P = .007). DHEA levels <7 nmol/l and CD4+ cell counts <0.5 x 109/l both proved to be independent predictors for disease progression in HIV-1-infected men.

Decreased serum dehydroepiandrosterone is associated with an increased progression of human immunodeficiency virus infection in men with CD4 cell counts of 200-499

J. INFECT. DIS. (USA), 1991, 164/5 (864-868)

Dehydroepiandrosterone (DHEA) and its interconvertible sulfate derivative (DHEA-S) are human androgenic steroids that have been reported to inhibit viral expression and have been associated with a decreased risk of cancer. The relationship between serum DHEA and DHEA-S levels and subsequent progression to AIDS was investigated in a sample of human immunodeficiency virus (HIV)-infected men from the San Francisco Men's Health Study followed prospectively since 1984. Among 108 men seropositive for HIV at study entry and with CD4 lymphocyte counts of 200-499 microl 24 months later, serum DHEA levels below the lower limit of normal (<180 ng/dl) at this later date were predictive of subsequent progression to AIDS (relative hazard = 2.34; 95% confidence interval = 1.18-4.63; P = .01) after controlling for hematocrit, age, and log absolute CD4 cell number in a Cox proportional hazards model. This is the first large prospective cohort in which an endocrinologic variable has been observed to independently predict progression to AIDS. These observations, in addition to recent in vitro data, suggest that DHEA might have a protective effect in HIV infection.

Adrenal puberty or adrenarche

Andrologie (France), 1997, 7/2 (165-186)

The androgens produced by the adrenal glands are mainly Deltleft arrow over right arrow steroids, first dehydroepiandrosterone (DHA) and its sulfate (DHAS). Adrenal androgens, very high at birth, decrease rapidly the first few months of life, remaining very low from 1 to 6 years of life. Adrenarche is defined as the changes in the pattern of adrenal secretions which occur several years before the onset of gonadal puberty (gonadarche). Developmental patterns of adrenal androgens differ markedly among species and only the chimpanzee exhibits an adrenarche comparable to that of man. Adrenarche starts in both sexes around age 7. The increase in DHA/DHAS has a rather abrupt onset and is thereafter progressive. Before the onset of gonadarche mean levels of DHA and DHAS have increased by about 10 and 20 fold respectively. The prepubertal rise in plasma Deltleft arrow over right arrow- androgens is accompanied by that of Delta4-androstenedione and 11B-hydroxy- Delta4-androstenedione occurring likely at about the same time but being very progressive and more modest are only significant after age 8 in both sexes. Adrenal androgens continue to rise during puberty. Plasma levels of DHA and DHAS continue to rise from pubertal stages 1 to 5 and remain similar in both sexes until age 15. At pubertal stage P5, plasma DHA levels are similar to that seen in young adults with no sex difference while that of DHAS continue to rise in boys and become significantly higher than in girls. Developmental changes in adrenal androgen secretions are also observed in the response to ACTH stimulation. Whether estimated as absolute levels or A of response, the rise in all unconjugated adrenal androgens to a short or prolonged ACTH stimulation, is greater with increasing age, with no sex difference, and is somewhat correlated to basal levels. Plasma levels of DHAS do not vary significantly the 2 hours following a bolus injection of ACTH (21, 34) but its response to long-term (3-days) ACTH stimulation is also increasing with age. Morphological and functional changes in the adrenal cortex also occur during development. Focal development of a Zona reticularis starts at 5 years of age, and progressively becomes continuous. The development of the zona reticularis is parallel to the increase in adrenal androgen secretions, and is completed only by age 15. This is accompanied by a rise in 17-hydroxylase and 17,20-desmolase activity in the adrenals. In a normal timing of physiological events, the onset of adrenarche occurs several years before the onset of gonadarche, 2-3 years in girls and 3-4 years in boys. This relation does not preclude that the processes are independent events. Indeed, the onset of adrenarche and gonadarche are dissociated in a variety of disorders of sexual maturation. Adrenal androgen secretions are under the control of ACTH, as shown by a series of observations. However, the specific increase of adrenal androgen secretions during development without any detectable change in ACTH stimulation, the dissociation between adrenarche and gonadarche in several conditions, have led to postulate that the biochemical differentiation of the zona reticularis may require the action of an <<adrenal factor>> in addition to ACTH. Among the proposed <<trophic>> factors of adrenal androgen secretion, LH/FSH and estrogens are no longer believed to be involved. The evidences for the existence of a separate and specific pituitary cortical androgen-stimulating hormone (CASH) are not yet convincing. Prolactin, linked to nutritional status, may stimulate the activity of the adrenal hydroxysteroid sulfotransferase. The functional zonal theory>> is attractive, but it does not explain why changes in adrenal androgens occur at a given age. Finally, the occurrence of familial cases of premature pubarche, the study of the changes in adrenal androgens in monozygotic or dizygotic twins and the observation that in idiopathic delayed puberty the delay in adrenarche is only one part of a generalized growth and developmental delay, strongly suggests that maturation of the adrenal cortex is regulated, at least in part, by genetic factors. The physiological importance of adrenal androgens remains a matter of controversy. Classical 'dogma' dictates that adrenal androgens are responsible for pubic hair development. It has also been suggested that they contribute to somatic growth or epiphyseal advancement in childhood. This is mainly based on the observation that premature adrenarche is accompanied by premature pubarche, tall stature and advanced bone age. However, adequate androgen secretion alone does not ensure normal sexual hair development in many patients with gonadal dysgenesis. Moreover, in children with a lack or delayed adrenarche long-term treatment with DHAS at dosages such as to restore normal levels for age, failed to induce growth of sexual hair or any change in growth rate, bone maturation velocity, or to advance puberty. Although new hypotheses favour the view that Deltleft arrow over right arrow-androgens, particularly Deltleft arrow over right arrow-androstenediol, have some characteristic properties of estrogens, the physiological role of adrenal androgens, if any, remains to be established. DHAS may well be only a prohormone. There are ample evidences that all tissues possess active sulfatases which transform it into DHA, asteroid with high turn-over. Administration of DHA to experimental animals has shown beneficial effects on various endocrine-metabolic parameters, enhanced immunoprotective functions and reduced carcinogenesis. DHA prevents diabetes in genetically diabetic and obese mice. The importance of in vivo and in vitro experimental findings is underscored by epidemiological data showing that low DHA levels are correlated with increased cardiovascular morbidity in men, breast cancer in women and a decline in immune competence. Human studies are at the moment controversial. It remains possible that DHAS influence breast cancer risk earlier in life, and/or that there are more complex interactions with other hormones or the intracellular metabolism of DHA/DHAS. Indeed, the tissue concentrations of DHAS may be important since it may act indirectly via its metabolism into estradiol or other steroids. Further long-term studies are needed to conclude whether DHA/DHAS are a youth fountain.

