Historical Perspectives in Equine Reproduction: Pioneers in the Age of Discovery

During the Frank J. Milne State-of-the Art Lecture, Dr. Pat McCue shared his views on decades of progress in equine reproduction.
Dr. Pat McCue delivering the Milne Lecture at the 2023 AAEP Convention
Dr. Patrick McCue delivered the prestigious Frank J. Milne State-of-the Art Lecture at the 2023 AAEP Convention. | Courtesy AAEP

At this year’s Frank J. Milne State-of-the Art Lecture, Patrick McCue, DVM, PhD, Dipl. ACT, Iron Rose Ranch Professor of Equine Theriogenology at Colorado State University, presented a celebration of past contributors to the field of equine reproduction. He highlighted some of the greatest discoveries and advancements over the past 50 to 80 years. Honoring contributing individuals, McCue’s lecture covered an array of topics, from mare evaluation and management to hormone therapy and various pathologic conditions. 

Reproductive Evaluation of Mares

“Transrectal palpation to find ovaries and identify cycle stage started in the 1920s, and there is a great description by Day published in 1939 that is still relevant today,” said McCue. 

Transrectal palpation, he said, is an important yet often underappreciated skill. He encouraged students to learn to palpate before moving on to ultrasound. He also explained that there are certain things ultrasound cannot show us, including tone of the uterus and cervix and softness of the ovary prior to ovulation. 

“Still, ultrasound has made one of the biggest impacts in reproductive medicine, which was first described by Palmer and Driancourt in 1980 in France,” said McCue. 

Uterine culture also revolutionized reproductive medicine, and it’s been known since 1920 that infections reduce fertility. Caslick and Dimock showed a correlation between conformation and ascending infection and were among the first to start culturing “problem mares.” Nonetheless, culturing didn’t become mainstream until the 1970s when veterinarians started looking for contagious equine metritis (CEM). 

Endometrial cytology was first described in the mid-1960s. Veterinarians initially acquired collections by manual curette, lightly scraping the endometrium and looking at white blood cells and the presence of inflammation. Today, practitioners prefer cytology brushes because they yield more cells and better-quality cells than other methods. 

“We routinely collect a guarded uterine swab for microbial culture and a guarded brush sample for cytology as an initial assessment of uterine health of mares,” said McCue. “And we know that the combination of culture and cytology gives more information than either technique alone.”

Although uterine biopsies were performed beginning in the 1920s, it wasn’t until the 1960s and 70s that we learned to look for fibrosis and inflammation. These parameters now allow us to evaluate uterine pathology and provide a prognosis for a mare becoming pregnant and carrying the foal to term. 

Mare Management

Artificial Photoperiod 

Researchers at the Animal Research Station in Cambridge first used an artificial photoperiod to advance the breeding season and a mare’s first ovulation in 1947. 

“The best way to get more opportunities to breed the mare is to advance the first ovulation of the year forward into February and not wait for the mare to start cycling in April or May,” McCue explained. 

In terms of technology, Barbara Murphy, PhD, and her team in Ireland developed a wearable light device (Equilume). The masks work like barn lights with the added benefit of allowing mares to remain outdoors, thus reducing bedding and labor costs. 

The Caslick

The Caslick’s procedure was a major advancement in its time that hasn’t lost its relevance. Back in the 1930s and 40s, E. A. Caslick, DVM, showed episioplasty prevents mares from aspirating air and bacteria. This surgical procedure alone reduced bacterial contamination and allowed infected mares to essentially clean themselves out, said McCue.  

Kerosene

“I heard about this as a veterinary student and thought it was highly unorthodox,” said McCue. “However, years later a hallway conversation at the AAEP piqued my interest in the technique for problem mares.” 

The initial use of kerosene as a uterine treatment is attributed to Charlie Roberts, DVM, a veterinarian from New Zealand. Since its inception, kerosene has been used in many problem mares as a last therapeutic resort, with moderate success. A study in England in the early 1990s evaluated the effect of kerosene infusion on the endometrium. 

“Uterine biopsies showed tremendous inflammation, as expected, but the kerosene infusion appeared to be a ‘chemical curettage’ that stripped off the superficial layer of endometrial cells,” explained McCue. “Over time the endometrium regenerated, and some older chronically infertile mares became pregnant after kerosene therapy.”  

Hormone Therapy and Prostaglandins

“In the 1950s and 60s, the reason for a mare to cease cycling during the physiologic breeding season was not known; we now presume that those mares likely had a persistent corpus luteum (CL),” said McCue. 

Prior to the availability of prostaglandins, veterinarians often flushed the uterus of noncycling mares with saline to stimulate a return to heat. Researchers subsequently determined the pH of the saline infusion created inflammation and caused endogenous prostaglandin release from the endometrium. The saline infusion technique preceded the identification of prostaglandins by two decades, McCue said. 

“Prostaglandins became available for clinical practice in large animals in the early 1970s,” he continued. “Research by Bob Douglas in Wisconsin and Twink Allen in England confirmed that systemic administration of prostaglandins resulted in lysis of the corpus luteum and an early return of the mare to estrus.”  

He then dove into the history of various hormones for inducing ovulation, beginning with the discovery of human chorionic gonadotrophin the 1930s and moving into gonadotropin-releasing hormone (GnRH); GnRH agonists such as buserelin, deslorelin, and histrelin; progesterone and altrenogest; oxytocin; prostaglandin E2; prostaglandin E1 (misoprostol); and dopamine antagonists such as domperidone.

