USE OF HORMONES IN CANINE REPRODUCTION
- S. K. Harichandan Ray, Ex- Prof. & Head, Deptt. of Animal Reproduction , Gynaecology & Obstetrics.
College of Veterinary Science and Animal Husbandry, O.U.A.T., Bhubaneswar-3
The reproductive processes of animals are primarily under endocrine control. Need based application of hormonal therapies to circumvent reproductive problems of animals require thorough knowledge about various endogenous reproductive hormones and their specific physiological role in performing various reproductive events pertinent to the species.
Reproductive activity in the bitch differs from polycyclic pattern of other animal species both clinically and physiologically. Initiation of estrus cycle is suggestive of attainment of puberty while it is basically regulated by complex interaction of hypothalamus-pituitary -ovarian axis. Unlike other species, the endogenous endocrine profile and their specific role in canine differs in many aspects for controlling estrus cycle and pregnancy. Generally bitches are considered monocyclic although many of them exhibit more than one estrus cycle in a year with marginal seasonal effect. The age of attainment of puberty varies between 6 to 30 month with late onset of puberty in larger breeds. The reproductive or estrous cycle of domestic dog (Canis familiaris) is classified into four phases i.e. proestrus, estrus, diestrus and anestrus. The first two phases are conspicuous and appreciable due to their clinical and physiological significance and express average duration of 9 days each. The diestrus phase roughly starts from ceassation of behavioral estrus in concurrence with rising level of progesterone and last about 75 days (60-90). Anestrus is the quiescent and functionless phase of estrus cycle with no reproductive activities with an average duratio of 125 days (15-265). In bitch the initiation of proestrus and late proestrus is under the influence of estrogen (17-â estradiol). Contrary to other species the bitch becomes receptive to male with rising level of progesterone along with receding estradiol. In bitch , prolactin maintains corpus luteum activity (luteotrophic ) in late diestrus both in pregnant and non pregnant bitches and physiologically uterine PGF2á may not be responsible for maintenance or regression of the corpora luteum in bitch. Moreover the pregnancy is basically maintained by luteal progesterone with tropic support from pituitary LH and prolactin in 2nd half of pregnancy.
With this preamble, exogenous administration of hormone in the dogs and bitches in the context of canine reproductive has been highlighted. Generally some steroid hormones or their analogues were routinely used in the control of canine reproduction and to resolve some pathological disorders. However, recently prostaglandin and hormones and anabolic agents have given a new dimension as a novel therapy to treat various reproductive disorders, pregnancy termination and estrus control. While treating canine patients many factors such as age, breed, breeding history, possible side effects and attitude of owner should be considered rationally before instituting hormonal therapy.
Induction of ovulatory estrus and its anomalies.
Estrus Induction:
Natural estrus expression requires synchronized action of hypothalamic pituitary –gonadal hormones. On the basis of this analogy various hormonal products or their analogs were attempted to mimic natural process to induce estrus and pregnancy. The most effective drug protocols to induce fertile estrus are suggested.
PMSG(eCG) and HCG (nCG) protocol
- 500-1000 iu PMSG i/m repeated after 6
- PMSG 20 IU i/m daily for 5 days and hCG 500 IU i/m on 6th Pretreatment with estrogen (estradiol 100 mg daily i/m for 5 days) showed better conception rate.
- Estrogen DES (Diethyl Stilbosterol) 5mg orally for 6 to 9 days (not recommended)
- GnRH analogues 25 µg s/c every 190 minutes for 11 days
- HCG + GnRH
HCG9(500 – 1000) IU i/m for two days followed by GnRH 50µg i/m daily for two days
- Dopamine agonist
- Bromocriptine 20µg/kg/bid/orally X 21 days
- Cabergoline 5µg/kg/once daily/orally X 7-10 days (pregnancy induced in 93%.)
Persistent estrus:
Defined as combined duration of proestrus and estrus is more than 6 weeks. This condition may arised due to prolonged estrogenic activity, functional ovarian follicular cysts and granulosa cell tumour . It may lead to bone marrow depression, anemia, leucopenia thrombocytopenia and cystic endometrial hyperplasia. LH or Progesterone treatment may resolve prolonged estrogenic activity.
Irregular estrus:
Endometrial involution and repair takes 130-150 days. Inter estrus interval less than 4 months usually infertile.
Causes – Hereditary, uterine disease and ovarian cyst.
Treatment: ( The aim of this therapy is to induce temporary anestrum.)