Role of glucose-6-phosphate dehydrogenase inhibition in the antiproliferative effects of dehydroepiandrosterone on human breast cancer cells

British Journal of Cancer (United Kingdom), 1997, 75/4 (589-592)

Epidemiological and experimental studies suggest that dehydroepiandrosterone (DHEA) exerts a protective effect against breast cancer. It has been proposed that the non-competitive inhibition of glucose-6-phosphate dehydrogenase (G6PD) contributes to DHEA antitumour action. We evaluated the effects of DHEA on G6PD activity and on the in vitro proliferation of two human breast cancer cell lines, MCF-7 (steroid receptor positive) and MDA-MB-231 (steroid receptor negative), in a serum-free assay. DHEA inhibition of G6PD was only found to occur at concentrations above in 10 microM; at these high concentrations, the growth curve was parallel to the enzyme inhibition curve in both cell lines. In contrast, at concentrations in the in vivo breast tissue concentration range, neither cell growth nor enzyme activity was inhibited. The results failed to confirm DHEA's putative anti-tumour action on breast cancer through G6PD inhibition, as the enzyme blockade only becomes apparent at pharmacological concentrations of the steroid.

Chemoprevention by dietary dehydroepiandrosterone against promotion/progressi on phase of radiation-induced mammary tumorigenesis in rats

Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 54/1-2 (47-53)

When pregnant rats received whole body irradiation with 260 cGy gamma-ray at day 20 of pregnancy, and were then implanted with a diethylstilbestrol (DES) pellet for an experimental period of 1 year under feeding of a control diet, a high incidence (96.2%) of mammary tumors was observed. Administration of dietary 0.6% dehydroepiandrosterone (DHEA) together with DES implantation significantly decreased the incidence (35.0%) of mammary tumors. The first appearance of palpable tumors in the DHEA-fed group was 4.5 months later than that in the control group. For clarification of the mechanism of the chemopreventive action, we measured hormone levels in the serum of DHEA-fed rats. In the DHEA diet rats, the concentration of estradiol-17beta exceeded, by approximately 6-fold, that in the control rats, while the levels of progesterone and prolactin were decreased by 30 and 45%, respectively, Interestingly, DHEA feeding prevented DES-induced hypertrophy of pituitary glands and DES-induced high level of prolactin in pituitary glands detected by immunohistochemical studies, but stimulated the development of mammary glands more than that in control rats treated with DES alone. These findings suggest that DHEA has a potent preventive activity against the promotion/progression phase of radiation-induced mammary tumorigenesis. The mechanism of chemoprevention by change of endocrinological environment is discussed.

Prevention by dehydroepiandrosterone of the development of mammary carcinoma induced by 7,12-dimethylbenz(a)anthracene (DMBA) in the rat

BREAST CANCER RES. TREAT. (USA), 1994, 29/2 (203-217)

The concentration of serum dehydroepiandrosterone sulfate (DHEA-S) and DHEA decreases markedly during aging, and low circulating levels of DHEA have been associated with a higher incidence of breast cancer in women. Using 7,12- dimethylbenz(a)anthracene (DMBA)-induced mammary carcinoma in the rat as model, we have studied the effect of increasing serum levels of DHEA released from Silastic implants on the incidence of these tumors in the rat. Treatment with increasing doses of DHEA leading to serum DHEA levels comparable to those observed in normal adult women (7.1plus or minus0.6 nM and 17.5plus or minus1.1 nM) caused a progressive inhibition of tumor development from 68% bearing tumors in control animals to 22% and 11%, respectively. The average tumor area per rat decreased from 2.81 cm2 in intact control animals to 0.96 and 0.09 cm2 in the groups treated with the same doses of DHEA, respectively. The present data indicate that circulating levels of DHEA similar to those found in normal adult premenopausal women exert a potent inhibitory effect on the development of DMBA-induced mammary tumors in the rat, thus suggesting the possibility of a new and more physiological approach for the prevention of breast cancer in women.

