Abnormalities in the Sexual Cycle of Bitches

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Chapter 6
Abnormalities in the Sexual Cycle of Bitches
Ali Risvanli, Halis Ocal and Cahit Kalkan
Additional information is available at the end of the chapter
http://dx.doi.org/10.5772/64648
Provisional chapter
Abnormalities in the Sexual Cycle of Bitches
Ali Risvanli, Halis Ocal and Cahit Kalkan
Additional information is available at the end of the chapter
Abstract
Sexual-cycle abnormalities are an important cause of infertility in bitches, with disorders
such as anestrus, split estrus, and persistent estrus having varied etiologies. Sexual-cycle
abnormalities in bitches may be addressed as follicular- or luteal-phase disorders.
However, pet owners should have a good working knowledge of the sexual cycles of their
animals in order to beer understand these disorders.
Keywords: abnormality, sexual cycle, bitch
1. Introduction
Sexual-cycle abnormalities in bitches may present as anestrous, shorter, or longer cycles, as well
as prolonged proestrus, prolonged estrus, split estrus, or anovulatory cycles. These cycle
disorders may result from abnormal ovarian functions and are a cause of infertility [1].
1.1. Anestrous
Anestrous cycles in bitches may be either primary or secondary. If a bitch does not show signs
of estrus despite having reached age of puberty, anestrous cycles are primary. The age of
puberty in bitches is 6–14 months. In general, the “primary anestrus” diagnosis may be used
if estrus has not occurred and the cycle has not started by 24 months of age. Although some
small breeds experience rst estrus at 6 months of age, cycles accompanied by estrus signs
may be delayed, since the rst cycles may be silent. Therefore, cycle problems are not usually
investigated until a bitch reaches 2 years of age. A diagnosis of “secondary estrus” is used if
estrus has not occurred for 10–18 months, although rst estrus had occurred. In other words,
secondary estrus is dened as the presence of a period longer than 10–18 months between
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© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.

estruses. Normally, bitches experience estrus at 4–10 month (mean 6–7 months) intervals.
Cycles shorter than 4 months or longer than 10 months are abnormal and can cause infertility
[2–6].
Factors that lead to primary anestrus include ovariectomy or ovariohysterectomy at early age,
silent heat (subestrus), abnormalities in sexual dierentiation (chromosomal and genetic
disorders), use of progesterone or glucocorticoids, congenital hypothyroidism, certain
systemic diseases, ovarian anomalies or ovarian aplasia, progesterone-releasing ovarian cysts,
and autoimmune oophoritis [2, 7].
Secondary anestrus may result from dysfunction of the thyroid gland or adrenal cortex, as well
as nonendocrinological disorders, cachexia, obesity, and use of cycle-inhibiting drugs. Silent
heat, luteal cysts, and some ovarian tumors may also lead to secondary anestrus as well as to
primary anestrus [4, 5].
1.1.1. History of ovariohysterectomy
If taken from another person, the bitch may have been sterilized, which a new owner may
overlook. Presence of a taoo in the inguinal region and palpation or inspection of a scar from
operation in the ventral wall of the abdomen may be indicators of ovariohysterectomy.
However, it should be kept in mind that such a scar may be present if any intra-abdominal
operation has been performed, so it may be premature to conclude that the scar resulted from
ovariohysterectomy. Serum LH level measurement may be used to identify bitches that have
undergone ovariohysterectomy, as serum LH is continuously high in such bitches as a result
of the absence of negative feedback on LH (because the ovaries have been removed). Although
elevation in serum LH provides information about ovariohysterectomy, note that this indicator
may also be seen in ovarian dysfunction or during the preovulatory period (i.e., the preovu-
latory LH peak). Therefore, repeated measurements are required to conrm and experimental
laparotomy may also be performed for a denitive diagnosis [8]. Whether ovariohysterectomy
has been performed may also be detected by measuring the serum estrogen level before and
60–90 min after intravenous administration of 0.02–0.03 μg/kg buserelin. If ovariohysterecto-
my has been performed, estrogen levels will be found above 15–20 pg/mL.
