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Original Studies |
Service de Gériatrie, Hôpital Bichat (S.L.), Centre d’Investigations Cliniques, Hôpital Broussais (C.M., M.A.), Hôpital Saint Vincent de Paul (N.L., M.R.), Service de Biochimie, Hôpital Paul Brousse (B.D.), Service de Pharmacologie, Hôpital Pitié-Salpêtrière (B.D., G.C.), Fondation Nationale de Gérontologie (V.F., F.F.), Debiopharm (H.P.), Service de Gérontologie, Hôpital Broca (F.F.), and INSERM, U-488, Collège de France (E.E.B.), F-94276 Le Kremlin-Bicêtre, France
Address all correspondence and requests for reprints to: Etienne-Emile Baulieu, M.D., Ph.D., INSERM, U-488: Stéroides et Système Nerveux, and Collège de France, Building Gregory Pincus, 80 rue du Général Leclerc, F-94276 Le Kremlin-Bicêtre Cedex, France. E-mail: baulieu{at}kb.inserm.fr
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Abstract |
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-androstan-3,17ß-diol
glucuronide, estradiol, and estrone. Relatively low background levels
of DHEA(S) were observed, and with the reestablishment of
"young" levels, four important results were obtained. 1) Blood
DHEA had an apparent terminal half-life of more than
20 h, the same order of magnitude as that of blood DHEAS, a result
explainable by back-hydrolysis of the large amount of DHEAS formed
after oral administration of DHEA, a mechanism providing
long-lived unconjugated DHEA and metabolites. 2) The
metabolic conversion of DHEAS to DHEA was significantly
greater in women than in men. 3) No accumulation of steroids was
observed. 4) No worrying transformation to androgen and estrogen was
recorded; indeed, the limited increased estradiol in aged women could
be predicted to be beneficial. These results suggested that daily oral
administration of DHEA (25/50 mg) is safe in elderly
subjects. The 50-mg dose was chosen for a 1 yr, double blind,
placebo-controlled trial of daily oral administration of
DHEA in 60- to 80-yr-old individuals (DHEAge). |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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) give rise to
other steroidal compounds (1, 6, 7, 8, 9), available and potentially active
in peripheral tissues, such as androgens [testosterone (Testo) and
5-dihydrotestosterone (DHT)], estrogens [estradiol
(E2) and estrone (E1), and
estrogenic 
5-androstene-3ß,17ß-diol]; and
3) neuroactive interactions of DHEA(S) with
neurotransmitter receptors are involved in several behavioral functions
and possibly neuroprotection (10, 11). The lack of an appropriate
animal model makes study of the role of the DHEA(S)
decrease in the aging process difficult (12). Studies have indicated
that the decrease in concentration is mainly, if not exclusively, due
to a decrease in adrenal output, initially on the order of 20–25
mg/day in young people, and not to a change in metabolism (13, 14). A
number of reports concerning animals have suggested effects on
metabolic parameters, immunological modulation, behavior, cancer
evolution, etc. However, the results are difficult or
impossible to extrapolate to the human situation and then to use
medically; very large doses, unrelated to the physiological amounts in
man, have been used, and the respective roles of both
DHEA(S) itself and its hormonal metabolites, which are
potentially involved, have not been studied properly. For humans, the
few controlled trials of DHEA administration, mostly to
elderly subjects, have, however, given promising results, such as
favorable immunomodulation (15, 16); increased insulin-like growth
factor I levels, which also decrease in aging (17); improvement of
well-being (17, 18); and, more generally, effects attributable to brain
activity (reviewed in Ref. 19). However, contradictory results have
been also reported for these and other parameters, such as
cardiovascular protection and neurodegenerative disease, in
epidemiological and clinical studies (20, 21, 22, 23). In any case, studies of
oral or percutaneous administration of DHEA with doses
varying from 25–1600 mg daily have indicated that DHEA is
well tolerated, and even during administration over several weeks, it
provoked no or minimal deleterious effects (24, 25).
