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Address reprint requests and correspondence to K. Sreekumaran Nair, MD, PhD, Endocrine Research Unit, Mayo Clinic, 200 First St SW, Rochester, MN 55905
Dehydroepiandrosterone (DHEA) and its sulfated ester are found in high concentrations in the plasma; however, their role in normal human physiology, other than as precursors for sex hormones, remains incompletely defined. Studies of rodent models have shown that these hormones have beneficial effects on a wide variety of conditions, such as diabetes, obesity, immune function, atherosclerosis, and many of the disorders associated with normal aging. However, rodents are not the best models to study the actions of these hormones because they have very little endogenous DHEA; thus, the doses given to these animals are usually suprapharmacological. Human studies have been performed to determine the potential beneficial effects of DHEA replacement in persons with low DHEA levels. Results have been conflicting. Human studies suggest a potential role for DHEA replacement in persons who have undergone adrenalectomy and possibly in the aging population. However, long-term studies assessing the benefits vs adverse effects must be done before DHEA replacement can be recommended.
Dehydroepiandrosterone (DHEA) and its sulfated ester (DHEAS) have been studied increasingly during the past few years, with substantial evidence emerging about their possible roles in normal human physiology. Recent data have shown that DHEA levels are highly correlated with longevity in healthy nonhuman primates,
and headline phrases such as “mother of all hormones,” “superhormone,” and “fountain of youth” have brought these hormones to the attention of the lay public. Use of the Internet search engine Google (www.google.com) in the last week of August 2003 revealed more than 400,000 Web sites mentioning DHEA. This review includes a MEDLINE search of English language articles thought to be relevant with the terms DHEA or Prasterone. Any related articles were also examined for potential inclusion in this review.
Low or absent levels of DHEA are found in healthy elderly individuals and those with adrenal insufficiency (hypoadrenal subjects). Long-term trials of DHEA replacement in these groups are currently in progress in the United Kingdom and in the United States. With the availability of DHEA as an over-the-counter product in the United States and on the Internet worldwide, this review provides generalists and specialists with information about these hormones and will aid them in determining whether DHEA replacement has a role in individuals in whom levels are low.
BIOCHEMISTRY AND PHYSIOLOGY OF DHEA
DHEA and DHEAS are 2 of the major C19 steroids secreted by the zona reticularis region of the adrenal glands. As with all C19 steroids, these hormones are products of cholesterol metabolism and are derived from the action of CYP11A (cytochrome P-450scc) on the inner membrane of the highly active mitochondria found in the adrenal cortex.
In humans, DHEA and DHEAS are the most abundant circulating steroid hormones. Their role remains to be fully elucidated. DHEAS can be readily converted to unconjugated DHEA by ubiquitous tissue steroid sulfatases and thus probably serves as a reservoir for DHEA. A simplified illustration of the steroid synthesis pathway is shown in Figure 1. Note that DHEA, testosterone, and estrogens are derived from the precursor 17-hydroxypregnenolone by the action of 17a-hydroxyprogesterone aldolase, a reaction catalyzed by cytochrome P-450c17. Investigators have proposed that the decline in DHEA levels (Figure 2) with senescence is associated with a decline in activity of this enzyme, resulting in low levels of DHEA and testosterone.
Often, DHEA and DHEAS are referred to as weak androgens; however, there is no evidence that they bind to the androgen receptor. Thus, DHEA and DHEAS have little or no intrinsic androgenic activity. However, they are converted into androstenedione and then further into potent androgens and estrogens in the liver and other target organs.
DHEA and DHEAS are adrenal precursor sex steroids produced in vast quantities. The active form is DHEA, and DHEAS is enzymatically converted into DHEA in peripheral tissues in an intracrine fashion.
Although both DHEA and DHEAS are bound to albumin in the plasma, DHEAS is bound more firmly, and, unlike DHEA, DHEAS is not bound to sex hormone–binding globulin but is free in the circulation. In addition, because DHEA is rapidly cleared from the circulation and has a half-life of 1 to 3 hours, it has a circadian rhythm related to that of the secretion of corticotropin.
Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity.
The direct mechanism of action of DHEA, if any, is unknown. The effects of DHEA are due to the actions of the sex hormones into which it is converted. Although recent studies found specific receptors to help explain some of the actions of DHEA, the mechanisms of other actions of this hormone remain elusive. An example of these receptors includes skeletal muscle binding sites.
Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy.
Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy.
Other receptors include those thought to be responsible for some of the protective cardiovascular effects of DHEA. These effects are mediated through a specific G protein–coupled plasma membrane receptor leading to an increase in endothelial nitric oxide synthase.
A DHEA-specific receptor-binding complex has also been found in murine and human T cells. In this model, DHEA binding to this receptor complex led to an increase in interleukin (IL) 2 production.
