DHEA (DEHYDROEPIANDROSTERONE)

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Topical DHEA Inhibits Tumors

Pashko LL Rovito RJ Williams JR Sobel EL Schwartz AG, Carcinogenesis (1984 Apr) 5(4):463-6

Long-term oral administration of the adrenal steroid, dehydroepiandrosterone (DHEA), has previously been shown to inhibit the development of spontaneous breast cancer and chemically induced lung and colon tumors in various mouse strains. Topical application of DHEA inhibits both 7,12-dimethylbenz[a]anthracene initiation and 12-O- tetradecanoylphorbol-13-acetate promotion of these tumors. The synthetic steroid, 3 beta-methylandrost-5-en-17-one, which, unlike DHEA, is not demonstrably estrogenic in the rat, also inhibits papilloma development.



DHEA and Thermal Skin Injury

Araneo BA Ryu SY Barton S Daynes RA, J Surg Res (1995 Aug) 59(2):250-62

Progressive ischemia and necrosis of the skin following thermal injury are reduced by postburn administration of the steroid hormone dehydroepiandrosterone (DHEA). Thermally injured animals were provided with a subcutaneous injection of DHEA, or a related species of steroid hormone, at various times after burning. During the 96 hr following administration of the scald burn, tissue necrosis was closely monitored. Subcutaneous administration of DHEA at approximately 1 mg/kg/day achieved optimal protection against the development of progressive dermal ischemia. DHEA, 17 alpha-hydroxy- pregnenolone, 16 alpha-bromo-DHEA, and androstenediol each demonstrated, a similar level of protection. Other forms of steroids, including DHEA sulfate, androstenedione, 17 beta-estradiol, or dihydrotestosterone, exhibited no protective effect under the conditions tested. Additionally, intervention therapy with DHEA could be initiated up to 4 hr, but not 6 hr, after burn without a marked reduction in therapeutic benefit. Examination of the microvasculature of thermally injured dorsal skin suggested that postburn intervention with DHEA, either directly or indirectly, maintained a normal architecture in most of the dermal capillaries and venules within burn-exposed tissue. These findings suggest that systemic intervention therapy of burn patients with DHEA or a similar acting steroid hormone may be useful in preventing the progressive tissue destruction caused by progressive ischemia.



High Bioavailability of DHEA

Labrie C Flamand M Belanger A Labrie F, J Endocrinol (1996 Sep) 150 Suppl:S107-18

Dehydroepiandrosterone (DHEA) administered percutaneously by twice daily application for 7 days to the dorsal skin of the rat stimulates an increase in ventral prostate weight with approximately one third the potency of the compound given by subcutaneous injection. The doses required to achieve a 50% reversal of the inhibitory effect of orchiectomy are approximately 3 and 1 mg respectively. By the oral route, on the other hand. DHEA has only 10-15% of the activity of the compound given percutaneously. Taking the bioavailability obtained by the subcutaneous route as 100%, it is estimated that the potencies of DHEA by the percutaneous and oral routes are approximately 33 and 3% respectively. Similar ratios of activity were obtained when dorsal prostate and seminal vesicle weight were used as parameters of androgenic activity. When examined on an estrogen-sensitive parameter, namely uterine weight in ovariectomized rats, the stimulatory effect of DHEA was much less potent than its androgenic activity measured in the male animal, a 50% reversal of the inhibitory effect of ovariectomy on uterine weight being observed at the 3 and 30 mg doses of DHEA administered by the subcutaneous and percutaneous routes respectively. When measured on uterine weight, percutaneous DHEA thus shows a 10% potency compared with the subcutaneous route. The sulfate of DHEA (DHEA-S), on the other hand, was approximately 50% as potent as DHEA at increasing ventral prostate weight after subcutaneous or percutaneous administration. When the effect was measured on dorsal prostate and seminal vesicle weight, percutaneous DHEA-S had 10-25% of the activity of DHEA. DHEA decreased serum LH levels in ovariectomized animals, an effect which was completely reversed by treatment with the antiandrogen flutamide. On the other hand, flutamide had no significant effect on the increase in uterine weight caused by DHEA, thus suggesting a predominant estrogenic effect of DHEA at the level of the uterus and an estrogenic effect on the feedback control of LH secretion. The present data show a relatively high bioavailability of percutaneous DHEA as measured by its androgenic and/or estrogenic biological activity in well-characterized peripheral target intracrime tissues in the rat.



Antioxidant activity of dioscorea and dehydroepiandrosterone (DHEA) in older humans

Araghiniknam M; Chung S; Nelson-White T; Eskelson C; Watson RR
Arizona Prevention Center, University of Arizona, School of Medicine, Tucson, 85724, USA
Life Sci (ENGLAND) 1996, 59 (11) pPL147-57,

Dioscorea is a yam steroid extract used in commercial steroid synthesis and consumed by people. DHEA is a steroid which declines with age, but without known activity. This study was designed to determine whether dioscorea supplementation could increase serum dehydroepiandrosterone sulfate (DHEAS) in humans and modulate lipid levels in older people. The subjects were selected volunteers aged 65-82 years. The serum DHEAS level, lipid peroxidation and lipid profile were assessed. Three weeks of dioscorea supplementation had no affect on serum DHEAS level. However DHEA intake of 85 mg/day increased serum DHEA levels 100.3%. DHEA and dioscorea significantly reduced serum lipid peroxidation, lowered serum triglycerides, phospholipid and increased HDL levels. Both DHEA and the steroid yam extract, dioscorea, have significant activities as antioxidant to modify serum lipid levels.



Replacement of DHEA in aging men and women-Potential remedial effects

Yen SS; Morales AJ; Khorram O
Department of Reproductive Medicine, University of California, San Diego, La Jolla 92093, USA
Ann N Y Acad Sci (U.S.) Dec 29 1995, 774 p128-42,

DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant adverse effects. Further studies are needed to confirm and extend our current results, particularly the gender differences



Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age

Morales AJ; Nolan JJ; Nelson JC; Yen SS
Department of Reproductive Medicine, University of California School of Medicine, La Jolla 92093
J Clin Endocrinol Metab (U.S.) Jun 1994, 78 (6) p1360-7,

