Urinary incontinence after gonadectomy is a condition first reported in 1965, characterized by the involuntary loss of urine following removal of the gonads. The disease is particularly frequent in countries where gonadectomy is performed on a large scale for birth control and to keep the number of stray animals under control. The disorder is rarely seen in the queen, or in male subjects, and over 90% of cases are found in neutered, female dogs.
AETIOPATHOGENESIS
To better understand the mechanisms that cause urinary incontinence, it is first necessary to briefly consider the normal status of urinary continence. Continence results from the combined effect of anatomical and functional factors that allow a normal deposition of urine in the bladder, the contraction of the bladder neck and closure of the urethra. The latter is controlled by the sympathetic nervous system via a connection between the alpha-adrenergic receptors of the urethra and the hypogastric nerve. Urethral closure is also regulated by other non-urethral factors, such as skeletal muscles, periurethral collagen and the blood supply of the urethral mucosa. It has recently been demonstrated, however, that in the periurethral tissues of sexually intact and gonadectomised female cats, the ratio between type I and type III collagen does not differ, unlike what is observed in menopausal versus pre-menopausal women. This consequently rules out any involvement of pelvic organ support mechanisms in the urinary incontinence of the female cat after gonadectomy.
Urinary incontinence may be caused by damage to the mechanisms of urine deposition, bladder neck closure or urethral release. Damage to the urethral mechanism of urine release is known as "incompetence of the urethral sphincter"; this can be congenital or acquired, and is the leading cause of urinary incontinence in the dog. In the bitch, urinary incontinence after gonadectomy is a complex form, involving several components, including the acquired incompetence of the urethral sphincter. In fact, gonadectomy is responsible for a reduction in the urethral closing pressure, with pressure values that go below the normal threshold within 12 months after surgery.
In dogs suffering from incontinence after gonadectomy, urinary bladder instability is often reported together with the incompetence of the urethral sphincter. In addition, gonadectomy modifies the turnover of various extracellular matrix components in the periurethral tissues. The ratio between collagen and muscle tissue plays an important role in the function of the lower urinary tract and is significantly different in gonadectomised versus non-ganadectomised animals as well as in different genders. In fact, gonadectomy determines a reduction in the muscle component and an increase in collagen and, irrespective of the gonadectomy, females have a higher proportion of collagen and a lower proportion of muscle tissue, compared to males. The excessive collagen deposit and inferior muscle component might therefore be involved in the modification of the structural and functional integrity of the lower urinary tract and become associated with the development of urinary incontinence after gonadectomy.
The involuntary loss of urine, typical of the condition of urinary incontinence, is frequently found in menopausal women and in female dogs undergoing the surgical removal of the ovaries. These two situations are both characterized by a reduction in the production of oestrogens; for this reason, oestrogens were thought to have a role in the regulation of the urethral sphincter closing mechanism, an assumption confirmed by the presence of oestrogen receptors at the level of the urethral sphincter and by the effectiveness of oestrogen replacement therapy in women and in female dogs. The role of oestrogens appears to be multifactorial, acting also by increasing the sensitivity of alpha-adrenergic receptors to catecholamines and thus helping to improve the urethral sphincter function. Sex steroid receptors were also localized at encephalic level, in the areas involved in the process of urination.
After the first report in 1965, there have been numerous reports on the association between removal of the ovaries and urinary incontinence in the female cat. In the last decade, in the bitch, the role of urethral sphincter incompetence in the pathogenesis of urinary incontinence after gonadectomy has been confirmed. Gonadectomy does in fact cause a reduction in the urethral closing pressure, compared to non-gonadectomised subjects, which is more evident in those cases which then develop incontinence (18.1 vs. 10.3 vs. 4.6 cm H2O, respectively). In reproductive physiology it is known that FSH (follicle stimulating hormone) and LH (luteinizing hormone) gonadotropins, produced by the pituitary gland upon stimulation of the GnRH (gonadotropin releasing hormone), act on the gonads which, in turn, control, through the so-called "feedback" mechanism, the release of GnRH and of the gonadotropins themselves, through the production of various hormones, including oestrogens and progesterone.
It is known that gonadectomy, by altering the feedback control of the hypothalamic-pituitary-gonadal axis, results in an increase of LH and FSH gonadotropins in circulation, which, in the bitch, stabilize, 42 weeks after ovariectomy, at levels 17 and 14 times greater than the normal levels of FSH and LH respectively. The absence of a feedback control of ovarian steroids in relation to the hypothalamic-pituitary axis and the concomitant reduction in the urethral closing pressure of female dogs subjected to gonadectomy led to the hypothesis that there could be an influence of the high levels of gonadotropins on the urethral sphincter function, setting the basis for pituitary desensitization as a possible treatment option for urinary incontinence after gonadectomy.