Anti-müllerian hormone (AMH) measurement may also show whether a bitch has undergone
ovariohysterectomy. AMH levels are found to be signicantly lower in bitches that have
undergone ovariohysterectomy compared to nonsterilized bitches [9, 10].
1.1.2. Silent heat (subestrus)
Silent heat is dened as the maintenance of ovarian functions without the presence of vulvar
edema, serosanguinous vaginal discharge, and charm for male dogs. Silent heat may be
observed for several cycles before rst estrus in younger bitches of smaller breeds. These
animals may be evaluated as “anestrus” because the pet owner may not nd the external signs
of estrus, or they may be identied as healthy male dogs although ovarian functions continue
normally.
Canine Medicine - Recent Topics and Advanced Research128

If silent heat is suspected, serum progesterone level should be measured once monthly in order
to verify that the ovaries are functioning. A serum progesterone level above 2 ng/mL indicates
functional luteal tissue. Observation of increasing supercial epithelial cells in regular vaginal
cytological examinations is an indicator of functional ovaries [5].
1.1.3. Disorders of sexual development
Normal sexual development occurs in three stages: (1) chromosomal (genetic) sex develop-
ment, (2) gonadal sex development, and (3) phenotypic sex development. Therefore, disorders
of sex development and dierentiation are classied into three matching groups: (1) sex
chromosome disorders, (2) gonadal sex development disorders, and (3) phenotypic sex
development disorders. All three groups of disorders result in abnormal sex dierentiation
and may vary in presentation between genital structure of normal and obscure appearance,
and all three groups of disorders may lead to sterility or infertility [11–13].
Chromosomal analysis, anatomical and histopathological denitions of the gonads, and
examination of the internal and external genitalia are required for the denite diagnosis of
dogs suspected to have disorders of sexual development [11, 14].
1.1.4. Drug-related anestrus
Long-term use of some drugs, such as androgen and progestogens, causes anestrus by
inhibiting cycles. Exogenous glucocorticoid administration is also reported to aect serum LH
level and the normal cycle. Puberty is inhibited due to suppression of genital-canal develop-
ment and ovarian activity in bitches that have undergone administration of long-acting GnRH
agonists like deslorelin [15].
Similarly, cyclic activity may not be observed for a long time in prepubertal bitches that have
been actively immunized against GnRH [16].
A comprehensive anamnesis should be obtained from the pet owner if drug-related anestrus
is suspected; sucient data must be obtained regarding the medical history of the bitch. If a
pet owner has recently acquired the bitch and if he or she has no or insucient information
about previous vaccinations and medications, drug-related anestrus should always be
considered. In such situations, the only treatment is to wait until the eects of the drug(s)
disappear or until the antibody titration decreases, if immunized against GnRH.
1.1.5. Thyroid dysfunctions
There is an indirect and strict association between thyroid dysfunction and reproductivity.
Hypothyroidism leads to reproductive disorders such as prolonged anestrus, silent heat,
prolonged proestrus, and ovulatory problems. The prolactin level increases, which leads to
impair or no development of ovarian follicles by inhibiting GnRH in bitches that have
insucient thyroid hormone release [17].
In bitches, hypothyroidism usually manifests as primary hypothyroidism, resulting from
destruction of the thyroid gland. The serum total and free thyroxin levels are low in bitches
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with thyroid dysfunction. Thyrotropin-releasing hormone (TRH) secretion from the hypo-
thalamus increases due to low levels of thyroid hormones; consequently, thyroid-stimulating
hormone (TSH) secretion from the pituitary gland increases. As a result of this totally phys-
iological process, low serum total and free thyroxin levels and elevated serum TSH levels are
observed in bitches with primary hypothyroidism [7].
