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Reproductive Endocrinology |
Medical Research Council Group in Molecular Endocrinology, Centre Hospitalier de l’Universite Laval Research Center, Le Centre Hospitalier Universitaire de Québec, and Laval University, Québec, G1V 4G2, Canada
Address all correspondence and requests for reprints to: Fernand Labrie, Laboratory of Molecular Endocrinology, CHUL Research Center, 2705 Laurier Boulevard, Québec, QC, G1V 4G2, Canada.
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Abstract |
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,17ß-diol-G, and androstane-3ß,17ß-diol-G
increased by about 75%, 50%, and 75%, respectively, whereas
androsterone-sulfate increased 115%. No consistent change was observed
in serum estrone (E1) or estradiol (E2) in men
receiving DHEA, whereas serum E1-sulfate and
E2-sulfate were slightly and inconsistently increased by
about 20%, and serum cortisol and aldosterone concentrations were
unaffected by DHEA administration. Almost superimposable results were
obtained in women for most steroids except testosterone, which was
about 50% increased during DHEA treatment. This increase corresponded
to about 0.8 nM testosterone, an effect undetectable in men
because they already have much higher (
15 nM) basal
testosterone levels. In women, the serum levels of the conjugated
metabolites of DHT, namely androsterone glucuronide,
androstane-3,17ß-diol-G, androstane-3ß,17ß-diol-G, and
androsterone-sulfate were increased by 125%, 140%, 120% and 150%,
respectively. The present study demonstrates that the serum
concentrations of testosterone, DHT, E1, and E2
are poor indicators of total androgenic and estrogenic activity.
However, the esterified metabolites of DHT appear as reliable markers
of the total androgen pool, because they directly reflect the
intracrine formation of androgens in the tissues possessing the
steroidogenic enzymes required to transform the inactive precursors
DHEA and DHEA-S into DHT. As well demonstrated in women, who synthesize
almost all their androgens from DHEA and DHEA-S, supplementation with
physiological amounts of exogeneous DHEA permits the biosynthesis of
androgens limited to the appropriate target tissues without leakage of
significant amounts of active androgens into the circulation. This
local or intracrine biosynthesis and action of androgens eliminates the
inappropriate exposure of other tissues to androgens and thus minimizes
the risks of undesirable masculinizing or other androgen-related side
effects of DHEA. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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One reason for the relative lack of attention to DHEA is that this adrenal steroid does not possess intrinsic androgenic, estrogenic, or other classical hormonal activity. Most significantly, the adrenals of the animal models usually used in the laboratory, namely rats, mice, and dogs, do no secrete significant amounts of DHEA (5, 7), thus attracting all attention to the ovaries and testes as sources of sex steroids. However, humans along with some other primates, are unique among animal species in having adrenals that secrete large amounts of the inactive precursor steroids DHEA, especially DHEA-S, which are converted into potent androgens and/or estrogens in peripheral tissues (6, 8, 9, 10). In fact, plasma DHEA-S levels in adult men and women are 100–500 times higher than those of testosterone and 1,000–10,000 times higher than those of estradiol, thus providing a large reservoir of substrate for conversion into androgens and/or estrogens in peripheral intracrine tissues. The term intracrinology was coined in 1988 (11) to describe the synthesis of active steroids in peripheral target tissues where the action is exerted in the same cells in which synthesis takes place without release in the extracellular space and general circulation (6).
Knowledge in this area has recently made rapid progress with the elucidation of the structure of most of the tissue-specific complementary DNAs and genes that encode the steroidogenic enzymes responsible for the transformation of DHEA-S and DHEA into androgens and/or estrogens in peripheral tissues (8, 9, 10, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21).
The marked reduction in the formation of DHEA-S by the adrenals during aging (4, 22, 23, 24, 25) results in a dramatic fall in the formation of androgens and estrogens in peripheral target tissues, a situation that is thought to be associated with age-related diseases such as insulin resistance (26, 27) and obesity (28, 29). Moreover, low circulating levels of DHEA-S and DHEA have been found in patients with breast (30) and prostate (31) cancer. DHEA has also been found to exert antioncogenic activity in a series of animal models (32, 33, 34). On the other hand, a stimulatory effect of DHEA on the immune system has been described in postmenopausal women (35). Moreover, the oral administration of DHEA has been reported to have beneficial effects in aged men and women (36, 37, 38, 39).
