History

A 7-year-old multiparous Thoroughbred mare presented on-farm for a routine reproductive examination 8 days after foaling in March. This was the mare’s second foal, and the 367-day pregnancy and foaling were uneventful. The breeding records from the previous season indicated that the mare conceived with twins on the first cycle and that 1 embryonic vesicle was successfully ablated. At the time of the examination, body condition score was 5/9, and the mare showed no outward signs of clinical disease or any aberrant behavior. Based on farm protocol, the mare had not been exposed to artificial lighting, and as a foal was at foot, the mare was not exposed to a teaser stallion to assess estrus behavior.

The reproductive examination included transrectal palpation and ultrasonography and vaginoscopy. The uterus and cervix were toned and involuting well. The ovulation fossa was palpable on both ovaries; however, the left ovary was approximately half the size of the right ovary. Transrectal ultrasonography revealed a cohort of small follicles on the left ovary and hyperechogenic structures on the right ovary with a corpora lutea (CL)–like appearance. There was no intrauterine fluid, and uterine edema was waning. Speculum examination revealed minimal bruising of the vagina and vestibule, and a contracted cervix. Based on the results of the examination, the mare was suspected of having completed a foal heat.

Five days later, a reproductive examination revealed the CL-like structures and a lack of uterine edema, which supported a diagnosis of diestrus. Prostaglandin F2α (PG; cloprostenol, 250 µg/mL, IM) was administered to hasten the return to estrus. Five days after PG, ultrasonography revealed persistent CL-like structures on the right ovary. A second dose of PG was administered. Ultrasound examination 5 days later revealed multiple small follicles measuring < 10 mm on the left ovary, CL-like structures with a follicle measuring 20 mm on the right ovary, and no uterine edema. After the exam, the mare was administered a third dose of PG and a fourth dose 24 hours later. Examinations were repeated 6 days after PG and on days 31 and 36 postpartum with no appreciable change. At this time, the mare’s owner elected to delay rebreeding and any additional investigations or treatments for the postpartum anestrus pending the results of progeny performance. Sixty-five days after foaling, the decision was made to rebreed the mare; transrectal palpation and ultrasonography revealed a small left ovary with a cohort of immature follicles and persistent CL-like structures on the right ovary (Figure 1).

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Transrectal ultrasonographic images of the left (A) and right (B) ovaries of the Thoroughbred mare 65 days post-foaling. The left ovary is approximately 30 mm in diameter with few multiple immature follicles. The right ovary is approximately 45 mm in diameter, with multiple CL-like structures. Tick marks on the right side of the image are at intervals of 10 mm.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.22.04.0163

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Question

What is the likely diagnosis for postpartum anestrus in this mare?

Answer

A granulosa cell tumor (GCT). The endocrinological function of the tumor increased during pregnancy to a level that suppressed the postpartum return to estrus.

Results

Blood was collected and submitted to the UC Davis Clinical Endocrinology Laboratory for analysis of serum concentrations of testosterone, inhibin B, anti-Mullerian hormone (AMH), and progesterone. Serum hormone concentration analysis revealed an elevated testosterone (75.7 pg/mL; reference range for nonpregnant mare, 20 to 45 pg/mL), inhibin B (55.9 ng/mL; reference range for nonpregnant mares, 2 to 100 pg/mL), and AMH (> 14 ng/mL; reference range for nonpregnant mares, 0.1 to 6.9 ng/mL). Progesterone was low (0.01 ng/mL; reference range for mares with absence of active luteal tissue, < 1 ng/mL).

The elevated hormone concentrations in conjunction with the clinical history of anestrus and persistent CL-like structures that did not respond to PG were indicative of a GCT affecting the right ovary (Figure 2). Seventy-eight days postpartum the mare was admitted to the clinic for a unilateral ovariectomy and fasted overnight. A catheter was placed in the left jugular vein, and the mare was administered broad-spectrum antimicrobials (ceftiofur sodium, 2.2 mg/kg, IV, q 12 h; and gentamicin, 6.6 mg/kg, IV q 24 h) and flunixin meglumine (1.1 mg/kg, IV, q 12 h).

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Transrectal ultrasonographic images of the left (A) and right (B) ovaries of the Thoroughbred mare 65 days post-foaling. The persistent CL-like structure on the right ovary (white arrows). Tick marks on the right side of the image are at intervals of 10 mm.