Aging in humans is accompanied by a progressive decline in the secretion of the adrenal androgens dehydroepiandrosterone (DHEA) and DHEA sulfate (DS), paralleling that of the GH-insulin-like growth factor-I (GH-IGF-I) axis. Although the functional relationship of the decline of the GH-IGF-I system and catabolism is recognized, the biological role of DHEA in human aging remains undefined. To test the hypothesis that the decline in DHEA may contribute to the shift from anabolism to catabolism associated with aging, we studied the effect of a replacement dose of DHEA in 13 men and 17 women, 40-70 yr of age. A randomized placebo-controlled cross-over trial of nightly oral DHEA administration (50 mg) of 6-month duration was conducted. During each treatment period, concentrations of androgens, lipids, apolipoproteins, IGF-I, IGF-binding protein-1 (IGFBP-1), IGFBP-3, insulin sensitivity, percent body fat, libido, and sense of well-being were measured. A subgroup of men (n = 8) and women (n = 5) underwent 24-h sampling at 20-min intervals for GH determinations. DHEA and DS serum levels were restored to those found in young adults within 2 weeks of DHEA replacement and were sustained throughout the 3 months of the study. A 2-fold increase in serum levels of androgens (androstenedione, testosterone, and dihydrotestosterone) was observed in women, with only a small rise in androstenedione in men. There was no change in circulating levels of sex hormone-binding globulin, estrone, or estradiol in either gender. High density lipoprotein levels declined slightly in women, with no other lipid changes noted for either gender. Insulin sensitivity and percent body fat were unaltered. Although mean 24-h GH and IGFBP-3 levels were unchanged, serum IGF-I levels increased significantly, and IGFBP-1 decreased significantly for both genders, suggesting an increased bioavailability of IGF-I to target tissues. This was associated with a remarkable increase in perceived physical and psychological well-being for both men (67%) and women (84%) and no change in libido. In conclusion, restoring DHEA and DS to young adult levels in men and women of advancing age induced an increase in the bioavailability of IGF-I, as reflected by an increase in IGF-I and a decrease in IGFBP-1 levels. These observations together with improvement of physical and psychological well-being in both genders and the absence of side-effects constitute the first demonstration of novel effects of DHEA replacement in age-advanced men and women.



DHEA's Effects on Weight

Coleman DL Schwizer RW Leiter EH
Diabetes (1984 Jan) 33(1):26-32

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 development of 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 years 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.



Anti-Obesity Properties of DHEA

Coleman DL
Prog Clin Biol Res (1988) 265:161-75

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.



DHEA And Lipids

Bednarek-Tupikowska G Milewicz A Kossowska B Bohdanowicz-Pawlak A Sciborski R
Gynecol Endocrinol (1995 Mar) 9(1):23-8

The authors estimated the influence of dehydroepiandrosterone (DHEA) administration, a potential antiatherogenic agent, on serum lipids, sex hormones and insulin levels in male rabbits fed on an atherogenic diet. They concluded that (1) DHEA administration has an unfavorable impact on the serum lipid profile; (2) an atherogenic diet causes insulin resistance; (3) the glucose and insulin levels are not related to DHEA in normally fed rabbits and in rabbits with hyperlipoproteinemia; (4) an atherogenic diet causes a slight increase of estradiol concentration; (5) DHEA treatment has no significant effect on testosterone and estradiol concentrations in both normally fed rabbits and those on an atherogenic diet; (6) DHEA administration has an anti-obesity effect.


DHEA's Effects on Weight

Coleman DL Schwizer RW Leiter EH Diabetes (1984 Jan) 33(1):26-32

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 development of 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 years 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.



Anti-Obesity Properties of DHEA

Coleman DL

Prog Clin Biol Res (1988) 265:161-75

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.



DHEA And Lipids

Bednarek-Tupikowska G Milewicz A Kossowska B Bohdanowicz-Pawlak A Sciborski R

Gynecol Endocrinol (1995 Mar) 9(1):23-8

The authors estimated the influence of dehydroepiandrosterone (DHEA) administration, a potential antiatherogenic agent, on serum lipids, sex hormones and insulin levels in male rabbits fed on an atherogenic diet. They concluded that (1) DHEA administration has an unfavorable impact on the serum lipid profile; (2) an atherogenic diet causes insulin resistance; (3) the glucose and insulin levels are not related to DHEA in normally fed rabbits and in rabbits with hyperlipoproteinemia; (4) an atherogenic diet causes a slight increase of estradiol concentration; (5) DHEA treatment has no significant effect on testosterone and estradiol concentrations in both normally fed rabbits and those on an atherogenic diet; (6) DHEA administration has an anti-obesity effect.



Does DHEA supplementation affect muscle mass?

Expert Opinion on Investigational Drugs (United Kingdom), 1996, 5/12 (1725-1728)

DHEA (dehydroepiandrosterone) production declines dramatically with increasing age in people as they loose muscle mass. Animal studies have not shown that DHEA replacement affects body or muscle weight in animals, but does reduce lipids and reduces oxidation, increased with ageing. One research group has shown that growth hormones increase while others decrease during DHEA supplementation of older people. However, DHEA's effect on muscle mass in humans is unclear. DHEA supplementation does restore DHEA levels without apparent toxicity.



Androgens and the menopause; a study of 40-60-year-old women

Clinical Endocrinology (United Kingdom), 1996, 45/5 (577-587

Objective: The impact of the menopause on androgen production is poorly understood. We have investigated the impact of the menopause, as well as other factors such as age, body mass index (BMI) and cigarette smoking, on ovarian and adrenal androgen levels in women aged 40-60 years. Design: Cross-sectional study of blood hormones sampled weekly over one month in volunteer 40-60-year-old women. Subjects: One hundred and forty-one women, aged between 40 and 60, recruited from community sources (non-clinical), not using hormone replacement or steroidal contraceptives, and with a current sexual partner. Fifty were categorized as premenopausal (ovulating), 37 as perimenopausal and 54 as post-menopausal. Measurements: The following variables were assessed; menopausal status (based on menstrual history and pattern and plasma progesterone), age, BMI, smoking, oestradiol (E2), oestrone (E1), LH, FSH, total testosterone (TT), androstenedione (A), SHBG, free androgen index (FAI), dihydroepiandrosterone (DHEA), dihydroepiandrosterone sulphate (DHEAS) and cortisol. Results: Results are based on multiple regression analysis. TT was positively related to A, BMI and LH. A was negatively related to age and FSH, and positively to DHEA, DHEAS and premenopausal status. SHBG was negatively related to BMI and positively to E1 and non-smoking. DHEA and DHEAS were negatively related to age and were higher in smokers. Both E1 and E2 were related to menopausal status and to FSH. Surprisingly, E2 was negatively related to BMI. Conclusions: A variety of factors influence androgen production in this age group. Whereas it is difficult to predict the effect of menopause on androgen levels, LH stimulation of post-menopausal interstitial cells, modulated by a variety of factors including nutrition, and smoking, are likely to be relevant.