Based on the observation that a large proportion of the active sex steroids in men and women originate from DHEA and DHEA-S (6), and the convincing demonstration of the important role of the androgens and estrogens synthesized in peripheral target tissues from DHEA and DHEA-S in aged men and women (6, 37), we studied the serum concentration of a large series of sex steroids after percutaneous administration of DHEA in 60- to 70-yr-old men and women. The percutaneous route was chosen to avoid the first passage of DHEA through the liver. This route of administration is supported by our recent data obtained in the rat showing that the bioavailability of DHEA is greater after percutaneous than oral administration (39).
This report thus describes the changes in the circulating levels of the most pertinent androgens, estrogens, and their metabolites following DHEA administration. It demonstrates the major changes in the concentration of the circulating metabolites of androgens and estrogens in the presence of little or no change in the concentration of the circulating active sex steroids. The present data support the major importance of the tissue-specific intracellular formation of sex steroids, which is only reflected in the circulation by the changes in the concentration of metabolites, but not of the active sex steroids.
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Subjects and Methods |
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Eight healthy 60- to 70-yr-old volunteer men and post-menopausal women participated in this study after IRB (Institutional Review Board) approval and having given their written informed consent. The participants were nonsmokers. No woman had taken hormone replacement therapy during the previous year. No subject was suffering from an endocrine disorder, and none was under treatment with lipid- or glucose-lowering agents. All participants had a medical history; complete physical examination; and serum biochemistry profile including lipids, complete blood count, urinalysis, and detailed serum hormone determinations during the screening phase of the protocol. Although there was no specific requirement for exercise and diet, no volunteer was involved in a weight loss program nor was following a special diet.
Study design, treatment, and measurements
DHEA (Diosynth, Chicago, IL) was administered percutaneously once daily for 14 days in the morning as a 20% solution (10 mL DHEA, 50% ethanol-50% USP propylene glycol). The DHEA solution was applied over an area of approximately 25 cm x 25 cm on the abdomen, followed by rubbing with the hand for a few seconds to optimize the absorption of DHEA.
Blood sampling was performed at 0800–0900 h before application of DHEA. Measurements of serum steroids were performed 2 days before and immediately before application of DHEA. Serum steroid measurements were also performed 3, 7, 11, and 14 days after first application of the precursor steroid. Following cessation of DHEA administration, serum steroids were analyzed on days 3, 7, 11, and 14 to determine the rate and degree of return towards basal levels.
Steroid analysis in serum
Steroid extraction. Ethanol (5 mL) was added to 1 mL serum and centrifugation was performed at 2000 x g for 15 min. The resulting pellet was further extracted with 2 mL ethanol and, after a second centrifugation at 2000 x g for 15 min, the two supernatants were combined. Pellets were then resuspended once again in 5 mL hexane to maximize the recovery of nonpolar steroids. The suspension was recentrifuged as described above, and the supernatant was decanted and combined with the previously obtained ethanol extracts. The organic solvent was then evaporated under nitrogen, and the residue was dissolved in 1 mL water/methanol (95:5, vol/vol). The C-18 columns (Bound-Elut, Amersham, Bucks, UK) were conditioned by passing consecutively 10 mL methanol, 10 mL water, and 10 mL methanol/water (5:95, vol/vol). The extracts were solubilized in water/methanol (95:5, vol/vol) then deposited on the C-18 columns. After washing the columns with 2 mL water/methanol (95:5, vol/vol), 5 mL methanol/water (50:50, vol/vol) were added to eluate DHEA-S after which 5 mL methanol/water (85:15, vol/vol) were added to eluate the nonconjugated steroids. The acylated steroids were then collected following the addition of 5 mL methanol.
Chromatography on LH-20 columns and RIA. Chromatography on Sephadex LH-20 columns (Pharmacia, Uppsala, Sweden) was performed as previously described (40). In brief, the nonconjugated steroids from the three fractions were solubilized in 1 mL isooctane/toluene/methanol (90:5:5, vol/vol/vol) and deposited on the LH-20 columns. The appropriate fractions were collected and, after evaporation of the organic solvent, the concentration of the various steroids was determined by RIA as previously described (40, 41, 42).
Calculations and statistical analyses
RIA data were analyzed using a program based on model II of Rodbard and Lewald (43). Plasma steroid levels are shown as the means ± SEM of duplicate determinations of individual samples. Statistical significance was measured according to the multiple range test of Duncan-Kramer (44).