McCue noted that a low-dose buserelin or low-dose deslorelin protocol can stimulate follicular development in mares in spring transition. The protocol, however, is not effective for stimulating follicular development in mares in deep winter anestrus (i.e., with follicles less than 20 mm in diameter).   

Pregnancy Physiology

endometrial cups mare
Researchers didn’t identify a link between endometrial cups and eCG production until the late 20th century. | Courtesy Dr. Pat McCue

McCue reminded practitioners the pregnant mare’s physiology is unique compared to other species. Key examples discovered over the past hundred years include:

  • The equine embryo produces prostaglandin E2 to facilitate its own transit down the oviduct to the uterus.
  • Embryos migrate multiple times a day as part of the maternal recognition of pregnancy process. They usually fix in position by Day 16, typically at the base of one uterine horn. 
  • A noncellular capsule that is not present in other species surrounds the early equine embryo. The capsule protects the embryo during the motility phase. Rupture of the capsule is why veterinarians might detect a “pop” when reducing a twin embryo.  
  • Scientists first identified the presence of endometrial cups in 1897. But it took another 100 years before they found a link between endometrial cups and equine chorionic gonadotropin (eCG) production. eCG production starts around Day 35, peaks at Day 60, and ends by Day 120-150 of gestation. 
  • A primary CL forms after ovulation. Accessory or secondary CLs begin to develop around Day 40 and produce additional progesterone in response to the presence of eCG secreted by the endometrial cups. 

“There are two clinically relevant points in the mid-gestation mare,” said McCue. “The first point is that by Day 150, the ovarian CLs are gone, and there is no more progesterone produced by the ovaries. Pregnancy in the mare is maintained by various progestins (i.e., dihydroprogesterone) produced by the placenta. A second point is the luteal-placental shift occurs at approximately 110 days of gestation. There is little evidence that supplementation with exogenous progesterone or altrenogest after the placenta has taken over progestin production is beneficial in the maintenance of pregnancy in mares.”  

Pregnancy Examinations

Hemagglutination inhibition (HI) assays were developed in the 1960s to detect eCG and confirm pregnancy. The HI assays were advertised to detect an equine pregnancy from Days 40 to 130 of gestation. Unfortunately, said McCue, false positive and false negative issues limited the clinical use of the tests. 

Veterinarians initially performed transrectal palpation for pregnancy of cattle and horses in the early 1900s. Early descriptions indicated they could detect an equine pregnancy by four months of gestation. Over time, veterinarians determined transrectal palpation could detect pregnancy in a mare by 30 days of gestation.   

The current state-of-the-art early pregnancy detection method in mares is transrectal ultrasonography, which McCue made the following key points about:

  • It is possible to detect pregnancy by ultrasound as early as Day 10 to 11 days post-ovulation, but in routine veterinary practice initial pregnancy exams are usually performed at 14 to 16 days post-ovulation or post-breeding. 
  • An equine embryo grows at a rate of approximately 3 mm per day. 
  • Embryos that are small for their gestational age and/or have a slow growth rate might be associated with an increased risk of pregnancy loss. 
  • An embryo proper and heartbeat are usually visible by Day 25 post-ovulation. 

Reproductive Pathology

Uterine Culture and Cytology
Uterine culture and cytology remain the standard for diagnosis of infectious endometritis. | Courtesy Dr. Pat McCue

Addressing the hot topic of endometritis, McCue reminded practitioners, “Every mare every time has inflammation in response to sperm that begins within 30 minutes after breeding or insemination. If the inflammation persists, we may see a reduction in fertility.” 

Today, veterinarians clear the fluid using a variety of techniques, such as lavaging the uterus four to six hours post-breeding. Practitioners use ecbolic agents and an array of other drugs to decrease inflammation, including platelet-rich plasma, non-steroidal anti-inflammatory drugs, corticosteroids, stem cells, immunomodulators, ozone, and interleukin-1 receptor agonist protein, among others. 

“There is no single therapeutic protocol that works on all mares,” said McCue. “Therefore, we need to tailor our treatment to individual mares.”

In terms of infectious endometritis, he said uterine culture and cytology remain the standard for diagnosis. 

“We still don’t have on-farm point-of-care options such as PCR for identification of uterine pathogens,” McCue said.   

The most common bacterial pathogens are Streptococcus equi subspecies zooepidemicus, Escherichia coli, Pseudomonas aeruginosa, and Klebsiella pneumoniae. Treating bacterial endometritis typically involves uterine lavage and three or more days of intrauterine infusion of an appropriate antibiotic based on results of antimicrobial sensitivity tests.  

McCue encouraged practitioners to be good antibiotic stewards using the right antibiotic at the right dose, frequency, and duration.

Assisted Reproduction

Touching briefly on this topic, McCue said embryo transfer was first described in rabbits well over a century ago (1891), and the first foal born following embryo transfer was reported in 1974. The 1990s yielded multiple advancements in assisted reproduction, including foals born by in vitro fertilization and intracytoplasmic sperm injection (ICSI). 

Final Thoughts

Veterinary practice has come a long way over the past 50 to 100 years. 

“We owe a debt of gratitude to our predecessors,” said McCue. “Advancements in knowledge in any discipline of veterinary medicine is derived from a combination of basic scientific discovery and clinical observations from individuals in private practice. We should all strive to contribute to the continued development of the veterinary profession.” 

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