Pharmacological effects of low- dose of aspirin on Corpus Luteum functions in mature cycling female mice
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Middle East Fertility Society Journal Vol. 10, No. 2, 2005
Copyright © Middle East Fertility Society
Pharmacological effects of low- dose of aspirin on Corpus
Luteum functions in mature cycling female mice
Adnan S. Al-Janabi, B.V.M.&S., Ph.D.
Ahmad M. A-lzohyri, B.V.M.&S., Ph.D.
Fouad K. Al-Rubayai, M.B.Ch.B., M.Sc.
Institute of the Embryo Research and Infertility Treatment, College of Medicine, University of Baghdad, IRAQ.
ABSTRACT
Objective: To investigate long-term effect of aspirin in low-dose on the corpus luteum functions and its hormonal
changes associated with ovarian and uterine structural changes.
Design: Prospective study.
Setting: Institute of the Embryo Research and Infertility Treatment- University of Baghdad.
Materials and methods: In the treatment group, 24 mature cycling female mice underwent subcutaneous
administration of aspirin at a dose level of (7.5mg/Kg b.w)twice daily at the beginning of diestrous phase of the
estrous cycle. In the control group, 24 mature cycling female mice underwent subcutaneous administration of a
placebo(distilled water) twice daily at the beginning of diestrous phase of the estrous cycle.
Main outcome measure: Uterine and ovarian morphological changes, uterine and ovarian weight changes, serum level
of (FSH,LH&Progesterone) and ovarian and uterine structural changes.
Results: There was statistically significant increase in progesterone level, number of corpora lutea, diameter of
granulosa cells. and a significant decrease in gonadotropins (FSH/LH) , number of growing follicles, uterine weight,
endometrial living cell height, endometrial and myometrial thickness, diameter of endometrial glands.
Conclusion(s): long-term administration of a low-dose of aspirin to mice at the beginning of diestrous phase, causes the
following changes: significant decrease in uterine weight with development of hemorrhagic spots on the external surface
of uterine horns of only those animals that receive treatment for 30 days, and a significant decrease in serum level of both
gonadotropins (FSH/LH) associated with significant increase in progesterone level, number of corpora lutea, diameter of
granulosa cells, congestion in the uterus, ovary and prolongation of the luteal phase in all 4 periods of treatment.
Keywords: Low-dose aspirin, Long-term treatment, uterine morphology, ovarian morphology.
Aspirin is one of the most famous, cheapest, pregnancy associated with decrease risk of ectopic
available and widely used drugs in the world in pregnancy (3). Also low-dose of aspirin may
patients with a wide range of therapeutic uses for improve ovarian responsiveness, uterine and
the treatment of inflammatory joint diseases, ovarian blood flow velocity, implantation and
prevention of thrombosis and many other causes pregnancy rates in patients undergoing IVF (4).
for its anti-inflammatory, analgesic antipyretic and Also, low-dose aspirin (100 mg/day) may improve
antiplatelets effects (1,2). And on the reproductive uterine perfusion in women with unexplained
system, however, there are several reports in infertility and impaired uterine blood flow (5). The
women indicating that the use of aspirin before life span of the corpus luteum has been linked with
prostaglandins (PG) since late sixties and early
Corresponding author: Adnan S. Al-Janabi, Dean of the
Institute of Embryo Research and Infertility Treatment, Bab-
seventies when it was found that PGF2α of
Al-Muadum, near the medical city, Baghdad, IRAQ. P.O.Box endometrial origin is responsible for luteolysis in
61183 several mammalian species (6,7).Moreover PGF2α
150 Al Janabi et al. Aspirin and the corpus luteum of mice MEFSJadministration could terminate pregnancy in freezer (-20c°) for the hormonal assay. After the
several laboratory animals(8,9).In primate, PGF2α killing the whole reproductive system was quickly
causes decreased progesterone production by removed, and was immersed in a Petri-dish filled
primate granulosa cells in vitro (10,11).In the with in vitro medium (IVF) (Universal IVF
present investigation effect of low-dose of aspirin medium, Medicult, Denmark) kept at 37°C. Both
on corpus luteum activity is detected. ovaries were quickly dissected out, cleared from
Prostaglandin synthesis has linked to aspirin action surrounding non-ovarian tissue and weighed using