In both sexes, DHEA levels vary profoundly throughout life (Figure 2). Levels are high at birth but quickly decline within a few months. Levels start to increase in children 8 to 10 years of age, peaking by the middle or end of the second decade of life. Levels then decline by 10% per decade, plateauing after a person is older than 80 years.
Evidence for this in humans is based on analyzing ethnic differences in DHEA levels, which suggests that life expectancy may be greatest in populations in whom DHEA levels are highest.
An alternative explanation for this finding is that people who are healthier have higher DHEA levels.
The decline in circulating DHEA levels parallels many age-related changes, such as sarcopenia and osteopenia. In studies of men who have undergone castration, approximately 30% to 50% of circulating androgens are derived from DHEA. The remaining androgens come from the testes as testosterone. Both DHEA and testosterone are then converted into the active androgen dihydrotestos-terone in the peripheral tissues.
In postmenopausal women, the origin of most circulating androgens is controversial. Some authors state that androgens are derived from DHEA and that production from the ovaries is minimal,
Subjects (especially female) with adrenal insufficiency have chronic DHEA deficiency because routine replacement therapy with glucocorticoids and mineralocorticoids fails to restore DHEA-derived an-drogens.
Therefore, replacement of these androgens in subjects with adrenal insufficiency should aim to restore concentrations to levels equivalent to those before the onset of the condition. A substantial amount of work has been done in both elderly subjects
to determine the optimal dose to restore DHEA levels to those seen in young adults; 50 mg/d is sufficient to increase DHEA levels into the reference range of age-matched young adults.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.
Clearly, differences are to be expected between the normal physiological process of aging and the pathological state of adrenal insufficiency. Hypoadrenal individuals have little or no circulating DHEA; however, elderly persons, although having substantially lower levels than healthy individuals in their second or third decade, have levels that may be several-fold greater than in those with adrenal insufficiency. These differences mean that relating and inferring results from one group to another is difficult; however, the premise of much of the current clinical research in both aging and hypoadrenal subjects is that the 2 groups are interchangeable. This link between elderly and hypoadrenal subjects is compounded by the findings of studies that have analyzed different measures of general well-being, libido, and mood and have found similar results in both groups.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Many disorders of aging, such as reduced immunocompetence, obesity, diabetes, and cancers, have been attributed to changes in DHEA based on animal studies
Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer.
EXPERIMENTAL EVIDENCE OF BIOLOGIC AND CLINICAL EFFECTS
Mood and Well-being
Sex hormones are known to play an important role in mood and well-being in both sexes (Table 1). Because levels of these hormones decline with aging, there is a parallel deterioration of mental function, and DHEA replacement is thought to be of potential benefit.
Table 1Summary of Human Studies Analyzing Effect of DHEA on Mood, Well-being, Cognition, and Memory
AD = Alzheimer disease; C = crossover design; DHEA = dehydroepiandrosterone; MID = multi-infarct dementia; NA = not applicable; O = observational; OL = open label; P = placebo controlled; R = randomized.
DHEA
Type of subject and age (y)
Sex (No.)
Type of study
Dose (mg/d)
Duration
Results
Reference
Healthy elderly
>65
M and F (622)
O
NA
NA
Low DHEA levels associated with depression (significant in women, trend in men)
Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study.
Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
* AD = Alzheimer disease; C = crossover design; DHEA = dehydroepiandrosterone; MID = multi-infarct dementia; NA = not applicable; O = observational; OL = open label; P = placebo controlled; R = randomized.
As a neuroactive neurosteroid, DHEA has become more important with the discovery that both DHEA and DHEAS are produced in the brain independently and are not influenced by factors that control adrenal DHEA secretion.
Simultaneous radioimmunoassay of progesterone, androst-4-enedione, pregnenolone, dehydroepiandrosterone and 17-hydroxyprogesterone in specific regions of human brain.
The role of DHEA in the brain also remains unclear, but recent work in mice suggests that the hormone is important in guiding thalamic fibers to their cortical targets in the embryonic brain by the regulation of motility and growth of corticothalamic projections.
Some in vitro and animal data provide biologic plausibility for the psychotropic effects of DHEA; DHEA acts as an antagonist on the receptor of the major inhibitory neurotransmitter γ-aminobutyric acid,
perhaps by acting close to or at the sites where barbiturates act. Administration of DHEA in rats has been shown to increase hypothalamic serotonin levels.
γ-Aminobutyric acid and serotonin are known to be mood-related receptors, and both have targeted, prescribable pharmacological agents (benzodiazepines and selective serotonin reuptake inhibitors, respectively) used as antidepressants, whereas NMDA (“ecstasy’) is a psychotropic drug of abuse.
There are several reasons why estrogens may play a role in ameliorating the cognitive and emotional disturbances associated with menopause. Estrogens have been shown to produce an increase in attention span, concentration, libido, and memory in postmenopausal women.
