Case Report

Infertility caused by oophoritis in a dog resolved by hemiovariectomy

Amber Nebel-Karp,^a David Mahoney,^b Michael Whitacre,^c Beth Bauer,^d Sara Lyle^c‡

^aAnimal Hospital of East Davie, Advance, NC, USA
^bSouth Mountain Pet Care & Canine Reproduction, Sandy, UT, USA
^cDepartment of Clinical Sciences, College of Veterinary Medicine, North Carolina State University, Raleigh, NC, USA
^dCarolina Ranch Animal Hospital & Resort, Garner, NC, USA

Abstract

Canine oophoritis is a rare ovarian pathology that has been reported to cause infertility. However, diagnostic work-up, treatment options, and prognosis of return to fertility after treatment for oophoritis were not reported. We report oophoritis in a dog that was diagnosed via histopathology after hemiovariectomy; diagnostic tests, treatment, and outcome of fertility are included and compared to other domestic species and women. Additionally, pathophysiology and prognostic outcome of oophoritis in women are discussed in the context of future directions and possible avenues of investigation in canine oophoritis.

Keywords: Canine oophoritis, infertility, ovarian nodule, hemiovariectomy

 

 

Background

Canine infertility is oftentimes a heartbreaking issue for breeders and veterinarians to deal with as there can be multiple facets to this problem. In certain cases, ‘apparent infertility’ may be due to inappropriate breeding time; it can be addressed by breeding at the most fertile window, 4-6 days after luteinizing hormone (LH) surge, depending on the type of semen utilized, and measuring serial blood progesterone concentrations. Most serious breeders utilize a veterinary team for breeding management to determine the optimal day(s) of estrus to breed. If dogs are bred at optimal day(s), the next step in a diagnostic work up for infertility is assessing semen quality. Good semen quality is > 70% normal morphology and progressive motility with at least 200 x 10⁶ progressively motile sperm per breeding dose.¹ After addressing appropriate breeding day(s) and semen quality, brucellosis should be considered; in negative brucellosis cases, determining the cause of infertility is challenging. A possible structural cause for female dog infertility is endometrial degeneration due to cystic endometrial hyperplasia (CEH) in dogs > 5 years or subclinical endometritis. Ovarian and/or uterine pathology was noted in 42/76 dogs presenting for elective ovariohysterectomy that were clinically normal.² Most common uterine pathologies observed were CEH, periglandular fibrosis, and endometritis. Most common ovarian pathologies observed were hyperplasia of the rete ovarii, follicular cysts, and oophoritis.^2,3

Canine oophoritis is a rare ovarian pathology that has been reported to cause infertility. In the past 3 decades, 3 cases^4,5 of canine oophoritis have been reported; a prospective study² investigated the prevalence of ovarian and uterine pathology in clinically normal dogs at ovariohysterectomy. We report the diagnosis and treatment of a dog with left ovarian granulomatous oophoritis.

Case presentation

A 5-year, maiden German shepherd dog, was presented in August 2020. The referring veterinarian determined ovulation via measuring serial serum progesterone concentrations. During breeding management, abnormal estrous cycles and shortened interestrous intervals were observed. Abnormalities noted were failure of appropriate progesterone increases above ovulation concentrations and split estrus with an interestrous interval of < 2-3 months. Similar to her dam, this dog had estrous cycles lasting for 21 days and cycled every 4 months.

The first breeding attempt was in November 2019 and ovulation was determined via serum progesterone concentrations (Chemiluminescence, IDEXX, Westbrook, ME). The dog tested negative for brucellosis (Rapid slide agglutination test; Zoetis, Parsippany, NJ). The estimated LH surge (2.3 ng/ml of progesterone) occurred on November 16, 2019. However, progesterone concentrations did not increase and the cycle was assumed to be a split estrus. The dog came into proestrus in late December 2019, ~ 4 weeks from the end of previous cycle. Progesterone concentrations never increased > 1.1 ng/ml in the following 20 days. The dog was prescribed compounded mibolerone (Safeway Compounding Pharmacy, Newark, DE) to assist in extending her interestrous interval to have a fertile estrous cycle. Mibolerone treatment was initiated on January 13, 2020 and discontinued on May 7, 2020 when the drug availability became limited. Her next estrous cycle began in July 2020, with proestrus starting on July 9, 2020 and followed via determination of serial progesterone concentrations every 2-4 days until they reached 3.2 ng/ml on August 4, 2020. Testosterone concentrations were 0.1 ng/ml (< 0.1 ng/ml normal for a female dog). Vaginal cytology revealed lack of cornification throughout the cycle. Since the dog had another slow increase in progesterone concentrations she was referred.

