Aspirin inhibits androgen response to
chorionic gonadotropin in humans
Domenico
Conte1,
Francesco
Romanelli1,
Silvia
Fillo1,
Laura
Guidetti2,
Aldo
Isidori1,
Francesco
Franceschi3,
Maurizio
Latini1, and
Luigi
di
Luigi2
1 Division of Andrology,
Department of Medical Pathophysiology, University "La
Sapienza," 00161 Rome;
2 Laboratory of Endocrinological
Research, University Institute of Motor Sciences, 00194 Rome; and
3 Department of Orthopedics,
Libera Universitá, Campus Biomedico, 00155 Rome,
Italy
 |
ABSTRACT |
Eicosanoids play
an important role in the regulation of the hypothalamic-pituitary axis;
less clear is their role in testicular steroidogenesis. To evaluate the
involvement of cyclooxygenase metabolites, such as prostaglandins, in
the regulation of human testicular steroidogenesis, we examined the
effects of a prostaglandin-blocker, aspirin, on plasma testosterone,
pregnenolone, progesterone, 17OH-progesterone, androstenedione,
dehydroepiandrosterone, and 17
-estradiol response to human chorionic
gonadotropin (hCG) in normal male volunteers in a placebo-controlled,
single-blinded study. To test the efficacy of aspirin, seminal
prostaglandin E2 levels were also
determined. hCG stimulation increased peripheral levels of
testosterone, 17OH-progesterone, androstenedione,
dehydroepiandrosterone, and 17
-estradiol, without affecting
circulating pregnenolone and progesterone values. Aspirin significantly
lowered seminal prostaglandin E2
levels, whereas it did not modify steroid concentrations not exposed to
exogenous hCG. Moreover, the drug significantly reduced the response of testosterone, 17OH-progesterone, androstenedione, and
dehydroepiandrosterone to hCG, as assessed by the mean integrated area
under the curve, whereas it did not influence 17
-estradiol response.
In conclusion, aspirin treatment inhibits androgen response to
chorionic gonadotropin stimulation in normal humans. The action of
aspirin is probably mediated via an effective arachidonate
cyclooxygenase block.
human chorionic gonadotropin; prostaglandin; androgens; testis
 |
INTRODUCTION |
PROSTAGLANDINS and other arachidonate metabolites,
generically named eicosanoids, play an important role in the regulation of the hormonal secretions of the hypothalamic-pituitary-testicular axis, as shown by in vivo and in vitro studies in animals. Indeed, it
is well established that at the hypothalamic level prostaglandin E2
(PGE2), synthesized by
cyclooxygenase enzyme, acts as an intracellular mediator of
gonadotropin-releasing hormone (GnRH) release (20, 21).
In this regard, one of our previous studies, which showed that aspirin,
a prostaglandin-blocker, inhibits luteinizing hormone (LH) response to naloxone in humans, suggested also
that this activity of eicosanoids of the cyclooxygenase pathway
operates in humans (2). It is well-known that at the pituitary step, the arachidonate lipoxygenase pathway is required for LH secretion (1,
19). Less clear is the role of eicosanoids at the testis site, in the
regulation of steroidogenesis. Indeed, it has been reported that
cyclooxygenase (29) or lipoxygenase metabolites (7) or arachidonic acid
(AA) itself (12) could be directly involved in the process of
testosterone (T) production. In a previous study, we showed that
exogenous AA stimulates T production in rat Leydig cells and that its
conversion to cyclooxygenated or lipoxygenated metabolites is not
required for the steroidogenic action (23).
