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Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
Address all correspondence and requests for reprints to: Yasunori Yoshimura, M.D., Department of Obstetrics and Gynecology, Keio University School of Medicine, 35 Shinanomachi, Shinjuku, Tokyo 160, Japan. E-mail: yasu{at}mc.med.keio.ac.jp
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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in response to hCG was
significantly blocked by L-NAME, and exogenous administration of NP
stimulated the production of PGs in the absence of gonadotropin.
Significant correlations were observed between the ovulatory
efficiencies and the production of PGs by rabbit ovaries perfused with
or without L-NAME. In conclusion, the ovarian NO/NOS system is involved
in follicle rupture during the ovulatory process. NO may induce
follicle rupture in rabbit ovaries at least in part by the
stimulation of PG production. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Evidence supports the involvement of NO in ovarian physiology. NO is synthesized by the rat ovary and is postulated to participate in ovulation and atresia (11, 12, 13, 14, 15). The inhibition of NO generation in the ovary by the administration of NOS inhibitors reduces the rate of ovulation in rats both in vivo and in vitro (13, 15). The control of ovarian vessel relaxation to accommodate the necessary changes in blood flow, blood volume, and plasma exudation that accompany follicle rupture (15, 16, 17) is likely to be the most important role of NO in ovulation. In addition, NO seems to contribute to the regulation of ovarian steroidogenesis. NOS is present in rat luteinized cells (18, 19) and human granulosa-luteal cells (20). Endogenously produced NO and NO-releasing agents inhibit steroidogenesis in granulosa and luteal cells (18, 20). In the present study, we examined the actions of the NO/NOS system in ovulation, oocyte maturation, and ovarian steroidogenesis and PG production using the in vitro perfused rabbit ovary preparation. This system of an isolated ovary has provided an opportunity to conduct detailed studies of the intact organ under carefully regulated conditions that are independent of systemic influences (17, 21). Using the well characterized NOS inhibitors, aminoguanidine hemisulfate salt (AG) and N-omega-nitro-L-arginine methyl ester (L-NAME), we investigated the role of endogenous NO in the process of ovulation induced by gonadotropin. In addition, we used sodium nitroprusside (NP) as a NO generator to further explore the effects of NO in the ovulatory process.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Ovarian perfusion
Although the standard perfusion system has been modified over
the years, its basic components remain constant (22). The ovarian
artery was cannulated in situ after ligating the major
anastomotic connections, as previously described (21, 22). The ovary
was removed along with its artery, vein, and supporting adipose tissue
and immediately placed in a perfusion chamber. The perfusion fluid
consisted of 150 ml medium 199 (Life Technologies, Gaithersburg, MD)
containing 1% BSA (fraction V powder; Sigma Chemical Co., St. Louis,
MO), which was supplemented with heparin sulfate, insulin,
streptomycin, and penicillin G and adjusted to a pH of 7.4. BSA was
added to the basic perfusion fluid to increase the oncotic pressure and
reduce edema formation. The ovaries were observed every 15 min
throughout the 12 h of perfusion for evidence of follicle growth
and rupture. At the time of follicle rupture, the ovulated ovum
surrounded by its cumulus mass was recovered carefully from the ovarian
surface with a Pasteur pipette. The time interval between the
administration of hCG and the follicle rupture was recorded. The
ovulatory efficiency (percentage of follicles >1.5 mm in diameter that
ovulated) was calculated for each group. Both the ovulated ova and the
follicular oocytes were assessed for their stages of maturity and signs
of degeneration (21, 23). The oocytes were placed on a slide, fixed in
2.5% glutaraldehyde, and stained with 0.25% lacmoid in 45% acetic
acid for microscopic evaluation. The degree of ovum maturity was
expressed as the percentage of ova that achieved germinal vesicle
breakdown (GVBD). Ovulated ova were also assessed for degenerative
changes that included vacuolization, cytolysis, necrosis,
fragmentation, and loss of spherical shape.
Experimental design
The first experiment using 18 rabbits was undertaken to
determine the role of endogenous NO in the ovulation induced by
gonadotropin. One ovary from each rabbit was perfused with AG (Sigma
Chemical Co.) in a concentration of 10-5,
10-6, or 10-7 M. The
contralateral control ovary was simultaneously placed in a separate
chamber containing medium alone. Thirty minutes after the onset of
perfusion, 50 IU hCG (CH-446; biological activity, 3830 IU/mg; Organon,
Oss, The Netherlands) were added to the perfusate of both ovaries. The
ovaries were perfused for 12 h after the administration of hCG.