Hypothyroidism should be kept in mind in the presence of numbness or mental fatigue, hair
loss, weight increase or obesity, dryness or loss of body hair, hyperpigmentation, cold intol-
erance, bradycardia, high plasma cholesterol level, or anemia in a bitch with an anestrous
problem. Measurement of only thyroid hormones may yield misleading or conicting results.
Therefore, a full thyroid prole should be obtained and a denitive diagnosis made in bitches
suspected of hypothyroidism. For this purpose, the serum-free thyroid hormone level
(particularly T4 measurement) and the response of the thyroid gland to TSH administrations
should be investigated. Furthermore, autoantibodies against thyroxin (T4) and triiodothyro-
nine (T3) or thyroglobulin should be investigated in serum, as they are produced in most
bitches with lymphocytic thyroiditis [7, 18, 19].
The sexual cycle may return to normal with hormone replacement therapy within 3–6 months
in bitches diagnosed with hypothyroidism. For this purpose, synthetic thyroid hormone
(levothyroxin) should be administered through the peroral route. A dose of 22 μg/kg b.i.d. is
usually sucient.
Although hyperthyroidism with consequent primary anestrus is a rare condition in bitches, a
case has been reported in a Pinscher dog with diet-related hyperthyroidism in which primary
anestrus developed; the bitch reached proestrus 13 days later after dietary regulation, with
estrus then induced by cabergoline [20].
1.1.6. Pituitary gland insuciency
The pituitary gland is important for the endocrinological functions of the adrenal glands,
thyroid gland, and the ovaries. Abnormalities of the pituitary gland also negatively aect these
organs. Prolonged anestrus is unusually seen in bitches with dwarsm caused by a congenital
anomaly. Ovariohysterectomy is recommended in bitches that show prolonged anestrus
related to pituitary gland insuciency [6].
1.1.7. Systemic diseases
Such diseases may negatively aect reproductive function. Cycles probably will not develop
if an animal is unhealthy.
1.1.8. Ovarian anomalies
Progesterone-releasing ovarian cysts, ovarian aplasia, and oophoritis may lead to primary
anestrus. Denitive diagnosis can be made by histopathological examination of the ovarian
tissue [21].
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1.2. Approach to bitches with anestrous problems
First, it should be determined whether the pet owner has correct and sucient knowledge of
the cycle and estrous signs of bitches. The age of the bitch and whether it has experienced
ovariectomy, ovariohysterectomy, or administration of any drug or vaccine (especially GnRH
vaccine) should be determined. Serum progesterone level should be monitored monthly for
6–8 months before any intervention in anestrous bitches. In normal bitches, the serum
progesterone level rises above 2 ng/mL within 2 months after estrus; progesterone level below
2 ng/mL for 6–8 months denitely indicates prolonged anestrus. In addition, vaginal epithelial
cells should be monitored for any alterations with weekly vaginal smears.
Routine blood and urine tests (complete blood count, biochemical analysis) and thyroid
function tests should be performed following general examination in anestrous bitches.
Progesterone measurement and ultrasonographic examination of the ovaries should be carried
out whenever luteal cyst or tumor of the ovaries is suspected. Karyotype analysis should be
performed if developmental anomalies of the genital organs are suspected (such as hermaph-
roditism) [5].
Treatment of primary or secondary anestrus is targeted towards its etiology. No treatment is
available if a bitch has undergone ovariectomy or ovariohysterectomy or in the presence of
congenital sex development or dierentiation anomalies, ovarian aplasia, or autoimmune
oophoritis. Ovariohysterectomy is recommended for autoimmune oophoritis. Hormone
replacement therapy may be administered in bitches determined to have hypothyroidism-
related anestrus [22].
