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Original Studies |
Department of Endocrinology, Medical University Clinic Wuerzburg (W.A., H.-G.J., F.C., M.R., B.A.), Wuerzburg; Jenapharm (D.H., M.O., M.E.), Jena; and Institute for Hormone and Fertility Research (H.M.S.), Hamburg, Germany
Address all correspondence and requests for reprints to: Wiebke Arlt, Department of Endocrinology, Medical University Clinic, Josef-Schneider-Str. 2, 97080 Wuerzburg, Germany.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Cross-sectional studies revealed a significant positive correlation between serum DHEA(S) concentrations and functional status in elderly people (7, 8) as well as to psychometric parameters of well-being in 40- to 60-yr-old women (9). In a recent study in age-advanced men and women, 50 mg DHEA restored adrenal androgen levels to youthful levels, whereas 100 mg induced supraphysiological levels in women but not in men (5). Moreover, administration of DHEA (50 mg/day) to elderly men and women led to an increase in self-reported well-being (10). As a neuroactive steroid DHEA may influence processes of cognition and memory as well as sleep architecture (11, 12). Furthermore, DHEA may have an important role in the regulation of the immune response and in the control of cell proliferation (13, 14, 15).
Patients with adrenal insufficiency suffer from chronic DHEA(S) deficiency, because routine replacement therapy with glucocorticoids and mineralocorticoids fails to restore adrenal androgen concentrations. It has been shown that DHEA(S) is transformed into potent androgens in a variety of tissues (16). Therefore, DHEA replacement therapy may be of special importance for female patients with adrenal insufficiency, because androgen deficiency in these patients is frequently neglected (17). Accordingly, it has been shown that despite an otherwise adequate replacement therapy in Addison’s disease, quality of life may be inferior to that of normal subjects (18). Thus, DHEA replacement in female patients with adrenal insufficiency may hold the potential to improve their functional status and well-being. Moreover, DHEA administration to these patients is well suited to gain further insight into the physiological role of DHEA, because a true deficit is replaced.
The aim of this study was, therefore, to define the optimum DHEA dose necessary to restore hormone concentrations in DHEA-deficient women to the normal range. To this end we studied the pharmacokinetics and biotransformation of orally administered DHEA in young females after suppression of adrenal steroid synthesis by dexamethasone (dex) and compared the results with baseline hormone secretion in these women.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Nine healthy female volunteers (age 19–30 yr, mean age 23.3 ± 4.1 yr; eight nonsmoking, one smoking) were included in the study. All subjects were nonobese with a body mass index of 19.5 to 25.1 kg/m2 (mean 22.5 ± 1.8 kg/m2) and were regularly menstruating. None of the women had baseline serum concentrations of DHEA(S), androstenedione and/or testosterone (T) above the normal range. No participant was using oral contraceptives or other medications. Further inclusion criteria were normal blood cell counts and normal hepatic and renal function parameters. Before the initiation of the study, the protocol had been approved by the Ethics Committee of the University of Wuerzburg and written informed consent was obtained from all volunteers.
Protocol
The study was performed in a single-dose, randomized, cross-over design. All subjects were studied during the early follicular phase of four subsequent cycles. Cycle 1 served as baseline. Preceding the study days during the cycles 2–4 all subjects were pretreated with oral dex (4 x 0.5 mg daily for 4 days). On the study days 2–4, either placebo or 50 or 100 mg DHEA were administered orally at 0900 h in a randomized order. On all four study days, 24-h frequent blood sampling was performed, starting after an overnight fast at 0830 h and ending at 0900 h the following day [-30 (0830 h), 0, 30, 60, 90, 120, and 150 min, and 3, 4, 5, 6, 7, 8, 10, 12, and 24 h]. Standardized meals were served at 1030, 1500, and 2100 h.
DHEA preparation
The capsules containing 50 mg DHEA as well as the placebo capsules were both provided by Jenapharm (Jena, Germany). As determined by high performance liquid chromatography (HPLC), the mean DHEA content of the capsules was 49.3 ± 0.20 mg. To assess the liberation rate, DHEA capsules (n = 20) were given in 1000 mL water with 0.4% SDS. DHEA was measured by HPLC at 10, 20, 30, and 45 min, respectively, giving an in vitro liberation rate of 82.8% within 45 min.