Mibolerone- 30µg/10kg/orally or Testosterone (0.5µg/kg/i/m at 5 days interval.
Primary anestrum denotes lack of estrus exhibition by 24 months of age. Hormonal assay of bitches show elevation of both FSH (>290 ng/ml) and LH (>200 ng/ml) indicating lack of negative feed back from ovarian steroid.
Incase of normal /intact bitches the same drug protocol may be used to induce estrus.
Silent heat:
Iin bitches it may be defined as no manifestation estrus symptoms including proestrus and male attraction, even though the animal possesses cyclic ovaries. In this condition progesterone level is more than 2ng/ml indicating functional ovary.
Estrogen therapy may induce overt heat symptoms.
Primary anestrum may precipitate due to hypothyroidism, which is a common cause of infertility. Anestrum, prolonged inter estrus interval, abortion, mummification and stillbirth are common gynecological complications.
Diagnosis – Assay of T4 ( T4D) and TSH in blood.
Treatment – Lthyroxine (0.01 to 0.02 mg/kg) orally twice daily with regular hormonal assay.
Drug induced anestrus :
Bitches receiving either androgen , progesterone or glucocorticoids for a long duration may not exhibit estrus symptoms. Withdrawal of inciting agents may cause recovery.
Secondary anestrus :
Prolongation of inter estrus interval or fails to cycle by 10 to 18 months of previous cycle. Estrus may be induced by hormonal applications such as FSH & LH.
Estrus suppression:
Progestin :
Megestrol acetate – 0.55 mg/kg /once daily orally 7 days prior to expected proestrus for 32 days. Or 2.2 mg/kg/once daily orally after onset early proestrus for 8 days.
Megestrol acetate for 3 days (2.2 mg/kg/orally) prior to mating will prevent conception. MPA( Medroxy progesterone) 2mg/kg/i/m every three month in anestrus period.
Proligestrone- the drug has antigonado-tropic properties.
Dose 30mg/kg/s/c to be repeated after 3 months and later every five months.
Androgens :
Mibolerone- Dose- 30 to 80 µg orally for 30 days or more could suppress estrus. On discontinuation the bitch returns to estrus.
Testosterone :
Dose- 100 mg testosterone propionate i/m once weekly and 25 to 50 mg (methyltestosterone) orally twice in a week could prevent estrus expression.
GnRH agonist :
Implants could prevent attainment puberty and suppress estrus expression in cyclic bitches.
Mismating:
Avoiding an unwanted pregnancy is best accomplished by preventing the access of fertile male to bitch. In bitch fertilization is nearly 100 percent and it is difficult to terminate pregnancy once the embryo is implanted. If accidental mating occurs the animal should be presented within 72 hrs post coitus for prevention of pregnancy.
Treatment:
Estrogens:
- DES (diethyl stilbosterol) 1 mg/kg orally for 3to 5 days.
- Estradiol benzoate – Dose – 01 mg/kg/i/m or s/c on day 3,5, & 7 after mating .
- Estradiol valerate 1mg/kg/i/m (should not exceed 3.0 mg)once
- Tamoxyfen citrate (Estrogenic activity in bitch)
Dose- 1mg/kg/twice daily /,,,,,,,,,,,,, / 10 days at late proestrus or estrus. It prevents conception or transportation of ovum to the uterus.
Termination of pregnancy:
Treatment:
PGF2á (lutalyse)
Dose- 20 µg/kg bodywt / s/c thrice daily . or
150-200 µg s/c twice daily till the pregnancy terminates.
(5 to 21 days of pregnancy could be terminated by above therapy) Cloprostenol- (for 14 to 28 days of pregnancy )
Dose- 10µg/kg /intravaginally
or
2.5 µg/kg/s/c three times a day till the pregnancy is terminated. How ever PGF2á not effective in vey early pregnancy (1-10 days).
Glucocorticoids (Late gestation)
Dexamethasone- 5mg i/m twice daily for 10 days. Or
Dexamethosone- 0.1 to 0.2 mg/kg body wt. orally /twice daily X 5 days followed by decreasing dose up to 10 days.
The oral therapy may be given along with PGF2á (250 µg/kg/s/c twice daily)
Prolactin inhibitors (25 to 40 days termination)
Bromocriptine- 20 to 100 µg/kg body wt/orally for 4 to 7 days. Cabergoline – 1.65 to 5.0µg/kg/once daily orally or s/c for 5 days.
Pre treatment with PGF2á (coloprostenol or lutalyse) for 3 days followed by Cabergoline could induce abortion in 100 percent of cases.
