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Application of Misoprostol as a Treatment of Unexplained Infertility in Mares

Article in Journal of Equine Veterinary Science · September 2018

DOI: 10.1016/j.jevs.2018.09.005

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Clinical Technique

Application of Misoprostol as a Treatment of Unexplained

Infertility in Mares
Marco A. Alvarenga*, Lorenzo G. Segabinazzi
Department of Animal Reproduction and Veterinary Radiology, College of Veterinary Medicine and Animal Science e UNESP, Botucatu, Brazil

a r t i c l e i n f o a b s t r a c t

Article history: Misoprostol is a synthetic Prostaglandin E1 (PGE1), one of the prostaglandin E (PGE) family hormones,
Received 18 July 2018 which promotes oviduct dilatation and motility, reestablishing fertility rates in mares suspected of
Received in revised form uterine tubal block. It is known that topical application of PGE on the surface of the uterine tubes via
11 September 2018
laparoscopic procedure improved embryo recovery and pregnancy rates in barren mares with unex-
Accepted 13 September 2018
Available online 29 September 2018
plained infertility. The aim of this study was to observe if the treatment using Misoprostol could be
performed via intrauterine application. Mares used in this study had been barren for at least 2 years
before the treatment, without embryo or pregnancy, with a history of unexplained infertility. Thus, 22
Keywords:
Uterine tube
subfertile mares, aged 5 to 26 years, were treated by a deep uterine horn application, using one Cytotec
Equine tablet (200 mcg of Misoprostol, Pfizer, USA) diluted in 3 mL of sterile water, in each horn, aiming the
PGE application as close as possible to the papilla of uterine tubes. These procedures were performed during
Fertility the diestrus period, and mares were bred in the next cycle. Embryos were produced, or a pregnancy was
obtained from 15 of the 22 mares within the first two cycles following Cytotec treatment. Ten of 15 mares
bred as embryo donors produced embryos (0.4 embryos/cycle) in the three subsequent cycles, and six of
seven mares bred to carry became pregnant after treatment. In conclusion, Misoprostol therapy can be
performed via intrauterine as a potential treatment for mares with unexplained infertility, making easier
and safer the treatment of these mares.
© 2018 Elsevier Inc. All rights reserved.

1. Introduction An improvement in fertility rates in mares with unexplained

Some studies [1e9] have reported the presence of masses in
the uterine tube in mares, which can cause subfertility or infer-
tility problems, because they block either sperm from reaching
the fertilization site or the embryo from reaching the uterus.
These obstructions usually occur at the ampule-isthmic junction
[8] and are resulted by fibroblast cells masses. However, this
abnormality is not easy to be diagnosed, and it was initially
observed investigating uterine tubes obtained from abattoirs
[5,6,10].
Animal welfare/ethical statement: The study “Application of misoprostol as a
treatment of unexplained infertility in mares” was approved by the Ethics and
Animal use Committee, with protocol number 0065/2018, from the S~ao Paulo State
University (UNESP), Botucatu campus, SP, Brazil.
Conflict of interest statement: None.
* Corresponding author at: Marco A. Alvarenga, Department of Animal Repro-
duction and Veterinary Radiology, College of Veterinary Medicine and Animal
Science - (UNESP), Univ Estadual Paulista, Botucatu, Brazil.
E-mail address: malvarenga@fmvz.unesp.br (M.A. Alvarenga).
infertility when these animals were treated in an attempt to unclog
the uterine tubes, by flushing the uterine tube using a ventral
midline surgical approach [11e13] or with laparoscopic application
of prostaglandin E2 (PGE2) on the uterine tubal surface [14,15], was
reported. However, any surgical procedure has risks, and compli-
cations associated with laparoscopic surgery have been well
documented [16e20]. In addition, the costs of a laparoscopic sur-
gery are higher, and an adequate postoperative management is
necessary for proper recovery after surgery, thereby raising the
costs of treatment.
Prostaglandin E is a prostanoid derived from arachidonic acid
[21]. This hormone is essential in many reproductive functions, such
as ovulation, luteal regression, pregnancy maintenance, parturition,
and other biological activities [22e36]. Specifically, the PGE is
secreted by equine embryos, involved in embryo transport through
the uterine tube to the uterus in mares. Nonfertilized oocytes do not
produce PGE and are retained [2,3,37e39], showing the importance
of this hormone on uterine tube relax and transportation.
Misoprostol is a synthetic analog of prostaglandin E1 (PGE1) and
has been used effectively for inducing abortions in women [40],