Hormone assays
All serum hormones were determined by established specific
direct RIAs. Cortisol: Diagnostic Systems Laboratories (Sinsheim,
Germany), cross-reactivities: DHEA 0.02%, T 0.14%, and
17ß-estradiol (E2) 0.02%; DHEA: Diagnostic Systems
Laboratories, cross-reactivities: DHEA(S) 0.04%,
4-androstene-3,17-dione 0.46%, and T 0.03%; DHEA(S): DPC Biermann
(Bad Nauheim, Germany), cross-reactivity to DHEA 0.08%,
androstenedione 0.12%, T 0.10%, E2 0.03%, estriol
0.03%; 4-androstene-3,17-dione (A'dione): Diagnostic Systems
Laboratories, cross-reactivities: DHEA 0.04%, 5
-dihydrotestosterone
(DHT) 0.05%, estrone (E1) 0.08%, estriol 0.03%;
5-androstane-3,17ß-diol-17-glucuronide (ADG): Diagnostic
Systems Laboratories, cross-reactivity to DHT-glucuronide 1.2%, no
cross-reactivity to 5-androstane-3ß,17ß-diol or
5-androstane-3,17ß-diol-3-glucuronide; T: DPC Biermann,
cross-reactivities: A'dione 0.5%, DHT 3.1%, E2 0.02%;
DHT: Diagnostics Biochem Canada (London, Canada), cross-reactivities:
5ß-DHT 4.1%, DHEA 5.5%; E2: Biochem Immunosystems
(Freiburg, Germany), cross-reactivities: E1 1.77%, estriol
0.47%; E1: Diagnostic Systems Laboratories,
cross-reactivities: E2 1.25%, E1 sulfate
2.02%, and estriol 0.22%. Cross-reactivities to other steroids
relevant to this study were <0.01%. For all assays the intra- and
interassay coefficients of variation were <8% and <12%,
respectively.
Statistical analyses
All data are reported as mean ± SEM. The
maximum serum concentration measured during a study period of a
volunteer was reported as cmax. The time at which
cmax occurred was reported as tmax. The
terminal elimination rate constant 
was calculated by means of
log-linear regression. The area under the concentration-time curve
(AUC) was calculated by means of trapezoidal integration. Because the
suppressive effect of dex on the measured serum concentrations was
markedly diminished after 12 h, we used AUC 0–12 h instead of AUC
0–24 h for data comparison. The mean concentrations of the various
hormones, AUC 0–12 h as well as tmax and cmax
were calculated and compared by ANOVA with repeated measurements,
t tests, and Wilcoxon signed rank tests for paired samples.
Significance was defined as P < 0.05.
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Results |
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The effect of dex suppression is shown in Table 1
. Pretreatment with dex led to a lasting
and pronounced suppression of cortisol, DHEA, DHEA(S), A'dione, ADG, T,
DHT, and E1. In contrast, E2 varied within a
wide range at baseline and remained unchanged after dex (Table 1).
Twenty-four hours after the end of dex treatment, the cortisol
concentrations rose to 60% of baseline levels (Fig. 1A), whereas the other steroids (except
E2) exhibited a prolonged suppressive effect (Table 1).
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After the administration of 50 and 100 mg DHEA, respectively, DHEA
serum concentrations increased in a dose-dependent manner to peak
between 60–480 min (tmax for 50 and 100 mg DHEA, 2.5
± 2.1 h and 2.4 ± 0.4 h, respectively) followed by a
slow decrease (Fig. 1B
). Also, DHEA(S) increased rapidly peaking
between 120–300 min (tmax for 50 and 100 mg DHEA, 2.9
± 0.9 h and 2.8 ± 0.5 h, respectively) followed by a
decrease to levels found at baseline at 12 h (50 mg DHEA) and at
approximately 18 h (100 mg DHEA) (Fig. 1C). Comparing the AUC
0–12 h, the administration of 50 mg DHEA led to a restoration of
baseline serum DHEA and DHEA(S), whereas 100 mg induced
supraphysiological concentrations (Table 2). Detailed data concerning the
pharmacokinetics of the two different DHEA doses are given in Table 3.