The influence of estrogens on the psyche in climacteric and post menopausal women.
in: van Keep PA Greenblatt RB Albeaux-Fernet M Consensus on Menopause Research: A Summary of International Opinion. University Park Press,
Baltimore, Md1976: 84-93
However, in aging men, despite DHEA administration increasing circulating estrogens and androgen metabolites, this beneficial effect on mood has been an inconsistent finding,
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
an endogenous opioid that causes an increase in well-being. Long-term large epidemiological studies in humans have shown that mood in elderly women correlates with DHEA, with low levels found in those with depression.
Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study.
Studies assessing the effects of DHEA replacement on sexual and psychological well-being have been performed in hypoadrenal subjects who have undergone adrenalectomy
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.
The various results are summarized in Table 1. Clearly, based on the reported studies, no consensus is available. In most studies, DHEA replacement in hypoadrenal subjects seems to lead to an improvement in mood. The effect on depression and other conditions appears to be dose dependent and is probably related to duration of administration. Carefully conducted long-term studies in well-defined populations are critical to make definitive conclusions on the effects of DHEA on mood and well-being.
Cognition and Memory
Alzheimer disease (AD) and multi-infarct dementia (MID) are relatively common in the aging population.
Some evidence shows that AD is due to hippocampal damage induced by free radicals, resulting in increased lipid peroxidation and alteration in free radical defense mechanisms.
Animal studies using the centrally administered β25-35-amyloid peptide as a model for AD have shown that administration of DHEA reduces the rate of decline of cognitive function usually associated with the introduction of this protein.
The manner in which this protection is afforded has yet to be fully established. In addition, DHEA use in vivo seems limited because doses were suprapharmacological.
The hippocampus is thought to be the area of the brain associated with memory. A substantial portion of the biochemical work analyzing the effects of DHEA is from in vitro and animal studies. In vitro work evaluating rat embryo hippocampal cultures showed a decline in cell numbers, a change in morphology, and an increase in the production of the stress-activated protein kinase 3 in those cultures exposed to corticosterone.
With aging, the rate of loss of hippocampal neurons in rats increases, and this loss is substantially accelerated with the addition of glucocorticoids.
Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures.
In other experiments that used cell cultures exposed to the excitatory amino acids NMDA and α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid, the expected decline in the hippocampal cell number was not seen when DHEA was added, but DHEA alone did not increase the number of cells in culture.
Adrenal secretion during major depression in 8- to 16-year-olds, I: altered diurnal rhythms in salivary cortisol and dehydroepiandrosterone (DHEA) at presentation.
Dehydroepiandrosterone antagonizes the neurotoxic effects of corticosterone and translocation of stress-activated protein kinase 3 in hippocampal primary cultures.
The mechanism of DHEA neuroprotection is unknown. However, it has been shown that in the rat hippocampus levels of the immediate precursor to DHEA production, pregnenolone sulfate, are highly correlated with spatial memory performance.
Confirmation that this occurs in humans has yet to be established. In the developing rat embryo, the rates of cell birth, migration, and survival are highly dependent on adrenal steroid levels. Whether this occurs in humans is unknown; however, in a postmortem study of 1 patient with Addison disease, there was evidence of dentate gyrus neuronal loss, suggesting a similar requirement for adrenal steroids.
Large-scale epidemiological work specifically analyzing DHEA and cognitive function has been conflicting. One study showed that the reduction in DHEA levels with normal aging did not correlate with cognitive decline.
That study also evaluated mortality and showed that subjects with a DHEA level in the lowest quartile at baseline were more likely to die at follow-up 15 years later compared with those whose levels were in the upper quartile.
This represented an increase in mortality of 40% and 24% in men and women, respectively. However, decline in cognitive function was not greater among those who died before follow-up.
Other epidemiological studies have supported the hypothesis of the link between low DHEA levels and AD. Luchsinger et al
reported that reducing caloric intake might reduce the risk of AD in individuals carrying the apolipoprotein E epsilon4 (APOE4) allele. People with APOE4 are more vulnerable to AD at an earlier age.
also found that caloric restriction delays the agerelated decline in DHEAS levels in nonhuman primates and suggest this may also be true in humans. Moreover, recent work from France analyzed DHEAS levels in postmortem specimens from 11 elderly subjects with and without AD; a significant correlation was found between areas of the brain that have high levels of both β-amyloid protein and the pathological tau protein seen in patients with AD and low levels of DHEAS.
Early data show that low DHEA levels were associated with both AD and MID. One such study compared DHEA levels in 50 independently living community men aged 55 to 94 years with levels in 61 male nursing home residents aged 57 to 104 years.
