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Experimental Studies |
Service d’Endocrinologie et des Maladies de la Reproduction, (J.Y., B.C., K.N., P.C., G.S.), Laboratoire de Biochimie Hormonale (S.B.); Inserm U 33 (E.E.B.) and IFR 21 (J.Y., E.E.B., G.S.), Hopital Bicêtre 94275 Kremlin Bicêtre, France
Address all correspondence and requests for reprints to: Gilbert Schaison, M.D., Service d’Endocrinologie et des maladies de la Reproduction, Hopital Bicêtre, 94275 Kremlin Bicêtre, France.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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5
derivatives, androgens, androgen metabolites, and estrogens was studied
in ten patients with complete panhypopituitarism. Sex steroid therapy
was withdrawn for at least 2 months. Each patient received, at 1-month
intervals and in a random order, two single oral doses of DHEA (50 mg
and 200 mg) and placebo. During each treatment, urine samples were
collected for 24 h, and blood samples were drawn at hourly
intervals for 8 h. In patients with pituitary deficiency, plasma
DHEA and DHEAS were not detectable and increased, with the 50 mg dose,
up to levels observed in young adults. The administration of 200 mg of
DHEA induced an increase of both steroids to supraphysiological plasma
levels. A small increase of 5-androstenediol was observed. In
contrast, the increase of plasma 4-androstenedione was important and
dose dependent. DHEA was also converted into the potent sex steroid
testosterone (T). The administration of a 50 mg dose of DHEA restored
plasma T to levels similar to those observed in young women. The 200 mg
dose induced an important increase of plasma T, sligthly below the
levels observed in normal men. The increase of plasma
dihydrotestosterone levels was small at both doses of DHEA, in contrast
with the large conversion of DHEA into androsterone glucuronide and
androstanediol glucuronide. Finally, DHEA administration induced a
significant and dose dependent increase of plasma estrogens and
particularly of estradiol.
In conclusion, this short term study demonstrates that: 1)
panhypopituitarism is a model of interest to study the metabolism of
DHEA; 2) in the absence of pituitary hormones and of adrenal and
gonadal steroids, DHEA given orally is mainly converted into 4
derivatives, which in turn are strongly metabolized into
5
-3keto-reduced steroids; 3) a significant increase of sex active
hormones was observed in plasma after 200 and even 50 mg of DHEA. Thus,
biotransformation of DHEA into potent androgens and estrogens may
explain several of the reported beneficial actions of this steroid in
aging people.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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In normal subjects, conversion of DHEA into active androgens and estrogens has been well documented by using high pharmacological doses of this steroid (1600 mg/day) (4). In contrast, treatment with low doses of DHEA (50 mg/day) induced significant increases in circulating active androgens in women, but not in men of advancing age (5, 6). Thus, beneficial effects observed at these low doses have been assigned to DHEA and/or to its intracrine conversion into active sex steroids (7). However, DHEA metabolism in healthy men and women can be masked by endogenous steroid secretion. Panhypopituitarism, characterized by the absence of secretion of adrenal and gonadal androgens and estrogens as well as the production of their metabolites, is thus a convenient model to study DHEA metabolism and action.
The purpose of the present short-term study was to assess, in this
model comparative to placebo, the conversion of a replacement dose (50
mg) and a high dose (200 mg) of oral DHEA into the 5 derivatives
DHEAS and 5-androsten-3ß,17ß-diol, androgens, androgen
metabolites, and estrogens in the absence of these endogenous
steroids.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Ten patients (six women and four men) with panhypopituitarism
participated in the study. The pituitary deficiency was the consequence
of hypothalamic or pituitary tumors treated by surgery and/or
radiotherapy in nine of them (Table 1
). In all patients,
the diagnosis was established following pituitary stimulation tests
(Table 2). The complete gonadotropic deficiency was
confirmed by the association of barely detectable or undetectable sex
steroid plasma levels, with low basal and stimulated (GnRH, 100 µg
iv) gonadotropin hormones. Plasma cortisol and ACTH were low and
unresponsive to ovine-CRH (o-CRH: 100 µg, iv). Plasma
FT4, FT3, and TSH (basal and after TRH) levels
were low before replacement therapy. Plasma GH levels were not
stimulated by GHRH (100 µg, iv). In all patients but one (patient 9),
plasma prolactin levels were low and not stimulated by TRH (200 µg
iv). All patients gave informed consent for participation in this
study, which was approved by the Human Investigation Committee of
Paris-Sud University.