Complete blood count and serum chemistry findings were normal. Breeding management consisted of progesterone assay (TOSOH Bioscience AIA 360, San Fransico, CA) and vaginal cytology. Progesterone concentrations on initial presentation were 5.91 ng/ml that suggested potential ovulation; however, her vaginal cytology revealed < 10% cornification with low cellularity. Disagreement between progesterone concentrations and vaginal cytology could not be immediately explained. Transabdominal ultrasonography was performed; the uterus was normal with no cystic endometrial changes. Ovaries were heterogeneous and asymmetrical; the right ovary measured 0.8 x 1.9 cm and the left ovary was 1.8 x 2.5 cm. A single anechoic structure on the right ovary measured 0.2 cm and a hypoechoic nodule in the left ovarian parenchyma measured 1.7 cm (Figure 1A); the left ovarian nodule was vascularized, as evidenced on Doppler ultrasonography. The radiologist labeled the anechoic structure on the right ovary as a potential cyst or cystic functional body. Potential differentials for the left ovary nodule were complicated cyst, atypical functioning body, or neoplasia. The decision was for another progesterone concentrations in 1 week to determine if the estrous cycle would continue to progress.

Figure 1. A. Ultrasonographic image of left ovary (craniocaudal view), note hypoechoic structure measuring 1 x 1.7 cm (asterisk) that remained consistent in size at reexamination; B. left ovary bisected after hemiovariectomy, note dark pedunculated mass containing debris (asterisks); and C and D. histopathologic (H&E stain) confirmation of granulomatous oophoritis (asterisks).

A week later, the dog was presented for follow up breeding management; her progesterone concentrations had decreased to 2.73 ng/ml (similar to findings on repeat vaginal cytology). A follow up ultrasonography was performed on September 9, 2020. Minimal changes were observed in the left ovary (still enlarged with a 1 x 1.7 cm hypoechoic nodule in the cranial aspect). The nodule appeared more cavitated in the center compared to initial ultrasonography. The right ovary appeared normal (no anechoic structure on reexamination). Mild development of mammary tissue was noticed; due to these findings and lack of change in the nodule, among previous differentials, neoplasia (with granulosa-theca cell tumor) appeared more likely. We suspected left ovarian abnormality as the reason for abnormal estrous cycles. Submitting a sample for antiMüllerian hormone (AMH) to UC Davis versus conserving the dog’s breeding potential via hemiovariectomy was discussed. Owners decided to have hemiovariectomy with histopathology submission via referring veterinarian and not to submit a serum sample for AMH.

Treatment

Surgery was scheduled via the referring veterinarian; left hemiovariectomy was performed on September 18, 2020. Surgery and recovery were uneventful. When the ovary was bisected, a cavitated center was identified and a black mucous material oozed from the cut surface (Figure 1B). Histopathology revealed that the structure was not neoplastic; diagnosis was granulomatous oophoritis characterized by lymphocytes, macrophages, plasma cells, fibrosis, and hemorrhage (Figure 1C and 1D).

Outcome

After left hemiovariectomy, the dog came into estrus in January 2021. She was naturally bred based on progesterone concentrations that measured > 20 ng/ml near the end of estrus; this time there was no abnormalities in cyclicity. The dog was diagnosed pregnant on February 25, 2021, and whelped 6 healthy pups on March 26, 2021. Since surgery, the dog whelped and reared 3 healthy litters: 6 (all surviving past weaning), 9 (8 surviving past weaning), and 7 pups (all surviving past weaning) before retiring from the breeding program.

Discussion

It is unclear what caused oophoritis in this case. Oophoritis has been reported² to be extremely rare with prevalence of 6.6-7.9% in 42/76 clinically healthy dogs with reproductive abnormalities at ovariohysterectomy. In other species (e.g. pigs and cattle) oophoritis has been linked with modified-live vaccinations of pseudorabies,⁶ infectious bovine rhinotracheitis,⁷ and noncytopathogenic bovine pestivirus (bovine viral diarrhea virus).^8,9 In mares, extremely rare cases of oophoritis or salpingo-oophoritis were reported in repeated transvaginal aspiration of oocytes.^10–12 In dogs, oophoritis was reported in a 3.5-year Rhodesian ridgeback⁴ that had prolonged estrus and an abnormal corpus luteal structure with inflammatory invasion leading to luteal insufficiency. Oophoritis⁵ causing primary anestrus in 2 dogs has been reported, but none presented ultrasonographic structure as we have described.