There was an inverse relationship between DHEA levels and the presence of either AD or MID. In addition, there was an inverse relationship between DHEA levels and the degree of dependence in activities of daily living. Further analysis showed that the plasma DHEA level was lowest in 80% of the male nursing home residents who required total care. In another observational study of patients requiring total care who had either AD or MID, the prevalence of low DHEA levels was 68% and 100%, respectively.
that elderly patients with organic brain disease have low DHEA levels. This group also found that the cortisol/DHEA ratio was high. High DHEA levels are associated with a lower cortisol/DHEA ratio, and this has been proposed as a mechanism that prevents cognitive decline in these individuals.
However, these results conflict with those from an observational study of 35 subjects with AD that found no differences in DHEA levels compared with age-and sex-matched controls.
Moreover, it remains to be determined whether decreases in DHEA levels cause physical and cognitive changes or whether DHEA levels represent an overall decline in physical function. However, data suggesting that DHEA levels are low in patients with organic brain disease conflict with more recent work suggesting that DHEA levels are increased in patients with AD and MID.
Low levels of DHEAS rather than of DHEA may be the cause of these dementias. In a descriptive study analyzing 40 elderly subjects with either AD or vascular dementia and their age-matched controls, serum concentrations of DHEA did not significantly differ.
However, subjects with dementia had lower concentrations of serum DHEAS and a lower DHEAS/DHEA ratio compared with normal controls. The significance of this has yet to be determined.
Evidence for the potential benefits of DHEA is available from several sources. A randomized double-blind study of 17 individuals showed that a supraphysiological dose of 90 mg of DHEA was associated with a substantial benefit in the treatment of midlife-onset dysthymia in both men and women.
was open-label. Results of these studies are summarized in Table 1.
Preliminary work with 10 healthy young volunteers showed that a single pharmacological dose of 500 mg of DHEA enhanced relaxation by increasing the amount of time spent in rapid eye movement (REM) sleep,
A study with electroencephalography analyzed the effects of various glucocorticoids, their biosynthetic precursors, and their metabolites on sleep patterns.
This work showed that the effects could be attributed to the mode of action of these neuronally produced steroids. Specifically, steroids such as pregnenolone and DHEA were thought to be produced in glial cells and act in a paracrine fashion, thus modifying the sleep electroencephalogram in humans in a manner that suggested their potential as memory enhancers.
However, a recent review article challenged this viewpoint, stating that REM sleep is not necessary for establishing memory because REM deprivation in humans is not associated with memory dysfunction.
Thus, the effects of glucocorticoids and DHEA on memory and sleep remain to be fully clarified.
Together, these findings suggest that reducing caloric intake extends the availability of DHEA and may be a causative factor in the delay or prevention of AD. This experimental evidence from observational studies remains to be established in interventional human studies.
Sexual Functioning
Various studies on the effect of DHEA on sexual function are summarized in Table 2.
Table 2Summary of Human Studies Analyzing Effect of DHEA on Sexual Functioning
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
The role of testosterone in the sexuality and sexual functioning of hypogonadal women was recently shown in a randomized crossover study involving 75 women who had undergone oophorectomy. Shifren et al
showed that testosterone supplementation in women taking estrogen replacement significantly improved sexual function and psychological well-being. Thus, the role of estrogens alone in sexual well-being is potentially limited.
A retrospective open-label study revealed an association between the complex relationship of sexual physiology, desire, arousal, and orgasm with DHEA levels.
The impact that this decrease in DHEA and testosterone has on overall sexual functioning is unknown because observational studies have shown a positive correlation between libido and testosterone levels.
In hypoadrenal women who have undergone natural or surgical menopause, androgens given in addition to estrogens provided a beneficial effect on sexuality.
showed that 50 mg/d of DHEA was associated with a highly significant improvement in all aspects of sexual well-being. In a randomized controlled trial, Johannsson et al
gave either placebo or DHEA to 38 androgen-deficient women with hypopituitarism. In the DHEA group, the subjects were further divided by age: women older than 45 years received 20 mg/d and women younger than 45 years received 30 mg/d of DHEA for 6 months. With both doses, there was an improvement in androgen-dependent effects such as in skin (oil, moisture, and elasticity) and increases in both axillary hair and pubic hair. In addition, with the dose of 30 mg/d, all subjects had an increased score in sexual interest and activity. With the dose of 20 mg/d, only 41% of subjects had these changes. Although there was a trend, this improvement was not statistically significant because a few subjects taking placebo also showed an improvement. In that same study, the women's partners were asked to grade changes in personality and mood. The partners of subjects taking DHEA replacement recorded a statistically significant overall improvement in alertness, stamina, and initiative. This difference in perception of well-being between participants and their partners remains unclear. As part of the trial, the last 6 months were an open-label treatment with DHEA. During that time, subjects who had initially been taking placebo reported changes similar to those who had been taking DHEA for the entire trial.
