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| ADRENAL ANDROGENS Chapter 12 - Wiebke Arlt, MD August 12, 2004 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE |
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| ADRENAL ANDROGENS Chapter 12 - Wiebke Arlt, MD August 12, 2004 TO OBTAIN A DOWNLOAD OF THIS CHAPTER IN WORD OR PDF FORMAT, CLICK HERE |
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Most of this chapter will focus on dehydroepiandrosterone (DHEA) while some mention of androstenedione will be made. DHEA and androstenedione are usually referred to as adrenal androgens, which is only in part correct. The adrenals clearly represent the most important source of circulating DHEA and androstenedione, with a significant, age- and sex- specific contribution of the gonads. However, they actually do not represent androgens as they do not bind to the androgen receptor but they may exert androgenic action by serving as a prohormone for downstream conversion to sex steroids.
DHEA and its sulfate ester DHEAS are the most abundant steroid hormones in human circulation. The physiological role of these steroid hormones has long remained elusive. However, during recent years a growing number of well-designed studies have helped to shed light on the role of DHEA in human health. Nevertheless, many aspects remain to be elucidated.
DHEA is distinct from other major adrenocortical steroids - cortisol and aldosterone - in declining with advancing age. This age-associated pattern is only seen in humans and higher non-human primates. Administration of large doses of DHEA to experimental animals has demonstrated a multitude of beneficial effects on the prevention of cancer, heart disease, diabetes and obesity (1). This has led to the assumption that the age-related decline of DHEA may play a role in the degenerative changes observed in human aging and that administration of DHEA may reverse some of these changes. Moreover, the availability of DHEA as a food supplement in the USA resulted in aggressive marketing of DHEA as an anti-aging drug and in large scale self-administration without medical supervision.
However, rodent adrenals are not capable of DHEA synthesis and thus circulating levels of DHEA and DHEAS in rodents are several orders of magnitude lower than in humans and no age-related decline in DHEA concentrations has been documented. This indicates that experimental studies in laboratory animals receiving high doses of DHEA have little bearing for human physiology.
This chapter, therefore, will focus on the available scientific data on DHEA which was generated in humans. DHEA(S) will refer to both DHEA and DHEAS.
In humans and in some non-human primates the secretion of DHEA(S) shows a characteristic pattern throughout the life cycle (2,3,4) (Fig. 1). DHEA(S) is secreted in high quantities by the fetal adrenal cortex leading to high circulating DHEAS levels at birth. As the fetal zone involutes, a sharp postpartal fall in serum DHEA(S) concentrations is observed leading to almost undetectable levels. However, during the 6th to the 10th year of age a gradual increase in DHEA(S) production is observed, a phenomenon termed adrenarche (4,5). The regulation of adrenarche remains elusive and it has shown to be independent of gonadarche. Intraindividual maximum concentrations are achieved during the third decade, followed by a steady decline with advancing age so that levels in the oldest-olds are only 10-20 % of those seen in young adults (6). This decline has been termed "adrenopause" in spite of the fact that cortisol secretion does not change considerably with age (7). The age-related decline in DHEA(S) levels shows high interindividual variability and seems to be associated with a reduction in size of the adrenal zona reticularis (8). Adrenopause is independent of menopause and occurs in both sexes as a gradual process at similar ages. While serum DHEAS concentration do not vary throughout the day, DHEA secretion follows a diurnal rhythm similar to that of cortisol. Liu et al. (9) observed an attenuation of the diurnal rhythm and the pulse amplitude of DHEA secretion with ongoing age. Moreover, the ACTH-induced increase in DHEA secretion is reduced in elderly subjects (10), whereas the cortisol response to an ACTH challenge is constant or even increases.
There is a clear sex difference in DHEA(S) concentrations with lower DHEAS concentrations in adult women compared to men (2). There is also a clear genetic component predetermining circulating DHEA(S) levels as they vary considerably between populations of different racial background (11). Moreover, the high interindividual variability in any group of similar age is apparently in part inherited and serum DHEAS has been suggested to be a specific individual marker (12).