since the late sixties of the last century (12,13) electronic precision balance (Sartorious -
Switzerland). The uteri were then quickly dissected
out slightly at the tubouterine junction from one
MATERIALS AND METHODS end and immediately close to the internal orifice of
the cervix from the other end, they were cleared
All experiments were performed on mature from surrounding non-uterine tissue and were dried
female Swiss White mice, 15-16 weeks old with a from IVF fluid using filter paper and they were
body weight ranging from 25-30g. The mice were then weighed using electronic precision balance
obtained from the colony of the animal house of (14). And the organs were then taken for
the institute for embryo research and infertility subsequent histological examination (both ovaries
treatment, University of Baghdad. They were kept and pieces from uterine horns). Animals (n=24
in an air-conditioned room (22-24°C) with an mice) were given distilled water and exposed to the
automatically controlled photo-period (14 hours same protocol of injection, duration, blood
light and 10 hours darkness). Mice were fed the collection and histological examination served as
standard balanced pelleted diet presented with tap control for the experimental group. The following
water "ad libitum". Before experimentation all parameters were used to evaluate ovarian and
mice were left for at least three weeks for uterine changes: Number of growing and Graffian
adaptation. Mice that showed at least three follicles; number of corpora lutea and the diameter
consecutive regular cycles were included in the of the granulosa lutein cells; endometrial lining
study (n=48 mice). Experimental animals (n=24 cell height; thickness of the endometrium and
animals) were injected subcutaneously with aspirin myometrium; and diameter of the endometrial
(Aspegic®, Laboratories synthelabo, France) at a glands. In all these histological measurements
dose level of 7.5mg/Kg. b.w given twice daily ocular and stage micrometers were used.
starting on the first day of diestrous phase. treated
animals (n=6 mice/group) were killed after 5,10,20 Statistical Analysis
and 30 days post-treatment. Changes in vaginal
smear were also measured daily. At the end of each Collected data were analyzed using SPSS
period of treatment and before killing of the version 10.0 for windows (SPSS, Chicago, Illinois,
anaesthetized animals (24 hours after the last USA). Differences of means between groups were
injection), blood was collected through cardiac examined by student t-test, P. valueFigure 1. Ovarian and uterine weight changes associated with long-term aspirin administration at the beginning of diestrous phase.
RESULTS of uterine horns were less prominent; as it was
seen with treated animals (Plates 1, 2).
Ovarian and uterine changes
A - Macroscopic morphological changes: B-Ovarian and uterine weight changes:
Ovaries Ovaries
Examination of the ovaries of experimental Ovarian weight of experimental mice revealed a
mice revealed the following morphological non significant changes as compared to the control
changes: congestion, cystic appearance due to the animals. (Table 1) and (Figure 1).
presence of many corpora lutea. On the other hand,
the ovaries of the control animals were pale with a Uteri
smooth surface associated with presence of few
Experimental animals that received aspirin for
number of copora lutea (Plates 1, 2).
5,10,and 20 days and killed on day 6,11,21 showed
a non significant changes in uterine weight when
Uteri
compared to the control animals. On the other
hand, when aspirin is administered for 30 days and
Examination of uteri of experimental animals,
killing on the 31st day, resulted in a significant
showed: congestion and lack of luminal fluid.
decrease (P = 0.003) in uterine weight as compared
However, those treated for 30 days and killed at
to the control animals. (Table 1) and (Figure 1).
the 31st day, showed presence of hemorrhagic
spots on the uterine surface of both uterine horns
(i.e., at the site of uterine wall vascularization). Hormonal changes
Uteri of control animals, on the other hand,
appeared congested and blood vessels over the area All aspirin treated mice for: 5, 10, 20 and 30 days
152 Al Janabi et al. Aspirin and the corpus luteum of mice MEFSJTable 2. Hormonal changes associated with long-term administration of Aspirin to mature cycling female mice at the diestrous
phase.