Relationship of serum dehydroepiandrosterone (DHEA), DHEA sulfate, and 5-androstene-3beta,17beta-diol to risk of breast cancer in postmenopausal women

Cancer Epidemiology Biomarkers and Prevention (USA), 1997, 6/3 (177-181)

Laboratory evidence suggests a role for dehydroepiandrosterone (DHEA) and its metabolite 5-androstene-3beta,17beta-diol (ADIOL) in mammary tumor growth. Serum DHEA also has been related to breast cancer in postmenopausal women, but the relationship of ADIOL to risk has not been evaluated previously. To assess the relationship of serum DHEA, its sulfate (DHEAS), and ADIOL, with breast cancer risk in postmenopausal women, we conducted a prospective nested case-control study using serum from the Columbia, MO Breast Cancer Serum Bank. Cases included 71 healthy postmenopausal volunteers not taking replacement estrogens when they donated blood and who were diagnosed with breast cancer up to 10 years later (median, 2.9 years). Two randomly selected controls, who also were postmenopausal and not taking estrogens, were matched to each case on exact age, date (plus or minus1 year), and time (plus or minus2 h) of blood collection. Significant (trend P = 0.02) gradients of increasing risk of breast cancer were observed for increasing concentrations of DHEA and ADIOL, and women whose serum levels of these hormones were in the highest quartiles were at a significantly elevated risk compared to those in the lowest; their risk ratios were 4.0 (95% confidence interval (CI), 1.3- 11.8) and 3.0 (95% CI, 1.0-8.6), respectively. The relationship of DHEAS to breast cancer was less consistent, but women whose serum DHEAS concentration was in the highest quartile also exhibited a significantly elevated risk ratio of 2.8 (95% CI, 1.1-7.4). Results of this prospective study support a role for the adrenal androgens, DHEA, DHEAS, and ADIOL in the etiology of breast cancer.

DHEA: a hormone with multiple effects.

Curr Opin Obstet Gynecol (UNITED STATES) Oct 1996, 8 (5) p351-4

Dehydroepiandrosterone (DHEA) and DHEA-sulfate (DHEAS) represent the major androgens secreted by the adrenal gland. Various functions including metabolic, immune, and cognitive effects have been attributed to this steroid and are reviewed here. Since the levels of DHEA correlate with general good health, and aging is associated with a decline in the secretion of this steroid, a growing interest in replacement of DHEA in elderly people has developed. The findings from recent studies of replacement of DHEA in elderly people are discussed.

Androgen replacement therapy in women: myths and realities.

Int J Fertil Menopausal Stud (UNITED STATES) Jul-Aug 1996, 41 (4) p412-22

In recent years, much attention has been directed at the potential of androgen replacement in the menopausal woman. Testosterone (T) replacement, in various forms, is widely used. However, evidence is lacking for a profound T deficiency state with natural menopause. Data confirming efficacy are also scant, and side effects have been demonstrated with prolonged therapy. The adrenal androgens, dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S), also in contradistinction to T, decline substantially with age. Preliminary studies involving replacement of physiologic levels of DHEA have demonstrated some potential benefits: enhancement of the immune system and enhancement of the growth hormone axis. However, long-term trials have not been performed to date, so this modality of androgen replacement remains in the realm of clinical investigation. Ovarian and adrenal androgen replacement in menopausal women, while theoretically appealing, remains imperfect to date and should be used judiciously, if at all.

Aromatase in bone cell: Association with osteoporosis in postmenopausal women

Journal of Steroid Biochemistry and Molecular Biology (United Kingdom), 1995, 53/1-6 (165-174)

To clarify the possible action of adrenal androgen on bone cell, the existence, characteristics and regulation of aromatase in human osteoblast-like osteosarcoma cells (HOS) and primary cultured osteoblast-like cells from normal human bones (HO) were examined in this study. Significant positive correlation between bone mineral density (BMD) and serum dehydroepiandrosterone sulfate (DHEA-S) was found in 120 postmenopausal women (51-99 years old) but no correlation was seen between BMD and serum estradiol (E2). In subset analysis, strongly positive correlation of serum DHEA-S and estrone (E1) with BMD was observed in postmenopausal women aged less than 69 years old. Administration of DHEA to ovariectomized rat significantly increased BMD and decreased relative osteoid volume in femur. These in vivo findings strongly suggested that serum adrenal androgen may be converted to estrogen in peripheral organ, especially, osteoblast and be important steroids to maintain BMD. (3H)DHEA was converted to (3H)androstenedione and (3H)androstenedione to (3H)estrone in primary cultured human osteoblast. Osteoblast-like cells showed aromatase activity, and an apparent K(m) and the V(max) were 4.74 plus or minus 0.78 nM (mean plus or minus SD, n = 3) and 0.83 plus or minus 0.79 fmol/mg protein/h for HOS, and 4.6 plus or minus 2.9 nM and 279 plus or minus 299 fmol/mg protein/h (mean plus or minus SD, n = 19) for HO, respectively. The aromatase activity was significantly increased by dexamethasone in a dose-dependent manner. Reverse transcription-polymerase chain reaction analysis revealed that dexamethasone increased the transcript of P450(AROM) gene. Osteoblast-specific promoters were also determined. Dexamethasone and 1alpha,25-dihydroxyvitamin D3 synergistically enhanced aromatase activity and P450(AROM) mRNA expression. These results demonstrate that adrenal androgen, DHEA, is converted to E1 in osteoblast by P450(AROM) which is positively regulated by glucocorticoid and 1alpha,25-dihydroxyvitamin D3 and important to maintain BMD in the 6 to 7th decade, after menopause.

