| Part 2: Infertility in the Bitch |
| Therapy aimed at terminating prolonged proestrus or estrus becomes necessary if spontaneous regression fails to occur, vaginal bleeding is a continuing nuisance, estrus behavior and the attraction of males is unacceptable, or other complicaations develop (blood loss, anemia, marrow dyscrasias, vaginal hyperplasia). Medical and sugical options exist for treatment of persistent pathologic follicular cysts. Medical therapies should not place the reproductive health of the bitch at risk: * Progesterone treatment of bitches with functional follicular cysts puts the bitch at increased risk for the development of cystic endometrial hyperplasia/ pyometra, and is not advised. * The use of GnRH (50-100ug/bitch IM every 24-48h for up to 3 doses) or human gonadotropin (hCG; 22 IU/kg, IM, every 24-48h) has been advocated as affective in inducing cyst regression or luteinization, although reported success rates for either vary. GnRH does not appear to be antigenic in the bitch, and may be the preferred treatment. Successful induction of cyst regression or lutenization is reflected by a reduction in vaginal discharge and vulval enlargement, change in vaginal cytology reflecting reduced estrogen effect, diminished attractiveness to males, and normalization of behavior. Serum estrogen concentrations fall, and increased progesterone concentrations can occur if luteinization results, but this is variable. Ultrasonographic monitoring of ovarian morphology shows regression of hypoechoic structures. It has been suggested, but not proven, that failure of medical therapies to resolve prolonged proestrus or estrus indicates that ovarian neoplasia is more likely than a follicular cyst. However, medical treatment of prolonged proestrus, or estrus is usually unrewarding and sugical removal of the cyst the most expedient means of managing the problem. Removal of the cyst alone is optimal, but resection of the associated ovary is usually necessary. Histologic evaluation of the removed tissue confims the diagnosis and, more importantly, permits evaluation for evidence of neoplasia that might warrant additional therapy and a different prognosis. Bitches exhibiting prolonged interestrus intervals may have prolongation of either anestrus or diestrus. Prolonged anestrus occurs when no ovarian activity occurs for longer than 16 to20 months in a bitch having previously experienced estrus cycles (secondary anestrus). An actual failure to continue to cycle must be differentiated from silent heats ( normal cycles not detected by the owner). Underlying disease and iatrogenic causes for failure to cycle should be ruled out by a careful history, physical examination and databse. The mechanism by which anestrus is normally terminated in the bitch is not well understood. Dopamine inhibits prolactin secretion and prolactin levels decrease from late diestrus to late anestrus. Both FSH and LH have been reported as the hormone initiating proestrus folliculogenesis. Dopamine agonists (cabergoline, bromocriptine) can be used to shorten anestrus in both the normal bitch and in bitches with secondary anestrus of unknown etiology. The mechanism by which dopamine agonists induce proestrus may be a direct reduction in prolactin levels or a direct dopaminergic action on either the gonadotrophic axis or on ovarian gonadotropin receptors. A bitch presented for evaluation of prolonged intervals between heat cycles may be under the influence of elevated progesterone concentrations (>2 to 5 ng/mL). When progesterone levels remain elevated for longer than 9 to 10 weeks, prolonged diestrus is probable. The clinical behavior of the bitch cannot be differentiated from one experiencing prolonged anestrus. The value of vaginal cytologies, serial serum progesterone levels and the ultrasonographic appearance of the ovaries and uterus become apparent in establishing a diagnosis. Prolonged diestrus can occur secondary to the presence of a luteinized (progesterone secreting) ovarian cyst. The progesterone presents negaive feedback to the pituitary/hypothalamic axis, preventing the stimulation of normal ovarian activity. Luteinized cysts can be single or multiple, involving one or both ovaries. Abdominal ultrasonography can identify hypoechoic structures within the affected ovaries and uterine wall changes resulting from prolonged progesterone exposure. Abdominal radiography rarely provides diagnostic information because the cysts are relatively small. Serum progesterone levels >2-5ng/mL confirm the diagnosis. Treatment with prostaglandin F2alpha usually causes only a transient decline in serum progesterone levels, indicating partial luteolysis. Surgical removal of the cyst with histologic analysis is the recommended treatment. Separation of the cyst from the affected ovary is optimal but is technically difficult, usually necessitating ovariectomy. Acquiring a uterine biopsy to evaluate the presence and extent of accompanying cystic endometrial hyperplasia is advisable, as it can provide valuable information to the owner concerning future fertility of the bitch, however, normal diestrual endometrial changes must be kept in mind, and evaluation in anestrus is likely to be more informative, but requires a second procedure. Cystic endometrial hyperlasia, if present, may resolve partially after elimination of the cyst. Nonfunctional ovarian cysts may cause failure to cycle due to their mass effect. Rete ovarii cysts and subsurface epithelial structure cysts are examples of such nonfunctional ovarian cysts. Increases in plasma estrogen or progesterone levels will not be identified, although these cysts have the potential to produce a wide variety of other steroidal compounds without systemic effect. This diagnosis, usually suspected using abdominal ultrasonography, is confirmed by histologic evaluation of surgically removed tissues. Premature ovarian failure can result in permanent anestrus. Although the functional longevity of the ovaries