Received: 02/11/2024 Accepted: 26/12/2024 Published: 20/02/2025 1 of 6
https://doi.org/10.52973/rcfcv-e35561 RevistaCientíca,FCV-LUZ/Vol.XXXV
ABSTRACT
This study aimed to assess the effects of post–mating treatment
with mefepronic acid on serum P4 concentrations and reproductive
parameters in early lactating Merino ewes during the non–breeding
season. A total of 92 Merino ewes, 40-50 days (d) postpartum,
were treated with an intravaginal sponge containing 60 mg of
medroxyprogesterone acetate for duration of 7 d during the
non–breeding season. On the day the sponge was removed (d
7), an injection of 500 IU eCG was administered. The mated ewes
were then randomly divided into two groups: a control group and
a treatment group. In the treatment group (MA) (n=28), ewes
received an intramuscular injection of 10 mg·kg
-1
mefepronic acid
on d 9 post–mating. In the control group (n=27), the ewes did
not receive any drug treatment on d 9 post–mating. The results
showed that there were no statistically signicant differences
(P>0.05) between the Control Group and MA Group in pregnancy
rates (33.3% and 39.2%), early fetal mortality rates (22.2% and
18.2), lambing rates (77.8 and 81.8%), twin rates (0 and 33.4%)
and litter sizes (1.0 and 1.44). The P4 concentration on d 11
post–mating in the MA group (2.74 ng·mL
-1
) was not signicantly
different from that of the control group (3.16 ng·mL
-1
) (P>0.05). It
is concluded that post–mating mefepronic acid treatment did not
improve the P4 and fertility in early lactating Merino ewes during
the non–breeding season.
Key words: 2-methyl-2-phenoxy propionic acid; ewe; fertility;
mefepronic acid; progesterone
RESUMEN
Este estudio tuvo como objetivo evaluar los efectos del
tratamiento post–apareamiento con ácido mefeprónico sobre
las concentraciones séricas de P4 y los parámetros reproductivos
en ovejas Merino en lactancia temprana durante la temporada no
reproductiva. Un total de 92 ovejas Merino, entre 40 y 50 días (d)
después del parto, fueron tratadas con una esponja intravaginal que
contenía 60 mg de acetato de medroxiprogesterona durante 7d en
la temporada no reproductiva. El día que se retiró la esponja (d 7),
se administraron 500 UI de eCG mediante inyección. Las ovejas
apareadas se dividieron aleatoriamente en dos grupos: un grupo
de control y un grupo de tratamiento. En el grupo de tratamiento
(MA) (n=28), las ovejas recibieron una inyección intramuscular de
10 mg·kg
-1
de ácido mefeprónico el d 9 después del apareamiento.
En el grupo de control (n=27), las ovejas no recibieron ningún
tratamiento farmacológico el d 9 después del apareamiento. Los
resultados mostraron que no hubo diferencias estadísticamente
signicativas (P>0,05) entre el grupo de control y el grupo MA en
las tasas de gestación (33,3 y 39,2 %), las tasas de mortalidad fetal
temprana (22,2 y 18,2 %), las tasas de parto (77,8 y 81,8 %), las
tasas de gemelos (0 y 33,4 %) y el número de crias (1,0 y 1,44).
La concentración de P4 en el d 11 después del apareamiento en
el grupo MA (2,74 ng·mL
-1
) no fue signicativamente diferente de
la del grupo de control (3,16 ng·mL
-1
) (P>0,05). Se concluye que
el tratamiento con ácido mefeprónico después del apareamiento
no mejoró los niveles de P4 ni la fertilidad en ovejas Merino en
lactancia temprana durante la temporada no reproductiva.
Palabras clave: Ácido 2-metil-2-fenoxipropiónico; oveja; fertilidad;
ácido mefeprónico; progesterona
Post–Mating Mefepronic acid treatment has no effect on Progesterone
levels and fertility in early lactating ewes during the non–breeding season
El tratamiento con ácido mefeprónico después del apareamiento, no tiene efecto en los niveles
de progesterona ni en la fertilidad de las ovejas durante la temporada no reproductiva
Metehan Kutlu* , Neffel Kürşat Akbulut
Necmettin Erbakan University, Faculty of Veterinary Medicine, Department of Obstetrics and Gynecology. Konya, Türkiye.
*Corresponding author: metehankutlu2@hotmail.com, metehan.kutlu@erbakan.edu.tr
Eect of mefepronic acid treatment on fertility in Merino ewes / Kutlu and Akbulut _______________________________________________
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INTRODUCTION
One of the most signicant reasons for the failure to achieve
targeted reproductive parameters in livestock is embryonic losses
[1]. In ewes (Ovis aries), it is estimated that 30-40% of fertilized eggs
are lost within the initial three weeks of pregnancy [2]. Embryonic
loss is often linked to inadequate progesterone (P4) secretion by
the corpus luteum (CL) during the pre–implantation period [3].