In women, oophoritis may be more common, albeit still rare, as there is more information available on lymphoplasmacytic oophoritis in women. The most common presentation and clinical history in women with oophoritis is premature ovarian failure, also known as premature ovarian insufficiency/dysfunction or premature menopause, affecting 1–2% of all women; autoimmune oophoritis is thought to cause 5% of POI cases.^13–18 Clinical signs of premature ovarian insufficiency (POI) in nulligravid to multigravid women < 40 years was amenorrhea (at least for 4 months); women commonly had pelvic pain, hot flashes, low libido, vaginal dryness, infertility, and changes in their menses cycle. Hormonal profiles of these women were hypergonadotropic hypogonadism characterized by hypoestrogenism (< 50 pg/ml), hypoandrogenism, and elevated (> 40 IU/ml) follicle-stimulating hormone (FSH) concentrations were on 2 occasions, 1 month apart. Most women had a medical history of either having autoimmune thyroiditis (Hashimoto’s) and adrenal insufficiency (Addison’s) known as autoimmune polyendocrine syndrome types I and II.^13–19 Studies suggested that 80% of women that had Addison’s disease usually developed autoantibodies against CYP21-ɑ-hydroxylase, CYP11, or CYP17-ɑ-hydroxylase in the adrenal cortex and ovary.^20–26 This caused a selective theca cell dysfunction in the ovary leading to decreased steroid production (diminished androstenedione and estrone precursors) and hypoestrogenism. Not only was steroid production affected due to the autoantibodies, lymphoplasmacytic destruction occurred primarily in secondary and Graafian follicles that have theca interna and externa layers, initially sparing primordial and primary follicles. Autoantibodies against oocytes ooplasma were identified in surveillance studies in cattle^27–29 presenting for infertility and in thymectomized mice studies.^30,31 Autoimmune oophoritis was definitively diagnosed solely through ovarian biopsy and histopathology (as in the case). Research to correlate less invasive testing with oophoritis diagnosis suggested testing for autoantibodies against CYP21-ɑ-hydroxylase using enzyme linked immunoassay or indirect immunofluorescence.¹⁹ Others have diagnosed salpingo-oophoritis via laparoscopy,³² ovarian cytology,³³ and ultrasonography.

Approximately 20% of women with POI and autoimmune oophoritis experience spontaneous ovulations, with 5-10% of these women conceiving naturally and delivering a child.^17,19,34 Apart from hormonal testing of estrogen, progesterone, testosterone, LH, and FSH, ultrasonography is a key feature in the preliminary diagnostic work-up for oophoritis.^35–37 Ovarian presentations were enlargement, asymmetry, multiple or singular cystic structures, or lack of follicular development;²⁰ it was theorized that the pathogenesis for women who developed multiple cystic follicles despite low estrogen was due to elevated FSH driving follicular development without estrogen’s negative feedback and producing higher concentrations of inhibin B.²⁰

Treatment for autoimmune oophoritis is difficult and most often unsuccessful. Most treatment entails assisted reproductive technologies in controlled ovarian hyperstimulation protocols. Protocols utilize gonadotropin-releasing hormone to aid in suppressing FSH, thus increasing ovarian sensitivity and human chorionic gonadotropin³⁸ for ovulation induction when follicles reach an inducible size (≥ 18 mm). This has limited success as observed in some studies where only 3/15 women ovulated after treatment³⁸ and might have interfered with spontaneous ovulation in a small subset of women with POI.¹⁷ Other reproductive laboratories added adjunct therapy,³⁹ supplementing women with dehydroepiandrosterone sulfate to improve androgen concentrations and secondary increase in estrogen. This group observed success with 5/6 women having ovarian responses of a single follicle and 3/6 resulting in ovulation. Two of the 3 ovulations were spontaneous resulting in pregnancies and delivery of healthy children in both women. Although results were substantial, the success of treatment can be limited depending on the definition of success. Is the definition of success having follicular development, even of a single follicle leading to ovulation or is it conceiving and delivering a child? These varying definitions of success, if not explicitly stated, can have substantial impacts on a patient’s expectations and compliance during treatment. Autoimmune oophoritis has been anecdotally treated successfully using glucocorticoids via immunosuppression in the early stages before complete follicle deprivation occurred. Glucocorticoids worked synergistically with controlled ovarian hyperstimulation and increased the success of treatment or return of menses in the short-term.^40,41