Six ovaries were treated with an individual concentration of AG.
In the second experiment, L-NAME was used as another NOS inhibitor. One
ovary was perfused with L-NAME (Sigma Chemical Co.) in a concentration
of 10-5, 10-6, 10-7, or
10-8 M. D-NAME (Sigma Chemical Co.) was used
as a control for the L-NAME perfusions. The contralateral ovary was
simultaneously placed in a separate chamber containing medium alone to
serve as a control. Thirty minutes after the onset of perfusion, 50 IU
hCG were added to the perfusate of both ovaries. Six ovaries were used
for an individual concentration of L-NAME or D-NAME. The ovarian
perfusion was performed for 12 h after hCG administration. Samples
of perfusate (2 ml) were withdrawn before and 1, 2, 4, 6, 8, and
12 h after the administration of hCG to determine the level in the
perfusate of progesterone (P), estradiol (E2),
PGE2, and PGF2. The withdrawn perfusate was
immediately replaced with an equal volume of fresh medium. Samples were
stored at -80 C until the concentrations of steroids and PGs were
determined.
The third experiment was undertaken to determine whether the
administration of the NO generator, NP, would induce ovulation in
vitro in the absence of gonadotropin, or whether the inhibitory
action of AG on hCG-induced ovulation could be reversed by NP. One
ovary from each rabbit was perfused with NP (Sigma Chemical Co.) in a
concentration of 10-4 or 10-5 M.
The contralateral control ovary was simultaneously placed in a separate
chamber containing medium alone. Six ovaries were used at each dose of
NP, and ovarian perfusion was performed for 12 h. The ovaries of
another 15 rabbits were individually perfused with either
10-5 M of AG alone, 50 IU hCG alone,
10-4 M NP in the presence of 50 IU hCG,
10-5 M AG in the presence of 50 IU hCG, or
10-4 M NP plus 10-5 M
AG in the presence of 50 IU hCG. Ovaries was perfused for 12 h
after the administration of hCG. Samples of perfusate (2 ml) were
withdrawn before hCG administration and 1, 2, 4, 6, 8, and 12 h
thereafter to determine the concentrations of P, E2,
PGE2, and PGF2 in the perfusate. The
withdrawn perfusate was immediately replaced by an equal volume of
fresh medium. Samples were stored at -80 C until the concentrations of
steroids and PGs were determined.
RIA
The concentrations of P and E2 in the culture medium
was measured by a direct, solid phase 125I-labeled steroid
RIA kit (Diagnostic Products Corp., Los Angeles, CA). These samples
were assayed in duplicate. The intra- and interassay coefficients of
variation were 7.2% and 7.9%, respectively, for P and 5.3% and
6.4%, respectively, for E2.
The extraction of PG from each sample was performed as described
previously (24). The average recovery rates of PGF2 and
PGE2 were 79.4% and 84.8%, respectively. The
concentrations of PGF2 and PGE2 were
measured using RIA kits (Amersham International, Aylesbury, UK).
Cross-reactions of PGF2 and PGE2 antibodies
with other closely related PGs were less than 2%. The intra- and
interassay coefficients of variation were 8.2% and 9.8%,
respectively, for PGF2 and 7.6% and 9.2%,
respectively, for PGE2. The sensitivities of the assays for
PGF2 and PGE2 were 3 and 43 pg/tube,
respectively. All of these samples were also assayed in duplicate.
Statistical analysis
Data for ovulatory efficiency, time of ovulation, percentage of
GVBD, percentage of degeneration, and concentrations of P,
E2, PGF2, and PGE2 are presented
as the mean ± SEM. A normal distribution of the data
on the ovulatory efficiency, the percentage of GVBD, and the percentage
of degeneration was obtained by arcsine transformation and was assessed
by ANOVA. The differences in the concentrations of P, E2,
PGF2, and PGE2 among the treatment groups
and during the perfusion were evaluated by two-way ANOVA, with the two
independent variables being the time of perfusion and the treatment
group. This analysis was followed by Scheffe’s test to determine the
significance of the differences between two groups. The correlation
between ovulatory efficiency and PG production in perfused rabbit
ovaries was also evaluated by a regression analysis. The regression
line for this correlation was estimated with the least squares methods
of curve fitting. P < 0.05 was considered
statistically significant.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). One of 6 ovaries treated with
10-6 M AG and 2 of 6 ovaries treated with
10-5 M AG failed to ovulate in response to hCG
administration. The addition of AG to the perfusate suppressed
ovulation in a dose-dependent manner, showing the maximal
inhibition (62.5%) of ovulatory efficiency in ovaries perfused with
hCG plus 10-5 M AG compared with that in the
contralateral hCG-treated control ovaries. However, exogenous AG
affected neither the maturation rate nor the degeneration rate of
ovulated ova in response to hCG administration.