Therefore, to verify the involvement of eicosanoids, particularly
cyclooxygenated compounds such as prostaglandins, in the regulation of
testicular steroidogenesis and to evaluate whether it also operates in
humans, the present study was designed to examine the effect of a
treatment with oral aspirin, an inhibitor of the cyclooxygenase pathway
of AA metabolism, on testicular steroidogenesis. To this end, during
short-term aspirin administration, when the subjects were not exposed
to exogenous human chorionic gonadotropin (hCG) and were under acute
stimulation with chorionic gonadotropin, the following hormone levels
were determined: plasma T, pregnenolone, 17
-estradiol,
4 [progesterone;
17OH-progesterone (17OH-P); androstenedione (A)], and
5 [dehydroepiandrosterone
(DHEA)] T precursors. To test the efficacy of
aspirin as a prostaglandin-blocker at the dose and times used in the
experimental protocol, seminal
PGE2 levels were also determined.
 |
MATERIALS AND METHODS |
Subjects. Eight healthy male
volunteers, aged 20-30 years, entered the study after giving
written informed consent according to the Helsinki II declaration. They
were nonsmokers and had been free of medication for at least 4 wk. All
had normal medical histories, physical examinations, serum chemistries,
full blood counts, urinalyses, and hormonal evaluations, including
dynamic pituitary-testis axis function tests (plasma LH levels before
and after 100 µg iv injection of GnRH at
30,
15, 0, +15, +30, +45, +60, and +90 min were the following: 5.2 ± 0.6, 4.8 ± 0.5, 6.1 ± 0.9, 11.3 ± 1.2, 21.2 ± 2.7, 19.1 ± 1.6, 14.3 ± 0.9, and 9.1 ± 0.8 mIU/ml, respectively).
Each subject received the following treatments, separated by an
interval of at least 1 mo. For the experimental study:
1) placebo aspirin plus hCG,
2) aspirin plus hCG; for the control study, 3) aspirin plus placebo hCG,
and 4) placebo aspirin plus placebo hCG.
Study design. All the treatments were
placebo controlled, single blinded, and approved by the local Ethical
Committee. Aspirin (Cemirit, Bayer, Milan, Italy) or
placebo was administered in an oral dose of 800 mg (1 tablet) two times
daily for 7 days (i.e., 2 days before and 5 days after hCG or placebo
administration). For the hCG test, the dose administered, the sampling
times, and the steroids evaluated were as reported in previous studies
(8, 25).
On the morning of the experiment, between 0800-0900, an indwelling
catheter was inserted after an overnight fast and basal blood sampling
was begun at
60 min and was continued at
20-min intervals
until intramuscular administration of 5,000 IU hCG (Profasi HP, Serono,
Rome, Italy) or normal saline at 0 min. Further blood samples were
drawn at 2, 24, 48, 72, and 96 h. Before aspirin (or placebo) ingestion
on the morning of hCG administration (2 h before the test) and 96 h
after chorionic gonadotropin injection (after the last blood sample),
the subjects were asked to collect semen specimens by masturbation for
seminal PGE2 measurement.
Hormonal assay.
PGE2 was extracted from seminal
plasma, as previously described (3), and measured by RIA (NEN- Du
Pont, Wilmington, DE). The intra- and interassay coefficients of
variation (CVs) were 6.4 and 8.2%, respectively
(n = 10).
T, pregnenolone, progesterone, 17OH-P, DHEA, A, and 17
-estradiol
were determined by RIA. T, progesterone, DHEA, and A kits were
purchased from DSL (Webster, TX). The intra- and interassay CVs were
7.8 and 8.1% for T, 6.6 and 11.7% for progesterone, 3.1 and 6.9% for
DHEA, and 4.3 and 7.7% for A, respectively
(n = 10). The sensitivity was 0.08 ng/ml for T, 0.12 ng/ml for progesterone, 0.009 ng/ml for DHEA, and
0.03 ng/ml for A. The pregnenolone kit was purchased from Diagnostics
Biochem (London, ON, Canada). The intra- and interassay
CVs were 13 and 15%, respectively (n = 10). The sensitivity for pregnenolone was 0.15 ng/ml. 17OH-P and
17
-estradiol kits were purchased from CIS (Cedex, France). The
intra- and interassay CVs were 5.9 and 6.9% for 17OH-P, respectively,
and 6.5 and 10.5% for 17
-estradiol, respectively
(n = 10). The sensitivity for 17OH-P
and 17
-estradiol was 0.02 ng/ml and 1.35 pg/ml, respectively.