Adrenal and gonadal steroid hormone deficiency in the etiopathogenesis of rheumatoid arthritis

Journal of Rheumatology (Canada), 1996, 23/SUPPL. 44 (10-12

Rheumatoid arthritis (RA) is a multifactonal disease in which both environmental and genetic factors play a role. Data also suggest that neuroendocrine factors are involved. I briefly summarize observations that support this hypothesis. RA is characterized by striking age-sex disparities. The incidence of disease in women increases steadily from the age of menarche to its maximal incidence around menopause. The disease is uncommon in men under age 45, but its incidence increases rapidly in older men and approaches the incidence in women. These observations strongly suggest that androgens play a major suppressive role, and, in fact, testosterone levels are depressed in most men with RA. Mechanistically, many data indicate that testosterone suppresses both cellular and humoral immune responses. Dehydroepiandrosterone (DHEA), an adrenal product, is the major androgen in women. Its production is strikingly dependent upon age. Peak production is in the 2nd and 3rd decades, but levels decline precipitously thereafter. DHEA levels are low in both men and women with RA, and recent data show that levels of this hormone may be depressed before the onset of disease. The role of DHEA in immune diseases, however, is controversial. The menopausal peak of RA onset suggests estrogen and/or progesterone deficiency play-a role in the disease, and many data Indicate that estrogens suppress cellular immunity but stimulate humoral immunity, i.e., deficiency promotes cellular (Th1-type) immunity. Recent data also indicate that progesterone stimulates a switch for Th1 to Th2-type immune responses, RA often develops or flares in the postpartum period, particularly if the mother breastfeeds. This is again consistent with gonadal steroid deficiency playing a role in the onset of disease. Breastfeeding Is associated with blunted hypothalamic-pitu itary-adrenal function and elevated prolactin synthesis. Gonadal and adrenal steroid hormone deficiency, plus elevated prolactin, probably greatly facilitates the expression of Th1-type immunity, which is widely believed to be critical in the pathogenesis of RA. By contrast, RA typically remits during pregnancy, in parallel with the increasing levels of corticosteroids, estrogens, and progesterone. Pregnancy is characterized by a shift in immune function from Th1-type to Th2-type. Oral contraceptives, which generate a condition of pseudopregnancy, also decrease the risk of RA. These data argue that adrenal and gonadal steroid hormones suppress the development. of RA. Several studies indicate that corticosteroid production is inappropriately low in patients with RA, and are reminiscent of observations in Lewis rat models of chronic erosive arthritis. In summary, a growing body of data indicate that RA develops as a consequence of a deficiency in both adrenal and gonadal steroid hormone production. This hypothesis clearly has potential clinical implications.



Changes in circulating steroids with aging in postmenopausal women

OBSTET. GYNECOL. (USA), 1981, 57/5 (624-628)

To examine the possible effects of aging on circulating steroid hormones in postmenopausal women, blood samples were drawn from 155 women, aged 34 to 83 years, with spontaneous ovarian failure. The C-21 steroids, pregnenolone and 17-hydroxypregnenolone; the Delta4 progestins, progesterone and 17-hydroxyprogesterone; and cortisol did not change with age and were similar in concentration to the levels measured during the follicular phase of premenopausal women. The Delta5 androgens, dehydroepiandrosterone and dehydroepiandrosterone sulfate, declined significantly (P<.001) with age, whereas no change was noted in the Delta4 androgens, androstenedione and testosterone. The levels of estradiol (Esub 2) and estrone (Esub 1) were strongly correlated with percent ideal weight but did not change with age. The authors conclude that 1) The production of progestins does not change with age in normal adult women, other than that resulting from the loss of secretion associated with ovarian corpus luteum function. 2) The decline of Delta5 androgens without corresponding changes in their precursors suggests an age-related change of adrenal 17,20 desmolase activity. 3) The levels of Esub 2 and Esub 1 reflect an effect of body size but not of age on peripheral aromatization of precursor androgens.



The effects of oral dehydroepiandrosterone on endocrine-metabolic parameters in postmenopausal women

J. CLIN. ENDOCRINOL. METAB. (USA), 1990, 71/3 (696-704)

To discern the pharmacological effects of dehydroepiandrosterone (DHEA) in older women with low endogenous DHEA and DHEA sulfate (DS), 1600 mg/day (in four divided doses) were administered orally to six postmenopausal women for 28 days in a double blind placebo-controlled cross-over study. Serum concentrations of androgens after the first 400-mg dose of DHEA increased rapidly and reached a maximum at 180-240 min, resulting in increases over baseline of 6-fold for DHEA (5.8 plus or minus 2.1 to 28.8 plus or minus 5.5 nmol/L), 12-fold for DS (3.0 plus or minus 1.6 to 28.2 plus or minus 4.6 micromol/L) and androstenedione (1.4 plus or minus 0.3 to 19.5 plus or minus 9.8 nmol/L), 2.5-fold for testosterone (0.7 plus or minus 0.1 to 2.2 plus or minus 0.6 nmol/L), and 15-fold for dihydrotestosterone (0.2 plus or minus 0.06 to 2.73 plus or minus 1.0 nmol/L), but estrone, estradiol, and sex hormone-binding globulin (SHBF) were unchanged. Assessment at weekly intervals revealed a further increase in all androgens which was maximal at 2 weeks and remained markedly elevated, although it declined somewhat by 4 weeks. The increments observed after 2 weeks of DHEA administration reached 15-fold for DHEA (71.9 plus or minus 14.2 nmol/L), 9-fold for testosterone (6.5 plus or minus 1.7 nmol/L), and 20-fold for DS (65.1 plus or minus 14.9 nmol/L), androstenedione (30.5 plus or minus 11.5 nmol/L), and dihydrotestosterone (3.8 plus or minus 1.5 nmol/L). Both estrone and estradiol showed a progressive increase to 2-fold the basal value at 4 weeks. Integrated SHBG and thyroid binding globulin levels decreased (P < 0.05) during DHEA treatment. However, LH, FSH, body weight, and percent bvody fat, as measured by underwater weighing, were unaltered during the 4-week experiment. A marked decline of 11.3% (P < 0.05) in serum cholesterol and 20.0% (P < 0.05) in high density lipoprotein noted within the first week of DHEA administration persisted for the 28-day period and was accompanied by a nonsignificant downward trend in low density lipoprotein, very low density lipoprotein, and triglycerides. Peak insulin levels during the 3-h oral glucose tolerance test were significantly higher (P < 0.05) after the 289 days of DHEA (1126 plus or minus 165 vs. 746 plus or minus 165 pmol/L) and were accompanied by a 50% increase in the integrated insulin response (P < 0.01) without a significant change in fasting glucose insulin or glucose-6-phosphate dehydrogenase values. These data show that oral DHEA is rapidly absorbed, and a prompt conversion to DS as well as all potent androgens and estrogens occurs with a sustained effect for the 28-day duration of treatment. Thus, in postmenopausal women there appears to be abundant and effective enzymatic systems for the biotransformation of DHEA to C-19 and C-18 sex steroids. Further, pharmacologically imposed DHEA in postmenopausal women induced insulin resistance, altered cholesterol and the high to low density lipoprotein ratio, and decreased circulating SHBG and thyroid binding globulin concentrations. Our findings, which contrast sharply with those of a previous experiment in young men, appear to result from the induction of a highly androgenic state and its impact on several endocrine-metabolic parameters in older postmenopausal women.