3beta-hydroxysteroid dehydrogenase/isomerase and aromatase activity in primary cultures of developing zebra finch telencephalon: Dehydroepiandrosterone as substrate for synthesis of androstenedione and estrogens

General and Comparative Endocrinology (USA), 1996, 102/3 (342-350)

3beta-hydroxysteroid dehydrogenase/Deltleft arrow over right arrow-Delta4 isomerase (3beta-HSD) activity was measured in primary dissociated cell cultures prepared from telencephalons of developing zebra finches. 3beta-HSD activity was confirmed after cultures were incubated with (7-3H)pregnenolone (Preg) or (1,2,6,7- 3H-) dehydroepiandrosterone (DHEA) and 3H-progesterone (Prog) and 3H- androstenedione (AE) were detected in the medium. Product identity was confirmed by recrystallizations and by HPLC analysis. When DHEA was used as substrate, 3H-estradiol and 3H-estrone were also detected in the culture medium, presumably derived from the aromatization of 3H-AE or 3H-T produced from 3H-DHEA. To test this idea, cultures were incubated with 3H-DHEA together with radioinert AE or with fadrozole HCl, a potent and specific aromatase inhibitor. In the presence of radioinert AE, 3H-AE increased but metabolites of 3H-AE decreased in the media; in the presence of fadrozole, 3H-estrogens decreased but 3H-AE and its androgenic metabolite 3H-5beta- androstanedione increased. These data demonstrate 3beta-HSD activity in the songbird brain. The presence of Prog and estradiol in these cultures suggest that Preg and DHEA can potentially serve as substrates for the ultimate formation of active sex steroids in the songbird telencephalon.

Abnormal production of androgens in women with breast cancer

ANTICANCER RES. (Greece), 1994, 14/5 B (2113-2117)

Two long and broad streams of medical literature, from the 1950's to date have established the existence of two unrelated abnormalities of androgen production in women with breast cancer: One is the genetically determined presence of subnormal production of adrenal androgens (i.e. DHEA and DHEAS) in women with premenopausal breast cancer and their sisters, who are at increased risk for breast cancer: The other is excessive production of testosterone, of ovarian origin, in subsets of women with either premenopausal or postmenopausal breast cancer and women with atypical breast-duct hyperplasia, who are at increased risk for breast cancer; along with the hypertestosteronism, there is frequently chronic anovulation in the premenopausal patients. The combination of ovarian hypertestosteronism and chronic anovulation is characteristic of the polycystic ovary syndrome and is also frequently seen in women with abdominal ('android') obesity; both PCOS and abdominal obesity are known to be characterized by high risk for postmenopausal cancer. The elevated testosterone levels and the increased levels of insulin, IGF-I, and IGF-II that are seen in PCOS and abdominal obesity could favor the development of breast cancer in several ways, all of which have been demonstrated experimentally binding of testosterone to cancer cells bearing testosterone receptors, with direct stimulation; intratissular aromatization of testosterone to estradiol, with stimulation of estrogen-sensitive cells; stimulation of the production of epithelial growth factor (EGF) by testosterone, with direct mitogenic effect of EGF on cancer cells; stimulation of aromatase by insulin and IGF-I; direct mitogenic stimulation of cancer cells by insulin, IGF-I, and IGF-II; and stimulation by IGF-I and IGF-II of the intratissular reduction of estrone to estradiol. Since PCOS is probably largely genetically determined, and abdominal obesity may also be, the hypertestosteronism of these conditions may represent a second genetically determined hormonal risk factor for breast cancer.

Dehydroepiandrosterone antiestrogenic action through androgen receptor in MCF-7 human breast cancer cell line

ANTICANCER RES. (Greece), 1993, 13/6 A (2267-2272)

The possible mechanisms of the inhibitory effect of dehydroepiandrosterone (DHEA) on the estrogen-induced growth of MCF-7 human breast cancer cells were explored. The impairment of metabolic pathways via the inhibition of glucose-6-posphate dehydrogenase (G6PD) activity was excluded: G6PD activity in MCF-7 homogenate was reduced by DHEA only at a very high concentration (50 microM) while no inhibitory action on the enzyme activity was detected when DHEA was added at the antimitotic concentrations (0.02-0.5 microM). A steroid receptor mediated effect was explored: DHEA might either activate androgen receptors (AR) or partially displace E2 from estrogen receptor (ER). The pure antiandrogens Flutamide and Hydroxyflutamide reversed the inhibitory effect of DHEA on MCF-7 cell growth, whereas both the nonsteroidal estrogen Diethylstilbestrol and the antiestrogen Tamoxifen were ineffective. Results demonstrate that the AR activation plays a pivotal role in the inhibitory action of DHEA on the E2-induced MCF-7 growth.

Dehydroepiandrosterone and diseases of aging

Drugs and Aging (New Zealand), 1996, 9/4 (274-291)

Dehydroepiandrosterone (DHEA; prasterone) is a major adrenal hormone with no well accepted function. In both animals and humans, low DHEB levels occur with the development of a number of the problems of aging: immunosenesence, increased mortality, increased incidence of several cancers, loss of sleep, decreased feelings of well-being, osteoporosis and atherosclerosis. DHEA replacement in aged mice significantly normalised immunosenescence, suggesting that this hormone plays a key role in aging and immune regulation in mice. Similarly, osteoclasts and lymphoid cells were stimulated by DHEA replacement, an effect that may delay osteoporosis, Recent studies do not support the original suggestion that low serum DHEA levels are associated with Alzheimer's disease and other forms of cognitive dysfunction in the elderly. As DHEA modulates energy metabolism, low levels should affect lipogenesis and gluconeogenesis, increasing the risk of diabetes mellitus and heart disease. Most of the effects of DHEA replacement have been extrapolated from epidemiological or animal model studies, and need to be tested in human trials, Studies that have been conducted in humans show essentially no toxicity of DHEA treatment at dosages that restore serum levels, with evidence of normalisation in some aging physiological systems. Thus, DHEA deficiency may expedite the development of some diseases that are common in the elderly.

Case report: amelioration of insulin resistance in diabetes with dehydroepiandrosterone.