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Results |
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). In parallel, DHEA-S increased from
1525 ± 120 nM to 3000 ± 150 nM on
day 7 for a 90% increase over pretreatment values (Fig. 1B). Serum
DHEA-fatty acid esters increased to a peak value of approximately 200%
above control on day 7 after starting treatment to return to basal
values on day 7 posttreatment (Fig. 1C).
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), whereas serum 5-diol-sulfate
(5-diol-S) increased approximately 100% above control during the
treatment period (Fig. 2B). The serum concentration of both steroids
returned to pretreatment values 3 days after cessation of DHEA
administration. As illustrated in Fig. 3, serum androstenedione (4-dione) increased from 3.05 ± 0.2
nM to 5.45 ± 0.35 nM (80% increase)
(Fig. 3A), whereas serum testosterone (Fig. 3B) and dihydrotestosterone
(DHT) (Fig. 3C) remained unchanged during the course of DHEA
administration.
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,17ß-diol (3-diol),
androstane-3ß,17ß-diol (3ß-diol) and, most importantly, the
glucuronidated derivatives of these steroids, androsterone glucuronide
(ADT-G), androstane-3,17ß-diol-G (3-diol-G), and
androstane-3ß,17ß-diol-G (3ß-diol-G). As illustrated in Fig. 4, serum ADT increased by about 40%
during DHEA treatment (Fig. 4A), whereas there was no significant
change in serum 3-diol (Fig. 4B), and the concentration of serum
3ß-diol increased by only about 20% (Fig. 4C). In contrast, serum
ADT-G, 3-diol-G, and 3ß-diol-G, increased by approximately 75%,
50%, and 75%, respectively (Fig. 5).
Similarly, the serum concentration of ADT-sulfate (ADT-S) increased by
115% from 740 ± 90 nM to a maximum of 1600 ±
175 nM (Fig. 6).
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) showed no
consistent change during DHEA administration, whereas serum
E1-sulfate (E1-S) (Fig. 8A) and E2-sulfate
(E2-S) (Fig. 8B) were slightly and inconsistently increased
by only about 20%. Serum cortisol and aldosterone remained unchanged
during the course of treatment (Fig. 9).
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). In contrast, serum 5-diol
increased by a maximum of 200% (Fig. 11), whereas serum 4-dione increased by
about 100% over control, serum testosterone increased approximately
50%, and serum DHT did not show a consistent change (Fig. 12).
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), whereas serum 3-diol and
3ß-diol increased by about 10% (Fig. 13B) and 40% (Fig. 13C),
respectively. As seen in men, the most important effects, however, were
observed on the glucuronidated and sulfate metabolites of ADT,
3-diol, and 3ß-diol. In fact, treatment with DHEA caused an
increase in serum ADT-G, 3-diol-G, 3ß-diol-G, ADT-S, and
3ß-diol-S of approximately 125% (Fig. 14A), 140% (Fig. 14B), 120% (Fig. 14C), 150% (Fig. 15A), and 75% (Fig. 15B), respectively. Again, no consistent effect was observed on serum
E1 or E2 (Fig. 16), whereas serum E1-S and
E2-S increased by about 70% and 30%, respectively, at the
maximal value observed (Fig. 17). In
agreement with the data obtained in men, no effect was detectable on
the serum concentration of cortisol or aldosterone (Fig. 18).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The low levels of serum DHEA and DHEA-S in 60- to 70-yr-old men and women offer the opportunity to measure with greater precision the changes in the serum levels of these precursor steroids, as well as their metabolites, in the circulation without undue interference by the high levels of adrenal precursor steroids in young adult men and women. The present data show a similar increase in serum DHEA of 175–200% over basal values in both men and women who received treatment with percutaneous DHEA. Basal serum DHEA-S levels, however, were approximately 50% lower in women than in men. The similar absolute increase in serum DHEA-S in subjects of both sexes led to a relatively higher relative increase in women than men, 130% and 90%, respectively, over basal values. A similar observation was made for 5-diol, with the basal values being lower in women than in men, 1.6 ± 0.2 nM and 2.9 ± 0.3 nM, respectively. These differences in basal values led to increases in serum 5-diol levels of 225% and 120% in women and men, respectively, following treatment with DHEA.