Catabolic effects and the influence on hormonal variables under treatment with Gynodian-Depot (Reg.trademark) or dehydroepiandrosterone (DHEA) oenanthate

SWEDEN MATURITAS (NETHERLANDS), 1981, 3/3-4 (225-234)

53 patients from a mainly climacteric population were treated monthly with 200 mg dehydroepiandrosterone (DHEA) oenanthate or with 1 ampoule Gynodian-Depot(Reg.trademark). Pronounced adiposity was present in 15 of these cases. Hormonal variables were determined before the treatment and during the depot effect of the preparations in order to study the principle which supports the oestrogenic influence and any weight-reducing influence under administration of DHEA. The elimination of low-polar oestrogens increased considerably in 4 out of 13 post-menopausal cases treated with DHEA. This effect is probably indirect and presupposes intact ovaries. The incorporation of exogenous DHEA into the excretion of 17-ketosteroids and of 17-ketogenic steroids, such as those of androsterone + aethiocholanolone, depends on the size of the initial pool inasmuch as it is higher in small initial pools than in saturated pools - the size of the pool being age-dependent. An average weight loss of >1 kg/mth was observed under DHEA treatment in 7 out 15 adipose cases. In comparison to the other 8 adipose cases, these 7 were younger and therefore also displayed higher values for 17-ketosteroids and their individual fractions. These ircumstances appeared to explain why the administration of DHEA resulted in higher levels of free plasma DHEA which, in contrast to the cases without loss of weight, also resulted in an increase of renal DHEA-sulphate clearance. It was concluded from the findings that this is the explanation for the catabolic effect of exogenous DHEA. Post- menopausally increased FSH and LH fractions were markedly suppressed in about half of the determinations after Gynodian-Depot administration, the findings indicating that DHEA is probably involved in suppression of the LH fraction.



Regulation of the immune response by dehydroepiandrosterone and its metabolites

Journal of Endocrinology (United Kingdom), 1996, 150/SUPPL. (S209-S220)

Dehydroepiandrosterone (5-androsten-3beta-ol-17-one, DHEA) has been shown to protect mice from a variety of lethal infections. This includes, but is not limited to, infection with viruses (herpes virus type 2, coxsackie virus B4 (CB4)), bacteria (Enterococcus faecalis, Pseudomonas aeruginosa), and a parasite (Cryptosporidium parvum). We have previously reported that androstenediol (5-androstene-3beta,17beta-diol, AED), derived from DHEA, is at least 100 x more effective in up-regulating systemic resistance against CB4 infection than its precursor. Furthermore, androstenetriol (5-androstene-3beta,7beta,17beta-triol, AET) which is formed by 7beta hydroxylation of AED, was more effective against CB4 infection than its precursor, AED. Neither steroid, however, has shown any significant direct antiviral effects. The in vitro influences of DHEA, AED and AET on a mitogen-induced mixed splenocyte proliferation assay were determined. The results showed that DHEA suppressed the proliferation of concanavalin A (ConA)- or lipopoly-saccharide-activated cultures in a dose-dependent manner. AED had little influence on the activation response. However, AET potentiated the response to both mitogens significantly above the control level. The regulation of interleukin (IL)-2 and IL-3 secretion from ConA-activated lymphocytes was analogous to these observations. These functions were depressed by DHEA, unaffected by AED, and potently increased by AET. Moreover, the classic immunosuppressive effects of hydrocortisone on ConA-induced lymphocyte proliferation, as well as IL-2 and IL-3 production, were unaffected by co-culture with DHEA and only minimally counteracted by AED. In contrast, AET significantly counteracted the effect of hydrocortisone when co-cultured together. These data show that while DHEA, AED and AET each function in a similar manner in vivo, in vitro their effects are dramatically different from one another with only AET potentiating the cellular response by increasing lymphocyte activation and counteracting the immunosuppressive activity of hydrocortisone.



Stress-induced suppression of the cellular immune reactions: On the neuroendocrine control of the immune system

Medical Hypotheses (United Kingdom), 1996, 46/6 (551-555)

Immune competence is considered as a state of equilibrium between humoral and cellular immunity. This notion fits well with the functionally antagonistic cytokine profiles in cell groups of CD4+-helper cells as described by Mosmann and Coffman. The Th-1 cells release mainly IL-2, IL-12 and IFNgamma and thereby stimulate the cellular immune reactions. Conversely, the Th-2 cells produce predominantly IL-4, IL-6 and IL-10, thus enhancing humoral immune reactions. Recently, it has been shown that the lymphokine profiles in Th-2 are linked to changes of the humoral balance between cortisol and dehydroepiandrosterone. These studies show that there exist states of equilibrium between T- and B-cell-mediated immune reactions, which may selectively be altered to the disadvantage of the T-cellular immunity by a stress-induced enhancement of cortisol release. In an attempt to restitute stress-induced immunosuppression, a dampening of the cortisol release hormone in the hypothalamus should, therefore, be of primary importance.



Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.

Vaccine (ENGLAND) 1995, 13 (15) p1445-8

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.



Replacement of DHEA in aging men and women. Potential remedial effects.

Ann N Y Acad Sci (UNITED STATES) Dec 29 1995, 774 p128-42

DHEA in appropriate replacement doses appears to have remedial effects with respect to its ability to induce an anabolic growth factor, increase muscle strength and lean body mass, activate immune function, and enhance quality of life in aging men and women, with no significant adverse effects. Further studies are needed to confirm and extend our current results, particularly the gender differences.



Dehydroepiandrosterone modulation of lipopolysaccharide-stimulated monocyte cytotoxicity.