DHEA exerts indirect action as it represents a crucial precursor for active sex steroid synthesis
As the human steroidogenic enzyme P450c17 converts almost no 17a-OH-progesterone to androstenedione, the biosynthesis of virtually all sex steroids proceeds through DHEA, which is synthesized by P450c17 from 17-OH-pregnenolone. DHEA is converted to androstenedione by the activity of 3a-hydroxysteroid dehydrogenase (3a HSD) and then further converted to testosterone and estradiol by isoenzymes of 17a-hydroxysteroid dehydrogenase (17a-HSD) and P450 aromatase, respectively (Fig. 2). Studies on the pharmacokinetics and bioconversion of DHEA in humans with low circulating DHEAS revealed that DHEA administration leads to sexually dimorphic conversion: significant increases in circulating androgens in women (13) and in circulating oestrogens in men (14). This suggests that DHEA may lead to androgenic effects in women and oestrogenic effects in men. However, tissue-specific androgenic action of DHEA may better be reflected by circulating androgen metabolites such as androstanediol glucuronide (ADG) and androsterone glucuronide (ATG) (15), which significantly increase after oral DHEA in men while circulating androgens do not (14). As ADG is the major metabolite of dihydrotestosterone (DHT) (16), it reflects increased DHT generation in peripheral androgen target tissues. Thus DHEA paradigmatically illustrates the concept of intracrinology that involves activation, action, and metabolism of steroids within one and the same peripheral target cell (17). The widespread expression of 3a HSD, 17a HSD, 5a-reductase and P450 aromatase in various target tissues results in almost ubiquitous peripheral generation of sex steroids from DHEA (18,19,20). Tissues involved include liver, skin, prostate, bone, breast, and brain. It has been estimated that 30-50% of androgen synthesis in men and 50-100 % of estrogen synthesis in pre- and postmenopausal women occurs from adrenal steroids in peripheral tissues (21). In addition, beyond its role as a crucial sex steroid precursor DHEA is also converted to intermediate steroids of yet unspecified but potentially distinct activity, as exemplified by androstenediol (D5diol) (Fig. 2).
Another important prerequisite of DHEA action is the interconversion of DHEA and DHEAS because only de-sulfated DHEA can be converted downstream. Thus the local availability and activity of DHEA sulfotransferase and steroid sulfatase (Fig. 2) determines the ratio of DHEA activation (via conversion to sex steroids) to inactivation (via secretion as DHEAS back into the circulation). Analysis of the pharmacokinetics of DHEA and DHEAS following oral administration of DHEA suggests that DHEA and DHEAS undergo continuous interconversion (13,14). Measured with a constant infusion technique the conversion ratios for the conversion of DHEAS to DHEA were 0.006 for men and 0.004 for women indicating that a significant amount of DHEA produced arises form DHEAS (22). However, the precise contribution of the DHEAS pool to DHEA re-generation remains to be clarified.
DHEA may act as a neurosteroid via direct interaction with neurotransmitter receptors
There is compelling evidence for DHEA synthesis and action in the central nervous system (23). Several studies have demonstrated the synthesis of P450c17 and other key steroidogenic enzymes in the brain (24,25) thereby providing the tools to generate DHEA in the absence of adrenal and gonadal function. DHEA influences neuronal activity via interaction with neurotransmitter receptors including N-methyl-D-aspartate [NMDA] receptor, sigma receptor, and g-aminobutyric acid [GABAA] receptor (26,27,28) thereby suggesting a putative anti-depressant action of DHEA. Animal and in vitro studies have shown that DHEA(S) stimulate neuronal outgrowth and development and improve glial survival, learning and memory (29,1).
DHEA may exert direct specific actions by serving as a ligand for a - yet to be identified - specific DHEA receptor
There is growing evidence for DHEA action via specific receptors, although such a DHEA receptor has not yet been fully characterized or even cloned. High affinity binding sites for DHEA have been described in murine and human T lymphocytes (30,31) but their specificity for DHEA as opposed to active androgens remained questionable. More recently, high affinity binding sites for DHEA were identified in bovine endothelial cells (32). DHEA has also been shown to activate endothelial nitric oxide synthase (eNOS) in endothelial cells (32,33), potentially via a G-protein coupled plasma membrane receptor (32). Similarly DHEA affects extracellular-signal-regulated kinase 1 (ERK-1) phosphorylation in human vascular smooth muscle cells independently of androgen and estrogen receptors (34). These observations strengthen the concept of a direct and specific hormonal activity of DHEA independent of its potential bioconversion to other steroids.