However, the attempt to correlate the reduction in the urethral closing pressure to the concentrations of circulating gonadotropins has not been demonstrated, thus making it impossible to find a cause-effect relationship between the elevated levels of gonadotropins and the urethral sphincter incompetence acquired after gonadectomy. It would seem instead that the positive effect resulting from the administration of GnRH for urinary incontinence after gonadectomy can be attributed to an increase in the bladder threshold volume, thereby modulating the intrinsic properties of the organ. It has also been suggested that there may be a direct hormonal effect on the bladder, in view of the demonstrated presence of receptors for FSH, LH and GnRH in the canine bladder and the fact that a significant difference in the density of these receptors in gonadectomised versus sexually intact bitches has been ascertained.
The direct effect of GnRH on many organs has recently been demonstrated and is based on the existence of two subtypes of GnRH: GnRH I and GnRH II; the second type is apparently responsible for the direct action on the target organs. The expression of GnRH-II receptors also within the lower urinary tract supports the hypothesis of the direct action of the peptide on these tissues. In this context, treatment of incontinent bitches with GnRH or its analogues would therefore determine an action on both GnRH I and on GnRH II receptors, thus resulting, on the one hand, in the down regulation of the pituitary receptors for GnRH and, on the other hand, in the beneficial effects (increased deposit capacity of the bladder) through direct action on the GnRH II receptors present in the peripheral tissues and probably also within the bladder itself. However, the lack of evidence on the presence of different receptor expressions of LH and GnRH in gonadectomised and sexually intact bitches raises doubts about the entire issue of the possible influence of gonadectomy on the expression of these receptors in the urinary bladder, the urethra, and the onset of incontinence. GnRH could also act through its action as co-transmitter in the sympathetic nervous control of bladder function.
Specialized literature reports that urinary incontinence after gonadectomy may arise in a highly variable percentage of female dogs subjected to gonadectomy, with a range of 3-20%, although many authors assert that the incidence is of around 5-8%. As regards the risk factors, the absence of any difference between the gonadectomy performed with only the removal of the ovaries (ovariectomy) as against the removal of the ovaries, fallopian tubes and uterus (ovariohysterectomy) has been confirmed, notwithstanding some initial investigations performed in the 1970s which had shown a higher predisposition to urinary incontinence in dogs undergoing ovariohysterectomy compared to those undergoing a simple ovariectomy.
The time interval between the onset of urinary incontinence and the date of the gonadectomy is variable (from immediately to 15 years later), but generally (in 75% of cases) it occurs within 3 years after surgery and more commonly (55-73%) within 1 year. As for the correlation between age at gonadectomy and the occurrence of urinary incontinence, different studies have produced conflicting results, also regarding the possible risk correlated to prepubertal gonadectomy. Urinary incontinence after gonadectomy has been associated with other factors, such as the large or giant size of the dog (both in purebreds and in mixed-breed dogs), a greater predisposition in certain breeds, such as the Boxer and Dobermann, but also the Irish Setter, Weimaraner, Rottweiler, German Shepherd, Giant Schnauzer, Bobtail, Golden retriever, a body weight of over 20 kg, with a state of obesity at the time of gonadectomy and to caudectomy.
SYMPTOMS
Bitches suffering from urinary incontinence frequently have an involuntary urine discharge during sleep or while lying down, but sometimes also when standing (Figs. 1 and 2), during walking or when barking, jumping, running, passing from standing to the sitting position. At times, the perineal area may be found wet, or with a colour alteration of the fur caused by the presence of urine which may also cause the development of dermatitis or encourage myiasis, mainly in the summer. The incontinence may be continuous or, more frequently, intermittent and with various degrees of severity, with a tendency to worsen over time. In addition to the more strictly medical aspects, urinary incontinence also creates problems for the owner in terms of hygiene and in the human-animal relationship (urinary contamination of the dog house or dripping of urine in the house).
DIAGNOSIS
The diagnosis of urinary incontinence after gonadectomy is made after having ruled out all other possible causes of acquired urethral sphincter incompetence, after a complete physical examination with the necessary additional tests, on the basis of findings typical for the disorder and on the results of the urodynamic test. This latter test makes it possible to define the urethral pressure profile and the maximum urethral closing pressure, but does not constitute a prognostic indicator. An additional test, cystometry, which measures bladder compliance, provides useful information about possible bladder dysfunctions. Unfortunately, neither the assaying of oestrogens nor of plasma gonadotropins is helpful in the diagnosis.
TREATMENT
Although the aetiology of urinary incontinence after gonadectomy still remains incomplete, the role of oestrogens, gonadotropins, and of the sympathetic nervous system in the control of the urethral sphincter function has been amply demonstrated. For this reason, the choice of treatment is based on the goal of restoring urethral sphincter function by means of a pharmacological therapy. However, the complexity of the aetiology is reflected by the fact that none of the above-mentioned approaches is totally effective; this, associated with the need for life-long treatment, makes the clinical management of this condition particularly complex and often frustrating for both the veterinary surgeon and the owner.