J Immunol (UNITED STATES) Jan 1 1996, 156 (1) p328-35

Dehydroepiandrosterone (DHEA), the predominant androgen secreted by the adrenal cortex, can be converted to both potent androgens and estrogens. In addition to its role as a precursor for other steroid hormones, DHEA has been proposed to play an important role in immunity. This study has investigated DHEA modulation of LPS-induced monocyte cytotoxicity. Cytotoxicity markers assessed include tumor cell killing, IL-1 secretion, reactive oxygen intermediate release, nitric oxide synthetase activity as measured by the release of reactive nitrogen intermediates, complement receptor-1 cell surface protein, and TNF-alpha protein presence. Monocytes stimulated with LPS concentrations of 1.0 micrograms/ml displayed the above cytotoxic markers, whereas monocytes stimulated with DHEA alone or with LPS at a lower concentration of 0.2 ng/ml did not. However, when used simultaneously, DHEA and LPS 0.2 ng/ml displayed a synergistic effect on monocyte cytotoxicity protein, and TNF-alpha cancerous cell lines, IL-1 secretion, reactive nitrogen intermediate release, complement receptor-1 cell-surface protein, and TNF-alpha protein to levels comparable with levels obtained using LPS 1.0 microgram/ml. Finally, Scatchard plot analysis demonstrated the presence of a DHEA receptor in monocytes, suggesting that DHEA effects on LPS-stimulated monocytes are mediated through a receptor-dependent process.



Dehydroepiandrosterone modulates the spontaneous and IL-6 stimulated fibrinogen production of human hepatoma cells.

Acta Microbiol Immunol Hung (HUNGARY) 1995, 42 (2) p229-33

The role of an androgen, dehydroepiandrosterone (DHEA) has been studied on the constitutive and IL-6 induced fibrinogen production of HepG-2 cells. DHEA markedly augments the constitutive fibrinogen production of the hepatoma cells in a dose dependent fashion. Oppositely, for IL-6 induced fibrinogen production, DHEA is strongly inhibitory. The effectiveness of DHEA on the constitutive fibrinogen production is further potentiated if the hepatoma cells are preincubated with a glucocorticosteroid, dexamethasone. These findings demonstrate that the complex interaction between the steroid- and cytokine-directed regulation of the production of acute phase proteins is further coloured by the action of androgens on immune and hormonal systems.



Administration of dehydroepiandrosterone reverses the immune suppression induced by high dose antigen in mice.

Immunol Invest (UNITED STATES) May 1995, 24 (4) p583-93

Several factors including antigen concentration, the route of antigen administration, hormones and cytokines have shown to affect T cells to produce the distinct patterns of lymphokines which exert regulatory and effector functions of immune response. In this study, we asked whether administration of dehydroepiandrosterone (DHEA) to mice which were tolerized by high dose of antigen could modulate T cell functions to restore the suppressed cellular immune response and to produce the distinct lymphokines. An intravenous injection of high dose of sheep red blood cells induced suppression of delayed type hypersensitivity (DTH) and a single subcutaneous injection of the tolerant mice with DHEA restored the suppressed DTH response. Furthermore, in vitro treatment of spleen cells from tolerant mice with DHEA abolished the transfer of tolerance to naive recipients. Lymphocytes from the DHEA-treated tolerant mice produced more IFN-gamma and less IL-4 and IL-6 than the cells from tolerant animals without DHEA treatment. These findings indicate that DHEA could recover antigen-specific immune suppression by differentially affecting T cells to produce the distinct lymphokines.



Effects of dehydroepiandrosterone in immunosuppressed adult mice infected with Cryptosporidium parvum.

J Parasitol (UNITED STATES) Jun 1995, 81 (3) p429-33

Cryptosporidiosis is a diarrheal disease in humans and other animals caused by the coccidian parasite, Cryptosporidium parvum. This study was undertaken to determine the effectiveness of dehydroepiandrosterone (DHEA) in reducing C. parvum infections in immunosuppressed adult C57BL/6N mice and to identify the immunomodulatory effects of DHEA that result in increased resistance to cryptosporidiosis. Dexamethasone-immunosuppressed mice were readily infected with C. parvum following orogastric intubation with 10(6) oocysts/mouse. DHEA treatment of these mice significantly reduced (P < 0.01) both fecal oocyst shedding and parasite colonization of the ilea. Immunosuppressed mice treated with DHEA had more splenic total T cells, CD4+ T cells, and CD8+ T cells than immunosuppressed mice that were not treated, but the differences were not always significant. Moreover, nonimmunosuppressed mice treated with DHEA had significantly more (P < 0.05) splenic total T cells, CD4+ T cells, and total B cells than nonimmunosuppressed mice that did not receive DHEA. Of particular interest was the significantly larger (P < 0.05) number of CD8+ T cells in immunosuppressed, C. parvum-infected, DHEA-treated mice compared with the same mice that were not treated. Up-regulation of the immune system by exogenous DHEA may be useful in the treatment and palliation of cryptosporidiosis.



Relationship between dehydroepiandrosterone and calcitonin gene-related peptide in the mouse thymus.

Am J Physiol (UNITED STATES) Jan 1995, 268 (1 Pt 1) pE168-73

Dehydroepiandrosterone (DHEA) and calcitonin gene-related peptide (CGRP) are naturally occurring substances that are reported to have both opposing and complementary effects on immune functions. In the current study, we sought to determine how they might work together to influence the mitogen-stimulated proliferation of thymocytes. In concanavalin A (ConA)-induced thymocyte proliferation assays, CGRP and DHEA each inhibited proliferation. When the CGRP antagonist CGRP-(8-37) was added to Con A-stimulated thymocytes, the proliferative response was significantly greater than the ConA response alone across a range of ConA doses. Moreover, CGRP-(8-37) blocked the inhibitory effect of DHEA. Individually, CGRP-(8-37), CGRP, DHEA, or their combination did not stimulate thymocyte proliferation in the absence of ConA. CGRP affects the proliferation of CD4+ T cells and thus may be a regional endogenous inhibitor of the proliferation of virgin mature T cells while they remain in the thymus. Furthermore, DHEA may act via endogenous CGRP on the thymus CD4+ T cell population.



Dehydroepiandrosterone functions as more than an antiglucocorticoid in preserving immunocompetence after thermal injury.