Taken together the available evidence clearly indicates that DHEA has a complex and specific activity profile, which is gender specific due to its sex-related differential pattern of downstream bioconversion to potent sex steroids.
Androstenedione - Mechanisms of action
Androstenedione is not only a product of DHEA metabolism but may be regarded as a prohormone itself as it can be converted to testosterone by 17aHSDs or to estrone by the P450 aromatase (Fig. 2). Accordingly, administration of androstenedione may alter circulating steroid hormone concentrations. In women pronounced increases not only in circulating androstenedione but also in testosterone have been described following administration of 100 mg androstenedione (35). By contrast, in men the effects of oral androstenedione have been variable with serum testosterone unaffected after 100 mg androstenedione (36,37) but significant testosterone increases after 300 mg androstenedione (38). Importantly, clear increases in estrogens were observed after oral ingestion of androstenedione in young and elderly men (36,37,38), an effect quite similar to oral DHEA administration. The intracrine activation of androstenedione - similar to DHEA - was highlighted by a detailed analysis of the metabolism of orally administered androstenedione in young men (39) observing significant increases in the excretion rates of conjugated androgens.
At present, there is no evidence that androstenedione has biological activity independent of its downstream conversion to sex steroids.
THE BIOLOGICAL ROLE OF DHEA - EPIDEMIOLOGICAL EVIDENCE
Barret-Connor et al (40) reported an inverse correlation between DHEAS levels and death from any cause in men >50 years of age, but not in women (41,42). In a prospective cohort study in 622 subjects of 65 years and older mortality at 2 and 4 years was associated with low serum DHEAS at baseline in men but not in women (43). Similarly, in a recent report including men (n=963) and women (n=1171) >65 years of age, all cause mortality and cardiovascular disease mortality were highest in individuals with serum DHEAS levels within the lowest quartile for men. Again, no significant association of circulating DHEAS and mortality was found in women (44). Accordingly, Mazat et al (45) found no association between mortality and DHEAS levels in women, whereas in men the relative risk of death was 1.9 (p<0.01) for those with the lowest concentrations of DHEAS. In a study of healthy very old men (90-106 years) low DHEAS concentrations were associated with poor functional status (46). From these studies an overall pattern of sex specific differences in DHEA action merges as most (but not all) studies observed differences between men and women. These difference may be in part explained by sex-specific differences in bioconversion of DHEA(S) (13,14).
In addition, low DHEAS levels may be a non-specific marker of poor health status and thereby associated with an increased risk of severe illness and death. Low DHEA(S) concentrations have been found in systemic lupus erythematosus, dementia, breast cancer and rheumatoid arthritis and there is an inverse relationship between serum DHEAS levels and severity of disease (47). Chronic disease often leads a shift of intra-adrenal biosynthesis away from DHEA(S) production favoring cortisol secretion (48). Thus, low DHEAS levels may indicate the presence of a not yet apparent disease, which determines the future risk of morbidity or even mortality. As cortisol is generally acting immune suppressive and DHEA may have immune-enhancing properties, the ratio between circulating levels of DHEA(S) and cortisol may be of particular importance.
THE BIOLOGICAL ROLE OF DHEA - EVIDENCE FROM CLINICAL INTERVENTION STUDIES
DHEA replacement in patients with adrenal insufficiency
Patients with adrenal insufficiency (AI) suffer from severe and premature loss of DHEA production and as they receive glucocorticoid and mineralocorticoid replacement they represent a pathophysiological model of isolated DHEA deficiency. Replacement of cortisol and aldosterone alone is not sufficient to fully restore well-being in AI. Lovas et al (49) have demonstrated in 88 patients with primary AI receiving GC and MC impaired self-perception of general health and vitality. In addition, the overall scores for fatigue clearly indicated more fatigue in this patient population. This also affected other important socio-economic parameters with significantly more AI patients out of job and receiving disablement pensions than to be expected from the numbers of the reference population (49). Gurnell et al (50) found similar impairments in a large cohort of patients with primary AI from England (n=106) further indicating that conventionally treated AI is associated with a specific pattern of chronic disability. Jakobi et al (51) have provided some more insight in the mechanism of increased fatigue in conventionally treated patients with AI. Muscle function (twitch tension, central activation) was reduced and patients self-terminated a submaximal fatigue protocol significantly earlier than controls (5ñ1 vs 10ñ1 min, p=0.006) (51).