Many different methods are being tried to prevent/reduce
embryonic death. In order to prevent embryonic losses and improve
reproductive performance in ewes, gonadotropin–releasing hormone
or human chorionic gonadotropin can be injected at various times
following sponge removal [4, 5, 6, 7, 8, 9]. Post–mating injections of
these hormones can enhance ovulation induction of or luteinization
of the dominant follicle, potentially increasing P4 concentrations
via through the formation of accessory CL [10]. In addition, non–
steroidal anti–inflammatory drugs inhibit prostaglandin production
by blocking both cyclooxygenase isoforms, COX–1 and COX–2 [11].
Non–steroidal anti–inflammatory drugs (NSAIDs) have been
reported to inhibit luteolytic prostaglandin F
2
α (PGF
2
α) release
resulting from insufcient IFN–τ secretion in farm animals and can
be administered post–mating to help prevent embryonic losses
during early pregnancy [12, 13].
Some researchers have demonstrated that peroxisome proliferator–
activated receptors (PPAR) can suppress COX-2 expression [14, 15,
16]. COX-2 also plays a role in the production of PGF
2
α [17]. The PPARs,
members of the nuclear receptor superfamily, regulates several genes
involved in lipid metabolism and adipocyte differentiation [18]. PPAR
activation is induced by fatty acids, prostaglandins, and brates,
which are used in human medicine for their lipid–lowering effects
[19]. PPAR activation enhances mitochondrial function, promotes
peroxisomal β–oxidation, stimulates hepatic gluconeogenesis,
regulates lipoprotein metabolism, and supports choleretic and
cholagogic activities [20].
Mefepronic acid (2-methyl-2-phenoxy propionic acid) is a
member of the brate family of compounds used in the treatment
of dyslipidemia [21]. In veterinary practice, it is utilized for the
treatment of ketosis, liver diseases, and fat cow syndrome [20, 22].
Limited studies on mefepronic acid have demonstrated its positive
effects on hepatic metabolism and reproductive parameters in
postpartum dairy cows [22, 23]. Ewes in early lactation have high
nutritional requirements [24]. Moreover, uterine venous PGF
2
α
rst increases in ewes between days (d) 11–13 [25], therefore,
administering mefepronic acid on d 9 post–mating is considered.
This study hypothesized that administering mefepronic acid
to lactating ewes in the early postpartum period could reduce
lipomobilization and prolong the lifespan of the CL by suppressing
PGF
2
α release during maternal recognition. To enhance fertility
under these conditions, the study aimed to assess the effects of
post–mating mefepronic acid administration on serum P4 levels
and fertility in early lactating Merino ewes during the non–breeding
season. To date, no studies have explored the effects of post–
mating mefepronic acid in early lactating Merino ewes.
MATERIAL AND METHODS
Animals
This study was carried out on a commercial sheep farm located
in Konya province, Türkiye (37°86'44.06" N, 34°16'33.55" E, Alt:
1020 m) during the non–breeding season in March 2024. The study
included 92 clinically healthy multiparous Merino ewes, aged 2
to 5 years, with weights ranging from 50 to 60 kg (Demirtaş tarti,
Tem, Türkiye). They were 40–50 d postpartum. The ewes were
allowed to graze on pasture for 12 hours (h) each d and were not
given with any compound feed. The ewes had unrestricted access
to water, with no nutritional flushing provided before mating. All
were lactating and nursing their lambs.
Synchronization and groups
An intravaginal sponge containing 60 mg of medroxyprogesterone
acetate (Esponjavet®, Hipra, Spain) was inserted into the ewes
for 7 d (D 0). On the d the sponge was removed (D 7), each ewe
received an intramuscular injection of 500 IU of eCG (Oviser®,
Hipra, Spain) administered into the neck muscles. Estrus detection
was conducted with a teaser ram, introduced twice daily for 1 h
each time over the 24–h period following sponge removal. Ewes
showing signs of estrus were hand–mated with proven rams,
maintaining a ewe–to–ram ratio of 7:1. The mated ewes were then
randomly assigned to one of two groups: Control and Treatment.
In the treatment group (Mefepronic acid) (n=28), ewes were
given an intramuscular injection of 10 mg·kg
-1
mefepronic acid
(100mg·mL
-1
, 2–methyl–2–phenoxy propionic acid, Hepagen®,
Fatro Günesli) on d 9 post–mating. The Control group (n=27)
received no drug treatment on d 9 post–mating.
Blood collection and hormonal assessment
Blood samples were collected from all ewes on d 9 and 11 post–
mating through jugular venipuncture to measure serum P4 levels.