Am J Med Sci (UNITED STATES) Nov 1993, 306 (5) p320-4

In hyperandrogenic females, the ratio of dehydroepiandrosterone (DHEA) to testosterone may be an important determinant of insulin sensitivity. This study involved changes in insulin sensitivity and glucose metabolism with therapeutic manipulation of DHEA (S)/testosterone in a female patient with non-insulin-dependent diabetes and hyperandrogenism. Therapeutic intervention included 1-month treatment with 0.25 mg dexamethasone at bedtime and 1-month dexamethasone + DHEA. Insulin sensitivity and glucose tolerance were assessed before and after each treatment regimen by examining: 1) fasting and oral glucose tolerance test glucose and insulin levels, 2) hypoglycemic response to intravenous insulin, and 3) erythrocyte insulin receptor binding. With dexamethasone alone, DHEAS, testosterone, and their ratio were reduced with a concomitant increase (30%) in oral glucose tolerance test insulin levels and a decrease (33%) in erythrocyte insulin binding. With DHEA + dexamethasone, the ratio of DHEAS/testosterone increased 16-fold along with a marked improvement in insulin sensitivity, as determined by a more than 30% reduction in fasting and oral glucose tolerance test insulin levels, a threefold stimulation of the rate of glucose disappearance with intravenous insulin, and a 30% increase in insulin binding. DHEA improved insulin sensitivity and reduced fasting and oral glucose tolerance test glucose levels and ameliorated the diabetic state. The ratio of DHEAS/testosterone is an important regulator of insulin sensitivity and glucose tolerance and that DHEA therapy may be beneficial in the treatment of certain forms of insulin resistance.

Therapeutic effects of dehydroepiandrosterone metabolites in diabetes mutant mice (C57BL/KsJ-db/db).

Endocrinology (UNITED STATES) Jul 1984, 115 (1) p239-43

Dehydroepiandrosterone (DHEA) fed at 0.4% in the diet is known to exert strong antihyperglycemic effects in C57BL/KsJ genetically diabetic (db/db) mice. Three of the major metabolic products of DHEA; DHEA sulfate, alpha-hydroxyetiocholanolone (alpha-ET), and beta- hydroxyetiocholanolone (beta-ET) when fed at 0.1% in the diet, and one putative product, 17 beta-estradiol, when fed at 0.005% also prevented the development of severe diabetes while having little effect on the amount of food eaten or the rate of weight gain. When suboptimal doses (5-20 micrograms/week) of estradiol were injected in combination with diets containing either alpha-ET or beta-ET, marked potentiating effect was noted, normalization of the hyperglycemia being produced with as little as 0.025% of beta-ET and 0.05% of alpha-ET. The ability of the etiocholanolones to maintain islet integrity and prevent the development of most diabetes symptoms suggests that these metabolites are not merely inactive end products of steroid metabolism, but are physiological effectors in their own right.

Diabetes and adrenal disease.

Baillieres Clin Endocrinol Metab (ENGLAND) Oct 1992, 6 (4) p829-47
Disorders of the adrenal cortex and medulla can result in glucose intolerance or overt diabetes mellitus. Cushing's syndrome, characterized by excessive secretion of glucocorticoids, impairs glucose tolerance primarily by causing insulin resistance at the post-receptor level. On the other hand, phaeochromocytoma and hyperaldosteronism, via the respective actions of catecholamines and hypokalaemia on the pancreatic beta-cell, impair glucose tolerance primarily by inhibiting insulin release. The glucose intolerance associated with these adrenal disorders is usually only mild to moderate in severity. Marked hyperglycaemia, glycosuria, and polyuria are uncommon and ketosis is rare. Moreover, the late complications of diabetes mellitus are distinctly uncommon in patients with these disorders, and the prognosis for morbidity and death is usually that of the underlying disease and not that of diabetes mellitus. The impaired glucose tolerance induced by all three of these adrenal disorders usually retur

in animal models will prove applicable to man. (99 Refs.)

Dehydroepiandrosterone, dehydroepiandrosterone sulfate, obesity, waist-hip ratio, and noninsulin-dependent diabetes in postmenopausal women: the Rancho Bernardo Study.

J Clin Endocrinol Metab (UNITED STATES) Jan 1996, 81 (1) p59-64

Dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEAS) levels were determined in morning specimens from 659 fasting postmenopausal women who were not using estrogen therapy or antidiabetic medication. All women had concurrent oral glucose tolerance tests and measurements of body mass index (BMI) and waist-hip ratio (WHR). DHEA levels were weakly and inversely associated with BMI but not with WHR or glucose tolerance status. DHEAS levels were not associated with BMI but were positively associated with WHR, diabetes, and impaired glucose tolerance. In analyses adjusted for or stratified by WHR, the DHEAS association with abnormal carbohydrate tolerance was reduced but still independent of fat distribution. Because this was a cross-sectional study, it was not possible to determine whether DHEAS levels were raised by central obesity or vice versa. At a minimum, these data strongly suggest that the positive association of DHEAS with both central obesity and abnormal glucose tolerance does not support the thesis that DHEAS protect against diabetes or obesity in older women as had been suggested by animal studies.

[Isolated gonadotropin deficiency and secretory discrepancy of cortisol and adrenal androgen by hemochromatosis secondary to congenital dyserythropoietic anemia]

Nippon Naibunpi Gakkai Zasshi (JAPAN) Jan 20 1994, 70 (1) p57-64

A 37-yr-old woman was admitted to our hospital for evaluation of diabetes mellitus, liver cirrhosis and primary amenorrhea. Serological and hematological examinations revealed that she suffered from hemochromatosis secondary to congenital dyserythropoietic anemia (CDA), characterized by ineffective hematopoiesis and erythropoietic dysplasia. Iron deposition was suggested by MRI on the pancreas, liver and pituitary gland. Endocrinological examinations demonstrated that she had isolated gonadotropin deficiency and ovarian failure, resulting in hypogonadotropic hypogonadism. In addition, despite normal responses of serum cortisol and plasma aldosterone to ACTH and furosemide-standing tests, respectively, serum dehydroepiandrosterone (DHEA) responded poorly to ACTH test, suggesting selective damage of zona reticularis in adrenocortical steroidogenesis in association with hemochromatosis.