For replacement of DHEA(S) in AI an oral dose of 25-50 mg DHEA per day has consistently been found to restore circulating DHEA(S) back into the normal range of young adults (52,53,54) with a single morning dose being efficient enough to maintain normal DHEA(S) levels for 24 hours. Due to downstream bioconversion of DHEA lasting increases in circulating androgens have been demonstrated in women with AI receiving DHEA replacement (13,52). In fact, the superior pharmacokinetics of oral DHEA suggest it to be a promising tool for androgen replacement in women, which has been previously hampered by pharmacokinetic problems with dose-adjusted testosterone delivery (55).
To date there are four published randomized double blind trials on DHEA treatment in patients with adrenal insufficiency (52,53,56,57). A fifth large trial has recently been completed in England, however, up to now the results have only been presented in abstract form (50). Three of the trials have studied women only (52,56,57), whereas the other two trials included both men and women (53,50).
In the first double-blind study (52) 24 women with primary and secondary adrenal insufficiency received in random order 50 mg of DHEA orally each morning for 4 months and placebo for 4 months with a 1 month wash out period. Treatment with DHEA raised the initially low concentrations of DHEA(S), androstenedione, and testosterone into the normal range. Serum concentrations of sex hormone-binding globulin (SHBG), total cholesterol and high-density lipoprotein (HDL) cholesterol decreased significantly. DHEA replacement significantly improved overall well-being, largely due to highly significant improvements in depression and anxiety scores as assessed by the SCL-90-R and the Hospital Anxiety and Depression Scale (HADS). Scores on all three subscales of the Multidimensional Mood Questionnaire also significantly improved after treatment with DHEA. A reduction in fatigue was evident from the Giessen Complaint List (p=0.03). Treatment with DHEA also resulted in significant increases in visual analogue scores assessing aspects of sexual function and satisfaction. DHEA did not affect fasting serum glucose, insulin and parameters of body composition (58). However, DHEA induced a significant decrease in serum leptin (p=0.01) and an increase in serum osteocalcin (p=0.02) compared to placebo. Androgenic skin effects of DHEA treatment were reported in 19 out of the 24 women but were mostly mild and transient (52).
Improvement in mood and fatigue was also observed after DHEA replacement in Addison's disease in the trial reported by Hunt et al (53). In this double blind, randomized crossover trial 39 patients (24 women, 15 men) received 50 mg oral DHEA and placebo, each for 12 weeks. The hormonal changes induced by DHEA in females were virtually identical to those reported by Arlt et al (52) with increases in both serum DHEA(S) and in active androgens back into normal range for women while in men DHEA(S) but not androgens increased. Hunt et al (53) found a significant increase in self-esteem after DHEA substitution (p<0.001). Using a Profile of Mood State Questionnaire evening mood and fatigue were shown to be improved after DHEA. No changes in bone mineral density, body mass index, serum cholesterol or insulin sensitivity were observed after 12 weeks of DHEA replacement. Adverse events of DHEA replacement were few and mild (facial acne in 9 patients vs. 5 patients receiving placebo). As the beneficial effects on well-being were observed also in male patients, it was concluded that DHEA may exert this action rather directly via its neurosteroidal action than as a consequence of its peripheral conversion to androgens (53). The same group followed up on these results and studied the effects of 12 months of DHEA replacement (50 mg/d) in 106 patients with primary AI employing a parallel group study design (50). Preliminary results of this phase III trial demonstrated significant improvements in health-related quality of life during DHEA replacement after three and six months and an attenuation of this effect after 12 months with dramatic falls in well-being scores following DEA withdrawal. In addition, they found DHEA-induced significant increases in femoral neck bone mineral density and in lean body mass (as assessed by dual energy x-ray absorptiometry (DXA)) (50).