The samples were centrifuged at 2514 g for 15 min (Elektromag,
M815 M, Türkiye), and the resulting serum was stored at -20°C
until analysis (Uğur Soğutma, UED 280D/S R65, Turkey). Serum P4
concentrations were measured using the ELISA method (BioTek
ELx800 microplate reader USA) with a species–specic commercial
kit (Sheep Progesterone Sunred 201–07–0084). The assay had
a detection limit of 0.048 ng·mL
-1
and was sensitive to P4 levels
ranging from 0.05 to 15 ng·mL
-1
.
Ultrasonography examination
Pregnancy examination was performed transabdominally using
real–time B–mode ultrasonography on the 50
th
d after mating
(Hitachi EUB–405, Japan, 3.5 MHz convex probe). Litter size was
recorded at the time of parturition.
Determination of reproductive performance
The following reproductive parameters were calculated;
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_________________________________________________________________________________________________Revista Cientica, FCV-LUZ / Vol.XXXV
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Statistical analysis
Statistical analyses were conducted using SAS 9.4 software.
Reproductive parameters were evaluated with the Chi–squared
test, Fisher’s exact test, and the PROC GENMOD procedure.
The Shapiro–Wilk test assessed the normality of serum P4
concentrations within each group. The GLIMMIX procedure
analyzed the effects of main factors (treatment and day) and their
interaction (Treatment × Day) on P4 concentrations. Results were
presented as percentages or means ± standard error of the mean
(± SEM), with statistical signicance set at P<0.05 [26].
RESULTS AND DISCUSSION
TABLE I presents the estrus detection rate, pregnancy rate, early
fetal mortality rate, lambing rate, twin rate, number of lambs, and litter
size. Statistical analysis showed no signicant differences between
the groups regarding these reproductive parameters (P>0.05).
Mefepronic acid treatment resulted in no signicant change in
serum P4 levels between days 9 and 11 post–mating (P>0.05)
(see FIG. 1).
In this present study, the efcacy of post–mating MA injection
in early lactation Merino ewes was investigated for the rst time.
There were no difference was observed between the groups in
reproductive performance parameters. PPAR𝛼 is predominantly
expressed in the sheep endometrium during the early stages
of pregnancy, with its levels declining between days 7 and 17.
PPAR𝛽/𝛿 is consistently expressed throughout pregnancy, while
the PPAR𝛾 is irregularly expressed [27].
Numerous studies have demonstrated that PPARs are functionally
expressed throughout the female reproductive system and suggest
they may play a signicant role in reproduction, largely due to their
involvement in energy homeostasis [28]. Furthermore, PPARs have
been implicated in ovarian dysfunctions associated with obesity
[29, 30], dyslipidemia [31, 32], hyperandrogenemia [33, 34, 35,
36] and insulin resistance [37, 38, 39, 40]. Only a few studies have
examined the reproductive effects of mefepronic acid (MA) in farm
animals. In the study by Rizzo et al. [22] reported that control
cows exhibited their rst estrus 74.36 ± 6.2 d after calving, while
in the MA cows, the rst estrus occurred 50 ± 3.7 d after calving
(P<0.05). Additionally, they reported that the pregnancy rate in
the rst and second inseminations of dairy cows treated with the
MA group increased by 7% numerically compared to the control
group. Kutlu et al. [41] have reported that no signicant difference
was observed in the estrus rate, pregnancy rate, lambing rate, and
litter size compared to the control group but numerically increased
15% pregnancy rate at rst service in the early group when the
sponges were removed during both the early and late postpartum
periods following the application of MA in Hungarian Merino ewes.
The results of the presented study are partially aligned with ndings
from previous studies. The variation in results may be attributed to
differences in animal subjects, breeds, timing of MA administration,
and drug dosage used.
In the presented study, early postpartum ewes were selected
during the transition period when they are faced with metabolic
and hormonal rearrangements. Also, the MA injection time was
chosen as the period when maternal recognition is critical which
a PPAR agonist is. In this study, post–mating MA injection did not
increase P4 concentration compared to the control group. Maternal
recognition is crucial for establishing pregnancy, with this essential
process occurring in ewes between d 11 – 16 post–mating, known
as the critical period [3]. During this period, if the embryo is unable
to synthesize interferon tau (IFN–τ), which is essential for maternal
TABLE I
Reproductive performance of ewes with Mefepronic acid treatment
Control Group
(n=27)
Mefepronic acid Group
(n=28)
P
Estrus detection rate (%)
59.8 (55/92)
Pregnancy rate (%)
33.3 (9/27) 39.2 (11/28)
0.647
Earlyfetalmortalityrate(%) 22.2 (2/9) 18.18 (2/11) 0.822
Lambingrate(%) 77.8 (7/9) 81.8 (9/11) 0.822
Twin rate (%) 0 (0/7) 33.4 (3/9) 0.999
NumberofLambs 7 13 –
Single 7 5 –
Twin – 4 (8) –
LitterSize 1.0 (7/7) 1.44 (13/9) 0.756
*Statisticalanalysisshowednosignicantdierencebetweenthegroups(
P>0.05).
