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Reproductive Endocrinology |
Laboratory of Molecular Endocrinology, CHUL 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 (Québec), G1V 4G2, Canada.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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,17ß-diol (3-diol-G), androstane-3ß,17ß-diol
(3ß-diol-G), and ADT-sulfate are the most reliable parameters of the
total androgen pool in both men and women, whereas serum testosterone
and DHT can be used as markers of testicular secretion in men and
interstitial ovarian secretion in women. The serum concentration of
these various conjugated androgen metabolites decreased by 40.8% to
72.8% between the 20- to 30-yr-old and 70- to 80-yr-old age groups in
men and women, respectively, thus suggesting a parallel decrease in the
total androgen pool with age. As estimated by measurement of the
circulating levels of these conjugated metabolites of DHT, it is
noteworthy that women produce approximately 66% of the total androgens
found in men. In women, most of these androgens originate from the
transformation of DHEA and DHEA-S into testosterone and DHT in
peripheral intracrine tissues, whereas in men the testes and DHEA and
DHEA-S provide approximately equal amounts of androgens at the age of
50–60 yr. An additional potentially highly significant observation is
that the majority of the marked decline in circulating adrenal
C19 steroids and their resulting androgen metabolites takes
place between the age groups of 20- to 30-yr olds and 50- to
60-yr-olds, with smaller changes are observed after the age of 60 yr. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It is remarkable that humans, in addition to possessing very sophisticated endocrine and paracrine systems, have largely vested sex steroid formation in peripheral tissues. In fact, although the ovaries and testes are the exclusive sources of androgens and estrogens in lower mammals (6), the situation is very different in higher primates, in which active sex steroids are in a large part or whole synthesized locally in peripheral tissues, thus providing individual target tissues with the means to adjust formation and metabolism of sex steroids to their local requirements (4, 5, 7, 8). Thus, humans and some other primates are unique in having adrenals that secrete large amounts of the precursor steroids DHEA-S and DHEA, which are converted into androstenedione (4-dione) and then into active androgens and/or estrogens in peripheral tissues (4, 7, 8, 9).
Transformation of the adrenal precursor steroids DHEA-S and DHEA into active androgens and/or estrogens in peripheral target tissues depends on the level of expression and activity of the various steroidogenic and metabolizing enzymes in each of these tissues. This new field of hormone formation and action has been called intracrinology (4, 8). 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 (5, 10, 11, 12, 13, 14). The particular importance of DHEA and DHEA-S is best illustrated by the finding that approximately 50% of total androgens in adult men derive from these adrenal precursors steroids (7, 15, 16). In women, our best estimate of the intracrine formation of active estrogens in peripheral tissues from adrenal precursor steroids is approximately 75% before menopause and close to 100% after menopause (4).
To gain a better knowledge of the role of DHEA and DHEA-S transformation in both men and women, we analyzed the serum levels of 18 conjugated C21- and C19-steroids. We wanted to precisely assess the changes occurring in the serum concentration of these steroids over the range of ages from the peak value of adrenal secretion of DHEA and DHEA-S at the ages of 20–30 yr to the nearly lowest values found at the ages of 70–80 yr.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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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 two 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 solubilized in water/methanol (95:5, vol/vol) were 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 (17). 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 (17, 18, 19).
Calculations and statistic analyses
RIA data were analyzed using a program based on model II of Rodbard and Lewald (20). 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 (21).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). This marked decrease in serum DHEA
corresponds to 80.1% and 69.7% declines between the ages of 20–30
and 70–80 yr in men and women, respectively. At the ages of 40–50 yr,
serum DHEA had already decreased by 40.9% (P < 0.01)
and 44.5% (P < 0.01) in men and women, respectively.
In analogy, at the ages of 50–60 yr serum DHEA was decreased by 74.4%
and 70.5% in men and women, respectively, compared with the peak
values measured at the ages of 20–30 yr. It can be seen in Fig. 1 that
the majority of the decline in serum DHEA occurred up to the age of
50–60 yr in both men and women, and that relatively smaller changes
were observed up to the last time interval studied, 70–80 yr.
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). From values of 11.5 ± 1.0
µM measured in the youngest age group of men, serum
DHEA-S decreased to 2.3 ± 0.3 µM at the ages of
70–80 yr, whereas in women serum DHEA-S decreased from 6.2 ± 0.5
µM to 1.6 ± 0.3 µM, thus representing
80% and 74% declines, respectively.