In a recent study DHEA (20-30 mg/ day) was used in 38 women with secondary AI due to hypopituitarism (56). DHEA or placebo was given for 6 months in a randomized, placebo-controlled double blind study, followed by a 6 months open treatment period. DHEA(S) increased into the normal range during DHEA administration whereas androstenedione and testosterone rose only to subnormal levels. The percentage of partners of the patients who reported improved alertness, stamina, and initiative by their spouses were 70%, 64%, and 55%, respectively, in the DHEA group and 11%, 6%, and 11%, respectively, in the placebo group (p<0.05) Sexual relations tended to improve (p=0.06). An increase in or the reappearance of axillary and/ or pubic hair was seen in all women given 30 mg DHEA and in 69% of women receiving 20 mg DHEA but was not found in women receiving placebo. Glucose metabolism and lipoproteins remained unaffected by DHEA with the exception of transient decrease in HDL cholesterol. Interestingly, based on age-adjusted reference values the study group had 79ñ20% and 67ñ23% of predicted values for peak and mean handgrip strength over 10 seconds. These values had significantly increased at 12 months (p<0.05).
In contrast, the most recent study using 25 mg DHEA in 39 patients with primary AI in a parallel group design failed to detect a benefit for subjective health status and sexuality (57). The reason for the negative result is most likely the fact that the study was grossly underpowered to detect significant changes. This trial, therefore, is a good example that inadequately designed studies can cause more harm than they provide benefits in the development of new treatment strategies (59).
DHEA supplementation in healthy elderly subjects
The age-related decline in circulating DHEA(S) has led to a number of randomized trials to assess the effect of oral DHEA in otherwise healthy elderly subjects. In a first double blind placebo-controlled trial using a cross-over design 13 men and 17 women aged 40-70 years received either 50 mg DHEA or placebo for 3 months (and vice versa) (60). The subjects reported an improvement in well-being using an non-validated questionnaire for self-assessment of well-being. No change in insulin sensitivity and body composition was found. Bioavailable IGF-1 increased slightly during DHEA, whereas HDL-cholesterol decreased in women. Short-term (2 weeks) randomized double blind studies by Wolf et al (61,62) failed to demonstrate any benefit of DHEA on well-being, mood and cognition. Similarly, in a double-blind placebo-controlled cross-over trial, Arlt et al (63) found no effect of four months of DHEA supplementation (50 mg/ day) on mood, well-being and sexuality in 22 men aged 50-69 years who had been selected for serum DHEAS in the lowest quartile of men of similar age. In another placebo-controlled randomized crossover trial van Niekerk et al (64) found no effect of 50 mg/ day DHEA for 13 weeks on well-being and cognition was found using a wide range of validated questionnaire and standardized test batteries. No effect of DHEA on activities of daily living was found after 3 months of 100 mg DHEA/d in 39 men aged 60-84 years in another placebo-controlled crossover trial (65).
In the largest study to date, Baulieu et al (66) studied the effects of 50 mg DHEA/ day vs placebo in a double-blind randomized parallel study including 140 men and 140 women aged 60-79 years. In general the results were disappointing. Neither well-being nor cognition was improved by DHEA using a wide range of validated tools. In women >70 years libido was increased and slight but significant gains in bone mineral density were observed in women but not in men.
Taking all studies on DHEA supplementation in elderly subjects together, the results show only very limited effects of DHEA compared to placebo. An important explanation for this lack of efficacy may be related to a selection bias. In almost all studies only healthy subjects with excellent performance status at baseline were included, thereby leaving limited space for further improvement. However, from these studies it can be concluded that age-related low DHEA concentrations do not necessarily lead to impaired well-being, cognition and sexuality per se (17). Thus an aging-associated decline in serum DHEA(S) differs by orders of magnitude from the very low DHEAS concentrations observed in adrenal insufficiency, a situation not dissimilar to natural menopause in comparison to premature ovarian failure.
DHEA treatment in patients with impaired mood, sexuality and cognition
Consistent with the effects of DHEA on mood and well-being in patients with adrenal insufficiency beneficial effects were also observed in randomized double-blind studies in patients with major depression (67) and midlife dysthymia (68). DHEA also improved scores on an ADL scale in patients with myotonic dystrophy (69). Recently Strous et al (70) have studied the efficacy of DHEA (100 mg/ day) in schizophrenic patients with prominent negative symptoms. In a double-blind trial a significant improvement in negative symptoms (p<0.001), as well as in depressive (p<0.05) and anxiety (p<0.001) symptoms was seen in individuals receiving DHEA. Reiter et al (71) have reported an improvement in erectile function, sexual satisfaction and orgasmic function in 40-60 year old men suffering from erectile dysfunction and receiving 50 mg DHEA/ day for 6 months in a randomized double-blind fashion. It seems noteworthy that the pattern of improvement observed in these trials closely resembled the changes observed in patients with adrenal insufficiency.