Further uncertainty about DHEA effects on sexual functioning in women was revealed in 2 recent placebo-controlled randomized studies of 16 postmenopausal and 12 premenopausal healthy volunteers who received a single 300-mg dose of DHEA.
All the women were sexually active. They were shown erotic videos after a period of “neutral” visual stimulation. Physical sexual responses were assessed using measurements of vaginal pulse amplitude and vaginal blood flow. These studies showed significantly greater mental and physical sexual arousal to visual stimulation in only the DHEA-treated postmenopausal women.
The reason for these differences is unclear but may be due to the effects of endogenous ovarian steroids negating the effects of DHEA.
Other studies have shown a correlation between serum levels of DHEA and testosterone with libido in young women who have a decreased or absent sexual desire
(Figure 3). An interventional study with 12 premenopausal women with sexual dysfunction and low libido showed that low libido occurred most frequently in women with low DHEA levels and that replacement of DHEA, either 50 mg/d or 100 mg/d, restored sexual function
Figure 3Dehydroepiandrosterone (DHEA) levels in women of all ages with reduced or absent libido compared with women with normal libido. P<.05 in all groups. Data from Guay and Jacobson.
Use of DHEA in men has not been researched as extensively as in women. In randomized crossover studies with healthy elderly or hypoadrenal men given 50 mg/d or 100 mg/d of DHEA for 3 months, there was no benefit in any of the indices of sexual function.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
This outcome may have occurred because the endogenous testosterone canceled the effects of the DHEA. This result contrasts that in a small randomized trial in elderly men that showed a daily dose of 50 mg of DHEA may be useful in the treatment of erectile dysfunction.
In summary, results are conflicting regarding the effects of DHEA administration in men, in premenopausal and postmenopausal women, and in normal and hypoadrenal subjects. Furthermore, large long-term randomized studies are needed to address this issue. Another issue that needs to be determined is whether replacement doses or pharmacological doses of DHEA are needed to achieve beneficial effects.
Insulin Sensitivity
Most of the work done on insulin sensitivity has been in animal models. Extrapolating these results to human studies is difficult because rodents produce very little endogenous DHEA and the demonstrated effect is pharmacological rather then physiological. However, human studies have been done and are reviewed subsequently along with relevant animal studies.
DHEA lowers serum insulin levels and increases insulin sensitivity in rodent models.
The mechanism of action is unclear because this reduction is achieved without improvement in insulin resistance in peripheral tissues and without lowering pancreatic insulin content. The decrease in insulin levels with DHEA supplementation may be a contributing factor in lowering body weight or altering metabolic efficiency in DHEA-treated rats. Lowered serum insulin levels may be responsible for reduced activities of lipoprotein lipase, glucose-6-phosphate dehydrogenase, and fatty acid synthetase measured in DHEA-treated obese rats.
Proposed mechanisms for this include improved muscle insulin signaling, as reflected in binding of phosphatidylinositol 3-kinase to the insulin receptor substrate 1. However, despite the decrease in insulin levels, there appears to be a lack of effect of DHEA on the glucose tolerance test, suggesting no effect on peripheral glucose metabolism. This is supported by other studies that showed no effect of DHEA on muscle glucose transport protein 4 content
Thus, the antiobesity effect of DHEA in rats may be due to a combination of elevated mitochondrial respiration and lowered insulin levels. There are divergent effects on food intake in lean and obese rats given DHEA. In obese Zucker rats, DHEA reduced food intake, whereas in lean rats, food intake was increased.
Studies analyzing the relationship between insulin sensitivity and DHEA-testosterone ratios have found it to be strongly associated, suggesting that DHEA affects insulin sensitivity.
Pyruvate dehydrogenase in T lymphocytes reflects the degree of glucose intolerance of hyperandrogenic women and diabetic subjects in whom enzyme activity is impaired.
Sensitivity of pyruvate dehydrogenase to insulin in activated T lymphocytes: lack of responsiveness to insulin in patients with polycystic ovarian disease and diabetes.
to achieve a serum level of 2.5 times greater than baseline may not have been long enough to produce a clinically significant change in insulin sensitivity in vivo.
Some results suggest that DHEA has a role in reducing age-related increases in insulin levels, insulin resistance, and blood glucose. In a few randomized studies of healthy elderly men and postmenopausal women, insulin sensitivity improved significantly.
Insulin sensitivity was measured indirectly by serum insulin or by formal testing. These results contrast those of studies in women with adrenal insufficiency that found that either 50 mg/d or 200 mg/d of DHEA supplementation had no effect on insulin sensitivity.
Christiansen JJ, Gravholt CH, Fisker S, et al. Short term restoration of androgen levels with dehydroepiandrosterone (DHEA) in female adrenal insufficiency does not affect insulin sensitivity [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 21, 2002.