Statistical methods. Steroid levels
after hCG (or placebo) administration are expressed as a percentage of
the basal values. Moreover, cumulative secretory areas under the curve
from 0 to 96 h (AUC) were calculated by the trapezoidal method and
expressed as percent differences between either placebo aspirin + hCG
or aspirin + hCG tests and placebo aspirin + placebo hCG test. Results are expressed as means ± SE.
Seminal PGE2 level comparisons
were performed by paired Student's
t-test. For all hormones, one-way
ANOVA with repeated measures was employed to determine the overall
response to hCG stimulation. The Dunnett's statistical test was used
for post hoc multiple comparison analysis against values before hCG
administration. Comparisons of the differences between tests were
performed by paired Student's t-test.
Statistical significance was considered as
P < 0.05.
 |
RESULTS |
Aspirin induced a significant reduction of seminal
PGE2 levels in the aspirin + hCG
test from 86 ± 5 µg/ml before the treatment to 12 ± 2 and 14 ± 3 µg/ml, during and at the end of its administration, respectively (P < 0.001). Seminal
PGE2 levels were not modified in
the placebo aspirin + hCG test (85 ± 4, 80 ± 5, and
89 ± 4 µg/ml before, during, and at the end of treatment, respectively).
During basal sampling (from
60 to 0 min), all steroids measured
were in the normal range and did not show significant differences for
the four tests (data not shown). Furthermore, no differences in
steroids and seminal PGE2 levels
were observed before and after placebo hCG administration (in aspirin + placebo hCG and placebo aspirin + placebo hCG tests; data not shown).
Because hormonal concentrations varied from one subject to the other,
to give more homogeneity to the results, the variations of plasma
steroid values after hCG injection were expressed as a percentage of
the levels not exposed to exogenous chorionic gonadotropin (each
subject as its own control).
After hCG administration, significant percent increases in plasma T
occurred at 2, 24, 48, 72, and 96 h (25.9 ± 5.8, 39.7 ± 11.7, 87.2 ± 16.8, 72.8 ± 19.3, and 76.3 ± 25.6, respectively; P < 0.01) in the placebo aspirin + hCG test and at 48, 72, and 96 h (38.3 ± 19.9, 43.3 ± 15.2, and
29.3 ± 19.9, respectively; P < 0.01) in the aspirin + hCG test, with significant decreases (P < 0.01) of T values in the latter
test, at any time considered (Fig. 1).

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Fig. 1.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent increment of plasma testosterone concentrations after im human
chorionic gonadotropin (hCG) administration to 8 normal volunteers.
Absolute values (means ± SE) at 0, 2, 24, 48, 72, and 96 h are the
following: 494.8 ± 30.8, 621.6 ± 37, 686.1 ± 33.8, 920.6 ± 53.9, 846.8 ± 45, and 870.1 ± 69 ng/ml, respectively, in
placebo (PL) aspirin (ASP) + hCG test and 569.6 ± 43.1, 594.6 ± 47.2, 653.6 ± 61.7, 781.1 ± 53.6, 803.4 ± 31.3, and 723.4 ± 35.4 ng/ml, respectively, in aspirin + hCG test. a:
P < 0.01, placebo aspirin + hCG and
aspirin + hCG vs. respective basal values. b:
P < 0.01, aspirin + hCG vs. placebo
aspirin + hCG.
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With regard to plasma pregnenolone and progesterone, hCG administration
did not induce significant variations in either placebo aspirin + hCG
or aspirin + hCG tests at any time considered (data not shown).