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A double blind, randomized, placebo cross-over study design was used. Two 8-day oral treatment periods (placebo or 25 or 50 mg DHEA given daily at 0900 h) were separated by a 2-week wash-out interval. Treatment assignment was performed according to a balanced incomplete block design. Each subject was instructed to ingest two tablets, which were both 25 mg DHEA, one DHEA and one placebo tablet, or both placebo tablets, once daily each morning at 0900 h. The two treatment periods were, for four subjects each: A, placebo then 25 mg DHEA; B, placebo then 50 mg DHEA; C, 25 mg DHEA then placebo; D, 50 mg DHEA then placebo; E, 25 mg DHEA then 50 mg DHEA; and F, 50 mg DHEA then 25 mg DHEA. As a consequence, 16 subjects (8 men and 8 women) received placebo, 16 subjects (8 men and 8 women) received 25 mg/day DHEA, and 16 subjects (8 men and 8 women) received 50 mg/day DHEA.
Subjects
Twenty-four subjects completed the study. The 12 men (age, 67.8 ± 4.3 yr) and 12 women (age, 67.9 ± 4.3 yr) had not had any health problem over the previous month. They were not obese (body mass index, 27 ± 3.7 kg/m2 in men, 25.0 ± 3.4 kg/m2 in women) and were not heavy smokers (<10 cigarettes/day). Illness was excluded by medical history, complete physical examination, and routine laboratory evaluation, including an electrocardiogram performed 14 days before the study. Subjects (5 women and 1 man) who took Testo or estrogen and progestin therapy were included after withdrawal of hormones for at least 1 month. Eight subjects took medication(s), for hypertension (n = 3), for hypercholesterolemia (n = 3), and for osteoarthritis (n = 3). No other drugs were allowed during the treatment period, except minor antalgics. All subjects gave their written informed consent to participate in the present experiment. The protocol was approved by the comité consultatif de protection des personnes se prêtant à des recherches biomédicales (Hôpital Cochin, Paris, France). The investigation was conducted in accordance with the guidelines proposed in the Declaration of Helsinki.
Drugs
DHEA was obtained from Akzo Laboratories (Diosynth France SA, St. Denis, France). DHEA (25 mg) and placebo were manufactured by Creapharm Laboratories (Le Haillan, France) as tablets identical in appearance.
Study protocol
Each subject was hospitalized twice for 36 h each time during each of both treatment periods, starting on the day before the first and the last oral dose. Subjects arrived at the Hôpital Broussais Clinical Investigation Center at 1900 h on the evenings preceding day 1 and day 8.
On days 1 and 8 at 0800 h, after overnight fasting, an indwelling cannula was inserted into a brachial vein of each subject for blood sampling. At 0900 h, after a 1-h rest in the semirecumbent position, subjects received the first oral dose of each treatment period. They remained in the same position until 1100 h. Fluid intake was unrestricted, and subjects were given a meal 2, 6, 12, and 24 h after treatment. Blood was sampled 15 min before and immediately before drug ingestion, and 0.5, 1, 1.5, 2, 6, 12, and 24 h after drug ingestion for determinations of serum steroid levels. Potential adverse effects were recorded by means of questionnaires.
Hormone assays
Serum DHEAS was measured in serum by an automated immunoenzymatic assay, on the Serono SR1 analyzer (Serono, Milan, Italy). The correlation coefficient with standard RIA (21) was r = 0.98. The lower detection limit of the assay was 0.044 µmol/L. The intraassay coefficient of variation was 6%. The interassay coefficient of variation ranged from 3% (concentrations <0.27 µmol/L) to 20% (concentrations >2.72 µmol/L). Mean reference values in women and in men aged 60–70 yr are 2.18 and 3.70 µmol/L, respectively.
