An Overview of Bovine Cystic Ovarian Disease

Abdullah Channo1*, Asmatullah Kaka1, Qudratullah Kalwar2, Imdadullah Jamali3, Ghulam Jelani2, Muhammad Bakhsh4, Ghulam Nabi Dahri5 and Jai Parkash Goil6 1Department of Animal Reproduction, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University, Tandojam, 70060 2Shaheed Benazir Bhutto University of Veterinary and Animal Sciences, Sakrand, 67210 3Department of Veterinary Pathology, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University, Tandojam, 70060 4Faculty of Veterinary Sciences, College of Veterinary and Animal Sciences, Jhang, 35200, UVAS Lahore, Pakistan 5Directorate of Animal Husbandry, Livestock and Fisheries Department, Hyderabad, Government of Sindh. 6Department of Animal Breeding, Livestock and Fisheries Department, Hyderabad, Government of Sindh Article Information Received 05 September 2021 Revised 03 December 2021 Accepted 15 December 2021 Available online 16 March 2022 (early access)


INTRODUCTION
T he fertility of animals is necessary for reproduction and it depends on the neuroendocrine function. Many factorsaffect the hypothalamus, pituitary, and ovary function that causes decrease infertility outcomes (Kovács et al., 2020). In good-yielding dairy animals, alteration infertility occurs by the reproductive disorder (mainly normal ovarian activity) (Mimoune et al., 2020;Szenci et al., 2018). The reproductive disease of animals increases the calving interval, low conception rate, improper sexual behavior that causes high economic loss of industrial and non-industrial farms (Cattaneo et al., 2014). In dairy animals, cystic ovarian disease (COD) is an influential reproductive dysfunction (Yimer et al., 2018). It has been reported in several species of animal such as ruminants, humans, bitches and rodents (Francou et al., 2008). COD is an exceeding reproductive disorder that causesa prolonged open period after parturition (Gobikrushanth et al., 2016). In high producing animals, COD causes subfertility, increasing postpartum open periods, and reduced reproductive performancethat causes huge economic loss in the dairy industry (Ortega et al.,

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2015; Garverick, 1997;Stassi et al., 2019;Sayad et al., 2019;Keslerand Garverick, 1982;Xu et al., 2021). The frequency of COD in cattle ranges from 5-30% in all reproductive diseases (Silvia et al., 2005). Reproductive disorder cystic ovarian degeneration has 10-13% prevalence that affects on the fertility level and causes high economic loss (Johnson and Coates, 2004). In 60% of cows follicular cyst develops before first ovulation and as parturition occurs (Peter, 2004;Mimoune et al., 2019). Alteration in normal ovulation and follicular development occurs by cystic ovarian (Ortega et al., 2016). Anovulation of dominant follicle occurred by cystic structure on ovary that interfere with normal ovarian function during estrous cycle (Peter, 2004;Ortega et al., 2015;Stassi et al., 2019). Ovarian cyst is a bladderlike watery-filled structure of about 25mm on ovary that remains for more than 10 days (Lüttgenau et al., 2016;Mimoune et al., 2020;Coleman, 2008;Polat et al., 2015). On ovary, one or more ovarian cyst (follicular and luteal) with size greater than 20mm in diameter in lack of corpus luteum formation. The wall of follicular cyst is less than 3mm and greater than 3mm in luteal cyst (Lüttgenau et al., 2016;Todoroki et al., 2001;Vanholder et al., 2006). The diagnosis of follicular and luteal cyst is very difficult in field condition (Probo et al., 2011;Gaebler et al., 2015). Heredity, body condition score, lactation period, seasonality effect, phytoestrogen, milk fever, metritis and retention of fetal membrane are included as the cause in the occurrence of COD (Canttaneo et al., 2014). Vanholder et al. (2006) have reported the relationship in between the mechanism of postpartum COD and endometritis. Plasma progesterone concentration in follicular cyst is less than 1ng/ml, whereas in luteal cyst it is greater than 1ng/ ml (Vanholder et al., 2006). Recently it is reported that in case of follicular cyst in cows, serum progesterone and estradiol concentration is 0-1ng/ml and 0-5pg/ml while its range is 8-9ng/ml and 15-20pg/ml in luteal cyst (Brodzki et al., 2019).
The basic purpose of this review is to reveal about COD incidence, economic loss, causes, manage mental techniques of the basic reproductive disorder that cause low production of animals in milk, meat etc.