With regard to the potential effects of DHEA on impaired cognition and memory there are only results from one double-blind placebo-controlled trial available. In this study 58 patients with Alzheimer's disease were randomized to either six months of treatment with DHEA (100 mg/ day) or placebo. A transient effect on cognitive performance narrowly missed significance (72), possibly because of the small patient sample.
DHEA supplementation in patients with immunological disorders
In a number of studies DHEA supplementation has been used to modify immune functions and alter the course of immunopathies. Most studies have been performed in patients with systemic lupus erythematosus (SLE), a chronic autoimmune inflammatory disease of unknown etiology (73,74,75). The concept to use DHEA in the treatment of SLE was based on the observation that women are more often affected and that androgens and DHEA concentrations are low in patients with SLE (76). Moreover, androgen treatment can modify the disease progression in an animal model of SLE (77). After preliminary evidence of a glucocorticoid-sparing effect of DHEA in patients with mild SLE (78) a randomized double-blind placebo-controlled trial was performed (200 mg DHEA orally for 3 months) (73). It demonstrated beneficial effects of DHEA on patient and physician overall assessment, SLE disease activity index (SLEDAI) and glucocorticoid requirements. This was confirmed in recent double-blind randomized, placebo-controlled trials demonstrating that DHEA (200 mg/ day) was well tolerated, reduced the number of SLE flares, reduced disease activity and allowed reducing the dosage of glucocorticoids (75,74). It is important to note, that these studies included women only and that it remains unclear whether similar results can be obtained in men. In a phase II uncontrolled pilot trial DHEA (200 mg/ day) was effective and safe in patients with refractory Crohn's disease and ulcerative colitis (79). However, to date no placebo-controlled trials have been performed in inflammatory bowel disease. In all these trials side-effects were mild with acne being the most frequently seen adverse event despite the use of undoubtedly supraphysiological DHEA doses (200 mg/d).
DHEA supplementation has also been used to enhance the antibody response to tetanus and influenza vaccines (80,81,82). However, in these randomized placebo-controlled trials no consistent effect of DHEA on protective antibody titers was found.
Androstenedione administration in clinical studies
Effects of oral androstenedione have not been studied in women and have been largely disappointing in men. Short-term (5 days) androstenedione (100 mg/ day) had no anabolic effect on muscle protein metabolism in eugonadal young men (83). In 30-56 year old men androstenedione (3 x 100 mg/ day) for 28 days slightly reduced HDL-cholesterol without affecting prostate specific antigen (PSA) suggesting some androgenic activity (37). Serum HDL-cholesterol was also reduced in an eight week randomized trial in 20 young men receiving oral androstenedione (300 mg/ day); androstenedione failed to enhance muscle adaptions to resistance training in this population (36).
At present both treatment duration and sample sizes have been too limited to draw any firm conclusions on the clinical efficacy of androstenedione. However, the profound increases in circulating testosterone observed in women after oral androstenedione deserve attention and should preclude its use as food supplement (35).
THE EMERGING PROFILE OF DHEA ACTION IN HUMANS
Effects on the central nervous system
Improvement in mood and well-being have consistently been observed in patients with adrenal insufficiency (52,53,56) and in patients with depressive disorders (67,68) and in schizophrenia (70), particularly improving symptoms of anxiety and depression and their physical correlates. It is important to note that improvements have only been observed in subjects with impaired mood and well-being at baseline and that DHEA-induced improvements led to scores in the range of normal healthy subjects. This indicates that DHEA may normalize impaired well-being but will not lead to supranormal "well-being" in otherwise healthy subjects (irrespective of the presence of low endogenous DHEAS concentrations).
The basis for the anxiolytic and antidrpressive activity of DHEA remains to be elucidated but may be related to both androgenic effects and neurosteroidal actions of DHEA. With proof for anti-GABAergic and NMDA-stimulating effects DHEA may be considered a stimulatory neurosteroid which leads to a word of caution. Some cases of mania occuring during DHEA treatment have been reported (84,85) and we also have observed a similar case in a woman with adrenal insufficiency receiving 25 mg DHEA/d, although a direct causal role for DHEA is difficult to establish.