Enhanced adrenocortical activity as a contributing factor to diabetes in hyperandrogenic women.

Metabolism (UNITED STATES) May 1994, 43 (5) p584-90

The high incidence of non-insulin-dependent diabetes mellitus (NIDDM) in women with polycystic ovarian syndrome (PCO) is believed to occur secondary to the insulin resistance associated with their androgenicity. In the present study, we have examined the interrelationships between glucose tolerance, androgenicity, and various in vivo and in vitro parameters of insulin sensitivity in 11 obese PCO patients with NIDDM, 14 PCO patients without diabetes, and 14 weight-matched controls. Both groups of PCO patients were hypertestosteronemic, hyperinsulinemic, and insulin-resistant when compared with a group of weight-matched controls. However, PCO patients with NIDDM differed from those without diabetes in that they had elevated basal and corticotropin-stimulated adrenal steroids (cortisol, dehydroepiandrosterone [DHEA], dehydroepiandrosterone sulfate [DHEAS]). The hyperglycemia of our diabetic patients was not related to their elevated testosterone levels or to their degree of insulin resistance, but was significantly and positively correlated with adrenal hypersecretion, which in turn was associated with postreceptor defects in insulin action. These findings would suggest that enhanced adrenocortical activity may be an important factor underlying the development of NIDDM in women with PCO.

Adrenal steroid and adrenocorticotropin responses to human corticotropin-releasing hormone stimulation test in adolescents with type I diabetes mellitus.

Metabolism (UNITED STATES) Sep 1993, 42 (9) p1141-5

To determine whether abnormalities of hypothalamic-pituitary-adrenal axis function occur in type I diabetes mellitus, corticotropin, cortisol, 17-hydroxyprogesterone (17-OHP), androstenedione (D4-A), dehydroepiandroste rone (DHEA), and DHEA sulfate (DS) levels were measured after an intravenous (IV) injection of 1 microgram/kg human corticotropin-releasing hormone (CRH) in diabetic adolescents and normal age-matched subjects. CRH produced a consistent increase in corticotropin blood levels that was comparable in the two groups. In contrast, both baseline and stimulated cortisol concentrations were greater in diabetic patients. Levels of 17-OHP increased after CRH administration, and the magnitude of increase was similar in all subjects. Stimulation with CRH determined an attenuated integrated DS response in diabetics compared with normal subjects with a different pattern of the hormone secretion, whereas no differences in D4-A concentrations were detected between the two groups. DHEA serum levels of subjects from both groups underwent similar changes following administration of CRH. In conclusion, patients with type I diabetes have a discrete response of adrenal steroids to CRH stimulation that appears to be independent of corticotropin secretion. This phenomenon might be related to a direct effect of insulin on enzyme systems involved in the biosynthetic pathway of adrenal steroids or, alternatively, to an intra-adrenal CRH/corticotropin mechanism acting on the adrenal cortex in a paracrine manner.

[Dehydroepiandrosterone. Renaissance after 13 years]

Cas Lek Cesk (CZECHOSLOVAKIA) Sep 8 1989, 128 (37) p1157-60

DHEA, a steroid precursor of androgens and estrogens has also an inhibitory effect on several enzymes, namely on 11 beta-hydroxylase, NADH oxidase and glucose 6-phosphate dehydrogenase. The latter is the rate limiting enzyme of the pentose phosphate cycle. This metabolic pathway provides the cells with extramitochondrial NADPH and pentose phosphates. NADPH is used for the synthesis of fatty acids and steroids. Together with ribose 5-phosphate, NADPH (as coenzyme of folate reductases) is required for the synthesis of nucleic acids. A deficient production of DHEA has been found to be responsible for several diseases obesity, diabetes type 2, hypertension, arteriosclerosis and hyperuricemia as well as malignant growth (low DHEA syndrome). DHEA administration favourably modified several of these metabolic disorders. These studies were started in our laboratory in 1962 and stopped in 1976 because we were short of DHEA. At that time the response to our results was rather theoretical, but the last years a new wave of interest in DHEA called for two consecutive symposia, where important findings were presented (Paris in January and Jena in April 1989). It is a damage that this new trend, started in our laboratory, could not be pursued up to now without interruption.

The influence of genetic background on the expression of mutations at the diabetes locus in the mouse. V. Interaction between the db gene and hepatic sex steroid sulfotransferases correlates with gender-dependent susceptibility to hyperglycemia.