Endocrinology (UNITED STATES) Feb 1995, 136 (2) p393-401

Reduced cellular immune responses and altered cytokine production by cells from mice exposed to thermal injury are minimized if dehydroepiandrosterone (DHEA) is administered after experimental burn injury in mice. An analysis of similar tests of immune function developed by mice given the antiglucocorticoid, 17 beta-hydroxy-11 beta-[4-dimethylaminophenyl]17 alpha-propynyl-estra-4,5-diene-3-one (RU486), after the burn revealed no difference in immune function between the RU486-treated mice and the untreated burn group. At the levels of drug used, both DHEA and RU486 were able to completely block the effects of glucocorticoid treatment on immune function in mice, establishing a direct antiglucocorticoid activity of each steroid. Because thermal injury-mediated changes in immunity could be overcome by the administration of DHEA, but not RU486, the data suggest that the elevations in adrenal output of glucocorticoids are not responsible for the alterations in immune function after experimental thermal injury of mice. The results of this study have provided further insight into the mechanism of action of DHEA in this experimental model. The ability of DHEA to preserve immune function in severely thermally injured mice appears to extend beyond an antiglucocorticoid activity.



Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice.

J Steroid Biochem Mol Biol (ENGLAND) Jul 1994, 50 (1-2) p91-100

Dehydroepiandrosterone (DHEA) and pregnenolone (PREG) were both metabolized by homogenates of brain, spleen, thymus, perianal skin, ventral skin, intestine, colon, coecum and muscle tissues from mice. The use of 2H-labeled substrates and of the twin ion technique of gas chromatography-mass spectrometry permitted identification of 7 alpha-hydroxy-DHEA and of 5-androstene-3 beta, 17 beta-diol as DHEA metabolites in digests of all tissues. The extent of PREG metabolism was much lower than for DHEA with all tissues but amounts of the main transformation product were sufficient in brain, spleen and ventral skin digests for identification with 7 alpha-hydroxy-PREG. Dimethylsulfoxide (DMSO) solutions of DHEA, PREG and of their 7-hydroxylated metabolites were injected at different doses and time intervals prior to proximal subcutaneous administration of a lysozyme antigen. Quantities of anti-lysozyme IgG were measured in the serum of treated mice and compared with that from sham-treated animals. Increase of anti-lysozyme IgG was obtained with DHEA and PREG (1 g/kg) when injected 2 h prior to lysozyme. Much lower doses (160 times less) of 7 alpha-hydroxy-DHEA and -PREG were also found to be significantly active when administered at the moment of lysozyme injection. A larger dose of 7 beta-hydroxy-DHEA (50 mg/kg) was necessary for a similar effect. These results suggest that in tissues where immune response takes place, the locally-produced 7-hydroxy metabolites of PREG and DHEA are involved in a process which may participate in the physiological regulation of the body's immune response.



In vitro potentiation of lymphocyte activation by dehydroepiandrosterone, androstenediol, and androstenetriol.

J Immunol (UNITED STATES) Aug 15 1994, 153 (4) p1544-52

Dehydroepiandrosterone (5-androstene-3 beta-ol-17-one, DHEA) has been shown to protect mice from lethal viral and bacterial infections. However, recently, androstenediol (5-androstene-3 beta-17 beta-diol, AED) and androstenetriol (5-androstene-3 beta-7 beta-triol, AET), metabolites of DHEA, have each shown to be more potent endocrine regulators of the immune response. In contrast to glucocorticosteroids, in vivo, these steroid hormones up-regulated the cellular immune response of the host to limit virus-mediated pathology. These experiments first examined the in vitro influences of DHEA, and AED, or AET on mitogen-stimulated activation of murine lymphocytes. From physiologic to pharmacologic doses, DHEA suppressed proliferation of mixed splenocyte cultures activated with Con A or LPS by 20 to 70% whereas AED had little influence on the response. In sharp contrast, AET potentiated the response with both mitogens to 50 to 70% above control. Analogous to these observations was the regulation of IL-2 and IL-3 secretion from Con A-activated lymphocytes by each of these hormones which again was depressed analyzed. The suppressive effects of hydrocortisone on Con A-induced lymphocyte proliferation and cytokine production were strongly counteracted by coculture with AET. DHEA did not counteract hydrocortisone activity whereas AED showed moderate antiglucocorticoid function.



Immune senescence and adrenal steroids: immune dysregulation and the action of dehydroepiandrosterone (DHEA) in old animals.

Eur J Clin Pharmacol (GERMANY) 1993, 45 Suppl 1 pS21-3; discussion S43-4

Immune senescence is characterized by dysregulation of the immune system. The disorder occurs during old age and is manifested by an increased production of autoantibodies and a decreased production of antibodies to most foreign antigens. These events seem to reflect an altered ratio of activity between the CD5+ and CD5- B cell subsets. Likewise, there is dysregulation of cytokine production with an increased production of IL-4, IL-5 and IL-6 associated with a decreased production of IL-2. This appears to reflect an altered ratio of activity between the Th1 and Th2 cell subsets. Dehydroepiandrosterone (DHEA) is one of the three principal adrenal steroids; its serum concentration declines with age. Recent results suggest that in vitro culture of lymphocytes, from aged donors, with DHEA or in vivo treatment of old mice with DHA sulphate results in the augmentation of the antibody response to foreign antigens and a reversal in the dysregulated cytokine production by T cells. Thus, a decline in one of the three principal adrenal steroids is associated with age-associated changes in the immune system. Some of these changes can be reversed by exposure to DHEA. (11 Refs.)



Effects of dehydroepiandrosterone in immunosuppressed rats infected with Cryptosporidium parvum.

J Parasitol (UNITED STATES) Jun 1993, 79 (3) p364-70

Cryptosporidium parvum is a coccidian parasite that causes diarrheal disease in animals and humans. Severe cryptosporidial infections were noted in young adult rats immunosuppressed with the glucocorticosteroid dexamethasone (DEX). B-cell and T-cell responses to the mitogens lipopolysaccharide and concanavalin A, respectively, were depressed in the DEX-treated rats. In addition, DEX treatment suppressed serum IgG levels, in vitro IgG production, and natural killer cell activities. Previous results have shown that DEX-immunosuppressed rats treated with dehydroepiandrosterone (DHEA) exhibit significant reductions in cryptosporidiosis as determined by monitoring oocyst shedding in the feces and parasite colonization of the small intestine. Results from this study indicated that B- and T-cell responses to their respective mitogens, serum IgG levels, and in vitro IgG production were greater in DHEA-treated immunosuppressed rats than in untreated DEX-immunosuppressed rats infected with C. parvum. Similar results were demonstrated in DHEA-treated versus normal control rats infected with C. parvum. These results suggest that the effects of DHEA in reducing cryptosporidiosis are the result of a potentiation of the immune system in the immunosuppressed rats.



Dehydroepiandrosterone protects mice inoculated with West Nile virus and exposed to cold stress.