By contrast, there is little evidence that DHEA affects memory or cognition. Negative results have been found not only in healthy elderly subjects (66) but also in adrenal insufficiency (86). Moreover, in Addison's disease cognition is not impaired despite severe endogenous DHEA deficiency (86). Thus it is unlikely that cognition is a major target of DHEA action.
Libido and sexual satisfaction are influenced by DHEA in women with AI (52) and in elderly women with age-related low DHEAS (66). Also in men, only impaired sexuality benefits from DHEA administration (71) while normal baseline performance cannot be enhanced (63). The effect of DHEA on libido and sexuality is most likely a consequence of increased androgenic activity derived from DHEA by peripheral bioconversion. In recent years it has become increasingly clear that androgens play a key-role for female sexuality (55,87). In fact, the adrenals are a major source of female androgens (88) and the fundamental role of the adrenals for female sexuality has been rediscovered by the studies on the therapeutic potential of DHEA. The available evidence and the superior pharmacokinetic properties make DHEA a highly attractive tool for treatment of impaired sexuality in women. However, firm conclusions must await the results of further trials.
Metabolism and body composition
The effects of DHEA on metabolic parameters (e. g. lipids, insulin sensitivity) and body composition are mostly not consistent and largely unimpressive. Insulin sensitivity was unaffected in women with adrenal insufficiency and also in healthy elderlies receiving replacement doses of DHEA (58,60,89,90,91), whereas Diamond et al (92) observed decreased fasting glucose and insulin in 15 women receiving DHEA cream (10%) but no effect on total areas under the curve during oral glucose tolerance test (oGTT). However, a recent study in 24 men with hypercholesterolemia demonstrated improved endothelial function and insulin sensitivity following three months of DHEA 25 mg/d (93).
Most studies were possibly of too short duration to detect reliably changes in body composition. Body composition remained either unaffected (60,91,92,63) or showed variable and gender-specific changes with reduction in fat mass in men only (89,90) and an increase in total body mass in women (89). Of note, in the only long-term study (12 months) in patients with adrenal insufficiency preliminary results suggest a DHEA-induced increase in lean body mass without effects on fat mass. Thus it may be possible that the androgenic activity of DHEA favors a shift in the ratio of lean mass to fat mass favoring muscle mass. This view is supported by the documentation of impaired muscle function in patients with adrenal insufficiency receiving glucocorticoid and mineralocorticoid replacement, but not DHEA (51,56). Accordingly, increased muscle strength after DHEA administration (100 mg/ day) was reported by Yen et al (90) and Morales et al (89). However, in the largest study to date in elderly subjects DHEA (50 mg/ day) failed to affect muscle area or strength (94). Thus at present a significant effect of DHEA on muscle remains uncertain.
In studies administering DHEA in physiological (25-50 mg/ day) or near physiological doses (100 mg/ day) a significant decrease in apolipoprotein A1 and HDL-colesterol was seen in women but not in men (60,89,92). This corresponded to an increase in circulating androgen concentrations in women but not in men. In one study employing a dose of 100 mg /day DHEA, a slight, but significant, HDL-cholesterol reduction was also seen in men (65), who concurrently showed an increase in both free testosterone and 17a-estradiol serum concentrations.
A slight but significant increase in serum IGF-I in response to oral DHEA treatment has been reported in some studies (60,89,95). However, others found no significant changes in parameters of the somatotropic axis (96,92,66). Thus, the significance of these findings remains questionable.
Possible effects of DHEA on bone mineral density and bone markers have been of considerable interest, as sex steroids have been demonstrated to influence bone remodeling and to prevent osteoporosis. However, small sample size and short duration of treatment precluded clear conclusions in many trials. Moreover, only randomized placebo-controlled trials allow a robust assessment of the effects of DHEA on bone. Some open label studies have reported increases in bone mineral density (BMD) (97,95) whereas in placebo-controlled trials DHEA failed to affect BMD or bone markers (90,89,98). In the DHEAge study (66) some increases in BMD were found in women (<70 years of age) at the femoral neck. However, no effects were observed in men. This finding is in keeping with preliminary results from patients with primary adrenal insufficiency (50) reporting also an increase in femoral neck BMD as assessed by DEXA. DHEA effects on bone markers were missing in men (63,98,66) and variable in women with either increases, decreases or no change in bone resorption markers (95,66,58) as opposed to increases or no change in osteocalcin (58,66).