Endocrinology (UNITED STATES) Feb 1989, 124 (2) p912-22

Steroid sulfurylation represents a potential mechanism for controlling the level of active steroids within a tissue. We have elucidated an inbred strain background-dependent interaction between the diabetes (db) mutation and steroid sulfotransferase (ST) enzymes, potentially modulating the level of active steroid hormones or their precursors in the liver. Gonadectomized mutants were analyzed to correlate how strain- and gender-dependent variation in ST activities interacted with db to achieve diabetogenesis. Both sexes on the C57BL/KsChp (BKs) background developed severe early-onset hyperglycemia, and gonadectomy failed to prevent diabetes. In contrast, C3HeB/FeChp (C3HeB)-db/db males, but not females, were diabetes susceptible, and the male susceptibility was completely dependent upon endogenous testes-derived testosterone. The female resistance, in turn, was dependent upon ovarian sex steroids. The differential requirements of BKs- and C3HeB-db/db males and females for gonadal sex steroids could be explained on the basis of the differential strength of the interaction between the db mutation and hepatic ST activities. Hepatic ST from normal adult females sulfurylated dehydroepiandrosterone (DHEA), whereas this activity disappeared in cytosols of normal adult males by 8 weeks of age. This sexually dimorphic inability to sulfurylate ()androgens was controlled by testosterone. Diabetogenic susceptibility in BKs mutant mice of both sexes was associated with marked depression of preandrogen/androgen sulfurylation [female mutants exhibiting at least a 5-fold reduced DHEA sulfurylation at a near-physiological concentration (0.2 microM)]. This reduced preandrogen/androgen sulfurylation occurred concomitant with a 10-fold acceleration of estrone (E1) sulfurylation at a limiting (0.2 microM) concentration, essentially producing a hyperandrogenized hepatic tissue state. These extreme shifts in ST substrate preferences were not observed in the diabetes-resistant C3HeB-db/db females. Kinetic analysis of semipurified hepatic ST from BKs-db/db females showed a 10-fold decrease in Km for E1 (apparent Km = 0.9 microM in mutants vs. 9.0 microM in normals). Whereas the Km for DHEA did not differ from the control value, hepatic ST from BKs-db/db females showed a 10-fold decreased maximal velocity for DHEA sulfurylation (1230 vs. 12750 pmol/mg.h in control preparations). The antihyperglycemic effects of dietary E1 therapy were associated with enhanced androgen sulfurylation in BKs-db/db females and restoration of androgen sulfurylation in BKs-db/db males.(ABSTRACT TRUNCATED AT 400 WORDS)

Therapeutic effects of dehydroepiandrosterone (DHEA) and its metabolites in obese-hyperglycemic mutant mice.

Prog Clin Biol Res (UNITED STATES) 1988, 265 p161-75

Dehydroepiandrosterone (DHEA) fed at 0.4%, and its metabolites, 3 alpha-hydroxyetiocholanolone (alpha-ET) and 3 beta-hydroxyetiocholanolone (beta-ET), fed at 0.1%, had marked anti-hyperglycemic and anti-obesity properties in mutant mice with single gene obesity mutations (diabetes, db; obese, ob; viable yellow, Avy). The therapeutic effects differed depending on the mutation as well as the inbred background on which the mutation was maintained. These steroids prevented onset of hyperglycemia and reduced the rate of weight gain in C57BL/6J-db/db and ob/ob mice, whereas in C57BL/KsJ-db/db mice, only hyperglycemia was prevented. The viable yellow (Avy) mutant, exhibiting a more slowly developing obesity condition, responded to all steroids with a marked decrease in rate of weight gain associated with decreased plasma insulin concentrations. Steroid treatment of most mouse mutants was associated with normal or increased food intake, a feature that suggests a decrease in metabolic efficiency. In order to assess any potential energy wastage by steroid stimulation of futile cycles we looked at the rates of lipogenesis, gluconeogenesis and oxygen consumption in steroid-treated normal and mutant mice. With the possible exception of the rate of gluconeogenesis that in obesity mutants was consistently reduced to normal by treatment, no metabolic changes were of sufficient magnitude to account for the marked decrease in metabolic efficiency. All treatments potentiated the action of insulin. This potentiation may change the hormonal balance such that minor changes in the rates of many metabolic pathways may interact to produce a large decrease in metabolic efficiency.

Modulation of growth, differentiation and carcinogenesis by dehydroepiandrosterone.

Adv Enzyme Regul (ENGLAND) 1987, 26 p355-82

Dehydroepiandrosterone (3 beta-hydroxy-5-androsten-17-one; DHEA) and its conjugates are abundant circulating steroids that originate largely from the adrenal cortex. Their levels decline profoundly with age in human beings of both sexes, as the incidence of most cancers rises. Low levels of these steroids have been associated with the presence and risk ofdevelopment of cancer. Administration of DHEA to rodents produces protection against spontaneous tumors and chemical carcinogenesis, suppresses weight gain without significantly affecting food intake, ameliorates the severity of diabetes in genetically diabetic mice, and restrains autoimmune processes. DHEA and related steroids also depress the mitogenic effects of carcinogens, tumor promoters and plant lectins, and block viral and carcinogen-induced cell transformations. DHEA and certain congeners are also potent and quite specific inhibitors of mammalianglucose-6-phosphate dehydrogenases. We have observed that the conversion of 3T3-L1 and 3T3-F442A preadipocyte clones to the adipocyte phenotype, in response to appropriate differentiation stimuli (fetal calf serum, insulin, dexamethasone, and 1-methyl-3-isobutylxanthine), is blocked by DHEA and other steroidal inhibitors of glucose-6-phosphate dehydrogenase. The structural requirements for blocking adipocyte differentiation and for inhibiting glucose-6-phosphate dehydrogenase are closely correlated. Evidence is reviewed suggesting that the inhibition of glucose-6-phosphatedehydrogenase is central to the anticarcinogenic and differentiation-blocking actions of DHEA and related steroids. The 3T3 preadipocyte clones provide a valuable system for the analysis of the mechanisms of the effects of DHEA on growth, differentiation and carcinogenesis. (94 Refs.)

Androgenic and estrogenic metabolites in serum of mice fed dehydroepiandrosterone: relationship to antihyperglycemic effects.