Possible sequelae to oophoritis reported in women are ovarian torsion from large cysts/follicles,⁴⁰ adrenal insufficiency within 9 years of POI, osteoporosis, ischemic heart disease, increased risk of mortality, and psychological distress.^13,15–19 Osteoporosis due to hypoestrogenism necessitates estrogen supplementation until menopausal age (50 years) to reduce pathologic fractures.^13,17 As mentioned, autoantibodies against adrenal CYP21-ɑ-hydroxylase is the main etiology causing autoimmune oophoritis.¹⁹ Women with these autoantibodies should be tested for adrenal insufficiency if not already diagnosed to avoid an adrenal crisis during pregnancy. Fasted baseline cortisol and ACTH stimulation tests are poor screening tools, as women in this population tend to have low sensitivity and specificity to these tests.¹⁷ Appropriate diagnosis and management of adrenal insufficiency have to be referred to an endocrinologist and are not discussed here. There are no reports of these sequelae occurring in dogs; however, they cannot be ruled out as a possible presentation for oophoritis.

Pathogenesis of oophoritis is multifactorial with various genetic and environmental components. In women, a hereditary link has been theorized as similar familial history was observed in some patients.^13–15 Other causes of oophoritis are vaccination against human papilloma virus,¹³ galactosemia,¹³ chemotherapy,^13,16 smoking,¹² mumps,^42,43 and Zika virus.^43,44 Mumps virus caused gonadal infection in 5% of women and 20% of men, with oophoritis reported more often in women affected before puberty.⁴² Interestingly, mumps caused transplacental infection of fetuses resulting in offsprings experiencing oligomenorrhea and ovarian hypoplasia.⁴² After the Zika virus epidemic in 2015, acute oophoritis and follicular apoptosis occurred in mice after infection with Zika-virus via T lymphocyte-mediated destruction.^42,43,44 Subsequently this was confirmed; however, no difference in oocyte yield, fertilization rate, or blastulation rate were observed between treated and control mice.⁴³

It is unclear in this case how or why this dog developed oophoritis, as no pertinent medical history of hypothyroidism or Addison’s was mentioned in the record. Furthermore, there is limited information on canine oophoritis to know if a similar pathogenesis occurs as in women. The only familial history mentioned was short interestrous intervals of 4 months. However, since she was a German shepherd dog, short interestrous intervals are fairly common in this breed.^45–47 Research is needed to determine whether there is a link with oophoritis and other endocrine insufficiencies like autoimmune thyroiditis and Addison’s in canine patients. To fully elucidate this, a complete thyroid panel with inclusion of autoantibodies could have been performed in this case. However, the inclination to have this bloodwork without any clinical signs was low at initial presentation. Typical Addison’s was also ruled out due to normal electrolytes (serum chemistry) and no clinical signs in the history. Testing for atypical Addison’s disease was not performed in our case. Additional serum hormonal testing in this case could have been recommended to describe the dog’s hormonal status that would include FSH, LH, estrogen, testosterone, and AMH. This would have provided more information in the disease process and would have allowed comparisons to women. However, other hormonal testing was declined in favor for a definitive diagnosis via histopathology after a hemiovariectomy. Although serum estrogen concentrations were not determined, one can suspect hypoestrogenism due to the indirect bioassay obtained via vaginal cytology. Throughout each bleeding episode, no cornification was observed from November 2019 to September 2020 on vaginal cytology and it was consistent with anestrus (low cellularity and low cornification). This provided preliminary evidence of hypoestrogenism in this dog as observed in women with POI. Progesterone concentrations reported previously were possible because of luteinization of the follicular wall without ovulation in any monitored cycle.

Despite the shortcomings of limited serum hormonal assays or endocrine tests, we have documented oophoritis as the cause for estrous cycle abnormalities and infertility. To the authors’ knowledge, for the first time, successful treatment and return to fertility in a dog diagnosed with unilateral granulomatous oophoritis is reported.

Learning points

• Oophoritis is a cause of infertility in dogs
• Hemiovariectomy may be curative in unilateral oophoritis
• Dogs can have a successful breeding career after hemiovariectomy

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