As for the effect of hCG administration on 17OH-P levels, significant
percent increases were observed at 24 and 48 h in both the placebo
aspirin + hCG (92.7 ± 36.2 and 81.4 ± 49.7, respectively; P < 0.01) and the aspirin + hCG
tests (55.5 ± 7.0 and 43.9 ± 12.6, respectively;
P < 0.01), with a significant
decrease (P < 0.05) in steroid
values at 24 h in the latter test (Fig. 2).

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Fig. 2.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent increment of plasma 17OH-progesterone concentrations after im
hCG administration to 8 normal volunteers. Absolute values (means ± SE) at 0, 2, 24, 48, 72, and 96 h are the following: 2.3 ± 0.1, 3.2 ± 0.3, 4.4 ± 0.1, 4.1 ± 0.2, 2.9 ± 0.3, and 2.4 ± 0.2 pg/ml, respectively, in placebo aspirin + hCG test and 2.7 ± 0.1, 2.9 ± 0.1, 4.1 ± 0.2, 3.8 ± 0.2, 3 ± 0.1, and 2.2 ± 0.1 pg/ml, respectively, in aspirin + hCG test. a:
P < 0.01, placebo aspirin + hCG and
aspirin + hCG vs. respective basal values. b:
P < 0.01, aspirin + hCG vs. placebo
aspirin + hCG.
|
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Regarding plasma A levels after hCG administration, significant percent
increases occurred in the placebo aspirin + hCG test at any time
considered (52.9 ± 50.9, 50.6 ± 48.7, 58.8 ± 33.7, 67.5 ± 18.8, and 63.0 ± 51.3; P < 0.05), whereas no increases were observed in the
aspirin + hCG test, with a significant decrease (P < 0.01) at 2, 72, and 96 h in the
latter test (Fig. 3).

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Fig. 3.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent increment of plasma androstenedione concentrations after im hCG
administration to 8 normal volunteers. Absolute values (means ± SE)
at 0, 2, 24, 48, 72, and 96 h are the following: 2.2 ± 0.2, 3.1 ± 0.1, 3.1 ± 0.2, 3.3 ± 0.2, 3.7 ± 0.5, and 3.4 ± 0.3 ng/ml, respectively, in placebo aspirin + hCG test and 2.6 ± 0.2, 2.4 ± 0.1, 2.6 ± 0.1, 3.2 ± 0.2, 2.9 ± 0.4, and
2.7 ± 0.3 ng/ml, respectively, in aspirin + hCG test. a:
P < 0.05, placebo aspirin + hCG vs.
basal values. b: P < 0.01, placebo
aspirin + hCG vs. basal values. c: P < 0.01, aspirin + hCG vs. placebo aspirin + hCG.
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When the effects of hCG stimulation on DHEA levels were evaluated,
significant percent increases were observed at 48 h in both the placebo
aspirin + hCG (67.8 ± 44.8;
P < 0.05) and the aspirin + hCG
tests (31.6 ± 20.9; P < 0.05),
with a significant decrease (P < 0.05) at 2, 48, 72, and 96 h in the latter test (Fig.
4).

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Fig. 4.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent increment of plasma dehydroepiandrosterone (DHEA)
concentrations after im hCG administration to 8 normal volunteers.
Absolute values (means ± SE) at 0, 2, 24, 48, 72, and 96 h are the
following: 6.5 ± 0.5, 9.5 ± 1.1, 10.3 ± 1.2, 10.8 ±
1.1, 10.1 ± 1.4, and 9.1 ± 1.2 ng/ml, respectively, in placebo
aspirin + hCG test and 9.2 ± 0.8, 9.6 ± 0.6, 9.9 ± 0.9, 12.2 ± 1.4, 9.7 ± 1.6, and 8.3 ± 0.8 ng/ml, respectively,
in aspirin + hCG test. a: P < 0.05, placebo aspirin + hCG and aspirin + hCG vs. respective basal values. b:
P < 0.05, aspirin + hCG vs. placebo
aspirin + hCG.