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The administration of 50 mg DHEA induced an increase in serum
A'dione concentrations to levels around 60% of baseline, and 100 mg
DHEA induced a further increase (tmax for 50 and 100 mg
DHEA, 2.6 ± 1.5 h and 2.6 ± 0.7 h, respectively)
followed by a decrease to levels paralleling baseline concentrations
from 6–24 h (Fig. 2A).
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). DHT serum concentrations peaked between 30–240 min after 50
mg DHEA (tmax 1.8 ± 0.7 h) to levels comparable
with baseline, whereas 100 mg DHEA induced a lasting increase in DHT to
levels above baseline (tmax 2.6 ± 0.8 h) (Fig. 2C).
The administration of 50 mg DHEA was followed by a sharp increase in
serum ADG concentrations to levels around baseline during the whole
sampling period, whereas 100 mg DHEA led to elevated ADG concentrations
around 200% of baseline levels (tmax for 50 and 100 mg
DHEA, 2.7 ± 1.1 h and 3.0 ± 1.2 h, respectively)
(Fig. 2D).
Estrogens
After 50 mg DHEA, serum E1 increased to levels
equivalent to baseline for at least 12 h. In a dose-dependent
manner, 100 mg DHEA led to an increase in serum E1 to
levels significantly above baseline (Fig. 3A). Peak concentrations were achieved
after 180–480 min (tmax for 50 and 100 mg DHEA, 4.0
± 2.2 h and 2.8 ± 0.6 h, respectively). Serum
E2 concentrations varied within a wide range on all 4 study
days with neither a significant influence of dex nor of DHEA
administration (Fig. 3B). The AUC 0–12 h after 100 mg DHEA was
significantly higher than during baseline but not higher than after
placebo (Table 2).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The increase in DHEA(S) shortly after oral ingestion of DHEA indicates an important contribution of extraadrenal sulfotransferases. The liver most likely plays a predominant role in this activity, because transdermal and transvaginal administration of DHEA avoiding the first-pass effect induces a higher DHEA/DHEA(S) ratio (26, 27). This was also observed during the early phase after sublingual DHEA administration (5). Moreover, the preparation of DHEA may also affect the pharmacokinetics, because Casson et al. (26) described a decrease of the DHEA/DHEA(S) ratio after oral administration of micronized DHEA in comparison with a crystalline preparation. However, despite the high sulfotransferase activity in the liver, a multitude of tissues contain sulfotransferases and may also contribute to the conversion of DHEA to DHEA(S) (28, 29). After peaking, serum DHEA concentrations showed a slow decline, although the reported half-life of endogenous DHEA is only around 50 min (30). This suggests that DHEA(S), with its much longer half-life, is continuously converted back to DHEA via widespread tissue sulfatase activity (31, 32, 33, 34).
Administration of 50 mg DHEA was sufficient to restore the serum
concentrations of DHT and ADG to nonsuppressed baseline levels, whereas
100 mg DHEA was required to fully restore A'dione and T concentrations
to baseline. This could be explained by high 5-reductase activity
with rapid conversion of T to DHT at a dose of 50 mg DHEA, whereas at
100 mg DHEA saturation of 5-reductase may be reached. However,
24 h after 100 mg DHEA, A'dione and T levels had not returned to
the mean levels seen after placebo, indicating that chronic
administration of 100 mg DHEA may bear the risk of supraphysiological
androgen concentrations. Our findings are in agreement with the study
of Young et al. (19) in patients with hypopituitarism. They
described an increase in T and A'dione to the lower normal range and of
DHT and ADG into the higher normal range of women after 50 mg DHEA,
whereas 200 mg DHEA induced supraphysiological androgen concentrations
(19). Labrie et al. (27) studied pharmacokinetics and
bioconversion during percutaneous administration of a 20% DHEA
solution in a daily dose of 20 mL for 2 weeks in elderly men and women.
In the female volunteers A'dione increased by 80% and T by 50%, with
DHT concentrations remaining unchanged, whereas ADG increased by 120%
(27). Therefore, transdermal administration of DHEA also increases
circulating androgens, but possibly to a lesser degree than oral DHEA.
In contrast, it has been reported that after transvaginal
administration of 150 mg DHEA serum T remained unaffected (26), also
indicating that biotransformation of DHEA may be modified by the route
of administration.