https://doi.org/10.1016/j.jevs.2018.09.005
0737-0806/© 2018 Elsevier Inc. All rights reserved.
 M.A. Alvarenga, L.G. Segabinazzi / Journal of Equine Veterinary Science 71 (2018) 46e50
increasing contractions of the uterus [41,42], and its use has also
been reported in mares for promoting cervical relaxation, however
with controversial results [43,44]. Thus, the aim of this study was to
evaluate if deep uterine horn application of misoprostol can work
on increasing fertility rates in mares with unexplained infertility.
2. Materials and Methods
Twenty-two mares (4 crioulos, 5 Mangalarga Marchadors, 1
Arab, 8 Quarter Horses, 2 Brazilian jumping horses, and 2 Thor-
oughbreds) with a history of unexplained infertility and that did
not produce an embryo or become pregnant after at least 2 years
after multiple estrous cycles were included in this study. The age
(mean ± standard deviation) of the mares was 16.1 ± 5.7 years, with
3.7 ± 1.6 years and 15.1 ± 6.3 cycles with unexplained infertility.
Transrectal palpation and ultrasonographic examinations were
performed in all of the mares, and no abnormalities or intrauterine
fluid accumulation was observed. These animals, also, did not have
any uterine or ovarian pathology detected during a breeding
soundness examination, with negative uterine culture and negative
cytology (<5% of PMNs) [45]. They were breeds with appropriated
breeding management and inseminated with semen of at least two
different stallions of proven fertility before the experiment.
2.1. Detecting the Estrous Cycle and Treatment Protocol
Mares were examined by transrectal palpation and ultraso-
nography. Ovulation induction was performed using histrelin ace-
tate (Strelin, Botupharma, Brazil) when a follicle measuring
>35 mm and endometrial edema were diagnosed. The treatment
was performed during diestrus between the sixth and the 10th day
after ovulation.
For the treatment, 200 mcg of misoprostol (CYTOTEC, Pfizer)
diluted in 3 mL of sterile water was applied in each deep uterine
horn, using a flexible equine insemination catheter (Minitube,
Porto Alegre, Brazil), aiming deposition on the uterotubal junction
as close as possible.
2.2. Breeding Management After Treatment
Mares were bred on subsequent cycle after the treatment. For
this, an intramuscular injection of 5 mg of dinoprost tromethamine
(LUTALYSE, Zoetis, SP, Brazil) was administered 1 day after the
treatment to interrupt the mare diestrus.
The mares were examined daily by transrectal palpation and
ultrasonography. When a follicle measuring >35 mm and endo-
metrial edema were detected, the ovulation induction was per-
formed using 250 mg of histrelin acetate (Strelin, Botupharma,
Brazil). Artificial inseminations were performed 24 hours after
ovulation induction, using shipped cooled semen (1  109 motile
spermatozoa), and the ovulation was confirmed during the subse-
quent day. Embryo-donor mares were flushed 8 days after ovula-
tion for embryo recovery, and carry mares had pregnancy diagnosis
performed between 12 and 16 days after ovulation by transrectal
ultrasonography.
2.3. Statistical Analysis
Descriptive statistics means ± standard deviations of the mare's
age, number of years with infertility, and number of stallions used
to breed the mare were the factors used to express the results.
Fertility rates between before and after treatment were compared
using chi-square analyses. Significance was set at P  .05.
47
3. Results
Sixteen mares (73%; 16/22) re-established fertility after treat-
ment. Fifteen of them (66.6%; 10/15) were bred as embryo donors
and seven mares (85.7%; 6/7) as carry (Table 1).