Thenumbersinparenthesesarenumberofanimalsusedforthecalculation
2.6
3.16
2.17
2.74
Day 9 Post Mating Day 11 Post Mating
1.0
1.5
2.0
2.5
3.0
3.5
P4 (ng·mL
-1
)
Control Mefepronic Acid
treatment = 0.181
day < 0.001
treatment × day = 0.952
FIGURE 1. Serum P4 concentrations in mated ewes
Eect of mefepronic acid treatment on fertility in Merino ewes / Kutlu and Akbulut _______________________________________________
4 of 6 5 of 6
recognition, for various reasons, it cannot inhibit the secretion of
luteolytic PGF
2
α from the endometrium [42, 43]. This disrupts
the necessary P4 secretion and causes embryonic death in early
pregnancy [44].
Some researchers have shown that PPAR can inhibit the expression
of COX–2, which also plays a role in the production of PGF
2
α [14,
15, 16, 17]. COX–2 also plays a role in the production of PGF
2
α, a
crucial factor in regulating the regression of the CL [17]. Previous
studies have shown that female rats with COX–2 deciency are
infertile due to defects in ovulation, fertilization, implantation, and
decidualization [45]. Mefepronic acid injection may help reduce
lipomobilization and extend the lifespan of the CL by inhibiting the
release of PGF
2
α during the maternal recognition period.
Additionally, MA elevates cholesterol levels, which are essential
for the formation of P4. Steroid synthesis typically starts with
cholesterol, which can originate from dietary sources or be
synthesized within the body. This cholesterol is then transported
to the ovaries by lipoproteins, primarily high–density lipoprotein
and low–density lipoprotein (LDL) [46]. P4 is crucial for regulating
blastocyst implantation [47] and must be maintained at an optimal
concentration following mating. Ewes with reduced P4 levels are
at a greater risk of experiencing embryo loss [48]. In previous
studies, Zerani et al. [49] reported that in vitro studies on CL
treated with PPAR𝛾 agonists revealed an increase in P4 and 3–
beta–hydroxysteroid dehydrogenase activity during the early and
mid–luteal stages, while concurrently decreasing prostaglandin–
endoperoxide synthase 2 activity and PGF
2
α levels at these same
stages in pseudopregnant rabbits.
Bogacka and Bogacki [50] demonstrated through quantitative
analysis of PPAR mRNA expression in the porcine endometrium
during the estrous cycle and early pregnancy that all three PPAR
isoforms are present in this tissue. Notably, a signicant increase in
PPAR𝛾 mRNA levels occurred on d 13–15 of the estrous cycle, while
PPAR𝛽/𝛿 levels decreased on d 11–12 of pregnancy, suggesting
that PPARs are involved in luteolysis and maternal recognition of
pregnancy in pigs. Additionally, PPAR ligands have been shown
to influence the secretion of P4 and 17β–estradiol by the porcine
CL during pregnancy [51]. PPARβ/δ appears to be essential in
embryo implantation, with several lines of evidence indicating
that the effects of PGI2, the key prostaglandin for xation and
decidualization, are mediated through PPARβ/δ [45].
Furthermore, Kang et al. [52] demonstrated through molecular,
pharmacological, and genetic methods that PGI2–induced
activation of PPARβ/δ enhances blastocyst hatching in mice.
Rizzo etal. [22] demonstrated that administering three doses of
mefepronic acid to dairy cows on the 1
st
, 3
rd
, and 5
th
d postpartum
increased cholesterol and high–density lipoprotein levels, thereby
supporting hepatic metabolism and lipogenesis, while showing
a reverse trend in non–esteried fatty acids. Additionally, they
reported that P4 concentrations (on the 13
th
d after insemination)
were higher in cows treated with MA (6.47 ± 0.37 ng·mL
-1
) compared
to the control cows (4.24 ± 0.37 ng·mL
-1
). The difference from
previous in vitro studies may be attributed to the use of mefepronic
acid, a PPARα agonist, in the current study. Furthermore, the
discrepancy with Rizzo et al. [22] could be attributed to the lower
intensity of liver metabolism in ewes compared to cows.
CONCLUSIONS
In conclusion, post–mating treatment with mefepronic acid
did not enhance serum P4 levels or fertility in early lactating
Merino ewes during the non–breeding season. However, further
research is recommended to evaluate the efcacy of mefepronic
acid, especially in ewes with high lactation.
Ethics approval
The present study was conducted with approval from Selçuk
University Animal Experiments Local Ethics Committee, Konya,
Türkiye (2024/065).
Conflict of interest
The authors declare no competing interests.
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