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With regard to plasma 17
-estradiol response to chorionic
gonadotropin, significant percent increases occurred at 24, 48, 72, and
96 h in the placebo aspirin + hCG test (241.8 ± 167.9, 370 ± 142.2, 253.0 ± 107.8, and 209.2 ± 119.3, respectively;
P < 0.01) and at 24, 48, and 72 h in
the aspirin + hCG test (354.3 ± 184.9, 279.8 ± 163.0, and 180.7 ± 131.2, respectively; P < 0.05), without any significant difference between the two tests
(Fig. 5).

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Fig. 5.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent increment of plasma 17 -estradiol concentrations after im hCG
administration to 8 normal volunteers. Absolute values (means ± SE) at 0, 2, 24, 48, 72, and 96 h are the following: 18.3 ± 2.2, 24.8 ± 2.2, 64.1 ± 12.8, 80.2 ± 4.7, 59.4 ± 2.5, and 51.6 ± 3.2 pg/ml, respectively, in placebo aspirin + hCG
test and 19.1 ± 3.3, 18.8 ± 2.7, 74.1 ± 3.3, 61.9 ±
4.3, 45.5 ± 3.5, and 36.6 ± 3.1 pg/ml, respectively, in aspirin + hCG test. a: P < 0.01, placebo
aspirin + hCG and aspirin + hCG vs. respective basal values. b:
P < 0.01, aspirin + hCG vs. placebo
aspirin + hCG.
|
|
To better evaluate and also to quantify the effects of aspirin on
hCG-induced testicular steroidogenesis, the percent differences (%
)
of the cumulative AUCs of the steroids after chorionic gonadotropin stimulation were also calculated (Fig. 6).
%
of T AUC response to hCG was significantly decreased by aspirin
treatment (148.23 ± 3.89 vs. 126.10 ± 3.53 placebo
aspirin + hCG vs. aspirin + hCG test, respectively;
P < 0.01). In the same way, %
of
17OH-P AUC response to hCG was significantly decreased by aspirin
(144.32 ± 5.30 vs. 129.05 ± 3.18 placebo aspirin + hCG vs.
aspirin + hCG test, respectively; P < 0.05). A significant decrease was also observed in %
of A AUC (138.13 ± 3.98 vs. 126.71 ± 7.42 placebo aspirin + hCG vs. aspirin + hCG test, respectively ;
P < 0.05) and in %
of DHEA AUC
(141.43 ± 11.67 vs. 112.40 ± 5.30 placebo aspirin + hCG vs.
aspirin + hCG test, respectively; P < 0.05) response to hCG. In contrast, %
of 17
-estradiol AUC
was not modified by aspirin treatment.

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Fig. 6.
Effects of oral aspirin (or placebo) treatment on means ± SE
percent differences of cumulative areas under the curves (AUC) of
steroid response after im hCG administration to 8 normal volunteers. T,
testosterone 170HP, 170H-progesterone; A, androstenedione;
E2, 17 -estradiol. a:
P < 0.01, aspirin + hCG vs. placebo
aspirin + hCG. b: P < 0.05, aspirin + hCG vs. placebo aspirin + hCG.
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 |
DISCUSSION |
First of all, the finding that chorionic gonadotropin induced the
expected increase of peripheral levels of T, its
4 (17OH-P and A) and
5 (DHEA) precursors, as well as
17
-estradiol, confirmed previous numerous reports present in
literature (8, 9, 14, 25). With regard to progesterone and
pregnenolone, the finding that their plasma levels were not increased
by hCG stimulation was also in agreement with a previous report (14).
The lack of chorionic gonadotropin effect on circulating progesterone
and pregnenolone values may have been due to their rapid conversion
into their metabolites under hCG stimulation inside the Leydig cells.