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). Three of six ovaries treated
with hCG plus 10-5 M L-NAME and two of six
ovaries treated with hCG plus 10-6 M L-NAME
failed to ovulate. The mean numbers of ovulations per ovary did not
differ significantly between the ovaries treated with hCG plus
10-5 M D-NAME and the contralateral
hCG-treated ovaries. However, the addition of L-NAME to the perfusate
in a concentration of 10-7, 10-6, or
10-5 M significantly reduced the mean numbers
of ovulations per ovary compared with those in the hCG-treated
controls. No significant difference was observed in the mean time of
ovulation between the L-NAME-treated ovaries and the hCG-treated
control ovaries. The ovulatory efficiency in ovaries treated with hCG
plus 10-5 M D-NAME was comparable to that in
the contralateral ovaries treated with hCG alone (Fig. 1). However, the addition of L-NAME to
the perfusate inhibited the ovulation induced by hCG in a
dose-dependent manner, showing the maximal inhibition (71.1%) of
ovulatory efficiency in ovaries perfused with hCG plus
10-5 M L-NAME compared with that in the
contralateral hCG-treated control ovaries. The majority of ovulated ova
in the ovaries treated with L-NAME resumed the meiotic maturation in
response to hCG exposure (Fig. 2). L-NAME
treatment did not increase the percentage of ovulated ova showing
degeneration in hCG-treated ovaries.
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). Neither D-NAME nor
L-NAME significantly affected the concentration of P in the effluent of
the hCG-treated ovaries. The addition of hCG to the perfusate also
stimulated the production of E2 by the rabbit ovaries
perfused in vitro. L-NAME significantly increased
hCG-induced production of E2 by the perfused rabbit
ovaries, whereas D-NAME had no effect.
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in the
perfusate with or without L-NAME in the presence of hCG are illustrated
in Fig. 4. The production of
PGE2 and PGF2 was significantly
(P < 0.05) increased at 4 and 6 h in response to
hCG administration, respectively. The hCG-stimulated production of
PGE2 and PGF2 was unaffected by adding
D-NAME to the perfusate (data not shown). However, 10-5
M L-NAME significantly inhibited the hCG-stimulated
production of PGE2 at 6, 8, and 12 h and that of
PGF2 at 4, 6, 8, and 12 h. When the levels of
PGE2 and PGF2 in the effluent in ovaries
treated with different concentrations of L-NAME were determined between
6–12 h after exposure to hCG, L-NAME resulted in a dose-dependent
inhibition of the hCG-stimulated production of PGs. The relationships
between the ovulatory efficiency and the PG production in rabbit
ovaries perfused with hCG alone or with hCG plus the different
concentrations of L-NAME are shown in Fig. 5. The ovulatory efficiencies in
hCG-treated ovaries with or without L-NAME were significantly
correlated with the levels of PGE2 and PGF2
in the effluent 12 h after exposure to hCG.
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). The majority of ovulated ova in the
NP-treated ovaries did not progress beyond the germinal vesicle stage
(percent GVBD in medium alone, 8.2 ± 2.5%; percent GVBD in
10-4 M NP, 10.3 ± 2.8%). The ovulatory
efficiency in ovaries perfused with hCG plus 10-4
M NP did not differ significantly from that in ovaries
perfused with hCG alone. Exogenous AG did not induce follicle rupture
in vitro in the absence of gonadotropin, but did
significantly reduce the hCG-stimulated ovulation. The concomitant
addition of NP to the perfusate reversed the inhibitory effect of AG on
the hCG-induced ovulation. The ovulatory efficiency in the ovaries
perfused with 10-4 M NP plus 10-5
M AG in the presence of hCG did not differ significantly
from that in ovaries treated with hCG alone.