J Med Virol (UNITED STATES) Nov 1992, 38 (3) p159-66

The protective effect of pretreatment with dehydroepiandrosterone (DHEA) on stress-enhanced viral encephalitis was studied in mice exposed to cold following inoculation with West Nile virus (WNV). Exposure of WNV-inoculated mice to cold water (1 +/- 0.5 degrees C, 5 minutes/day for 8 days) resulted in a mortality rate of 83% as compared to 50% in nonstressed mice (p < 0.05). The effect of cold stress was more pronounced when mice were inoculated with WN-25, a noninvasive neurovirulent variant of WNV. Mice infected with WN-25 showed no mortality, whereas cold stressed mice inoculated with the same virus had a mortality rate of 67% (p < 0.05). The administration of DHEA (serial injections of 10-20 mg/kg with or without a loading dose of 1 gm/kg) resulted in a significant reduction in the mortality rate of stressed mice inoculated with either virus (p < 0.05). Virus levels in the blood and brain of the DHEA-treated mice, were significantly lower than in the control groups. DHEA also prevented the involution of lymphoid organs in stressed mice. The present study provides direct evidence of the protective effects of DHEA as an "anti-stress" agent. Its ability to prevent mortality associated with WNV or WN-25, and involution of lymphoid organs caused by stress-induced immunosuppression, supports the notion that its activity is based on the modulation of the host response.



The relationship of serum DHEA-S and cortisol levels to measures of immune function in human immunodeficiency virus-related illness.

Am J Med Sci (UNITED STATES) Feb 1993, 305 (2) p79-83

Human immunodeficiency virus (HIV) is a major cause of immunoincompetence. Whether the virus, itself, accounts for all the deficiency remains in question. Steroids can also influence immune function; glucocorticoids cause immunoincompetence while dehydroepiandrosterone (DHEA) enhances immune function. Changes in the levels of such hormones during the course of HIV illness might result in significant changes in immune competence. The purpose of this study is to investigate whether dehydroepiandrosterone-sulphate (DHEA-S) or cortisol levels correlate with absolute CD4 lymphocyte levels. Plasma for cortisol and DHEA-S was drawn from 98 adults with HIV. Of these, 67 had simultaneous CD4 levels. Cortisol levels were 12.4 +/- 4.6 micrograms/dl, DHEA-S 262 +/- 142 micrograms/dl, and CD4 levels were 308 +/- 217/mm3 (mean +/- SD). Correlational analysis revealed a significant relationship between DHEA-S and CD4 levels (r = 0.30; p = 0.01) but not between CD4 levels and cortisol (r = 0.11; p = 0.36) or cortisol/DHEA-S ratios (r = 0.17; p = 0.16). When analyzed by clinical subgroups, significant differences were also found with a decrease in DHEA-S levels seen in persons with more advanced illness. The data exhibit a positive relationship between the immune status of patients with HIV-related illness and DHEA, leading to the hypothesis that DHEA deficiency may worsen immune status.



Mobilization of cutaneous immunity for systemic protection against infections.

Ann N Y Acad Sci (UNITED STATES) Apr 15 1992, 650 p363-6

This laboratory reported that a single subcutaneous (SC) injection of the natural steroid hormone dehydroepiandrosterone (DHEA) resulted in significant protection against a lethal herpes virus type 2 encephalitis or a systemic coxsackievirus B4 infection. Our previous results have shown that SC injection of DHEA resulted in upregulation of the specific host immune response resulting in protection against a lethal infection. This hormone did not have any direct antiviral effects in vitro. Furthermore, results indicate that, in vivo, DHEA is not the agent directly mediating the upregulation of the immune response. In the skin, DHEA is converted to androstenediol (AED) and it, in turn, is converted to androstenetriol; this is a metabolic process which appears unique to the skin. This report demonstrates that SC injection of AED results in markedly greater resistance against both viral and bacterial infection. Both DHEA and AED appear to function by facilitating and upregulating host immune responses via mobilization of cutaneous immunity to obtain systemic protection against infections. Because these steroids are native to the host and are regulated by the central nervous system, it is suggested that they may be an integral element of neuroimmunomodulation.



Dehydroepiandrosterone-induced reduction of Cryptosporidium parvum infections in aged Syrian golden hamsters.

J Parasitol (UNITED STATES) Jun 1992, 78 (3) p554-7

Cryptosporidiosis, a parasitic disorder caused by Cryptosporidium parvum, is frequently a fulminating and life-threatening disease in immunocompromised hosts. The immune status of the host plays a critical role in determining the length and severity of the disease. Dehydroepiandrosterone (DHEA) is an immunomodulator that has been demonstrated to upregulate immune parameters. Ten aged (20-24 mo) Syrian golden hamsters were treated with DHEA for 7 days prior to intragastric inoculation with 1 x 10(6) C. parvum oocysts. An additional 10 aged hamsters were infected similarly but retained as untreated controls. The untreated hamsters presented with generalized infections as determined by oocyst shedding in the feces and parasite colonization of the small intestine. Hamsters treated with DHEA exhibited a significant reduction in cryptosporidial infection when compared to untreated hamsters. These results suggest that DHEA may be an effective prophylactic agent for cryptosporidiosis in immunocompromised patients.



Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells.

Clin Immunol Immunopathol (UNITED STATES) Nov 1991, 61 (2 Pt 1) p202-11

Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it is well established that DHEA serves as an intermediate in sex steroid synthesis, recent studies in mice suggest that DHEA may also be a physiologic regulator of IL2 secretion. To explore the effect of DHEA on the human immune system, T lymphocytes from healthy adults were exposed to DHEA followed by stimulation with mitogens or antigen. Upon activation with a variety of stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA produced significantly greater amounts of IL2 and mediated more potent cytotoxicity than T cells activated in the absence of this steroid hormone. The peak effect of DHEA was observed at 10(-9) M, the concentration of hormone present in the blood of normal adults. In contrast to its effect on murine T cells, the IL2 enhancing effect of DHEA on human lymphocytes was limited to fresh CD4+ T cells and CD4+ clones; neither fresh CD8+ cells nor CD8+ clones were directly affected by DHEA treatment, although CD8+ cells stimulated in the presence of CD4+ cells and DHEA demonstrated enhanced cytotoxicity. The enhancing effect of DHEA was also detected at the level of IL2 mRNA, suggesting that DHEA may act as a transcriptional enhancer of the IL2 gene in CD4+ T cells. These results corroborate and extend earlier studies in mice and suggest a physiologic role for DHEA in regulating the human immune response.



Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone.