Mifepristone – (Ru 486)- it is generally used as abortificant drug in human female
Dose- 2.5 mg/kg/orally twice daily for 4-5 days and could terminate canine pregnancy at 32 days and abortion occurs 3-5 days following treatment . Higher doses (10-20mg/kg body wt.) could terminate early pregnancy (10-26 days)
Hormonal infertility:
Anovulation : Administration of hcg (25 IU/kg/i/m) will induce ovulation in bitches at mid estrus,
consistent with the rising of progesterone (>1µg/ml)
Hypoluteoidism (Lutal deficiency) – Pregnancy is maintained by luteal progesterone and should be more than 2ng/ml. Less than this level will terminate pregnancy indicating luteal insufficiency.
Progesterone in oil 8 mg/kg body wt/i/m at 48 hrs interval and should be discontinued 1 week before expected date of parturition.
Ovarian follicular cyst (anovulatory):
Treatment:
Surgical removal of ovary or ovario hysterectomy (OHE) most effective.
Hormonal treatment
GnRH (50µg/i/m) as a single dose or two does LH (500 IU) through intra-muscular route
at 48 hrs. interval may be effective in some cases.
Cystic endometrial hyperplasia -pyometra complex (CEH- Pyometra)
It is a progesterone mediated uterine disease associated with bacterial colonization and retained corpus luteum. Treatment of such cases involves surgical (ovario hysterectomy) and medicinal approach. The PGF2á is most preferred drug of choice which causes luteolysis, myo-
metrial contraction, cervical relaxation and expulsion of pyomic content.
Treatment- serum progesterone should be measured prior to treatment
Lutalyse- 100 µg/kg body wt/s/c TID for two days followed by 200 µg/kg/s/c once for 2-7 days or until the uterus size returns to normal (Progesterone should be >1ng/ml).
If the serum progesterone is less than 1ng/ml lutalyse 200 µg/kg/s/c once or twice daily for
2 to 7 days.
In both types, antibiotics and other supportive treatment is indicated until cleared clinically.
Other anomalies:
Expulsion of foetus, uterine inertia, post partum haemorrhage ,post partum endommetritis, retention of fetal membranes and milk obstruction may be treated with Oxytocin , which induces contraction of smooth muscle of uterus and mammary gland. Oxytocin is contraindicated in obstructive dystokia
Oxytocin 5-10 IU given as intravenous drip or repeated small doses in case of uterine inertia since it may result in uterine rupture.
Vaginal prolapse:
Prolonged estrogenic stimulation during late proestrus and estrus lead to vaginal prolapse with higher incidence in large breeds.
Spontaneous regression occurs following ovulation with concurrent rise in LH Treatment-
GnRH (2.2 µg/kg/im) or hCG (500-1000 IU/im) will induce ovulation and suppression of
prolapse by 7 days.
Other reproductive anomalies Pseudopregnancy/ pseudocyesis Urinary inconsistency-
Following ovario hystectomy (OHE) many bitches suffer from micturition difficulty. Estrogen treatment for a short duration may relieve micturition difficulty.
Mammary neoplassia:
Testosterone or Tamoxifen(estrogen receptor blocker) may reduce its progression.
Tamoxifen at the dose rate of 0.5 to 1 mg/kg body wt. /orally once daily proved to be more effective.
Adverse Effect of Hormonal Therapy:
Estrogen:-
Bone marrow depression, Applastic anemia , leucopenia, thrombocytopenia, bleeding into body cavities, endometritis , cystic endometrial hyperplasia, pyometra and dibetes.
Progesterone:-
Increased appetite , weight gain , lethargy ,mammary development , masculinization of fetus, adrenal suppression, pyometra, acromegaly and mammary tumors.
Androgen:-
Clitorial hypertrophy, thick vaginal discharge, increased mounting, aggressive behavior and masculinization of female fetus.
PGF2á :-
Vomition, hypersalivation, anorexia, defecation, polyurea, polydipsia, dehydration and lactation. Side effect is minimized by giving atropine sulphate (0.025 mg/kg i/m ) 15 minutes prior to PG treatment.
Bromo criptine:
Vomition & anorexia
Conclusion :
There is no area of veterinary therapeutics in which there is a greater uncertainty than the use of drug specifically hormones in breeding canine species and risk is far greater while treating pregnant animals. Hormonal treatment behaves as two edged weapon and individual idiosyncrasies are not ruled out. Hence hormonal treatment may be undertaken with utmost caution following rational evaluation of requirement and post treatment side effect.