Estrous stimulation may be performed in anestrous bitches for which the underlying cause
cannot be detected. Synthetic estrogens (diethylstilbestrol), dopamine agonists (bromocriptine
and cabergoline), GnRH agonists (lutrelin, buserelin, fertirelin, deslorelin, leuprolide), or
exogenous gonadotropins (LH, FSH, hCG, PMSG) may be administered for this purpose [23,
24].
Dopamine agonists are eective for stimulating fertile estrus in most bitches; however,
prolonged use may be required. Bromocriptine (Parlodel, Gynodel) or cabergoline (Galastop,
Dostinex) is used for this purpose. Bromocriptine is less preferred, as it causes vomiting and
requires lengthy periods of administration in order to stimulate estrus. Although more
expensive than bromocriptine, cabergoline may induce estruses eectively and safely with
fewer side eects. Cabergoline is usually recommended at a dose of 5 μg/kg daily via the
peroral route until 3–8 days after proestrus has begun [23–25].
Using GnRH and its analogs may also induce estruses. However, prolonged use for 8 days or
longer or long-acting analogs such as lutrelin, deslorelin, or leuprolide is needed to induce
fertile estrus. It is impractical to induce estrus by using short-acting natural GnRH or GnRH
agonists, because GnRH should be given as a pulsatile continuous infusion at a dose of 0.2–
0.4 μg/kg every 90 min via the intravenous or the subcutaneous route for 3–9 days. This requires
3–9 days of hospitalization and the availability of a pulsatile infusion pump. Long-acting
formulations of GnRH analogs such as lutrelin, deslorelin, and leuprolide have been quite
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successful when implanted subcutaneously or submucosally. Deslorelin-containing implants
(Suprelorin®, 4.7 mg deslorelin) are used most frequently for this purpose [23–27].
Hypophyseal (FSH and LH) and chorionic (PMSG and hCG) gonadotropins are also used for
inducing estruses. It has been found that chorionic gonadotropins are more successful than
hypophyseal gonadotropins in bitches. Although various protocols have been aempted,
successful results have been reported with 20 IU/kg/d PMSG applied subcutaneously for 5
days, with 500 IU intramuscular hCG on day 5. PG600, a preparation containing PMSG and
hCG rst produced for pigs (80 IU PMSG and 40 IU hCG/mL), is quite eective for inducing
estruses [8, 28].
1.3. Recurrent estrus (shortened interestrous intervals or polyestrous)
The mean duration between estruses is 7 months (4–13 months) in bitches, and the long part
of the cycle (2–10 months) comprises a mandatory anestrus phase following diestrus. In the
anestrous phase, the uterus enters the involution process and the endometrium is regenerated.
Anestrus shorter than 2 months naturally results in repetition of estrus at 4-month or shorter
intervals, which is dened as “recurrent estrous.” It should be kept in mind that the estrous
period is shorter in breeds such as the German Shepherd Dog, Roweiler, Basset Hound, Cocker
Spaniel, and Labrador Retriever. Fertility decreases in bitches with recurrent estrus [29] from two
major causes: (1) overstimulation of the ovaries due to the formation of follicular cysts and
granulose cell tumors and (2) a premature decrease of progesterone during diestrus [21].
The period between estruses may be prolonged up to 6 months by using a weak androgen,
mibolerone (Cheque Drops), recommended at a dose of 30–180 μg per day to suppress es-
truses [1, 30].
Furthermore, if infertility resulted from short estrous period, bitches are reported to return to
normal fertility in the following cycles when estrus is suppressed with synthetic progestin
administration. For this purpose, 2 mg/kg per day megestrol acetate or 0.5 mg/kg per day of
chlormadinone acetate may be administered for 8 days, so administration should begin within
a maximum of 3 days following the beginning of proestrus [29].
1.4. Prolonged interestrous interval
Prolonged interestrous interval is dened as an interestrous period longer than 12 months.