Serum DHEA, E1, and ADG were measured by RIAs with reagents from Diagnostic Systems Laboratories, Inc. (Webster, TX). In the DHEA assay, only Adione and ADG cross-reacted significantly (0.46 and 0.24%, respectively). The intra- and interseries coefficients of variation at the level of 3.4 nmol/L were 3.1% and 4.5%, respectively. The sensitivity was 0.01 nmol/L. Reference values in women and in men, aged 60–75 yr, were 1–14 and 5–20 nmol/L, respectively. In the E1 assay, only E2 cross-reacted significantly (1.25%). Intra- and interseries coefficients of variation at the level of 370 pmol/L were 5.6% and 11%, respectively. References values in women and in men, aged 60–75 yr, were 22–222 and 33–240 pmol/L, respectively. In the ADG assay, only DHT glucuronide cross-reacted significantly (1.2%). The intra- and interseries coefficients of variation at levels of 0.8 and 20.0 nmol/L were 7.6% and 4.2%, and 8.1% and 4.5%, respectively. Reference values in women and in men, aged 60–75 yr, were 0.2–8.5 and 7–40 nmol/L, respectively.
Testo and E2 were measured by RIA as previously described (27). In the Testo assay, only DHT exhibited a significant cross-reactivity (4.5%). Intra- and interseries coefficients of variation at the level of 2 nmol/L were 8% and 8.5%, respectively. Reference values in women and in men, aged 60–75 yr, were 0.17–1.7 and 8.0–35 nmol/L, respectively. In the E2 assay, the cross-reactivity of E1 was 0.6%. Intra- and interseries coefficients of variation at the level of 96 pmol/L were 5.8% and 2.4%, respectively. Reference values in women and in men, aged 60–75 yr, were 18–110 and 30–240 pmol/L, respectively.
Normal values for young adults, 20–40 yr old, indicated below (see Results and figures) were obtained by the same assays in the same laboratories.
Statistical analysis
The design was a balanced incomplete block design, and results were analyzed separately for men and women. Data for the corresponding periods were pooled because the 2-week washout interval led to patients restoring their initial hormonal status at H0 by day 1 of the second period.
We used the appropriate ANOVA method to analyze the data. When the F test was significant (P < 0.05), paired comparisons were performed using the Scheffe method to avoid type I error due to multiple testing. The appropriate variance estimate was taken from ANOVA for performing pairwise tests. Assumptions of ANOVA (homogeneity of variance and normality) were verified for each variable, and a natural logarithmic transformation was applied when appropriate.
As the procedure included determination of steroid levels as a function
of time, we performed the above analysis on the values at 0 and 24
h and on two summarizing parameters: the maximum increase in
concentration between successive determinations (Cmax) and
the area under the curve (AUC) of concentration as a function of time.
AUCs were calculated using the trapezoidal rule over the 24 h,
except that for plasma Testo, which was over 12 h because of the
nychthemeral cycle. These kinetic values for the steroids are shown in
Tables 1, 3, and 4 and Figs. 2 and 4.
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). The AUCs were extrapolated to infinity. At steady state (day
8), the AUC was calculated by the trapezoidal rule between a dosing
interval. The elimination rate constant was estimated by log-linear
regression. The maximum blood concentrations
(Cmax) and the time to Cmax
(Tmax) were taken directly from the observed
values.
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50%) than the classical value of 80% of the
individual AUC extrapolated to infinity (28). In all groups no deviation from linearity and no pattern consistent with zero order absorption was observed. The variability was very large, but no evidence of dose dependency was found.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Serum DHEAS (Tables 1
and 2 and Fig. 2)
Baseline serum DHEAS levels remained unchanged with placebo. No nychthemeral cycle was noticed, similar to data observed in young adults (3).
A significant, rapid, and dose proportional increase in serum DHEAS levels was observed after oral DHEA administration. The mean maximal DHEAS concentration (Cmax) was observed 2 h after DHEA ingestion. After 8 days of treatment with 25 or 50 mg DHEA, Cmax reached 8.98 ± 2.7 and 13.70 ± 3.92 µmol/L, respectively (P < 0.05) in men and 7.70 ± 2.26 and 13.10 ± 3.80 µmol/L (P < 0.05) in women. Thereafter, administration of 25 mg DHEA restored serum DHEAS to levels similar to those observed in young women in the early follicular phase (1.1–7.3 µmol/L) and in young men (4.1–13.6 µmol/L). In contrast, 50 mg DHEA induced levels within the normal range for young men, whereas it increased DHEAS levels above the upper values observed in young women.