Oestrogen replacement therapy draws insight from human medicine, where urinary incontinence in menopausal women is successfully treated with oestrogens. The success rate of oestrogen replacement therapy, which has been used for years also in female dogs for the treatment of urinary incontinence after gonadectomy, ranges between 18 and 100%, considering as success not only the full restoration of continence but also a simple improvement of the condition, making the case acceptable both in terms of health management of the bitch and in terms of improvement in the human-animal relationship.
The mechanism of action of oestrogens results in an improvement in the bladder urine-depositing phase and in an increase in the urethral closing pressure. In particular, oestrogens increase the urethral closing pressure through an interaction with adrenergic receptors and have a synergistic action with alpha-agonist receptors. Furthermore, with the resulting hypertrophy of the musculature and protection from the deposition of collagen, oestrogens increase the contractility of the bladder and urethra, as well as favour the urethral vascular supply.
Among the various pharmaceutical formulations available, oestriol and conjugated oestrogens have been the most commonly used. The administration of oestriol requires a single daily oral dose of 0.25-2 mg/animal for 14 days, followed by the progressive tapering of the dose and/or frequency of administration depending on the response, until the minimum effective dose is determined. The side effects of oestrogen treatment include vulvar and mammary gland swelling, vaginal discharge, attraction of males, signs of oestrus, behavioural changes, alopecia, impaired hepatic metabolism and bone marrow hypoplasia. In fact, the most common undesirable side effect is a slight attraction of males. The bone marrow hypoplasia and the alteration of hepatic metabolism, attributable to the use of estradiol benzoate, cypionate, and diethylstilbestrol, were not observed even after 60 months of treatment with natural oestrogen in bitches regularly subjected to half-yearly monitoring with a complete blood count and a blood chemistry panel.
The increase in gonadotropins after gonadectomy, which seems more pronounced in incontinent females, has been at the basis of the desensitization of the pituitary gland, which results in lower circulating levels of gonadotropins. For this purpose, both GnRH antagonists, which are very expensive and not available in formulations for veterinary use, and GnRH agonists have been proposed. After a short initial phase of increase in gonadotropins, the prolonged administration of GnRH agonists determines a reduction of pituitary receptors for GnRH, resulting in a reduced production of gonadotropins. In addition, and especially in forms which are resistant to treatment with GnRH alone, treatment with GnRH seems to have an indirect effect on the urethral alpha-adrenergic receptors, which can be favoured by the simultaneous administration of alpha-adrenergic drugs. In conclusion, the efficacy of treatment with GnRH would not be attributable to an improvement in the urethral closing pressure, but rather only in view of its impact on the bladder filling threshold-volume or, possibly, of a direct effect on the lower urinary tract and/or of an autocrine /paracrine effect.
To date, the prolonged use of GnRH analogues has provided positive results in no more than 58% of the patients, while reports on any side effects, if any, are not yet available. One therapeutic possibility might be the use of drugs having an alpha-adrenergic action, given the direct involvement of alpha-adrenergic receptors in the control of the urethral sphincter. These substances, which include phenylpropanolamine, ephedrine and pseudo-ephedrine, favour the closure of the urethral sphincter by means of an increase in the urethral smooth muscle tone. The efficacy of this therapy, as reported in literature, is in the order of 75-90%. Drawbacks of this approach are the multiple daily dosing (2 to 3 doses, depending on the active ingredient) and the prolonged treatment time required. Among the side effects reported were fatigue, restlessness, lethargy, dysorexia, gastrointestinal effects, cardiac arrhythmias and possibly a decreased efficacy over time. Since for any of the above mentioned treatments the efficacy is not absolute, in cases of relapse a combination therapy of oestrogens and alpha-adrenergic agents, or of GnRH and alpha-adrenergic agents is recommended, exploiting the effect of oestrogens on the urethral muscle contraction induced by the alpha-adrenergic receptors and the direct and indirect effects of GnRH on the alpha-adrenergic receptors in the urethral tissue, the mechanism of which has not yet been determined.
Surgical therapy, an alternative in cases of failure of the pharmacological approach, has shown a certain degree of efficacy, with at least a temporary restoration of continence in around 50-55% of cases, regardless of the technique used. Surgery can also be used in support of medical therapy or, according to some authors, as a first approach in young animals, in order to avoid treatments for life with molecules such as oestrogens or sympathomimetic drugs. The surgical approach involves the execution of a pexy: urethropexy, cystourethropexy, deferentopexy, bladder pexy, the latter only in the male. Colposuspension is today only of historical significance, because in the incontinent female dog, unlike in women, urethral hypermobility does not seem to be an important component of urinary incontinence. Additional techniques that can be used in females consist in the reduction of the urethral lumen by injection of collagen or Teflon into the urethral submucosa, the side effects of which may include foreign body reactions or migration of material from the site of injection, or the use of transurethral slings.
The endoscopic-guided injection of porcine urinary bladder derived extracellular matrix around the circumference of the internal urethral sphincter has been used experimentally. The treatment, performed on a limited number of female dogs resistant to medical treatments, resulted in the restoration of continence for a period ranging between 84 and 616 days, making this approach a possible treatment in the female dog with acquired urethral sphincter incompetence.
Suggested readings
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