Furthermore, the results of the present study indicate that aspirin
treatment, at the dose and times used in the experimental protocol, is
effective as a cyclooxygenase inhibitor because it significantly
reduced seminal PGE2 levels. In
addition, the inhibitory activity of the drug on hCG-induced T
production seems to suggest that the cyclooxygenase pathway of the AA
metabolism could be involved in hCG-stimulated testicular
steroidogenesis in humans, whereas it was not required when the
subjects were not exposed to exogenous chorionic gonadotropin, as shown
by the lack of aspirin effect in this condition. Moreover, aspirin
treatment inhibited the
4 T
precursors, such as 17OH-P and A, and also the
5 T precursor, DHEA, whereas it
did not modify the 17
-estradiol response to chorionic gonadotropin.
This lack of aspirin effect could reflect the small testicular
contribution to the overall amount of plasma 17
-estradiol levels
(30). Theoretically, the simultaneous inhibition of T and some of its
4 and
5 precursor responses to hCG
induced by aspirin treatment could be due to a specific block of the
enzymatic activities involved in the production of 17OH-P, DHEA, A, and
T (i.e., 17
-hydroxylase, 17,20-lyase, and 17
-hydroxysteroid
dehydrogenase) and/or to higher enzymatic inhibitions.
In this regard, it has been reported that another cyclooxygenase
inhibitor, indomethacin, is able to inhibit 3
-hydroxysteroid
dehydrogenase and 17
-hydroxysteroid dehydrogenase activities in rat
testis (22). On the other hand, more recently, it has been shown that
AA by itself exerts a specific inhibitory effect on
17
-hydroxysteroid dehydrogenase in rat Leydig cells (13). However,
with regard to human testis, these possibilities seem to be unlikely
because the present study indicates that aspirin treatment does not
affect steroidogenesis in conditions of nonexposure to exogenous
hCG. As a consequence, the aspirin inhibition of androgen response to chorionic gonadotropin may more likely be explained by the drug's interference with the LH-hCG action on the
plasma membrane of Leydig cells. It is well established that steroidogenesis in Leydig cells is mainly regulated by LH, via the
interaction with its receptors coupled to the adenylate cyclase-cAMP signaling pathway. It is also well-known that occupied LH receptors can
activate a phospholipase C signaling cascade, but only at high hormone
concentrations, with consequent stimulation of phosphatidylinositol turnover leading to intracellular release of diacylglycerol, inositol triphosphate, calcium, AA, and its metabolites (4, 10, 24, 28). This
fatty acid, once released into the cytosol, may act itself directly as
a signaling molecule and/or via its metabolic pathways (18). Indeed, AA
may undergo different metabolizations via cyclooxygenase, lipoxygenase,
and cytochrome P-450-dependent epoxygenase pathways, leading to the formation of
1) prostaglandins and thromboxanes,
2) hydroxyeicosatetraenoic acids and
leukotrienes, and 3)
epoxyeicosatetraenoic acids, respectively. Therefore, it is possible
that aspirin can block the coupling of occupied LH receptors to
phospholipase C, considering that the dose of chorionic gonadotropin
used in the present study was high, compared with the endogenous LH
levels. Moreover, this hypothesis could explain the discrepancy between
the results obtained when the subjects were not exposed to exogenous
hCG and under chorionic gonadotropin stimulation.
Several experimental evidences, obtained in animals, indicate the
involvement of AA and its metabolites in gonadal function. In
particular, it has been shown that these compounds seem to be required
in the regulation of testicular steroidogenesis. Indeed, it has been
reported that LH induces a rapid release of AA from Leydig cells (5),
which is dependent on and directly proportional to the membrane
concentration of LH-hCG receptors (17). Moreover, different findings
suggest that this fatty acid displays a steroidogenic effect that could
be either direct or mediated by its metabolic pathways. The results of
studies on the effect of AA itself on testicular steroidogenesis seem
to be quite variable and sometimes contradictory, depending on the
different experimental conditions. In fact, it has been reported that
exogenous AA is able to stimulate basal T production (6, 7). When the
effect of exogenous AA on LH-hCG-induced T secretion was evaluated, a
direct biphasic (stimulatory/inhibitory) activity was observed,
depending on the time of incubation (12) or its concentrations (6).