On day 8, the AUC0–24h of serum DHEAS concentrations with both 25 and 50 mg doses were significantly greater than that with placebo (P < 0.05). In women only, AUC0–24h was greater with 50 mg (220 ± 63 µmol/h·L) than with 25 mg (122 ± 41 µmol/h·L; P < 0.05).
In men, daily administration of 25 or 50 mg DHEA for 8
days did not cause a trend toward DHEAS accumulation, and serum DHEAS
AUC0–24h values on day 8 were significantly
smaller than extrapolated AUC0-
values on day
1 (Table 2). The apparent half-life of DHEAS measured on day 1 and day
8 after 25 or 50 mg DHEA varied from 19.4 ± 3.9 to
28.3 ± 13.7 h.
In women, there was no accumulation of DHEAS, and the AUC at steady state (day 8) is equivalent, although smaller than that in men, to the AUC after the first dose extrapolated to infinity. As in men, there was a large intersubject variability in half-life, but mean values appeared nearly constant and independent of the dose, which further confirms the linearity of the drug disposition. The DHEAS half-life measured on day 1 and day 8 after 25 or 50 mg DHEA varied from 18.7 ± 2.5 to 21.7 ± 6.0 h.
Serum DHEA (Tables 1 and 2 and Fig. 2)
Baseline levels of serum DHEA levels were within the
normal range. In men, both doses of administered DHEA
increased serum DHEA levels. After 8 days with 25 or 50 mg
DHEA, Cmax and
AUC0–24h differed significantly from placebo
(P < 0.05), with a dose-proportional response in men
but not in women. In men and women, Cmax with 50
mg reached 34 ± 12 and 34 ± 10 nmol/L, respectively, just
above normal values observed in young men (5.2–26.0 nmol/L) and women
(4.2–27.7 nmol/L; Table 1).
In men, and like DHEAS, no trend toward accumulation of
DHEA on day 8 was demonstrated for either dose (Table 2).
The half-life varied from 18.7 ± 5.5 to 25.1 ± 10.7 h,
very similar to that of DHEAS.
In women, for DHEA, no trend for accumulation by day 8 was observed, and drug exposure, estimated through AUC, held a fairly constant level compared to day 1 in each dose group. The half-life varied from 23.6 ± 8.5 to 26.6 ± 8.6 h, also very similar to that of DHEAS.
Metabolites of the C19 steroidal series:
Testo and ADG (Tables 3 and 4 and Fig. 3)
In elderly men, the serum Testo profile with placebo followed a circadian cycle similar to that observed in young men (29). In both sexes, the Testo level reached after DHEA administration was, after a modest initial increase, practically constant for the following 24 h.
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1 nmol/L) and was
only significant for women whose baseline levels were lower. In both sexes, baseline serum ADG levels were within the normal range for young adults. In men, after DHEA administration, serum ADG levels increased significantly, but peak values on day 8 were within the normal range observed in young men (7.5–49 nmol/L). The AUC0–24h of serum ADG with DHEA differed significantly from that with placebo, but not in a dose-proportional manner. In women, after DHEA administration, serum ADG levels increased with a dose proportional effect. The AUC0–24h of serum ADG significantly differed on day 8 among placebo and 25 and 50 mg DHEA. With 50 mg DHEA, serum ADG levels increased from 3 ± 2 nmol/L on day 1 to 15 ± 11 nmol/L before administration on day 8 and reached 23 ± 12 nmol/L at the peak, above the normal range for premenopausal women (1.1–10.0 nmol/L).
Serum estrogens (Tables 3 and 4 and Fig. 4)
In men, serum E2 levels did not change after placebo or DHEA treatment, whereas serum E1 concentrations increased dramatically after DHEA administration. Peak values and changes in serum E1 vs. time significantly differed compared with placebo values. Cmax, but not AUC 0–24h, differed significantly according to the dose. Peak values of E2 and E1 were within the normal levels range for young men (36.7–147 and 55–333 pmol/L, respectively).