Basal serum levels of 4-dione were only slightly higher in men than in women (3.05 ± 0.2 nM vs. 2.8 ± 0.2 nM), whereas the basal circulating levels of testosterone were measured at 14 ± 1.1 nM and 1.3 ± 0.2 nM in men and women, respectively. The 50% increase in serum testosterone from approximately 1.3–2.3 nM observed in women during DHEA treatment corresponds to an increase in serum DHEA of approximately 20 nM DHEA. These data are in agreement with the information obtained in men after medical or surgical castration in which the serum levels of testosterone decrease from 15 nM to about 1.5 nM after elimination of testicular androgens. The 1.5 nM serum testosterone originates from adrenal DHEA (5, 46). The present data thus offer an independent measure of the amount of testosterone that diffuses into the circulation from the androgens synthesized from DHEA and DHEA-S in various peripheral intracrine tissues (6). The present data also indicate, as previously suggested (5, 45), that the testicles and adrenals are responsible for approximately equal amounts of androgen biosynthesis in adult men. In women, an important proportion of circulating testosterone is secreted directly by the interstitial cells of the ovary, the estimate from the present data indicating a contribution of approximately 1.0 nM or 67% of circulating testosterone.
The most striking effects of DHEA administration, however, are on the
circulating levels of the glucuronide and sulfate derivatives of the
metabolites of DHT, namely ADT, 3-diol, and 3ß-diol. These
metabolites are produced locally in the peripheral intracrine tissues
that possess the appropriate steroidogenic enzymes to synthesize DHT
from the adrenal precursors DHEA and DHEA-S (6, 8). It can be noted
that if ADT-G is taken as the main marker of DHT metabolism, the
circulating levels of ADT-G are approximately 100% higher in men than
women, thus suggesting that women synthesize approximately 50% as much
DHT as men. Although the absolute increase in the circulating levels of
ADT-G, 3-diol-G, and 3ß-diol-G are comparable in men and women,
because of the lower basal levels in women the percentage increase is
of greater magnitude in women.
After 12 weeks of daily oral administration of 50 mg DHEA, serum DHEA levels increased from 8.5 to 14.7 nM in men and 7.2 to 16.1 nM in women (37), whereas serum DHEA-S increased from 3.5 to 10.1 µM in men and from 1.8 to 9.3 µM in women. The serum 4-dione concentration was increased slightly from 1.9 to 2.2 nM in men, although serum testosterone and DHT levels were unchanged. In contrast, in women serum 4-dione, testosterone, and DHT levels were increased by about 50% following DHEA treatment. Serum E1 or E2 was unaffected by DHEA treatment in either men or women. The difference in the present data in which only serum testosterone was stimulated by DHEA administration in women is possibly because of the effect of first passage of DHEA through the liver after oral administration in the study of Morales et al. (37).
Using a high daily 1.6-g oral dose of DHEA for 4 weeks in
postmenopausal women, the increases observed were 9-fold for serum
testosterone, 20-fold for serum 4-dione and DHT, and 2-fold for serum
estrone (E1) and E2 (36). In addition, a
decrease was observed in serum SHBG, total cholesterol high density
lipoprotein, and insulin resistance was noted. The high levels of
circulating DHT compared with testosterone in the study of Mortola and
Yen (36) possibly reflect the high level of reduction by liver
5-reductase following oral administration of DHEA. Following a
similar duration of daily oral administration of the same high dose of
1.6 g DHEA for 28 days, serum DHEA-S levels increased 2.0- to
2.5-fold above control, whereas serum 4-dione increased 1.0-fold, and
no significant change was seen in serum E2, E1,
testosterone, and SHBG (sex hormone binding globulin) (28).
The present data permit the first direct analysis of the correlation between the serum levels of DHEA and DHEA-S with the serum concentration of active androgens and estrogens and their corresponding glucuronidated and sulfated metabolites. It can be concluded that although measurements of serum testosterone and estradiol reflect testicular and ovarian steroid secretion, respectively, the important contribution of the adrenals is not accurately reflected in the circulating levels of these active sex steroids. The present data thus clearly demonstrate that DHEA and DHEAS are converted in specific intracrine tissues into the active androgens and/or estrogens and are metabolized locally into inactive glucuronidated and sulfated metabolites, which in turn can be measured in the circulation. Measurement of the conjugated metabolites of androgens is the only approach that permits an accurate estimate of the total androgen pool in men. It is likely that a similar situation exists in women for estrogens, although a precise evaluation of the pharmacokinetics of estrogens and their inactive metabolites remains to be performed.
Received November 18, 1996.
Revised May 6, 1997.
Accepted May 12, 1997.
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