Serum level
5 Days 10 Days 20 Days 30 Days
Hormones Control Treated Control Treated Control Treated Control Treated
* * *
LH mIu/mL 3.01±0.21 1.02±0.39 3.08±0.17 0.81±0.05 3.06±0.21 1.05±0.22 2.00±0.18 0.63±0.12*
FSH 1.76±0.18 1.11±0.06* 1.65±0.15 1.09±0.21* 1.73±0.17 1.11±0.09* 1.73±0.15 1.09±0.17*
mIu/mL
Progesterone 22.05±0.39 24.12±0.51* 22.09±0.83 24.07±0.28* 22.07±0.85 24.22±0.33* 22.05±0.67 24.34±0.30*
ng/ml
- Values are mean ± standard error (SEM), (n=6 animals/group).
* = Significant changes.
and killed at the: 6th, 11th, 21st and 31st days Ovaries
respectively, showed a significant decrease in the
level of both gonadotropins: LH and FSH when A highly significant increase, in the number of
compared to the control animals. However, a intact corpora lutea; in the diameter of the
significant increase in the level of progesterone granulosa lutein cells as compared to the control
was seen in aspirin treated mice as compared to the animals.
control (Table 2) and (Figure 2). A highly significant decrease, in the number of
the growing follicles as compared to the control
Structural changes of both ovaries and uteri animals. On the other hand, no regressed corpora
lutea and no Graffian follicles were seen in treated
Mice treated with aspirin showed the following mice as compared to the control animals. (Tables
structural changes in the ovaries and uteri: 3, 4, Figures 3, 4, and Plates 3-6).
Figure 2. Hormonal changes associated with long-term aspirin administration at the beginning of diestrous phase.
Vol. 10, No. 2, 2005 Al Janabi et al. Aspirin and the corpus luteum of mice 153Table 3. Structural changes of the ovaries and uteri associated with long-term administration of Aspirin to mature cycling female
mice at the diestrous phase.
Structural Duration of treatment
changes of
5 Days 10 Days 20 Days 30 Days
the ovaries
and uteri Control Treated Control Treated Control Treated Control Treated
(µm)
Endometrial 21.23±0.80 14.30±0.47* 21.02±0.62 13.65±0.44* 21.45±0.27 13.43±0.43* 20.80±0.89 11.05±0.44*
lining cell
height
Endometrial 339.75±19.30 187.20±6.22* 352.80±10.50 186.97±10.86* 348.30±8.68 198.55±6.77* 343.80±4.76 142.65±5.68*
thickness
Diameter of 92.70±0.90 70.35±1.67* 91.80±0.99 67.95±1.77* 92.25±0.45 67.50±1.84* 92.25±1.08 66.60±1.66*
the
Endometrial
glands
Myometrial 243.90±3.25 242.10±2.93 245.70±3.39 244.8±1.14 246.10±3.03 244.80±1.80 244.80±2.67 181.83±3.04*
thickness
Diameter of 14.08±0.52 19.72±0.40* 13.65±0.29 19.50±0.34* 13.43±0.34 19.28±0.40* 13.87±0.27 19.50±0.47*
the
granulosa
lutein cells
- Values are mean ± standard error (SEM), (n=6 animals/group).
* = Significant changes (P < 0.001)
Uteri significantly decreased in animals that received,
A highly significant decrease, in the height of aspirin treatment for 30 days while it was not
the endometrial lining cells; in the endometrial significantly changed for the remaining 3 groups
thickness and in the diameter of the endometrial i.e.: that were received treatment for: 5, 10, and 20
glands as compared to the control animals. days respectively (Table 3, Figures 5, 6 and Plates
On the other hand, myometrial thickness was 7-15).
Table 4. Structural changes of the ovaries, associated with long-term administration of Aspirin to mature cycling female mice at the
diestrous phase.
Structural Duration of treatment
changes of 5 Days 10 days 20 days 30 days
the ovaries Control Treated Control Treated Control Treated Control Treated
No. of 4.00±0.37 7.67±0.49* 4.00±0.52 7.33±0.42* 3.67±0.42 7.50±0.22* 3.67±0.33 7.17±0.31*
functioning
C.L
No. of 12.83±0.60 8.17±0.60* 13.17±0.65 7.50±0.43* 13.50±0.43 7.83±0.31* 13.17±0.48 7.33±0.42*
growing
follicles
- Values are mean ± standard error (SEM), (n=6 animals/group).