As illustrated in Fig. 1C, the concentration of serum DHEA-fatty acid
esters decreased from 9.2 ± 0.6 nM in 20- to
30-yr-old men to 1.9 ± 0.3 nM in the 70- to 80-yr-old
group age (79.3% decline). In women, on the other hand, serum
DHEA-fatty acid esters decreased from 9.3 ± 0.9 nM in
the 20- to 30-yr-old group to 4.1 ± 0.5 nM (56%
decline) in the 60- to 70-yr-old group and to 3.8 ± 0.5
nM (59% decrease) in the 70- to 80-yr-old group of
women.
Aging had similar effects on serum androst-5-ene-3ß,17ß-diol
(5-diol), the steroid formed by 17ß-hydroxysteroid dehydrogenase
(17ß-HSD) from DHEA and the immediate precursor of the androgen
testosterone obtained through 3ß-hydroxysteroid dehydrogenase
(3ß-HSD) activity (Fig. 1D). Serum 5-diol decreased from 5.1 ±
0.2 nM in 20- to 30-yr-old men to a value of 2.0 ±
0.2 nM in 60- to 70-yr-old men (60.7% decrease). This was
followed by a nonsignificant slight increase at 2.5 ± 0.2
nM measured in the 70- to 80-yr-old group. In women, serum
5-diol decreased from 3.0 ± 0.2 nM in the youngest
age group to 1.5 ± 0.1 nM in 70- to 80-yr-old
subjects (50% decrease).
It was next of interest to see the changes associated with aging on the
serum concentration of 4-dione, the immediate product of DHEA formed by
3ß-HSD (22). 4-Dione is the precursor of the androgen testosterone
and the estrogen estrone (E1) through the action of
17ß-HSD and aromatase, respectively. As can be seen in Fig. 2A, serum 4-dione decreased in men from 3.5 ± 0.3
nM in the 20- to 30-yr-old group to 1.7 ± 0.2
mM in the oldest age group (51.4% decline). In contrast,
in women serum 4-dione decreased from 3.7 ± 0.3 nM to
1.4 ± 0.2 nM at the age of 50–60 yr (62% decrease),
with a slight but not significant increase at the later ages.
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).
Serum dihydrotestosterone (DHT) showed a decrease in men at the ages of
50–70 yr, whereas in women a progressive decrease from 0.9 ± 0.1
nM to 0.5 ± 0.05 nM (44% decrease) was
seen between the age ranges of 20–30 and 70–80 yr (Fig. 2C).
Because the serum concentrations of testosterone and DHT in men are
90–95% related to the secretion of androgens by the testes (7, 16),
these measurements do not reflect the total pool of androgens,
especially the important contribution of the adrenals in the total
androgen pool. It is thus of particular interest to measure the
metabolites of DHT, namely androsterone (ADT),
androstane-3,17ß-diol (3-diol), androstane-3ß,17ß-diol
(3ß-diol) and, most importantly, their glucuronidated derivatives
ADT-G, 3-diol-G, and 3ß-diol-G.
ADT, the 17ß-oxidized form of DHT, showed a nonsignificant trend
towards a decrease with aging in both men and women (Fig. 3A). As can be seen in Fig. 3B, aging led to a maximal
30.9% decrease in the serum levels of 3-diol of 60- to 70-yr-old
men compared with 20- to 30- yr-old men, whereas in women there was no
consistent trend. In contrast, serum 3ß-diol decreased from 3.1
± 0.2 mM in 20- to 30-yr-old men to 1.8 ± 0.14
mM in 60- to 70-yr-old men (41.9% decrease) (Fig. 3C). In
women, the values decreased from 1.8 ± 0.17 mM in 20-
to 30-yr-old women to 1.3 ± 0.15 mM in 60- to
70-yr-old subjects.