Citation: Journal of the American Veterinary Medical Association 260, 15; 10.2460/javma.22.04.0163

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Sedation and analgesia were achieved with detomidine hydrochloride (0.01 mg/kg, IV) and butorphanol tartrate (0.01 mg/kg, IV). The right paralumbar fossa was clipped, prepped, and aseptically draped. Standing unilateral laparoscopic ovariectomy using a vessel-sealing device facilitated removal of the right ovary.¹ Surgery and recovery from sedation were otherwise unremarkable. The mare was discharged to the care of the farm 2 days postoperatively with instructions for stall rest and continued antibiotic and NSAID treatment for a total of 7 days.

The approximately 5.5 × 4.5-cm ovary was fixed in formalin and submitted for histopathology. The histological examination revealed a solid and rarely cystic mass composed of polygonal cells forming nests and sheets, in a vascular stroma, with regions of fluid-filled cystic spaces containing Call-Exner bodies. In addition, there were no developing follicles or CL. These findings confirmed the diagnosis of a GCT.

Discussion

The mare in this report was evaluated for routine breeding management and did not return to estrus postpartum. Postpartum anestrus in the mare is the temporary lack of cyclicity after foaling, characterized by a lack of follicular development or moderate follicular development without ovulation.² The anestrus period may be proceeded by a normal fertile foal heat ovulation.²

Lactation, poor body condition, season, and retained endometrial cups have all been implicated as predisposing factors for postpartum anestrus.² In the present case, the cause of postpartum anestrus was the result of an endocrinologically functional GCT that developed during pregnancy. In the mare, GCTs are the most common ovarian neoplasms.³ The hormonally active neoplasms are typically benign, but malignancy has been reported. There is no reported predilection for breed, reproductive status, or age, as GCTs have been identified in maiden, barren, pregnant, and foaling mares as well as females of any age.^3–5

The traditional presentation for a GCT often includes stallion-like behavior, a unilaterally enlarged ovary lacking an ovulation fossa with a honeycomb-like appearance on ultrasound, and a very small, inactive contralateral ovary.^3,4 Androgenized mares may fight with or attempt to mount other horses, demonstrate flehmen response, or scent mark by defecating or urinating on manure piles. Presumptive diagnosis is often based on clinical history, palpation and ultrasound of the ovaries, and hormone analysis, while a definitive diagnosis is determined by histopathology.

Researchers recently highlighted some of the diagnostic challenges when presented with nontraditional GCTs.⁵ In the cases reviewed, the researchers noted that some affected ovaries were normal in appearance with palpable ovulation fossa and an atypical ultrasonographic appearance similar to that of the mare described here.⁵ Based on the initial reproductive examination findings, the authors made several clinical assumptions, concluding that the mare had experienced a foal heat and that the asymmetrical ovarian size was attributable to the season, as supplemental lighting was not provided prior to foaling. In addition, the persistent CL-like structures on the affected ovary were initially presumed to be the product of foal heat ovulation.⁵ Furthermore, the authors initially hypothesized that the lack of a luteolytic effect following the first PG injection could be attributed to CL age; the luteolytic effects of PG are expected when treatment is initiated at least 5 days after ovulation when the CL is mature.

The fact that multiple doses of PG failed to induce luteolysis raised the suspicion of a GCT. Even though this mare was never presented to a teaser stallion, ultrasonographic findings were consistent with a 65-day period of anestrus after foaling. The prolonged anestrus combined with the persistent CL-like structures despite appropriately timed luteolytic doses of prostaglandin was highly suggestive of a nontraditional GCT. Results of the hormonal assays aided in the diagnosis. The low progesterone concentration confirmed that the persistent CL-like structures were not producing progesterone, while the elevated concentrations of testosterone, inhibin B, and AMH were indicative of a GCT.

For most mares experiencing postpartum anestrus, the passage of time with exposure to increasing day length is necessary to restore cyclicity. The use of hormonal therapies targeting the hypothalamic-pituitary-gonadal axis has been effective to hasten the return to cyclicity as well. In this mare, the hormonal influence of the GCT suppressed activity of the contralateral ovary, and surgery was needed to restore cyclicity postpartum. The time for resumption of cyclicity is based on the time of year that surgery is performed, but most mares return to estrus between 2 and 16 months after ovariectomy.⁴

While GCTs have been diagnosed postpartum, to the authors’ knowledge, there is little evidence in the literature of a GCT resulting in anestrus in the postpartum mare. The mare described here demonstrates the importance of considering a GCT as a differential diagnosis for postpartum anestrus. This case also highlights the importance of hormone analysis for cases that do not have the traditional presentation and serves as a reminder that there is a wider spectrum of presentations for GCTs.

Outcome

The mare recovered from the unilateral ovariectomy without complications. While a follow-up reproductive examination was not available, breeding records show that the mare was successfully rebred the following season and delivered a live colt.