Again, the issue arises when the absolute DHEA deficiency in hypoadrenal subjects is compared with the relative DHEA deficiency in healthy elderly subjects. These studies are summarized in Table 3. Insulin sensitivity is currently one of the outcomes being assessed in long-term DHEA replacement studies of hypoadrenal and healthy elderly subjects.
Gurnell EM, Hunt PJ, Curran SE, et al. A long term trial of DHEA replacement in Addison's disease [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 20, 2002.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.
Christiansen JJ, Gravholt CH, Fisker S, et al. Short term restoration of androgen levels with dehydroepiandrosterone (DHEA) in female adrenal insufficiency does not affect insulin sensitivity [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 21, 2002.
In summary, in contrast to animal studies, in humans, although there are intriguing measurable effects of DHEA on plasma insulin and glucose levels, these changes have not been translated into a clinically significant beneficial effect on insulin sensitivity and glucose disposal.
Reduction of atherosclerosis by administration of dehydroepiandrosterone: a study in the hypercholesterolemic New Zealand white rabbit with aortic intimal injury.
showed that hyperinsulinemia reduces serum DHEA levels. Because insulin is thought to be proatherogenic, this reduction in DHEA levels is a possible explanation for the loss of antiatherogenic actions of DHEA.
Although this hypothesis remains to be formally tested in human studies, some animal data and human epidemiological data suggest that this is the case.
Reduction of atherosclerosis by administration of dehydroepiandrosterone: a study in the hypercholesterolemic New Zealand white rabbit with aortic intimal injury.
Most of the current data are summarized in Table 4. The epidemiological evidence in humans is conflicting because some studies show an inverse relationship between DHEA levels and increased cardiovascular risk in men but not in women.
In a large ongoing observational study analyzing cardiovascular risk factors, diabetes in men older than 50 years was associated with a low DHEA level.
Relation of dehydroepiandrosterone and dehydroepiandrosterone sulfate with cardiovascular disease risk factors in women: longitudinal results from the Massachusetts Women's Health Study.
In healthy volunteers, some observational studies attempting to correlate DHEA levels with muscle strength and body composition failed to find an association,
However, in both the observational studies, body composition was determined by anthropomorphic measure only, whereas the studies that showed no association used dual x-ray absorptiometry.
Several interventional studies in healthy subjects and hypoadrenal women failed to show any changes in body composition with DHEA administration.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.
The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.
The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.
showed that a 100-mg daily dose of DHEA for 6 months was associated with a reduction in fat mass in healthy elderly men but not in women. Additionally, the study by Diamond et al
showed that topical application of a 10% cream of DHEA for 1 year was associated with a statistically significant reduction in femoral fat, an increase in femoral muscular area, and decreased skinfold thickness. These findings are consistent with those in a smaller study by Nestler et al,
who found a change in body composition in a small number of healthy young men given a highly suprapharmacological dose of 1600 mg/d of DHEA for 28 days. They showed that body fat decreased, with an overall increase in skeletal muscle tissue. Villareal et al
showed that a 50-mg daily dose of DHEA for 6 months was associated with a statistically significant reduction in body fat and an increase in lean mass in 18 healthy elderly men and women.
Muscle strength in healthy elderly volunteers has been assessed. In observational studies, quadriceps strength was positively correlated with circulating DHEA levels in men
Valenti G, Maggio M, Ceresini G, et al. The relationship between DHEAS levels and muscle strength in men: results from the InCHIANTI Study [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 21, 2002.
The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.
Valenti G, Maggio M, Ceresini G, et al. The relationship between DHEAS levels and muscle strength in men: results from the InCHIANTI Study [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 21, 2002.
The effect of six months treatment with a 100 mg daily dose of dehydroepiandrosterone (DHEA) on circulating sex steroids, body composition and muscle strength in age-advanced men and women.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Christiansen JJ, Gravholt CH, Fisker S, et al. Short term restoration of androgen levels with dehydroepiandrosterone (DHEA) in female adrenal insufficiency does not affect insulin sensitivity [abstract]. Presented at: The Endocrine Society 84th Annual Meeting; San Francisco, Calif; June 21, 2002.
In general, long-term studies tend to show changes in body composition and muscle strength. Long-term placebo-controlled double-blind studies are needed to determine the effects of DHEA on body composition and muscle strength.
Bone
Rat studies have shown that DHEA administration reduces the rate of bone loss usually seen after oophorectomy.
Evidence concerning the influence of DHEA on bone turnover in humans is conflicting. Gonadal androgen deficiency is associated with osteoporosis in men.
Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D- and androgen deficiency-induced bone resorption.
Studies of individuals with receptor defects or enzyme deficiencies have shown that in men estrogens are also necessary for normal bone maturation and formation.