In women, E2 peak values and AUC0–24h increased significantly compared with placebo values after 8 days with 25 or 50 mg DHEA. Peak levels, reaching 40 pmol/L, were less than the normal levels in young women during the early follicular phase (70–345 pmol/L). No difference in Cmax or AUC related to DHEA dose was observed. For E1, a significant increase was observed with DHEA treatment compared with placebo, within the normal values (37–333 pmol/L). Cmax, but not AUC0–24h differed significantly according to the dose.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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DHEAS-DHEA
At baseline, serum DHEAS levels were significantly higher in men
than in women (130%). This difference has been reported by numerous
researchers (3, 5, 30). No gender difference was demonstrated for
DHEA levels at baseline.
After DHEA administration, in both sexes there was a rapid and dose proportional increase in DHEAS levels. In men, 25 or 50 mg DHEA administration restored levels to the normal range for young adults. In women, 50 mg DHEA administration induced peak levels just above the normal levels observed in young adults on day 8. No accumulation was observed in either sex after administration for 8 days.
The apparent half-life of DHEAS was about 24 h, longer than that
determined after iv administration of radioactive DHEAS tracer to young
adults (1, 13). It has been reported that an increase in
DHEA(S), whether secreted or administered, tends to
increase its MCR and/or its volume of distribution (30, 31, 32). Fifty
milligrams of DHEA is a high daily dose compared to the
adrenal physiological secretion observed in young adults (25 mg
daily). After ingestion, DHEA is mostly sulfated in liver.
Most DHEAS is bound to plasma albumin, but no specific high affinity
transport protein has been described. Whether an entero-hepatic cycle
is involved is unknown (33, 34). No data concerning the age-related
modifications of DHEA(S) distribution are available (13).
The MCR seems to be unaltered with aging. The mechanisms underlying
this long apparent half-life of DHEAS have to be further studied.
DHEA levels also showed a notable significant increase. In both sexes, levels reached were just above normal values observed in young adults. As described in Materials and Methods, our free DHEA assay is highly specific and cannot be significantly contaminated by DHEAS and other steroids. Technically, we carefully tried to avoid any contamination of the DHEA levels by artifactual release of the unconjugated steroid from the large concentrations of DHEAS (12). Therefore, the endogenous DHEA levels measured should represent the sum of DHEA taken orally and having escaped liver and gut sulfation, plus DHEA originating from the sulfatase hydrolysis of DHEAS formed. The latter is by far the most important quantitatively. This very likely explains a most striking result of the present study: the apparent half-life of DHEA was much longer than expected in both men and women and was similar to the DHEAS half-life. This suggests a role for the rate-limited production from long-lived DHEAS and therefore a so called flip-flop phenomenon, i.e. the apparent half-life mainly reflects the metabolic back-conversion of DHEAS to DHEA. As no iv data with the same amount of DHEA are available, a definite conclusion is not possible; however, experiments with iv administration of radioactive DHEAS strongly suggest the preponderant role of this metabolic back-conversion to DHEA. It had been previously reported that the DHEA half-life and MCR, as measured from isotopic steroid iv experiments, were about 30 min and 2000 L/h, respectively (1, 13, 35, 36), similar to those of other hormonal steroids.
Our hypothesis is that oral administration of DHEA leads to the synthesis of the limiting step for DHEA availability. Our results are consistent with studies of the pharmacokinetics and peripheral conversion of DHEA to androgens and estrogens in young healthy females after dexamethasone suppression, where it was demonstrated that 50 mg was the suitable dose for DHEA replacement for adrenal insufficiency (18, 37). After an oral dose, the half-life of DHEA is much longer than that previously described in tracer iv studies (1, 13, 35, 36). In the rat (admittedly very different from the human in steroid metabolism), it was observed that the bioavailability of DHEA was greater after percutaneous than oral administration, avoiding the hepatic first pass effect (38). From our data, oral administration to humans should be preferred to obtain an as high as possible long-lived DHEA level, derived from metabolically formed DHEAS.