* = Highly Significant changes (P < 0.001)
154 Al Janabi et al. Aspirin and the corpus luteum of mice MEFSJFigure 3. Changes in the number of graafian follicle(GF) and corpura lutea(CL) of mice treated with aspirin for 5,10,20 and 30 days
at the beginning of diestrous phase .
DISCUSSION thrombin, thromboxane A2 (TXA2), adenosine
diphosphate (ADP) and dense and alpha granules
The morphological changes of both ovaries and produce platelet activation (15).
uteri seen in the experimental group, may be due to Activated platelets, release calcium from the
the vascular properties of aspirin. It is well known dense granules into the cytoplasm (16).
that several platelets substances such as: Collagen,
Figure 4. Changes indicated by aspirin administration on (diameter of the granulosa lutein cells).
Vol. 10, No. 2, 2005 Al Janabi et al. Aspirin and the corpus luteum of mice 155Figure 5. Changes associated with aspirin administration in endometerial lining cell height(ELCH)
and diameter of the endometerial glands(EG) .
Calcium causes platelets contraction with a further significant decrease in the uterine weight of
release of serotonin, ADP, and arachidonate, this in experimental animals received aspirin for 30 days
turn is converted into TXA2 by the as compared to the control animals.
cyclooxygenase enzyme, this enzyme could be Absence of changes in ovarian weight
irreversibly inhibited by low-dose aspirin treatment experimental groups as compared to the control
thus vasoconstriction and platelet aggregation may animals may be due to the balanced changes in the
be avoided (17,18). main component of ovarian weight i.e.: number of
This in turn may improve blood flow to these corpora lutea, growing and Graffian follicles in
organs (19). Animals receiving long-term treated and control animals.
administration of aspirin for 30 days, developed an The prolongation of the diestrous phase and
areas of hemorrhagic spots, at the site of uterine delayed luteolysis in aspirin treated mice in the 4
wall vascularization and this may be due to blood periods of the treatment may be attributed to
vessels weakness induced by the prolonged inhibition of PGF2α more than other
program of aspirin-induced treatment (20). Such prostaglandins.
hemorrhagic spots may also develop due to Prostaglandin F2α known to be the physiologic
cumulative effect of repeated daily administration uterine luteolysin in non-primate species including
of aspirin. In human, daily administration of 30-50 mice (26,27). This luteotrophic effect of aspirin
mg of aspirin, results virtually complete may have been augmented by PGE2 present in
suppression of platelet thromboxane biosynthesis ovarian tissue which was not affected by
after 7 to 10 days (21-23). These changes in administered aspirin. The luteotrophic activity of
platelet biochemistry are associated with maximal this type of prostaglandin is well known (28).
inhibition of thromboxane - dependent platelets It has been shown that, repeated injection of
aggregation and prolongation of the bleeding time PGF2α during the luteal phase (i.e.: diestrous
(23-25). Such a disturbances in the vascular blood phase) of the estrus cycle of some mammals
supply of the uterine wall may explain the hastened luteolysis, similar injection of PGF2 in indo-
158 Al Janabi et al. Aspirin and the corpus luteum of mice MEFSJFigure 6. Structural uteri changes associated with long-term aspirin administration at the beginning
of diestrous phase (endometerial and myometerial thickness) .
-methacin treated animals failed to induce both FSH and LH serum level (37,38). Conversely,
luteolysis (29). Also, it was demonstrated that a significant increase in progesterone level was
treatment of hysterectomized pseudopregnant rats seen in animals who have received long-term
with indomethacin, results in both lengthening of aspirin administration for (5, 10, 20 and 30 days)
diestrous phase and delayed luteolysis (30). with no variation in the level of progesterone seen
The hormonal changes seen in the present between them. This may mean that, aspirin
study, demonstrate that, the level of progesterone administration persistently arrest luteolysis (i.e.