Life Sci (ENGLAND) 1990, 46 (22) p1627-31

Dehydroepiandrosterone (DHEA), the most abundantly secreted human adrenal steroid, has no known specific function. In spite of this fact there is an abundance of data associating DHEA with "health" in both man and experimental animals. Research in our laboratory has demonstrated evidence for an antagonistic interaction between DHEA and glucocorticoids (GC) in liver and brown adipose tissue. We hypothesized that DHEA also antagonized effects of GC on the immune system and that this "immune protective effect" might explain the diffuse positive effects of DHEA reported in the literature. Effects of GC on the immune system include involution of the thymus when given in animals in vivo and death of thymic lymphocytes in vivo with exposure to these steroids. We hypothesized that DHEA would block this GC mediated thymocyte destruction in vivo and in vitro. Pretreatment with DHEA for three days blocked approximately 50% of the thymic involution seen with dexamethasone. Results of in vitro experiments confirmed protective effects of DHEA in pretreated animals. (less than 50% of cell death in lymphocytes from pretreated mice compared with lymphocytes from control mice.) We conclude from these studies that DHEA protects against at least one GC anti-immune effect, thymic lymphocyte lysis.



Regulation of murine lymphokine production in vivo. II. Dehydroepiandrosterone is a natural enhancer of interleukin 2 synthesis by helper T cells.

Eur J Immunol (GERMANY, WEST) Apr 1990, 20 (4) p793-802

Dehydroepiandrosterone (DHEA) is an adrenal steroid hormone produced in abundance by humans and most other warm-blooded animals, is uniquely sulfated (DHEAS) prior to export into the plasma, and exhibits an age-related decline in production with progressive age. No major physiological functions have been ascribed to the activity of this steroid, although DHEA is known to serve as an intermediary in sex steroid synthesis. Studies on the effects of glucocorticoids (GCS) on the immune system led us to question whether DHEA had effects on the ability of activated lymphocytes to produce interleukin 2 (IL 2). We determined that (a) lymphocytes from DHEA- or DHEAS-treated mice consistently produced much greater levels of IL 2 than normals in response to stimulation, (b) direct lymphocyte exposure to DHEA at low doses (10(-10)-10(-7) M) caused an enhanced capacity to secrete IL 2 following activation, (c) IL 2 production by activated cloned T cell lines could be augmented by DHEA treatment, and (d) GCS-induced depressions in IL 2 synthesis by T cells or T cell clones could be overcome in vitro and in vivo by exposure to the effects of DHEA. These findings suggest that DHEA, presumably through receptor-mediated mechanisms similar to other types of steroid hormones, may represent a natural and important regulator of IL 2 production in both normal and pathologic conditions.



Protection against acute lethal viral infections with the native steroid dehydroepiandrosterone (DHEA).

J Med Virol (UNITED STATES) Nov 1988, 26 (3) p301-14

A significant protective effect of a native adrenal steroid, dehydroepiandrosterone (DHEA), was demonstrated in studies of two lethal viral infection models in mice: systemic coxsackievirus B4 and herpes simplex type 2 encephalitis. The steroid was active either by long-term feeding or by a single subcutaneous injection. A closely related steroid, etiocholanolone, was not protective in these models. Histopathological analysis, leukocyte counts, and numbers of spleen antibody forming cells in the coxsackievirus B4 model suggests that DHEA functions by maintaining or potentiating the immune competence of mice otherwise depressed by viral infection. DHEA was not effective in genetically immunodeficient HRS/J hr/hr mice and did not demonstrate antiviral activity in vitro. While the molecular basis for DHEA's effect on the immune system is not known, studies by others suggest that it may counteract the stress related immunosuppressive effects of glucocorticoids stimulated by viral infection. Because DHEA is a native steroid that has been used clinically with minimal side effects, the utility of DHEA in the therapeutic modulation of acute and chronic viral infections including the acquired immune deficiency syndrome deserves intensive study.



Food intake reduction and immunologic alterations in mice fed dehydroepiandrosterone.

Exp Gerontol (ENGLAND) 1984, 19 (5) p297-304

A diet containing 0.4% DHEA was fed to male mice of a long-lived strain from 3 weeks until 18 weeks of age. These mice were compared with others fed a control diet ad libitum and with mice pair-fed the control diet in amounts approximating the intake of the DHEA-fed group. Mice fed the DHEA diet failed to eat all of the food presented to them whereas the pair-fed mice ate all of their food. All mice were studied at 18 weeks of age for two age-sensitive immune parameters (spleen lymphocyte proliferation induced by T-cell mitogens [PHA or ConA] and natural killer cell lysis of an allogeneic tumor). DHEA feeding led to: 1) a decrease in food intake (approximately 30% less than for mice fed the control diet ad libitum), 2) a lower body weight at 18 weeks of age (approximately 40% lower than for ad libitum controls) due to a decrease in the body weight gained from 3 weeks through 18 weeks of age (approximately 55% lower than controls), 3) a lower spleen weight (approximately 30% lower than controls) but without lower numbers of nucleated cells per spleen, 4) an increase in PHA-induced proliferation by spleen lymphocytes (approximately 100% higher than for controls) and, 5) no influence on splenic natural killer cell activity. The inhibition of body weight gain for mice fed DHEA appeared due to both a reduction in food intake and a metabolic effect since mice eating DHEA gained less body weight per gram of food eaten than did mice in either group eating the control diet.



Steroid induction of gonadotropin surges in the immature rat. I. Priming effects of androgens.

Endocrinology (UNITED STATES) Nov 1978, 103 (5) p1822-8

Sexually immature female rats were either primed with estradiol benzoate on day 23 or given daily injections of various androgens on days 23--25. Plasma for LH and FSH determinations was collected on day 26, 5 h after an injection of progesterone. Massive gonadotropin surges were found after priming with estradiol benzoate or treatment with dehydroepiandrosterone (DHEA), delta 4-androstenedione, and testosterone, but not with ring A-reduced androgens (5 alpha-dihydrotestosterone, 5 alpha-androstane-3 alpha,17 beta-diol, its 3 beta-epimer, and androsterone) or the nonaromatizable 11 beta-hydroxy- and 11-ketoderivatives of delta 4-androstenedione. Rats bearing DHEA-containing Silastic implants also produced LH surges in response to progesterone. A single injection of an antiestrogen antiserum abolished gonadotropin surges in rats primed with estradiol benzoate or DHEA and greatly reduced the accompanying uterine hypertrophy. DHEA and delta 4-androstenedione were barely uterotrophic in ovariectomized rats but sustained progesterone-induced gonadotropin surges. The results indicate that certain (adrenal?) androgens are able to induce maturation of the steroid-sensitive surge system via extragonadal aromatization, whereas their uterotrophic effect is largely mediated by the ovaries. Coordinated increased conversion of androgens at central and peripheral sites may be of physiological importance for the triggering of puberty.