However, because LH induces AA release from Leydig cells, as previously mentioned, when exogenous AA was added to Leydig cells stimulated by
LH-hCG, the effect on T production appeared to be cumulative to that of
its endogenously released amount, so that physiological considerations
must be taken into account with caution. Furthermore, several studies
have been carried out to evaluate the role of AA metabolites on
testicular steroidogenesis. (7, 11, 15, 22, 23, 29)
However, the results of these studies are conflicting. Indeed, it has
been reported that eicosanoids of both cyclooxygenase (29) and
lipoxygenase (7, 15) pathways may be involved in the stimulation of T
production, whereas other authors (11, 23) indicate that the conversion
of AA to the cyclooxygenase or lipoxygenase metabolites is not required
for its steroidogenic effect. On the other hand, evidence has been
provided suggesting the involvement of both cyclooxygenase and
lipoxygenase metabolites in the stimulation of testicular
steroidogenesis (22). However, most of these in vitro studies were
carried out with arachidonate pathway inhibitors, such as indomethacin
and nordihydroguaiaretic acid (NDGA, a lipoxygenase blocker). In this
regard, it has been reported that indomethacin, which at low doses is
an inhibitor of the cyclooxygenase pathway, at higher concentrations
inhibits lipoxygenase activity (26). In the same way, in a previous
study we observed that NDGA at low concentrations is a specific
lipoxygenase inhibitor, whereas at higher concentrations it also
inhibits cyclooxygenase activity (23). Because in most of these reports
indomethacin and NDGA were used at higher concentrations, caution is
required when interpreting the results of these studies.
The present study indicates that in humans the conversion of AA to its
cyclooxygenase metabolites could be required for the expression of its
steroidogenic effect. An alternative explanation of the effect of
aspirin treatment observed in this study could be theoretically
considered: the drug-induced inhibition of androgen response to hCG
might not be related to a direct cyclooxygenase block but rather to an
indirect stimulation of other arachidonate metabolic pathways (i.e.,
lipoxygenase and/or epoxygenase), caused by increased substrate
availability, and consequent production of some metabolite(s) with
inhibitory activity on Leydig cells steroidogenesis. However, this
possibility should be excluded because has been shown that lipoxygenase
metabolites display stimulatory rather than inhibitory effects on T
production (22, 27), and no evidence of stimulatory activity of the
epoxygenase pathway has been obtained (13). Finally, the results
observed might be explained by a prostaglandin-independent action of
aspirin. This hypothesis, however, raises certain difficulties in that 1) the drug effects were observed
only under hCG stimulation and not in conditions of nonexposure to
exogenous chorionic gonadotropin and
2) considerably higher doses of
aspirin than those used in the present study are needed to induce
effects not mediated by cyclooxygenase block (16).
In conclusion, the present study shows, for the first time to our
knowledge, that in humans androgen response to chorionic gonadotropin
is inhibited by aspirin treatment and that the action of the drug is
probably mediated via an effective arachidonate cyclooxygenase block.
 |
ACKNOWLEDGEMENTS |
This study was supported by a grant of Ministero
dell'Universitá e della Ricerca Scientifica e Tecnologica, Rome, Italy.
 |
FOOTNOTES |
The costs of publication of this
article were defrayed in part by the
payment of page charges. The article
must therefore be hereby marked
"advertisement"
in accordance with 18 U.S.C. §1734 solely to indicate this fact.
Address for reprint requests and other correspondence: D. Conte,
Dipartimento di Fisiopatologia Medica, Policlinico Umberto I, Viale
del Policlinico 155, 00161 Rome, Italy (E-mail:
domenico.conte{at}usa.net).
Received 22 February 1999; accepted in final form 28 July 1999.
 |
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