for the control animals are lower than that of intact and functional corpora lutea), which has
treated animals and this implies the beginning of been confirmed by daily vaginal smear, that reflect
luteolysis in the control. In the process of a cellular picture of diestrous phase during all the
luteolysis, a decrease in progesterone production time of treatment.
marks the early phase of luteolysis, whereas The vaginal epithelium undergoes well marked
structural involution occurs later (31-33). In changes during the estrous cycle in mice. Heat or
human, luteolysis ensues with a prompt linear estrous phase is characterized by marked
decline in circulating progesterone, estradiol and squamification and cornification of cells and the
inhibin A levels during the last 4 or 5 day of the disappearance of leukocytes (39). At the end of the
functional life of the corpus luteum (34,35). While estrous phase the cornified layer sloughs of and
it is immediate in the absence of mating in mice invasion of leukocytes occurs (40).
(36). During the luteal - follicular transition, Inhibitors of PGF2α and synthesis
waning luteal cells biosynthetic capacity results in (indomethacin and acetylsalicylic acid) as the
the loss of both inhibin and steroids (progesterone endogenous mediator of luteolysis, were shown to
and estrogen) production (34). Decreased delay the regression of the corpora lutea and to
circuiting levels of inhibin allow an increase in prolong the luteal activity in pseudopregnant rats
FSH production, which in turn rescues the (41). The inhibition of prostaglandins by
developing cohort of follicles (primarily through antiprostaglandins appear to be unrelated to
induction of aromatase activity). Increased GnRH produce any change in the secretion of
pulsatility secondary to the loss of inhibitory progesterone of bovine corpora lutea (42). In mice,
steroidal feedback also contributes to the rise in indomethacin administration did not affect
Vol. 10, No. 2, 2005 Al Janabi et al. Aspirin and the corpus luteum of mice 159progesterone synthesis (43). Also serum mid-luteal progesterone associated with a significant
progesterone levels were unaffected by suppression of both FSH and LH, may provide a
administration of Ibuprofen to normally cycling strong support to the structural ovarian changes
women during the luteal phase (44). These changes seen: significant increase in the number of corpora
reflect the presence of functional corpus luteum lutea and a significant increase in the diameter of
with increasing ability to synthesize mainly large the granulose lutein cells, with absence of
amount of progesterone and to a lesser extent regressed corpora luteal when compared to the
estradiol, as well as, inhibin hormone which is control animals.
secreted along with the steroid sex hormones by The structural uterine changes namely: the
the granulose lutein cells of the active ovarian significant decrease in the endometrial lining cell
corpus luteum (45). All these hormones together height, endometrial thickness and diameter of
have a combined negative feedback effect on the endometrial glands in all 4 periods of aspirin
anterior pituitary gland and hypothalamus to cause treated mice (5, 10, 20 and 30 days), might be due
suppression of both FSH and LH secretion (46). to the strong anti-inflammatory effect of
The continued secretion of low level of LH, with progesterone hormone secreted by the active
no variation between our four treated periods (in corpora lutea, on the uteri of the treated mice (56).
the present study) is essential for the production of The other possibility is that, the effect exerted by
progesterone from the corpora lutea and it's progesterone hormone, cause prolonged
maintenance. The secretary activity of the corpus suppression of the ability of estrogen to promote
luteum and it's functional life-span are dependent uterine growth (protein synthesis and cell division)
on appropriate LH support (47- 49). Which is and vaginal cornification (57). During the luteal
known to play a major role in the sustenance of the phase, progesterone decrease the number of
corpus luteum function (50). The endogenous low estrogen receptors and increase the activity of 17-
pulses of LH have a role in the development and B-HSD (17-B hydroxy steroid dehydrogenase
maintenance of the corpus luteum during the enzyme), which enhance the conversion of
estrous cycle of the bovine female (51), while the estradiol to estrone and of estrone sulfotransferase.
FSH is not required for the maintenance of the The net effect of all these actions of
corpus luteum (52); however, it's low level during progesterone is to decrease the biological action of
the luteal phase is important to prevent the estradiol on the endometrium during the luteal
initiation of folliculogenesis (53). Moreover, it has phase (58).
been shown that inhibin A will reduce bioactive
FSH blood level and prevent follicular
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