A syndrome of female pseudohermaphrodism, hypergonadotropic hypogonadism, and multicystic ovaries associated with missense mutations in the gene encoding aromatase (P450arom).
In women, aging is associated with a decline in estrogens and adrenally derived androgens. This decline may be causally associated with the development of osteoporosis because DHEA is converted to estrone within osteoblast-like cells by aromatase cytochrome P-450 in culture.
Dehydroepiandrosterone (DHEA) as a possible source for estrogen formation in bone cells: correlation between bone mineral density and serum DHEA-sulfate concentration in postmenopausal women, and the presence of aromatase to be enhanced by 1,25-dihydroxyvitamin D3 in human osteoblasts.
Thus, DHEA may contribute to the maintenance of bone mineral density (BMD) in postmenopausal women. In addition, cross-sectional and longitudinal data show a correlation between DHEA levels and lumbar BMD.
Interventional studies of healthy subjects showed that DHEA supplementation had no effect on markers of bone turnover or on BMD measured by dual x-ray absorptiometry.
In hypoadrenal subjects, the issue of whether osteoporosis is due to a lack of adrenally derived androgens or to overtreatment with glucocorticoids is controversial. Some evidence of uncertain importance from 1 study showed that DHEA replacement is useful in hypoadrenal subjects.
Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.
Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.
Dehydroepiandrosterone replacement in women with adrenal insufficiency: effects on body composition, serum leptin, bone turnover, and exercise capacity.
Thus, the role of DHEA in preventing osteoporosis in elderly or hypoadrenal subjects remains uncertain.
Immune Function
On the basis of animal and in vitro studies, DHEA has several effects on immune function. Work with rodent models has shown that DHEA protects mice from lipopolysaccharide-induced endotoxic shock.
That study reported that mortality of mice exposed to a lethal dose of endotoxin was reduced from 95% to 24% by treatment with a single dose of DHEA, given 5 minutes before the intervention.
The applicability of these findings to humans is unknown.
In humans, there is a strong correlation between DHEA levels and helper T-cell type 1 cytokine levels. These cytokines are IL-2 and interferon γ. However, levels of the helper T-cell type 2 cytokines, IL-4, IL-5, and IL-6, increase with age.
High IL levels are implicated as a causal factor in many conditions, such as rheumatoid arthritis, osteoporosis, B-cell cancers, atherosclerosis, and Parkinson disease.
Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.
Because these ILs help regulate immune activity, it is possible that the increased susceptibility to illness associated with chronic disease and aging occurs as a result of changes in the levels of these cytokines.
Serum dehydroepiandrosterone (DHEA) and DHEA sulfate are negatively correlated with serum interleukin-6 (IL-6), and DHEA inhibits IL-6 secretion from mononuclear cells in man in vitro: possible link between endocrinosenescence and immunosenescence.
found a decrease in CD4+ cells, with an associated enhancement in natural killer cell (CD8+/CD56+) activity and cytotoxicity. Also, DHEA appeared to suppress the increase in stimulated IL production seen in the placebo group.
showed that the effect of DHEA on T cells is to enhance their ability to produce other cytokines, such as IL-2, IL-3, and interferon γ. Such effects occur only if the cells are activated while under the influence of this hormone, and they appear to be most prominent in lymphoid organs that contain the greatest ability to convert DHEAS to DHEA. Investigators argue that replacement therapy with DHEA should restore the normal immunocompetence that tends to be lost with aging.
found that DHEA had beneficial effects on immune function by increasing the number of B cells, monocytes, natural killer cells, T-cell receptors, and IL-2 receptors. This increase in the expression of the IL-2 receptor enabled enhancement of the T-cell responsiveness to mitogen stimulation. All these effects decline during physiological aging. The significant increase in natural killer cell cytotoxicity in DHEA-treated subjects was potentially related to the increased number of natural killer cells, both events being mediated by DHEA-induced IL-2 stimulation.
Reversal of the immunosenescent phenotype by dehydroepiandrosterone: hormone treatment provides an adjuvant effect on the immunization of aged mice with recombinant hepatitis B surface antigen.
Randomized controlled trials with several hundred women have analyzed the effect of DHEA supplementation on autoimmune conditions such as systemic lupus erythematosus, with some success in reducing glucocorticoid dose and symptom scores without increases in disease activity.
Dehydroepiandrosterone treatment of women with mild-to-moderate systemic lupus erythematosus: a multicenter randomized, double-blind, placebocontrolled trial.
However, in a smaller open-label trial of 6 postmenopausal women and 5 elderly men with rheumatoid arthritis, supplementation with 200 mg of DHEA daily for 16 weeks was of no benefit in either clinical or laboratory measures of disease activity.