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). The serum levels of 3ß-diol-G, the second
quantitatively most important metabolite of androgens, decreased from
47 ± 8 nM in the youngest group of men to 16 ±
3 nM (65.9% decrease) in the oldest group. In contrast, in
women serum 3ß-diol-G decreased from 22 ± 4 nM in
the 20- to 30-yr-old group to 6.0 ± 1.7 nM in the
oldest group (72.7% decrease) (Fig. 4B). Similarly, the serum
concentration of the third most important metabolite of androgens,
3-diol-G, decreased from 11.1 ± 0.57 nM in the 20-
to 30-yr-old group of men to 6.57 ± 0.5 nM in the
oldest group (40.8% decrease), whereas in women serum 3-diol-G
decreased from 6.1 ± 0.6 nM to 3.2 ± 0.2
nM (47.5% decrease) (Fig. 4C). The serum levels of the
most abundant metabolite of DHT, ADT-sulfate (ADT-S), decreased from
1380 ± 93 nM in the youngest group of men to 523
± 49 nM (62% decrease) in the 60- to 70-yr-old group of
men (Fig. 4D). In women the values in the same age groups were
1025 ± 112 nM and 344 ± 34 nM,
respectively, (66.4% decrease) (Fig. 4D).
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, A and B), whereas in women the usual decline of serum
E2 was observed at menopause. It is of interest to see that
serum pregnenolone (Fig. 5C) and pregnenolone-fatty acid esters (Fig. 5D) showed a decline with age somewhat comparable with that of DHEA and
the metabolites of androgens. In fact, serum pregnenolone decreased
from 5.5 ± 0.5 nM in 20- to 30-yr-old men to 1.2
± 0.6 in the 70- to 80-yr-old group (78% decrease). In constrast, in
women serum pregnenolone decreased from 3.8 ± 0.6 nM
in the youngest age group to 2.06 ± 0.38 nM in the
70- to 80-yr-old group (45% decrease). Similarly, serum
pregnenolone-fatty acid esters decreased from 11.0 ± 0.8
nM in the youngest age group to 4.3 ± 0.4
nM at 70–80 yr of age in men (60.9% decrease), whereas in
women the serum concentration of the same steroid decreased from
11.0 ± 1.2 nM to a nadir of 6.2 ± 0.7
nM at 60–70 yr of age (43.6% decrease).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-diol-G,
3ß-diol-G, and ADT-S occurs between the ages of 20–30 yr and 50–60
yr, whereas smaller changes are seen after the age of 60 yr. The above-described changes with age of the circulating levels of the metabolites of androgens are likely to be almost or exclusively caused by to the dramatic decreases in DHEA and DHEA-S secretion by the adrenals during aging. As measured in a population of 2423 men, we recently found 66%, 67%, 41%, 60%, and 45% decreases during a 40-yr period of the concentration of the major C19 steroids, DHEA, DHEA-S, 5-diol, 5-diol-sulfate (5-diol-S), and 4-dione, respectively (1).
Although some studies show no change in the circulating levels of testosterone and DHT during aging, most report only a slight decrease in the value of these parameters (23). In a recent study performed in a large population of men, the stability of serum testosterone with age was illustrated by the finding that it decreased at a rate of 0.4% per year between the ages of 40–80 yr for a total of 16% over the 40-yr period (24). It is noteworthy that serum testosterone and DHT levels in women are approximately one-third of those measured in men through the ages of 20–70 yr. As mentioned above, circulating testosterone and DHT are almost exclusively of testicular and ovarian origins in men and women, respectively.
Because the concentration of serum DHEA is comparable in men and women, and serum testosterone levels decrease from approximately 15 nM to 1.5 nM following castration in men (7, 25), the low 1.5 nM levels of serum testosterone found in castrated men result from leakage into the circulation of testosterone synthesized locally from DHEA in the peripheral intracrine tissues. It is thus reasonable to suggest that approximately 3.0 nM of serum testosterone measured in women is secreted by the ovaries (67%), whereas in men approximately 13 nM of serum testosterone originates from the testes (90%). This estimate assumes that the same 1.5 nM value of serum testosterone is derived from intracrine DHEA transformation in both men and women. In agreement with these calculations, LHRH agonists have been found to reduce serum testosterone levels by 65% in women (26). However, during the early natural postmenopausal period, serum testosterone remains relatively stable (27, 28, 29). This apparent discrepancy can possibly be explained by the fact that at postmenopause, 4-dione continues to be secreted by the ovarian interstitial cells, expecially by the hyperplastic stroma, resulting from high circulating gonadotropin levels (30, 31).
In the 20- to 80-yr age range, the average sum of concentrations of the
unconjugated metabolites of DHT, specifically ADT, 3-diol, and
3ß-diol, are 3.45 nM, 1.77 nM, and 2.19
nM in men and 2.98 nM, 1.79 nM, and
1.57 nM in women, respectively. The sum of the serum
concentrations of these three unconjugated DHT metabolites is thus, on
average, 7.41 nM in men and 6.34 nM in women
over the age range of 20–80 yr. On average, there is only a 14% lower
serum level of the unconjugated DHT metabolites in women compared with
men.