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). Exposure to NP or AG did not affect
the basal production of P and E2. In contrast to its effect
on ovarian steroidogenesis, NP significantly stimulated the production
of PGE2 and PGF2 compared with that in
ovaries perfused with medium alone (Fig. 8). In the hCG-treated ovaries, the
addition of AG to the perfusate significantly increased the
hCG-stimulated production of E2, but had no effect on P
production (Fig. 7). The addition of NP significantly reduced the
AG-stimulated production of E2 in the presence of hCG. The
concentrations of E2 in the effluent of ovaries perfused
with 10-5 M AG plus 10-4
M NP did not differ significantly from those in hCG-treated
ovaries.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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A recent study has demonstrated that endogenous or exogenous NO plays a
critical role in the release of PGE2 in the mouse
macrophage cell line RAW 264.7 by the direct activation of
cyclooxygenase (25). Many effectors of NO production promote the
stimulatory release of PGE2 and prostacyclin from the
cyclooxgenase pathway. This is true for rapidly acting agonists such as
bradykinin (26) and for the longer acting agents such as
lipopolysaccharide or interleukin-1ß (IL-1ß) (27, 28). When both
the NOS and cyclooxygenase systems are present, an NO-mediated increase
in the production of PGs may exacerbate the inflammatory response (25).
Ovulation, the process by which a mature oocyte is generated and
released, has been described as an orderly sequence of events that
resembles the acute inflammatory response (29, 30, 31). Evidence indicates
that PGs are involved in the ovulatory process via local actions at the
level of the ovary (17, 29, 30, 31, 32). In the present study, the in
vitro ovarian production of PGE2 and
PGF2 in response to hCG was inhibited by L-NAME, and the
exogenous administration of NP induced ovulation and also stimulated
the production of PGs by the perfused rabbit ovaries in the absence of
gonadotropin. The effect of NO on PG release occurred during the time
that the first ovulation occurred in this preparation. In addition,
significant correlations were observed between the ovulatory efficiency
and the production of PGs by rabbit ovaries perfused with or without
L-NAME. This suggests that NO induces ovulation in the rabbit ovary at
least in part by stimulating the production of PGs. The NOS and
cyclooxygenase enzymes may thus be key regulators that enhance the
initial inflammatory response during follicle rupture. However, several
studies raise questions about the specific roles of PGs in the process
of ovulation (33, 34). Data on the response to graded doses of
indomethacin demonstrate no significant correlation between the
ovulation rate and PG levels at the expected time of ovulation (33).
This implies that there may be other mediators of inflammations that
are produced independent of PG biosynthesis. Further studies are needed
to evaluate the relative contribution of the NO-stimulated PGs in the
ovulatory process.
An overproduction of NO appears to contribute to the pathology of the inflammatory process (2, 35, 36). Inhibition of the inducible isoform of NOS effectively reduces tissue damage in several models of inflammation (37, 38, 39). The differential effects of AG and L-NAME on NO production by the inducible and constitutive isoforms of NOS have been demonstrated in intact cells and tissues (38, 39). Corbett et al. (38) demonstrated that AG, a bifunctional molecule containing the guanido group of L-arginine linked to hydrazine, is at least equipotent to L-NAME as an inhibitor of inducible NOS, but is 10- to 100-fold less potent as an inhibitor of the constitutive isoform, which suggests that AG selectively inhibits the inducible NOS. Because the constitutive enzyme plays an important role in physiological processes such as neuromodulation, the inhibition of platelet aggregation and adhesion, and the maintenance of vascular tone (2), selectivity for the inducible isoform of NOS is an essential characteristic of any agent that is used to explore the precise mechanism of action of NOS on ovulation. The inhibitory effect of AG on hCG-induced ovulation in the present study was equipotent to that of L-NAME. The blockade of ovulation by AG was significantly reversed by the addition of the NO generator, NP. These findings suggest that ovulation may in part be the consequence of NO production by the inducible isoform of NOS after exposure to hCG. NO induces relaxation and vasodilation of vascular smooth muscle (2, 40). The ability of NO has been implicated as an important mediator in ovarian function, including the regulation of the blood-follicle barrier and ovulation (41, 42). The blood-follicle barrier exists at the level of the ovarian microvasculature and is regulated by a gonadotropin-mediated vasodilatory factor (41). Preovulatory events include such morphological changes in the microvasculature of the preovulatory follicles as vasodilation, increased blood flow, and hyperpermeability (16, 43, 44). The potent vasodilatory activity of NO (2, 4, 40) is thus relevant to these preovulatory events.