ADVERSE EFFECTS AND POTENTIAL LIMITATIONS OF DHEA USE
In most studies, adverse effects are common but minor. They usually occur in women and are due to the androgenic effects. The most common adverse effect is increased skin sebum production, leading to perceived “greasiness” and acne.
However, many women previously reported that this change is beneficial and that before DHEA replacement their skin was excessively dry. This effect is reversible when DHEA is withdrawn.
Of greater concern are the reports of mild elevations in serum transaminase levels. These occur within a few weeks after initiation of DHEA. However, these increases have not caused any subjects to withdraw from a study. Additionally, effects have either been reversed when the drug was discontinued or have regressed after a few weeks of drug therapy.
Because of the conversion of DHEA into androgens and estrogens, use of supplemental DHEA in individuals with a history of sex hormone–dependent malignancy, such as prostate, breast, or endometrial cancer, remains a valid concern. This issue needs to be fully addressed in long-term studies in humans.
AVAILABILITY OF DHEA IN THE UNITED STATES
The International Olympic Committee banned DHEA use because of its conversion to sex hormones and thus its potential to be used as a drug of abuse. The Food and Drug Administration also banned the substance until the passage of the Dietary and Supplement Health and Education Act of 1994, when this ruling was overturned. DHEA is now freely available in pharmacies and health food stores, where it is classified as a food supplement. This is despite the fact that DHEA is not a food, that DHEA does not naturally appear in the human food chain, and that no foodstuff can perform the physiological role of DHEA. It can be sold directly to the public as long as no claims are made about therapeutic efficacy. In an attempt to reduce the potential abuse of DHEA, a bill was recently introduced to the US House of Representatives that aims to restrict over-the-counter sale of DHEA and other androgenic steroid precursors.
Sweeney JE, Osborne T. To Amend the Controlled Substances Act With Respect to the Placing of Certain Substances on the Schedules of Controlled Substances, and for Other Purposes, HR 207 IH, 108th Cong, House of Representatives, 1st Sess (January 7, 2003).
The manner in which passage of this bill would affect those who may derive benefit from DHEA, such as hypoadrenal and elderly subjects, remains to be determined.
In the United States, food supplements are not required to undergo strict safety and efficacy testing, and thus there are issues of quality control.
One study showed that the quantity of DHEA from different manufacturers in several different doses varied from 0% to 150% of what the label claimed was in the product.
SUMMARY AND CONCLUSIONS
DHEA and DHEAS are intriguing hormones. Their metabolites have a variety of effects on several physiological systems, and yet little is known about the role of either DHEA or DHEAS in normal physiology. It is still unclear whether aging should be classified as a DHEA-deficient state. In hypoadrenal subjects, DHEA deficiency is associated with a lower quality of life. However, these hormones are not essential for life because hypoadrenal subjects and those who have undergone adrenalectomy who have little or no circulating DHEA do not have shortened life spans.
Evidence supports the use of DHEA in hypoadrenal subjects (Table 1, Table 2, Table 3, Table 4, Table 5). The lay press has widely promoted the use of DHEA in normal healthy individuals, and bodybuilders promote its use as a method to increase muscle mass. However, many of the claims made on Internet Web sites (“fountain of youth,” “prevents diabetes,” “prevents aging,” “boosts the immune system,” etc) fail to mention that most of these studies were performed either in vitro or in animals. These reports are further misleading because they fail to state that the results were usually a response to highly suprapharmacological doses of DHEA. The degree of quality control of the substances currently marketed is a concern. Finally, there are valid concerns about the use of DHEA in individuals with a history of sex hormone–dependent malignancies. Large-scale human studies are needed to address these intriguing issues.
REFERENCES
Roth GS
Lane MA
Ingram DK
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Biomarkers of caloric restriction may predict longevity in humans?.
Marked attenuation of ultradian and circadian rhythms of dehydroepiandrosterone in postmenopausal women: evidence for a reduced 17,20-desmolase enzymatic activity.
Specific binding and effects of dehydroepiandrosterone sulfate (DHEA-S) on skeletal muscle cells: possible implication for DHEA-S replacement therapy in patients with myotonic dystrophy.
Effects of replacement dose of dehydroepiandrosterone in men and women of advancing age [published correction appears in J Clin Endocrinol Metab. 1995;80:2799].
Oral dehydroepiandrosterone for adrenal androgen replacement: pharmacokinetics and peripheral conversion to androgens and estrogens in young healthy females after dexamethasone suppression.
Relationship of prediagnostic serum levels of dehydroepiandrosterone and dehydroepiandrosterone sulfate to the risk of developing premenopausal breast cancer.
Relationships of dehydroepiandrosterone sulfate in the elderly with functional, psychological, and mental status, and short-term mortality: a French community-based study.
Endogenous levels of dehydroepiandrosterone sulfate, but not other sex hormones, are associated with depressed mood in older women: the Rancho Bernardo Study.
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