INCIDENCE OF CYSTIC OVARIAN DISEASE
The COD incidence in milking animals has been reported from 5% to 30%, which are occurred due to improper management system, the prevalence of this disease occurred is mostly associated with heredity, age, high milk production, body condition score, lactation period, seasons, retained placenta, stress, metabolic disorders and hormonal imbalance (Cattáneo et al., 2014). COD is generally at highest from 30 to 60 days of postpartum (Kim et al., 2005). COD has occurred with increases of parity which may be associated with physiological and pathological conditions which leads to an increase in parity, such as parturient paresis or milk fever (Fleischer et al., 2001). Another incidence is the selection, because most of farmers choose high milk yield animals which affects genetics and its surrounding environment may also lead to COD mostly in last lactation (Vanholder et al., 2006). Herd size and housing may produce negative impact on the reproduction of animals and lead to COD because of limitations in their natural performance in herds such as in free stalls (Simensen et al., 2010;Nelson et al., 2010). Seasons such as in autumn and winter calving season, the occurrence of COD is higher as compared to spring and summer calving season (Peter, 2004;Cattáneo et al., 2014). Nutritional management, stress, infectious diseases, decrease level of insulin in blood and increase level of blood cortisol which leads to COD (Jafari et al., 2015;Silvia et al., 2002). Decreased level or absence of luteinizing hormone (LH) may also lead to the occurrence of COD (Mimoune et al., 2019).

PATHOGENESIS
Due to complex disorder and clinical signs, exact pathogenesis of COD is unknown (Vanholder et al., 2006). In COD, pathogenesis depends on the abnormality in neuroendocrine reflex of the hypothalamic pituitary gonadal axis (Noakes et al., 2001;Scully et al., 2021). And also in COD pathogenesis, molecular alteration in growing follicle is key component (Çolakoğlu et al., 2021;Stassi et al., 2019). It is difficult to differentiate in follicular and luteal cyst diagnosis in field condition so GnRH over prostaglandin recommended for treatment (Bors et al., 2018).

Hypothalamic-pituitary dysfunction
Hypothalamic-pituitary gonadal axis has a great role to maintain endocrine balance for normal follicular growth, rupture of the follicle and ovulation at a time (Marelli, 2014). For ovulations, a reproductive mother hormone gonadotropin-releasing hormone (GnRH) causes discharge of luteinizing hormone (LH). While, granulosa cells, inflammatory process and dysfunction of follicle cellular components have key role in cyst formation (Silvia et al., 2002;Yoshioka et al., 1996;Matiller et al., 2014;Baravalle et al., 2015). In COD hypothalamus show an unusual response by releasing of high estradiol by which concentration of progesterone in blood circulation is increased (Diaz et al., 2015). By endogenous and exogenous factor hormonal imbalance of hypothalamic-pituitary gonadal axis occur O n l i n e

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that formed the ovarian cyst (Silva et al., 2002;Cook et al., 1991;Xu et al., 2021). Alteration of preovulatory LH surge from hypothalamus-pituitary dysfunction leads to the formation of cyst on dominant follicle (Yoshioka et al., 1996;Vanholder et al., 2005). During follicular growth follicle are not able to ovulate then an unusual response of estradiol feedback from hypothalamus occurs and that results in cyst formation (Giimen and Wiltbank, 2002;Vanholder et al., 2006). Cystic follicle have less reactive oxygen species (ROS) comparison to normally ovulating follicles for inflammatory reactions during ovulation (Rizzo et al., 2009).