At present it seems likely that beneficial effects of DHEA on BMD are small and restricted to women, possibly due to androgenic biotransformation of DHEA. However, only large prospective controlled trials will allow to investigate this properly.
Based on data from animal experiments (1) and from in vitro studies (30,31) DHEA has been suggested as a steroid with immune regulatory activity. This view is supported by the clinical studies in patients with SLE demonstrating glucocorticoid-sparing activity of DHEA and clinical improvement (75,74,73). However, in these studies DHEA was given in a clearly supraphysiological dose (200 mg/day) and physiological replacement doses (50 mg/d) given to healthy elderlies in the DHEAge study did not have any effect on B- and T-cell populations, cytokine production or natural killer cell cytotoxicity (unpublished observations). In vitro studies with human cells also show DHEA-induced increases in IL-2 secretion (99) and NK cell activity (100) and inhibition of IL-6 release (101,102). IL-2 secretion in SLE correlates with circulating DHEAS and in vitro DHEA restores IL-2 secretion from T lymphocytes of SLE patients (103). No consistent in vivo data on immune effects of DHEA in humans are reported. Again it is likely that beneficial effects of DHEA are more easily detectable in patients with immunopathies and an altered immune system at baseline.
At present there is no established indication and no generally accepted pharmacological preparation of DHEA for treatment. However, there is growing acceptance (104,105,106) of the view that DHEA replacement in patients with adrenal insufficiency may be beneficial in a substantial percentage of cases. In these patients not only very low or absent circulating DHEA(S) is demonstrated, but there is evidence of impaired well-being, reduced vitality and increased fatigue (49), symptoms that are likely to respond to DHEA replacement (25-50 mg/day). Treatment usually starts with 25 mg/ day. Serum DHEAS concentrations can easily be monitored and should be within the respective sex- and age-adjusted reference range (2); in women, additional monitoring of serum androgens is recommendable. It is important to know that significant improvements in mood and health-related quality of life may occur only after three to four months of treatment, possibly as a result of a requirement for gradual adjustment to a new neurosteroidal equilibrium.
By contrast to patients with adrenal insufficiency who suffer from premature, severe DHEA deficiency, healthy elderlies present with a physiologic age-associated decline in circulating DHEA(S) which per se does not justify DHEA supplementation. All available evidence indicates that DHEA supplementation offers no apparent benefit for such a population. This does not exclude the possibility that certain subgroups of elderly subjects may benefit from DHEA supplementation, but these subgroups need to be defined. In particular, to date there is little evidence that DHEA supplementation reverses relevant aspects of aging. If the patient opts for DHEA supplementation he or she clearly needs to be informed on the experimental nature of such treatment. The possible risks of androgenic side-effects and the potential promotion of sex steroid dependent tumor growth specifically needs to be addressed.
In less than a decade tremendous progress has been made in the field of DHEA research. The therapeutic potential of DHEA is now more clearly visible (see table 1) and it is predicted that DHEA will become part of routine replacement for the majority of patients with adrenal insufficiency, although large phase III trials will be necessary to firmly establish the role of DHEA in the treatment of adrenal failure. While the hopes to use DHEA as an anti-aging remedy have not been fulfilled, there is growing evidence that DHEA may have therapeutic potential for other patient groups. These include patients with psychiatric illnesses (depression, schizophrenia, dysthymia), immunopathies (systemic lupus erythematosus) and women with androgen deficiency related complaints (e. g. loss of libido). In these patient groups administration of DHEA must not be regarded as substitution therapy but rather as pharmacotherapy. Accordingly, only large prospective randomized double-blind trials will allow us to define the benefits and also the risks of such DHEA pharmacotherapy.
An important contribution to the development of treatment strategies with DHEA will evolve from a better understanding of the tissue-specific mechanisms of action of DHEA, mediated via tissue-specific downstream conversion or even via binding to a yet to be identified DHEA-specific receptor.
In conclusion, DHEA has emerged as a fascinating adrenal steroid but its physiology and therapeutic potential are still awaiting future research.
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