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All patients were studied after withdrawal of testosterone or estrogen and progestin therapy for at least 2 months. Hydrocortisone (20 mg/day) and thyroid hormone replacement therapy were maintained. None of the patients received GH therapy. The study was randomized and placebo controlled. Each patient received in a random order two single oral doses of DHEA (50 mg and 200 mg) or a single oral dose of placebo. Each dose of DHEA or placebo was administered at a minimum interval of 4 weeks. Placebo tablets were identical to DHEA tablets (50 mg). Blood samples were drawn at baseline and at hourly intervals for 8 h. Plasma samples were stored below -20 C until assayed. Twenty-four-hour urine samples were collected during each treatment.
Hormone assays
Plasma steroid levels were determined by radioimmunoassay after
chromatographic separation on a sephadex LH 20 or celite column as
previously described (8, 9, 10, 11, 12, 13). The following steroids were measured:
DHEA and DHEAS, 5-androsten-3ß,17ß-diol (5 ADIOL),
androsten-3,17-dione (4 ADIONE), testosterone (T),
5-dihydrotestosterone (DHT), estrone (E1), and estradiol
(E2). Androstane-3,17ß-diol glucuronide (ADG) and
androsterone glucuronide (ADTG) were first hydrolyzed with
ß-glucuronidase, separated by chromatography, and then
radioimmunoassayed (RIA) as nonconjugated steroids as previously
described (11). Assay sensitivity was 0.17 nmol/L for DHEA, T, 4
ADIONE, DHT, 5 ADIOL, ADG, and ADTG, and 0.17 µmol/L for DHEAS.
The detection limit for E1 and E2 was 25.8 and
18.3 pmol/L respectively. Inter- and intraassay precision coefficients
of variation (CV) for these plasma steroid RIAs were 8 and 7.8% for
DHEA, 5 and 4.7% for DHEAS, 6.2 and 6% for 5 ADIOL, 7.6 and 4.6
for 4 ADIONE, 6 and 5.8 for T, 8 and 5.8 for DHT, 13.2 and 10.8 for
E1, 8.5 and 5.1 for E2. Inter- and intraassay
CV were 7 and 5.4% for ADG and 6.8 and 6.2 for ADTG.
Statistical analysis
The data are presented as the mean ± standard error (SE). Statistical significance was considered at P < 0.05. Statistical analyses were performed with the nonparametric paired Wilcoxon test for comparison between treatments (14).
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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). Consequently, data from male and female
patients were analyzed simultaneously.
Plasma 5 steroids
Plasma DHEA, 5 ADIOL, and DHEAS levels were not detectable in
these patients with panhypopituitarism. A prompt and dose dependent
increase in all these 5 steroids occurred after an oral dose of DHEA
compared with placebo (Fig. 1). Mean maximal increment
in plasma DHEA levels was seen 2 h after DHEA ingestion. With the
50 mg dose, mean plasma DHEA levels reached levels (12.8 ± 1.4
nmol/L) observed in normal young adults. With the 200 mg dose, plasma
DHEA levels peaked 4-fold above the peak observed with the 50 mg dose
(45.8 ± 4.9 nmol/L). Plasma DHEAS levels increased dramatically
4 h and 3 h after the 50 and the 200 mg doses respectively.
With 50 mg of DHEA, mean plasma DHEAS levels increased from 0.15
± 0.10 to 15.6 ± 2.5 µmol/L and were above the upper values
observed in normal young individuals, whereas with 200 mg, the peak was
4-fold more important (41.0 ± 3.7 µmol/L). In contrast, plasma
5 ADIOL levels showed a small increase 3 h and 1 h after
the 50 and the 200 mg doses respectively (Fig. 1).