While estrus repeats 12–13 months after the previous estrus (prolonged interestrous interval)
in some adult bitches, some are not observed to experience estrus again for a long time
(secondary anestrus). It should be kept in mind that the interestrous period is longer in breeds
such as the Basenji and Tibetan Masti compared to other breeds. Secondary anestrus may result
from hypothyroidism, administrations of hyperadrenocortisolism, hyperprolactinemia,
progesterone-secreting ovarian cysts, progestogen, androgenic or anabolic steroid substances,
systemic diseases, poor nutrition, or housing in an inappropriate environment. Thyroid
function should be evaluated rst in bitches with prolonged interestrous intervals. Cycles
typically return to normal when the underlying cause is treated [5].
Canine Medicine - Recent Topics and Advanced Research132

1.5. Prolonged estrus (persistent estrus)
The mean duration of estrus is 9 days in an adult dog, which may sometimes be prolonged up
to 3 weeks. Estrus of longer than 21 days with the absence of ovulation at the end of this long
period is dened as prolonged estrus. Prolonged estrus is related to persistent and elevated
estrogen levels, which remain continuously high during the estrous phase of the cycle. This
disorder is encountered frequently in younger bitches, especially during the second cycle [1].
The most important clinical signs of the continuation of estrus include cornication in vaginal
epithelial cells, continuation of the desire for copulation, vulvar edema and swelling, and
hyperemia in vaginal mucosa for longer than 21 days. The serum progesterone level is low,
while estrogen level is high.
Persistent estruses are usually related to an estrogen-releasing source, which may be an
anovulatory follicle, follicular cysts, or functional ovarian tumors (granulose cell tumors). The
follicles that develop in bitches receiving exogenous gonadotropins in order to experience
estrus may sometimes lead to prolonged estruses. Exogenous estrogen administration for the
treatment of urinary incontinence or vaginitis, hormone replacement therapy, and prevention
of undesired pregnancy may also cause persistent estruses. Persistent estrus may also develop
alongside tumors of the hypophysis or the hypothalamus or in a hepatic disease dened as
portosystemic shunting in which an abnormal vascular junction is formed between the hepatic
portal vein and the systemic circulation. In these cases, metabolism of estrogen in the liver is
impaired.
Determination that 90% or more of the cells in a vaginal smear specimen are permanently
cornied on cytological examination and nondetection of the normal increase in serum
progesterone levels (remaining within the preovulatory range <2 ng/mL) indicate prolonged
estrus. Detection of serum estrogen level is not a reliable method for diagnosis [1].
The rst step in treatment should include a determination of the source of estrogen causing
prolonged estrus. For this purpose, the ovaries should be examined ultrasonographically for
the presence of abnormal structures (e.g., ovarian cyst, granulose cell tumor); if ovarian
structures cannot be identied by ultrasonographic examination, exploratory laparotomy
should be performed, followed by biopsy, if required.
Follicles or follicular cysts causing prolonged estrus may heal spontaneously. If estrus is
determined to last longer than 3 weeks, interventions are recommended in order to prevent
bone marrow hypoplasia and/or pyometra. Treatment options should match the pet owner’s
expectations regarding having a puppy; if a puppy is not expected, ovariohysterectomy is the
best option.
Ovulation or luteinization may be obtained by GnRH or hCG injections into follicles if the pet
owner wants a puppy. hCG administration at a dose of 22 IU/kg via the intramuscular route
for 3 days and GnRH (gonadorelin) administration at a dose of 10 μg/kg via the intramuscular
route for 3 days are recommended. Copulation is not recommended, as the target of these
applications is not the induction of ovulation but rather the termination of the signs of
prolonged estrus [1]. Ovariohysterectomy is inevitable in cases in which no response is
obtained from medical applications and in prolonged estrus cases due to ovarian tumors [5].
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Megestrol acetate (Ovaban, Ovarid) may be applied to reduce the signs of prolonged estrus.
Low doses of megestrol acetate are recommended via the peroral route for 2 weeks. A dose of
0.1 mg/kg is proper for the rst week, and a dose of 0.05 mg/kg is proper for the second week.