Ovarian/ follicular dysfunction
In cyst formation, alteration in preovulatory LH surge and steroid hormone production have great role (Mimoune et al., 2017). Lack of LH receptors in granulosa cells and theca cell of ovary and irregular response of follicular cells to the preovulatory LH surge is included in cyst formation (Shimizu et al., 2018). In cyst formation leutinizinghormone have great role. By the absence of preovulatory LH surge, alteration in maturion of dominant follicle occurred that altered to cyst formation (Lima et al., 2019;Yoshioka et al., 1996). Intermediate progesterone concentration in blood circulation can cause cystic ovaries (Silva et al., 2002;Hatler et al., 2003;Dhara and Sharma, 2019). Hormonal receptors have a key role for the hormone to perform the function at proper cite (Robker et al., 2000). Lack of steroid receptor (follicle-stimulating hormone receptor, estrogen receptor, leutinizing hormone receptor) is included in the molecular pathogenesis of bovine ovarian cyst (Marelli et al., 2014;Salvetti et al., 2010). Negative energy balance occurs by imbalance of energy intake and production that effects on ovarian function by hormonal and metabolic alteration can cause COD (Opsomer et al., 2000). Low insulin-like growth factor-1 and insulin in early days after parturition results in an-ovulation and cystic ovarian follicular development (Zulu et al., 2002;Vanholder et al., 2005) (Fig. 1).

Losses due to COD
The main loss that occurred due to COD is a reduction in reproductive performance which affectsthe fertility of animals by disturbing the normal ovarian cycle, failure of successful ovulation, increased interval between parturition and conception (Isobe, 2007), low conception rate, decrease in calving rate, increase in number of inseminations at each conception and because of this condition animals have been eliminated by culling from the herd which leads to financial loss to farmers (Sayad et al., 2019;Ismail et al., 2017;Hooijer et al., 2001).

DIAGNOSIS
The fertility of the dairy animals in the postpartum period is very important in terms of economics and dairy herd management. In this period, COD is very common without clear signs and symptoms. COD is one of the most important ovarian disorders, affecting the modern dairy cattle breeds. Most of the time, this disease is diagnosed without obvious signs, in recent times (Vanholder et al., 2006). The diagnosis of COD at farm can be observed by animal behavioral changes, frequent, intermittent, extended or continuous signs of estrus called nymphomania and anestrus, repeat breeding, pelvic ligament relaxation, tails head elevation and in chronic condition masculine characteristics may be observed in bovines (Bartolome et al., 2005;Brito and Palmer, 2004).
The cyst is a fluid-filled structure present on the ovary and can be detected by manual palpation through rectum of the animal. The follicular cysts are thin walled while the luteal cysts are thick. Ovaries can be examined ultrasonographically and a non-echogenic area of at least 25 mm diameter is present there. The follicular cyst has non-echogenic antrum and thin walled <3 mm while the luteal cysts has gray patches within antrum and a wall of <3 mm thick in diameter. An electronic caliper is used to Cystic Ovarian Disease

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measure the internal diameters of the cysts (Douthwaite and Dobson, 2000). For the confirmation and effective diagnosis of COD, Rectal palpation and the trans-rectal ultrasonography have been used and progesterone level in plasma and milk are analyzed by using kits of progesterone assay, mostly veterinarians rely on trans-rectal palpation and trans-rectal ultrasonography in the field with accuracy which ranges from 75-95%. (Borș et al., 2018;Peter, 2004). There is about 74% of follicular cysts and 85% of luteal cysts that could have been interpreted with accuracy by using ultrasonography (Hanzen et al., 2000). The cyst thickness is correlated in plasma progesterone concentration (Peter, 2004). The cyst wall thickness is analysed by using ultrasonography and the size of ovaries is diagnosed by rectal palpation, rectal palpation is the convenient technique which is mostly followed by veterinarians to diagnose COD in animal (Tebble et al., 2001).