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4 steroids and DHT
Plasma 4 ADIONE, T, and DHT levels were very low or
undetectable in patients with complete panhypopituitarism (Fig. 2). A significant and rapid increase in plasma 4
ADIONE levels was observed after oral DHEA administration
(P < 0.01). With 50 mg, plasma 4 ADIONE levels
increased after 3 h to physiological levels observed in normal men
and premenopausal women (6.2 ± 0.7 nmol/L). With the 200 mg dose,
the peak occurred after 2 h and was 5-fold more important
(23.0 ± 2.6 nmol/L). Plasma T levels after treatment (1.5 ±
0.3 nmol/L) with 50 mg of DHEA were, after 3 h, within the normal
values observed in premenopausal women. A 7-fold increase in plasma T
levels (6.9 ± 1.3 nmol/L) compared with the 50 mg dose was
observed 2 h after a 200 mg dose of DHEA. The rise in plasma DHT
levels was small in both groups of patients and occurred 3 h and
4 h after the 50 and the 200 mg doses respectively.
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Plasma ADTG and ADG levels were undetectable or barely detectable
in patients with panhypopituitarism (Fig. 3A). A prompt
and dramatic increase of ADTG levels was observed after DHEA ingestion.
After a 50 mg DHEA dose, plasma ADTG levels increased after 1 h,
from 0.1 ± 0.08 to 342 ± 63 nmol/L, within the normal range
of healthy subjects. With the dose of 200 mg, the peak was 10-fold more
important than with the 50 mg dose (3276.0 ± 635.0 nmol/L) and
occurred after 3 h. A parallel increase of ADG was observed.
However, plasma ADG levels were two orders of magnitude below those of
ADTG, 7.1 ± 1.3 and 45 ± 7.8 nmol/L, after the 50 and the
200 mg doses respectively.
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). After ingestion of 50 mg of DHEA, ADG reached
levels (85 ± 7 µmol/24 h) seen in normal young women but
remained below normal values observed in young men. After 200 mg, 24-h
urinary ADG levels were 5-fold above the levels observed with 50 mg
(450 ± 50 µmol/24 h). Plasma estrogens
Basal plasma E1 and E2 levels were very
low. A dose dependent increase in both estrogens was observed after
DHEA administration after 3 h and 4 h respectively (Fig. 4). The peak of plasma E2 levels was higher
than that observed with E1. With 50 mg of DHEA, plasma
E2 levels (87 ± 7 pmol/L) were within the normal
range observed in men. With a 200 mg dose, plasma E2 levels
were within the normal range observed in the early follicular phase
(294 ± 60 pmol/L).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The increase of plasma 5 ADIOL levels was small. In contrast, an
increase in plasma 4 ADIONE of similar magnitude to that of plasma
DHEA levels was observed within hours of DHEA administration. This
increase implied an extensive conversion of the 5 steroid into the
4 derivative as previously reported (20). In patients with
panhypopituitarism, this process clearly confirms the physiological
relevance of the extraadrenal and extragonadal 3ß-hydroxysteroid
dehydrogenase activity (3ß-HSD) and indicates the persistent
expression of the peripheral 3ß-HSD isozyme (type I) despite the
absence of pituitary trophic hormones (21). In addition, 4 ADIONE
was significantly reduced into the active sex steroid T by the
peripheral, extragonadal, 17ß-hydroxysteroid dehydrogenase (isozyme
type 2) (22, 23). Thus, the administration of a 50 mg dose of DHEA
restored plasma T to levels observed in young women, whereas with the
200 mg dose, plasma T levels increased, reaching levels observed in
normal men. Although, the increase of plasma DHT was modest at both
doses of DHEA, the physiological importance of both the 5-reductase
and the 3-ketoreductase metabolic pathways in these patients was
indicated by the large conversion of DHEA into ADTG and ADG (24, 25).