No accumulation of DHEA(S) was demonstrated after this daily administration of a physiological dose of DHEA (39). These results are reassuring in terms of safety and led us to choose the 50-mg DHEA dosage for the 1-yr clinical trial to try to maximize the exposure to DHEA(S) without risk. The same conclusion has been reached when S. Tummala and F. Svec analyzed published data of serum levels after DHEA administration (unpublished results).
Sex differences
The DHEA(S) results differed greatly according to gender. On day 8 of DHEA administration, whatever the dose, the DHEAS AUC0–24h values were greater in men than in women. Clearly, after either daily dose of administered DHEA, DHEA blood levels were persistently higher in women than in men (although DHEAS levels remained higher in men than in women). The DHEA AUC0–24h values in women were about twice those in men. The relatively higher exposure to DHEA observed in women might be related to the higher dose they received per kg BW. However, the results may indicate an intrinsic sex difference in steroid metabolism; the metabolic conversion of DHEAS to DHEA appears more effective in women. From a pharmacokinetic point of view, this would suggest that the optimal dose to be administered to women in a chronic regimen could be smaller than that for men; indeed, such a deduction is consistent with the clinical results of the DHEAge trial (26). Several reports have previously outlined that DHEA(S) metabolism differs between men and women (34, 36, 40, 41, 42). This difference may be of importance when considering the peripheral effects of DHEA metabolites vs. the impact on nervous system DHEAS, as discussed previously (12).
Hormonal metabolites
In both sexes, whatever the DHEA dose, peak levels of E2 and Testo remained within the normal range for young adults. These results are also relevant to the safety of DHEA administration. Interestingly, the increase in E2 peak levels after administration of 50 mg DHEA are compatible with some estrogenic action, especially for the prevention of bone loss in postmenopausal women. E2 levels about 23 pmol/L at baseline reached 42 pmol/L on day 8. A specific study of the effect of DHEA(S) on bone loss and risk of fractures would be of interest, as several researchers have demonstrated the role of low doses of estrogen in both sexes (43, 44, 45), and the limited transformation of DHEA(S) into active hormones such as E2 may be beneficial as replacement therapy and safe for prolonged administration.
ADG levels are considered a reliable marker of the total pool of Testo and may indicate Testo production otherwise undetectable from blood levels (via an intra/paracrine system) (8), but possibly active if the steroid formed interacts locally with an androgen receptor. These ADG levels reflect the increase in the 17ß-hydroxyl pathway of Testo metabolism in tissues (46) better than the increase in serum Testo levels, and therefore, Testo is not the only index of potential androgenic activity. ADG levels observed after DHEA administration vary greatly in both sexes. In women, ADG levels increased in a dose proportional manner to reach supraphysiological levels, even with large SDs; clinically, the 1-yr trial has not produced evidence of deleterious androgenic symptoms. In any case, ADG may not be a perfectly reliable index of androgenic activity; the formation of Testo and its degradation to ADG may occur in cells or tissues devoid of androgen receptor, and in addition, ADG may derive from DHEAS without intermediary conversion to Testo (47). Therefore, ADG is more an index of androgen consumption than of androgenic activity.
Conclusion
From all these considerations, the present report suggest that, in healthy 60–79 year old subjects, 50 mg DHEA is a safe and potentially effective dose. But these results may apply only to elderly subjects with relatively low DHEAS levels at baseline, as compared to young individuals; whether the same 50 mg DHEA administration earlier in life would give excessive steroid concentration cannot be known from this study. Globally the results of the one-year trial implemented in Assistance Publique - Hôpitaux de Paris (DHEAge) (26) are consistent with the data reported in this paper.
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Acknowledgments |
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Footnotes |
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Received January 10, 2000.
Revised May 25, 2000.
Accepted June 6, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-3H to 5- and
5ß-androstane-3:17ß-Diol-17-3H: a new
"17ß-hydroxyl pathway." J Biol Chem. 239:1569–1577.- and ß-androstanediols and
testosterone glucuronide from testosterone and dehydroisoandrosterone
sulfate in normal people and hirsute women. J Clin Endocrinol
Metab. 25:1167–1178.[Medline]
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).
Androstanediol, 5