It seems clear from recent observations reported in both men and women
that the most valid and possibly the only reliable estimate of the
total androgen pool is the measurement of serum ADT-G, 3-diol-G, and
3ß-diol-G (1, 7, 16, 32). It was first suggested that 3-diol-G
could be a good marker of testosterone metabolism in peripheral tissues
(33, 34). The major significance of the serum concentrations of
3-diol-G and also ADT-G was most clearly demonstrated in men with
prostate cancer treated by medical castration with an LHRH agonist or
orchiectomy. In those castrated men, the serum levels of 3-diol-G
and ADT-G decreased by only 50–70% (7, 15), whereas the plasma
testosterone concentration was decreased by 90–95% (7, 16, 25).
From the data available describing the serum levels on androgens
and their metabolites, as well as from direct measurement of DHT in the
prostatic tissue, it can be estimated that the adrenals contribute
40–50% of total androgens in 60- to 70 yr-old men (16). The present
data further suggest that measurements of serum ADT-S could be another
useful parameter reflecting the total androgen pool in men and women.
However, because the serum levels of ADT-G, 3-diol-G, 3ß-diol-G,
and ADT-S change in parallel, at least during aging, measurement of the
serum concentration of any one of these metabolites, possibly ADT-G,
can provide a reliable marker of total androgen activity in both men
and women. However, because different enzymes
(ADT-glucuronyltransferase and steroid sulfotransferase) catalyze the
conjugation of the various androgen metabolites, differential changes
in the levels of ADT-G, 3-diol-G, 3ß-diol-G, and/or ADT-S are
possible and should be taken into account.
The small or absence of change in serum 3-diol in the present study
as a function of age is in agreement with the data previously obtained
at peripubertal age, in which the serum 3-diol concentration was not
sensitive to marked changes in serum DHEA and testosterone levels (32).
It was clear from those data that in contrast to the small changes
observed in unconjugated 5-steroids during maturation, plasma
3-diol-G and ADT-G were much more sensitive to changes in the
circulating levels of adrenal and testicular C19
steroids.
Using the serum concentrations of ADT-G, 3-diol-G, 3ß-diol-G, and
ADT-S as estimates of total androgens, the average sum of the serum
concentrations of these conjugated metabolites of DHT are 37.5
nM, 8.47 nM, 30.2 nM, and 833.5
nM, respectively, in men compared with 32.5 nM,
4.28 nM, 17.3 nM, and 547.8 nM,
respectively, in women. The average serum concentrations of ADT-G,
3-diol-G, 3ß-diol-G, and ADT-S measured in women between the ages
20–80 yr are thus 86.6% (ADT-G), 50.5% (3-diol-G), 57.2%
(3ß-diol-G), and 65.7% (ADT-S) compared with those found in men of
the same age. Although the metabolic clearance rates of these four
metabolites are likely to show some differences between men and women,
an estimate of the relative amount of total androgens in women and men
calculated on the basis of the sum of the serum concentrations of these
four metabolites suggests that total androgen production in women is
about two-thirds or 66% of that present in men. Such data strongly
suggest that androgens play a major biological role in women. The
44.5% fall in serum DHEA from 20–30 yr to 40–50 yr of age in women
could well explain the bone loss and increased FSH/LH ratio that
precede menopause and occur before a detectable decrease in ovarian
steroidogenesis in perimenopausal women. An example of such a role of
androgens could be the increasingly recognized role of androgens on
bone physiology (35).
As mentioned above, the present data have major implications for a correct interpretation of serum testosterone, DHT, and E2 concentrations in men and women, as well as serum steroid levels in humans or experimental animals treated with DHEA or intracellular inhibitors of sex steroid formation. As an example, the observation that serum testosterone and E2 levels were not increased after treatment of male rats with finasteride led the authors to exclude the potential and even the most likely role of increased intracellular levels of testosterone (36). The present data clearly show that the increased intracellular levels of testosterone and DHT do not translate into parallel changes in circulating levels of these active androgens, and that measurement of the circulating levels of the conjugated metabolites of androgens is the most reliable marker of total androgen formation and action in the human.
Received November 18, 1996.
Revised May 6, 1997.
Accepted May 12, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductase. Endocrinology. 131:1571–1573.[Abstract]
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