In patients receiving the 50 mg replacement dose, the increase of
plasma and urinary ADG to levels observed in normal women is consistent
with previous reports, indicating that DHEA is a main precursor of ADG
in women (26). In contrast, this dose failed to restore plasma and
urinary ADG into the range of normal men, confirming that T is the
principal source of this metabolite in men (27, 28). On the other hand,
the plasma ADTG levels obtained were two orders of magnitude above
those of ADG. This difference, associated with the small increase of
5 ADIOL and higher 4 ADIONE levels than T levels, indicates that
in these patients DHEA administered orally was preferentially converted
into C19 17-keto steroids than in the 17-keto reduced corresponding
metabolites. Finally, there occurred a significant and dose dependent
conversion of DHEA into estrogens by the widely distributed
extragonadal aromatase (29). In opposition to DHEA metabolism into C19
metabolites, DHEA conversion to estrogens was preferentially directed
into the 17-keto reduced pathway. This result suggests that, in
contrast with in vitro reported data (30), the peripheral
17ß-HSD type 2 preferentially catalyzes the reductive reaction when
estrogens are used as substrates (22). Indeed, the two gonadal
isozymes, 17ß-HSD type 1 and 17ß-HSD type 3, which preferentially
catalyze the reductive reaction, are not expressed in these patients
lacking gonadotropin secretion.
The metabolism of DHEA into potentially active sex steroids can occur inside many cells containing androgen and/or estrogen receptors that may interact with them. This is the case in adipose tissue, bone, muscle, breast, prostate, skin, brain, and particularly in the liver where the metabolism of DHEA is quantitatively important (31). This intracrine mechanism may explain many androgenic and estrogenic properties of DHEA observed in vivo (7, 32). However, the present study clearly demonstrates that these active DHEA metabolites may be released into the circulation and reach target tissues lacking DHEA metabolizing enzymes. Therefore, estrogenic and androgenic effects of DHEA can be mediated by a classic endocrine pathway.
In the absence of a clearly demonstrated peripheral DHEA receptor, a number of previously reported effects assigned to this steroid in humans could be related to its conversion to sex steroids. Conversion of DHEA into potent androgens probably accounts for the increased index of sebum secretion reported in postmenopausal women as well as acne in addisonian female patients treated with the 50 mg DHEA replacement dose (7). In addition, the high androgen environment induced by pharmacological doses of DHEA could explain the previously reported induction of an atherogenic lipid profile and an insulinoresistant state in postmenopausal women (4). At both replacement and pharmacological doses of DHEA, the active steroid E2 reached levels compatible with the occurrence of estrogenic actions. This result could explain the number of beneficial effects induced by DHEA in postmenopausal women, like vaginal epithelium maturation, decrease of fasting insulin levels, and increase of bone mass density and plasma osteocalcin levels (7, 33, 34). The increase in IGF-I plasma levels previously reported after DHEA administration may also be explained by its conversion into sex steroids (5, 35, 36).
The ability of DHEA to undergo biotransformation into potent androgens and estrogens implies that hormonodependent diseases like prostate, endometrium, or breast cancer should be carefully ruled out before any long-term administration.
In conclusion, 1) panhypopituitarism represents a convenient model to
assess in humans the metabolism and actions of DHEAS; 2) the present
report shows that, in the absence of adrenal and gonadal steroids, oral
DHEA is mainly converted into 4 derivatives, which in turn are
metabolized into active sex steroids. This biotransformation may
explain some reported beneficial actions of DHEA; 3) long-term studies
are needed to carefully assess in panhypopituitarism the therapeutic
effects of DHEA in addition to the usual sex hormone replacement
therapy.
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Footnotes |
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Received January 31, 1997.
Revised April 24, 1997.
Accepted May 5, 1997.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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-reductases. Proc Nat Acad Sci USA. 87:3640–3644.-hydroxysteroid
dehydrogenase activity. Biochem J. 282:741–746.
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indicates
P < 0.01 compared with 50 mg. In parentheses, the
normal range in young individuals; f = women in the early
follicular phase; m = men.