We also investigated the effect of NO on ovarian steroidogenesis. Inhibition of endogenous NOS by AG and L-NAME led to a significant elevation of the production of E2, but not of P, stimulated by hCG. Addition of the NO generator, NP, significantly reduced the AG-stimulated production of E2. These data suggest that NO functions as an antisteroidogenic agent, especially in the synthesis of E2. NO has also been shown to negatively regulate steroidogenesis in the rodent testes (45), cultured rat Leydig cells (46), human granulosa-luteal cells (20), and rat luteinized ovarian cells (18). NO inhibits aromatase activity directly in human granulosa-luteal cells and is postulated to be an autocrine regulator of E2 synthesis (20). As the cellular localization of the two isoforms of NOS in the rabbit ovary remains to be clarified, it is not known whether NO acts to control steroidogenesis in an autocrine manner similar to that seen in the human granulosa-luteal cell (20) or whether NO is synthesized by nonsteroidogenic cells and operates in a paracrine manner to depress E2 synthesis. In the present study, the stimulatory effect of AG on hCG-induced E2 production was equipotent to that of L-NAME, which suggests that E2 synthesis may be stimulated by the inhibition of inducible NOS. A high production of NO is characteristic of its synthesis by inducible NOS, whereas a much greater proportion of cells express the constitutive form of NOS (2, 9). Thus, the possibility that the constitutive form of NOS functions to regulate E2 synthesis in the ovary cannot be ruled out.
In contrast to the significant effects of manipulation of the NO/NOS system on follicle rupture, neither NOS inhibitor affected the hCG-induced meiotic maturation of the ovulated ova. The administration of the NO generator, NP, induced follicle rupture, but did not induce oocyte maturation in the absence of gonadotropin. It is thus unlikely that the NO/NOS system in the ovary is involved in the process of oocyte maturation. Nevertheless, these findings provide additional evidence that the normally simultaneous processes of follicle rupture and oocyte maturation are two independent phenomena (17, 21, 30).
Evidence suggests that the biological effects of IL-1ß in the ovulatory process are mediated by NO (11, 12, 14, 15). The addition of L-NAME to the rat ovarian follicle reduces the IL-1ß-induced suppression of follicular apoptosis, suggesting that NO has an intermediary role in regulating such apoptosis (14). NO and IL-1ß act as follicle survival factors by suppressing the apoptotic fragmentation of DNA (14). In contrast, 1L-1ß leads to apoptotic cell death by generating NO in pancreatic ß-cells (47). NO induces the death of macrophages by apoptosis (48). Conversely, NO inhibits apop-tosis in B lymphocytes (49). These discrepant findings suggest that NO can be either toxic or protective depending on the type of cell involved (49). Although in the present study, neither NOS inhibitor increased the degeneration rate of the hCG-induced ovulated ova, additional studies are required to evaluate the effects of the NO/NOS system on follicle apoptosis, including the degeneration of oocytes.
A recent study in patients who underwent in vitro fertilization demonstrated that the circulating nitrite/nitrate levels increase with follicular development (50). Follicular nitrite/nitrate concentrations are also correlated with follicular size in human ovaries (51), suggesting that a functional relationship exists between the NO pathway and folliculogenesis. In addition to its stimulatory effects on follicle rupture, NO may be responsible for regulating the volume of intrafollicular fluid by inducing a shift in fluid from the extracellular compartment into the follicle. It is also possible that NO participates in the preovulatory modulation of ovarian blood flow via its potent vasodilatory activity (52).
In conclusion, the exogenous administration of NOS inhibitors significantly blocked hCG-induced ovulation and hCG-induced production of PGs by perfused rabbit ovaries. The significant correlations between the ovulatory efficiencies and the production of PGs by rabbit ovaries perfused with or without L-NAME suggest that NO may induce ovulation at least in part by stimulating the production of PGs in rabbit ovaries. The inhibition of endogenous NOS by AG and L-NAME led to a significant elevation in the production of E2, but not of P, stimulated by hCG, suggesting that NO negatively regulates the ovarian synthesis of E2. As neither NO nor the NOS inhibitors affect oocyte maturation, the ovarian NO/NOS system appears to be involved in follicle rupture during the ovulatory process.
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Footnotes |
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Received March 31, 1997.
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,
P < 0.05 (vs.. ovaries perfused
with hCG alone). §, P < 0.05 (vs.
ovaries with perfused with 10-5 M AG in the
presence of hCG).