TREATMENT OF CYSTIC OVARIAN DISEASE
There are so many efforts that have been taken to treat COD effectively to control financial losses which have been faced by farmers as a result of this disease (Stassi et al., 2019). Before the first postpartum ovulation, about 60 % of the cows recover at their own place (Peter, 1997(Peter, , 2000Woolums, 1994;Kesler and Garverick, 1982). Manual rupture, injection of ovarian extract, injection of CL extract, ovariectomy, antibiotics infusion, and injections of adrenaline chloride and pituitrin are some of the oldest forms of treating COD. Administration of GnRH alone usually results in the luteinizing the cyst and the animal shows estrous within 4 weeks. The epidural injection of lecirelin (GnRH analog) is good for reproductive improvements (Jeengar et al., 2018).
According to a research report, prostaglandin F2-alpha (PGF2α) is the most effective treatment and used because of its luteolytic activity and the animal shows estrous signs within 2-3 days (Probo et al., 2011;Brito and Palmer, 2004). In addition, to treat COD ultrasonography should be done to diagnose the type of cyst such as follicular cysts and luteal cysts, the luteal cysts should be better treated by using dinoprost (prostaglandin F2-alpha or PGF2α) or gonadotrophin releasing hormone (GnRH) analogues, whereas follicular cysts should be better treated by using with buserelin acetate (GnRH) agonist or human chorionic gonadotropin (hCG). At the farm, if an ultrasonography facility would not be available to diagnose the type of ovarian cysts, then mostly gonadotrophin releasing hormone (GnRH) has been recommended to treat COD (Borș et al., 2018;De Rensis et al., 2010). Furthermore, the COD is treated by giving GnRH followed by giving PGF2α after 10 days of GnRH, highest recovery of COD has been observed which was about 87% and the pregnancy rate was recorded about 65.21% in treated animals. Mostly farmers culled their animals which are infected by COD, that's why to avoid culling, cases of COD should be treated by applying other treatment procedures such as ovsynch synchronization protocol, Ovsynch+CIDR synchronization protocol and CIDR-GnRH-PGF2α or potassium iodide which have equal efficacy against COD (Khalil, 2019;Ismail et al., 2017;Bartolome et al., 2005).
Progesterone releasing intra-vaginal devices (PRID) with estradiol-benzoate combination for 12 days are also effective therapy against COD in postpartum animals, whereas instead of PGF2α, progesterone is mostly used for the process of estrus synchronization after collection of embryo, resulting in the COD developing chances in animal decreased from ~25% to <3%. The suggested drugs dose and protocols are also described in Table I to treat COD (Brito and Palmer, 2004;Hatler et al., 2003;Zulu et al., 2003). (1) GnRH (or hCG) + PGF2α (day 0); PGF2α (day 9 if no estrus) (2) Ovsynch: GnRH (day 0); PGF2α (day 7); GnRH (day 9); fixed-time AI, 16 h after last GnRH treatment (3) Progesterone implant for 12 days (not for dairy cows) COD can be treated by using homeopathic drugs such as homeopathic Apis which is prepared from Apis mellifica that is common homeopathic medicine obtained and manufactured from female honeybee, it is used to treat the right side ovarian cyst while homeopathic Lachesis which is prepared from the fresh venom of south American snake called bushmaster, is used to treat left side ovarian cyst, this treatment have been used twice (BID: bis in die) in a day daily for 5 days. Another homeopathic drug homeopathic Natrum Mur which is prepared from sodium chloride, or table salt, which is used twice in a day for 3 days for O n l i n e

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Cystic Ovarian Disease 5 effective treatment of COD. In addition, botanical herb called heat seek made 10 tablets can be given orally every other day, twelve doses for 24 days to enhance the estrus signs, while manual rupture of cysts is not recommended because this procedure cause trauma and haemorrhage which leads to a reduction in fertility (Teshome et al., 2016).

CONCLUSION
This review reveals the major reproductive disorder ovarian cyst (follicular and luteal cyst) in a high-yielding dairy animal. It involves the knowledge of molecular factors for the complex pathogenesis of COD. It also helps the clinician to diagnose, manage mental techniques and treatment for COD in cattle. While, strategies to reduce the incidence of postpartum disease mainly ovarian cyst by better management. The different definitions and diagnostic methods used for the pathology are accessible, with the value of each hormonal treatment. This leads the veterinary practitioner to the best therapeutic choices. It also helps to maintain animal body condition score that is the key factor to reduce the metabolic disorder and other reproduction disorders before and after parturition. Further elucidation of the complex pathogenesis of the disease will continue to improve our capacity to prevent, diagnose, and treat COD.

ACKNOWLEDGEMENT
The Author cordially acknowledges to Dr. Asmatullah Kaka (Assistant Professor, Department of Animal Reproduction, Faculty of Animal Husbandry and Veterinary Sciences, Sindh Agriculture University, Tandojam, 70060) and Dr. Qudratullah Kalwar (Assistant Professor, Shaheed Benazir Bhutto University of Veterinary and Animal Sciences Sakrand, 67210) for their kind support and inspiration.

Statement of conflict of interest
The authors have declared no conflict of interest.