Metabolism (UNITED STATES) Sep 1987, 36 (9) p863-9

The steroid prehormone, dehydroepiandrosterone (DHEA) has potentanti hyperglycemic effects when fed in the diet of genetically diabetic C57BL/KsJ-db/db mice. The purpose of this investigation was to analyze changes in sex steroid levels in serum of mice fed DHEA, and to compare the antihyperglycemic potencies of the various metabolites in order to clarify the mechanism of DHEA action. Steroid radioimmunoassays showed that dietary DHEA entered the blood in high concentrations and was actively metabolized to both androgens (testosterone, T; dihydrotestosterone, DHT) and estrogens (estrone, E1; 17 beta-estradiol, E2). This metabolism did not require intact adrenal glands or gonads. In C57BL/KsJ normal (+/+) males, conversion of DHEA to androgens was the prominent feature; in db/db males, DHEA feeding not only increased serum T and DHT, but also serum E1 and E2 levels. The db/db mice had increased amounts of adipose tissue that sequestered more intravenously injected 3H-E2; this additional body fat could account for increased aromatization of DHEA-derived estrogen precursors. Comparisons of the relative antihyperglycemic potencies of androgenic and estrogenic steroid metabolites of DHEA in db/db mice showed that the estrogens and metabolites with estrogenic properties (androstenediol) or those convertible to estrogens (DHEA sulfate) were the most potent. Although 17 beta-E2 was effective by injection or per os, DHEA was effective only when administered per os, implicating alimentary tract conversion of DHEA to more biologically active reactants. Based on the pivotal position of DHEA as a prehormone for androgens, estrogens, andetiocholanolones, an explanation of the seemingly paradoxical effects exerted by this compound in blocking autoimmune disease, hyperglycemia, obesity, and neoplasia was proposed.

Antiobesity effects of etiocholanolones in diabetes (db), viable yellow (Avy), and normal mice.

Endocrinology (UNITED STATES) Dec 1985, 117 (6) p2279-83

Two metabolites of the adrenal steroid dehydroepiandrosterone (DHEA), 3alpha-hydroxyetiocholanolone and 3 beta-hydroxyetiocholanolone, were found to have antiobesity properties with respect to both prevention of the development of obesity as well as weight reduction after obesity was established. All of the obesity types studied responded to metabolite therapy to a greater or lesser extent. The more natural obesity seen in certain strains of mice with aging responded most rapidly to the feeding of either metabolite. The effective dosage (0.1%) fed in the diet was only one quarter the dosage required for DHEA to produce the same effect in preventing diabetes symptoms in C57BL/Ks diabetic (db) mutant mice. Unlike DHEA, neither metabolite produced any undesirable estrogenic or androgenic side-effects. 3 alpha-hydroxyethiocholanolone and 3 beta-hydroxyetiocholanolone, formerly considered only as inert end products of steroid metabolism, have beneficial actions in mice with various diabetes-obesity conditions and may be metabolic effectors in their own right.

Effect of genetic background on the therapeutic effects of dehydroepiandrosterone (DHEA) in diabetes-obesity mutants and in aged normal mice.

Diabetes (UNITED STATES) Jan 1984, 33 (1) p26-32

Dehydroepiandrosterone (DHEA) was fed at 0.1-0.4% in the diet to genetically diabetic (db/db) or obese (ob/ob) C57BL/KsJ (BL/Ks) or C57BL/6J (BL/6) mice. Treatment of BL/Ks-db/db or ob/ob mice with 0.4% DHEA prevented hyperglycemia, islet atrophy, and severe diabetes associated with this inbred background, but did not affect weight gain and food consumption. Homozygous obese (ob) or diabetes (db) mice on the BL/6 background were more sensitive to DHEA, and the mild, transient hyperglycemia associated with ob or db gene expression on the BL/6 inbred background could be prevented by 0.1% DHEA. Both body weight and food consumption were decreased in BL/6 mutants maintained on 0.1% DHEA whereas this effect was not seen in BL/Ks mutants fed up to 0.4% DHEA. Early therapy with 0.4% DHEA, initiated at 2 wk of age, prevented the developmentof most diabetes symptoms and decreased the rate of weight gain in pups of all genotypes. In addition to therapeutic effects on both obese mutants, DHEA effected significant changes in an aging study using normal BL/6 female mice. Four weeks of DHEA treatment initiated at 2 yr of age improved glucose tolerance and at the same time reduced plasma insulin to a "younger" level. This suggests that DHEA may act in insulin-resistant mutant mice and in aging normal mice to increase the sensitivity to insulin.

Therapeutic effects of dehydroepiandrosterone (DHEA) in diabetic mice.

Diabetes (UNITED STATES) Sep 1982, 31 (9) p830-3

Dehydroepiandrosterone (DHEA), a major adrenal secretory steroid in humans, was therapeutic when fed in a concentration of 0.4% to C57BL/KsJ mice with either non-insulin-dependent or insulin-dependent diabetes. Genetically diabetic (db/db) mice of both sexes develop obesity and aglucose intolerance and hyperglycemia associated with insulin resistance by 2 mo of age, and exhibit beta-cell necrosis and islet atrophy by 4 mo. In contrast, DHEA feeding initiated between 1 and 4 mo of age, while only moderately effective in preventing obesity, did prevent the other pathogenic changes and effected a rapid remission of hyperglycemia, a preservation of beta-cell structure and function, and an increased insulin sensitivity as measured by glucose tolerance tests. DHEA feeding was also therapeutic to normal C57BL/KsJ male mice made diabetic by multiple low doses of streptozotocin (SZ). While DHEA treatments did not block either the direct cytotoxic action of SZ on beta-cells or the development of insulitis, the steroid significantly moderated the severity of the ensuing diabetes (reduced hyperglycemia and water consumption, and increased plasma insulin and numbers of residual, granulated beta-cells.