In embryo-donor mares, six mares (40%) produced at least one
embryo in the first cycle after treatment and four mares (26.7%) in
the second cycle. Four mares (57.1%) were bred as carry, also
became pregnant in the first cycle after treatment and two (28.6%)
in the second cycle. Mares that did not produce an embryo three
cycles after treatment, continued in a normal reproductive man-
agement, but the subsequent cycles were not consider for this
study.
4. Discussion
This study was performed with mares that supposedly pre-
sented oviduct blockage because other infertility problems, such as
endometritis [46e49], anatomical problems of the reproductive
system [50e53], poor quality semen [54e56], or breeding man-
agement factors [57], were discarded after multiple cycles failing to
produce an embryo or become pregnant. This hypothesis is based
on studies [1e9] that showed the presence of gelatinous masses
inside the uterine tubes that may occlude the lumen, which would
either prevent the passage of sperm to the fertilization site or an
embryo from reaching the uterus. These masses are histologically
described as collagen type 1 [7,9] and apparently derive from
follicular fluid and follicle cells that enter the oviduct at ovulation
[5,9].
The uterine tube is an important reproductive organ that makes
the communication between the uterus and ovaries, having both
transport and secretory functions. This organ is essential for early
reproductive events in mares because it serves as a sperm reservoir,
a point of collection and nourishment for the oocyte, a fertilization
site, and an incubation and maturation site for the early embryo
[15] until the stage at which the matured embryo (5e6 days after
ovulation) enters into the uterus [39,58,59]. However, some studies
[4e6,8,9,39] described collagenous masses into the oviduct, that
can vary considerably in size [3], occluding the uterine tube lumen
resulting in infertility [7]. Nevertheless, some authors reported that
oviduct patency can be confirmed by applying a dye or microscopic
fluorescent beads into the ampulla, and subsequently the markers
should be collected from the uterus [12,60e62], or in a retrograde
way, the marker can be flushed via uterotubal junction [11,63] and
confirmed by examination of the contents in the peritoneal fluid.
But, this test may not be conclusive because it does not necessarily
indicate that the uterine tubal lumen supports the embryo passage
as the markers (15 mm) are smaller than early embryos
(150e200 mm [64]). Thus, uterine tubes patency and the presence
of collagen masses were not determined in this study before
treatment, but the mares showed reproductive histories with un-
explained infertility, presuming oviductal blockage after exhaustive
attempts to identify other subfertility causes.
Mares used in this study were from private owners; therefore, a
control group using a placebo was not possible. So, mares served as
their own controls, considering before and after treatment times.
Therefore, the treatment with deep uterine horn application of
misoprostol, aiming deposit on uterotubal junction, restored
fertility in 16 of 22 (73%) mares with unexplained infertility, a very
strong clinical evidence.
Misoprostol is a synthetic prostanoid analog (PGE1 analog) that
binds prostaglandin type E prostanoid family of receptors as it does
PGE2. This hormone can be used to induce abortion in women in
the first trimester of gestation [40], achieve cervical ripening and
labor induction [65,66], and also induce parturition in goats at term
48 M.A. Alvarenga, L.G. Segabinazzi / Journal of Equine Veterinary Science 71 (2018) 46e50