Although progesterone treatment with megestrol acetate is eective in bitches with persistent
estrus, there is the potential to trigger the development of cystic endometrial hyperplasia.
Therefore, the treatment is contraindicated for bitches to be later considered for copulation. In
general, ovariohysterectomy is performed within 3 weeks after treatment with progesterone
in bitches with persistent estrus.
Bone-marrow suppression related to long-term estrogen toxicity may develop in bitches with
persistent estrus. Nonregenerative anemia and thrombocytopenia are observed in such
bitches [31]. Therefore, erythropoiesis-stimulating agents, such as synthetic erythropoietin,
darbepoetin, granulocyte-colony stimulating factor, and granulocyte-macrophage colony-
stimulating factor, may be used beside proper antibiotic and blood products in bitches that
have anemia due to bone-marrow suppression. In addition, lithium [30, 32], synthetic anabolic
steroids such as nandrolone decanoate (Deca-Durabolin), or a dihydrotestosterone derivative
such as stanozolol (Winstrol) can be quite useful [33, 34].
1.6. Prolonged proestrus (persistent proestrus)
Prolonged proestrus is dened as a proestrous phase that is not followed by an estrous phase
and that lasts 3 weeks or longer. In bitches with prolonged proestrus, estrus and ovulation do
not occur, as the estrogen level insuciently increases during the proestrous phase.
Prolonged hemorrhagic vaginal discharge, cornied cells higher than 50–90% on examination
of vaginal smear, and serum progesterone level remaining below 2 ng/mL indicate prolonged
proestrus. Treatment principles are similar to those for prolonged estrus.
1.7. Split estrus
Split estrus is a disorder in which no or quite short estrous signs develop despite the presence
of proestrous signs. In this situation, pregnancy usually does not develop even if copulation
occurs; the bitch is observed to enter proestrus again within 3–4 weeks. In these bitches, the
next cycle is usually a normal ovulatory cycle.
Split estrus is usually seen in young bitches that have shown rst estrus. However, continuous
or frequent split estruses should suggest chronic premature luteolysis or hypothyroidism. Split
estrus may be confused with recurrent estrus (short interestrous interval). Ovulation will not
develop in dogs showing split estrus but without the typical progesterone elevation. The
condition usually recovers spontaneously [1, 7].
1.8. Anovulatory cycle
A serum progesterone level not exceeding 2 ng/mL despite cytological estrous signs is dened
as anovulation. Although the cell type in vaginal cytology is noncornied, diestrous-specic
progesterone elevation does not occur, and the bitch enters anestrus.
Canine Medicine - Recent Topics and Advanced Research134

The most typical signs are low serum progesterone levels and the absence of ovulation during
the days after copulation in a bitch showing proestrous and estrous signs. Its incidence is about
1%. The following ovulatory cycles were observed to be normal in 45% of bitches that had an
anovulatory cycle [1, 21, 35].
Thus, treatment is usually not required in bitches with an anovulatory cycle. hCG or GnRH
may be administered, if desired; however, their application carries the potential to trigger
pyometra [1, 21].
2. Conclusion
There are many factors leading to abnormalities in the sexual cycle of bitches. A decent
anamnesis is required to nd out the causes of these abnormalities. Supporting the anamnesis
information by clinical and laboratory examinations is of importance for the accuracy of the
diagnosis. Vaginal cytology among the diagnostic methods should be used and interpreted
eciently. Accuracy of the diagnosis forms the rst step of an eective treatment. Uses of
hormones, particularly gonadotropins, come into prominence in the treatment of sexual
abnormalities in these animals.
Author details
Ali Risvanli*, Halis Ocal and Cahit Kalkan
*Address all correspondence to: arisvanli@rat.edu.tr
Department of Obstetrics and Gynecology, Faculty of Veterinary Medicine, University of Firat,
Elazig, Turkey
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