DHEA is generally assumed to exert its effects mainly via bioconversion
to androgens (or estrogens) rather than by direct action (5). Recently
published results on a DHEA-specific binding site on human
T-lymphocytes (35) have not yet been reconfirmed. However, serum
concentrations of androgenic and estrogenic steroids may not correctly
reflect the bioconversion of DHEA, because a considerable amount of
DHEA is converted into active androgens (or estrogens) directly in the
cells of peripheral target tissues thereby exerting an intracrine
action (36). In a variety of tissues steroidogenic enzymes responsible
for DHEA conversion to androgens (and estrogens) have been demonstrated
including 3ß-hydroxysteroid dehydrogenase, 17ß-hydroxysteroid
dehydrogenase, 5-reductase, and aromatase (16). ADG is a major
metabolite of DHT as well as of A'dione (37) and has been suggested to
be a marker of T metabolism in peripheral tissue (38). Therefore, the
proportionally higher increase of ADG observed in our volunteers as
well as in the studies of Young et al. (19) and Labrie
et al. (27) may be because of enhanced bioconversion of DHEA
to potent androgens inside the peripheral target cells. This may
indicate that local hormone concentrations are not adequately reflected
by the androgen concentrations measured in the circulation but rather
by the level of their metabolite ADG.
Interestingly, following ingestion of DHEA a dose-dependent increase in circulating estrone also was observed. This supports the recent report by Young et al. (19) in patients with hypopituitarism describing a dose-dependent increase in E1 as well as in E2 levels. Unfortunately, no gender-specific analysis of estrogen increases was given (19). Serum E2 concentrations in our female volunteers with intact ovarian function were unaffected by DHEA administration. Mortola and Yen (24) saw no change in serum E1 or E2 within 4 h after administration of 400 mg DHEA to six postmenopausal women, but a 3-fold increase in E1 and E2 after 14 days of treatment with a daily dose of 1600 mg. Buster et al. (21) found no change in E1 and E2 concentrations during 12 h following oral intake of 150 and 300 mg DHEA. In a study of 17 females treated with 50 mg DHEA for 12 weeks no effect on estrogens was seen, but this may have been because of the heterogeneity of the volunteers, because 2 of the 17 women were premenopausal and 8 of the 15 postmenopausal women were current users of estrogen replacement therapy (10).
In our study the role of DHEA as an androgen precursor is not only reflected by the increase in androgens after oral administration of DHEA, but also by the dex-induced suppression of androgens. Only a few studies have analyzed the effect of dex on circulating androgens in healthy, nonhyperandrogenemic young females (39, 40). During the early follicular phase, the adrenal contribution to serum T and A'dione has been calculated as 66% and 55%, respectively (39). However, from our results an even higher adrenal contribution can be calculated, because after dex pretreatment the serum concentrations of both steroids fell below 30% of baseline levels. Additionally, it has to be taken into account that a significant proportion of the ovarian contribution to peripheral androgens may derive from DHEA(S), which has been suggested as a precursor of ovarian steroidogenesis (41, 42). Thus, our study highlights the importance of adrenal steroid secretion for female androgen physiology. Moreover, dex pretreatment also induced a significant suppression of serum E1 to 50–60% of baseline levels thereby supporting the view that DHEA(S) serves as a prohormone for some 30% of serum E1 in normal young women (42).
In conclusion, our results suggest a daily dose of 50 mg DHEA as suitable for replacement therapy in females with adrenal androgen deficiency. According to cross-sectional studies (7, 8, 9), as well as to the first clinical experiences with DHEA replacement (10) in elderly people, DHEA(S) seems to have a positive influence on well-being. An even more pronounced effect of DHEA has to be expected in patients with adrenal insufficiency, especially females. Moreover, the observed kinetics of DHEA biotransformation with a lasting androgen increase after a single oral dose make DHEA a promising tool for any kind of androgen replacement in females (e.g. postmenopausal women). On the other hand, the generation of highly active circulating steroids after DHEA ingestion suggests that DHEA may possibly have unfavorable effects in a variety of clinical settings, e.g. hormone-dependent cancer (28). Therefore, the widespread uncontrolled use of DHEA should be discouraged until more data concerning adverse effects have become available. Long-term studies in patients with adrenal insufficiency are now needed.
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Acknowledgments |
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Received November 6, 1997.
Revised February 9, 1998.
Accepted February 23, 1998.
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References |
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