of bitches is not known, on average the decline in function would not be expected before 7-10 years of age. Prolonged anestrus due to premature ovarian failure could be supported by documenting markedly elevated FSH and LH concentrations as would be seen following ovariohysterectomy. Such increases indicate a lack of negative feedback to the pituitary and hypothalamus, without any other identifiable cause for anestrus. Immune mediated oophoritis, diagnosed by ovarian histopathology, could result in prolonged anestrus. A mononuclear infiltrate predominated by lymphocytes, plasma cells and macrophages has been reported to occur in both ovaries in a bitch experiencing estrus cycle abnormalities. This is an extremely rare disorder. Failure to cycle can occur with disorders of sexual differentiation. Hypothyroidism is a potential cause for failure to cycle; but the diagnosis should be well supported by other clinical signs (lethargy, weight gain, bilaterally symmetric alopecia) and clinical pathologic data, as well as confirmation of subnnormal serum thyroid (total T4 and free T4 by equilibrium dialysis) levels, ideally supported by elevated endogenous canine TSH levels. Hypothyroid bitches placed on adequate replacement therapy should begin to cycle within six months of becoming euthyroid. The breeding soundness of such bitches should be addressed with clients. Glucocorticoids can feedback on pituitary gonadotropins FSH and LH, causing a failure to cycle. Therefore, administration of any steroid medication must be discontinued in a bitch with prolonged anestrus. Bitches with short interestrus intervals (less than 4.5 months) can fail to conceive due to incomplete uterine involution and repair, precluding implantation and pregnancy maintenance. Classically, bitches experiencing shortened interestrus intervals are normal in other respects. Ovulation and lutenization occur, the secondary oocyte is fertilized but fails to implant successfully. Documentation of this disorder requires evaluation of serial vaginal cytology during estrus and diestrus, and serum progesterone levels during the luteal phase of at least 2 consecutive cycles. Currently, there is no reliable, commercially available, consistend pre-implantation method of confirming fertilization in the dog. The occurance of folliculogenesis without ovulation (split heat) and hypoluteiodism (premature luteal failure) shuld be ruled out. Shortened inestrus intervals occur because anestrus is abbreviated. A defect in the hypothalamic-pituitary-ovarian axis may exist, causing interference with the normal maintenance of anestrus, or an imbalance of dopamine versus prolactin levels have been theorized as contributing to this syndrome. Anestrus can be abbreviated clinically in the normal bitch by the administration of prolactin inhibitors such as cabergoline and bromocriptine. Intervention should not take place unless the bitch is older than 3 years, because these abnormalities may naturally resolve with maturity. One suggested therapy consists of prolonging anestrus through the use of megestrol acetate during the first three days of the impending estrus, but the use of progestational compounds in reproductively valuable bitches is risky due to the potential for inducing uterine pathology. Other causes of Infertility: Uterine disorders Uterine pathology, such as cystic endometrial hyperplasia (CEH), must be considered as a cause of infertility should all other possibilities be excluded. Interestingly, uterine disease is less of a problem in breeding establshments where bitches are bred and conceive oon a regular basis, as pregnancy may have a protective effect on the endometrium. Cystic endometrial hyperplasia is a hormonally dependent, predictable condition in the bitch that results from repeated cycles of progesterone stimulation inducing endometrial glandular proliferation and secretion. Glandular changes may be forcal or diffuse and may interfere with implantation and placentation. Pyometra can eventually result. Definitive diagnosis of CEH requires biopsy at an affected site. Ultra sonography of the uterus can be very helpful in evaluating the uterine wall structures over time. Hydrometra or mucometra can be precursors to CEH and subsequent pyometra. All three disorders care poor prognosis for fertility. Open cervix pyometra in a valuable breeding bitch in her prime can be treated with specific antibiotics and PGF2 induction of luteolysis and uterine evacuation (0.1mg/kg sc bid for 2 days, then 0.2mg/kg sc bid to effect). Breeding on the next cycle is advised. Infectious disease Infectious diseases (contagious and not) of the canine reproductive tract can occasionally be responsible for infertility and should be investigated early in the diagnostic work up, as contagion may be a problem in addition to the infertility. Bacterial infection such as Brucella Canis, salmonella, streptococci and Eschericha coli species, viral infection (herpes, distemper, parvovirus 1 and 2) and parasitic disease (toxoplasma gondii and neospora caninum) have been implicated as causes of infertility in the bitch. Idiopathic infertility Physiologic processes that control folliculogenesis in the bitch are complex and involve precise, minute amounts of hypothalamic and pituitary hormones that are sensitively controlled by the ovarian feedback loop. To interrupt the hypothalamic-pituitary-ovarian axis pharmacologically usually leads to dysfunction rather than an augmentation of the system. The rational administration of GnRH requires pulsatile administration, the use of GnRH analogues results in down-regulation, and the use of gonadotropins is largely unsuccessful to induce fertile estrus in known fertile bitches. There is no evidence to support the use of these homones in bitches with a history of infertility or decreased fecundity. Careful evaluation of the underlying causes of infertility and optimal breeding management/husbandry with ovulation timing is instead recommended. |