Table 1
Data from 19 mares with unexplained infertility, treated with deep horn application of misoprostol.

Mare Age (years) Breed Years with Cycles with Result after treatment
unexplained infertility unexplained infertility

ET-1 9 Crioula Neverd5 y 15 One embryo in the first cycle after treatment
ET-2 15 MM 3 10 One embryo in the first cycle after treatment
ET-3 20 Arab 8 22 Two embryos in the first cycle after treatment
ET-4 18 MM 2 7 Two embryos in the second cycle after treatment
ET-5 7 MM Neverd4 y 7 One embryo in the first cycle after treatment
ET-6 10 QM 3 11 One embryo in the first cycle after treatment
ET-7 18 QM 2 9 One embryo in the second cycle after treatment
ET-8 22 QM 4 15 No embryo after treatment
ET-9 25 QM 6 26 No embryo after treatment
ET-10 18 BH 3 17 No embryo after treatment
ET-11 16 MM 3 11 One embryo in the first cycle
ET-12 14 MM 4 17 No embryo after treatment
ET-13 26 QM 2 16 Two embryos in the second and third cycles
ET-14 16 QM 6 32 No embryo after treatment
ET-15 20 QM 4 23 No embryo after treatment
Carry-1 17 BH Neverd 4 years 14 Pregnant in the first cycle after treatment
Carry-2 25 Crioula 2 12 Pregnant in the second cycle after treatment
Carry-3 5 Crioula Neverd2 years 7 Pregnant in the first cycle after treatment
Carry-4 6 Crioula Neverd2 y 7 Pregnant in the first cycle after treatment
Carry-5 12 QM 4 17 Pregnant in the first cycle after treatment
Carry-6 18 TB 3 15 Pregnant in the second cycle after treatment
Carry-7 17 TB 6 22 No pregnancy after treatment

Abbreviations: BH, Brazilian jumping horses; MM, Mangalarga Marchador; TB, Thoroughbred; QM, Quarter Horse.
ET, mares bred to donate embryos; Carry, mares bred to carry their own pregnancy. “Never” in “Years with unexplained infertility” means that mare never had an offspring in
all life.

[67], increasing uterine tone and contractions [41,42]. In horses,
misoprostol has been recommended to treat gastric ulcers [68e71]
and has been used to promote cervical relaxation in mares [43,72].
In this sense, Allen et al. [14] and Ortis et al. [15], using topical
application of PGE2 on the surface of the uterine tube by laparos-
copy, also reported re-establishment on fertility rates in mares with
unexplained infertility, strengthening our results. In addition, a
potential effect of PGE facilitating sperm transport has already been
reported [73,74], with an improvement on fertility with the addi-
tion of exogenous PGE into equine [73] and human semen [75].
Some authors [14,15,76,77] suggest that PGE2 would promote
oviduct dilation and contractility, resulting in expulsion of these
masses from the uterine tube and hasten oviductal transport of
equine embryos [78]. In addition, it is known that equine embryos
secrete PGE2 to promote passage through the uterine tube to the
uterus [76,78] and unfertilized oocytes, that do not synthesize this
hormone, are retained in the oviduct [3,37e39,58].
In addition, Chiossi et al. [79] reported an in vitro study that
PGE1 significantly increases myometrial contractility when
compared with PGE2, in the first 90 minutes after the treatment and
up to 180 minutes when compared with the control group, which
may favor the uterine tube delivery. Local administration of PGE1 or
PGE2 has been reported to promote labor induction in women
[65,66]; however, apparently PGE1 is more effective to promote
myometrial contractility and vaginal delivery in induced labor in
women [80,81].
In other studies, aiming to unlock the way, the uterine tube was
flushed via the ampulla [12,13,62] or via the uterotubal junction
[11,82]; a return of fertility rates in mares was also reported. All
these results may reinforce the suspicion about uterine tube oc-
clusion causing unexplained infertility in these animals.
In addition, the treatment described in this study is safe,
inexpensive, easy-handling, and noninvasive, not requiring sur-
gical interventions, high-cost equipment, and management and
costs with postoperative procedures. Moreover, risks associated
with surgery or anesthesia [16e20] are not provided in this
therapy. In conclusion, deep uterine horn application of
misoprostol may be considered as a treatment of mares with
unexplained infertility.
Acknowledgments
This study had no financial support and was approved by the
Institutional Ethics Committee of S~ ao Paulo State University
(UNESP, Botucatu, SP, Brazil), according to Brazilian Council for the
Control of Animal Experimentation (CONCEA).
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