Efficacy of medroxyprogesterone in suppression of estrus in mares Patrick McCue, DVM, PhD Diplomate ACT

Estrus Suppression in the Mare Options: Hormone administration Progesterone/progestins Oxytocin GnRH vaccine ‘Equity’ vaccine (Australia) Intrauterine devices Marbles, etc. Herbal supplements Surgery Ovariectomy

Progesterone Compounds Natural progesterone Intramuscular injection preparations Subcutaneous cattle implants (Synovex®) Synthetic progestins (i.e. Regu-Mate®) Other synthetic progestins Hydroxyprogesterone caproate (Hyproval®) Norgestomet (Synchro-Mate B®) Megesterol acetate (Ovaban®) Medroxyprogesterone acetate (Depo-Provera®)

Medroxyprogesterone Acetate (Depo-Provera®) Hormonal birth control agent for women Complete inhibition of follicular development and ovulation Compounded medroxyprogesterone acetate is used to suppress estrus in performance mares Dose regimens utilized by owners, trainers, DVMs 1,600 mg - once per month 800 mg - once every 2 weeks 400 mg - once per week No controlled studies to determine efficacy for suppression of estrus in mares Dose rates and frequencies reported

Research Goals Determine the effect(s) of administration of medroxyprogesterone acetate on Behavioral estrus Does MPA block or prevent expression of heat? Follicular activity and ovulation Does MPA prevent cycling and ovulation? Endocrine parameters Does MPA suppress luteinizing hormone (LH) secretion from the pituitary?

Materials and Methods 18 normal, healthy light horse mares Age range: 5 to 13 years Parameters for inclusion in study: Expression of normal estrous behavior Cycling with normal follicular development and ovulation as detected on transrectal ultrasonography

Materials and Methods Mares were randomly assigned to one of 3 treatment groups (n=6 mares per group) Treatment was initiated 7 days after ovulation; mares were treated for 6 weeks Group 1. Sterile saline injection once each week for 6 weeks (control) Group 2. MPA injection once each week for 6 weeks 1,600 mg loading dose (1st treatment) 400 mg once per week (all additional treatments) Group 3. Altrenogest (Regu-Mate®; 10 ml, orally, once daily for 6 weeks)

Materials and Methods Mares were teased to a stallion once per day, every day, to monitor estrous behavior (direct contact) Transrectal ultrasound initially performed 3 times per week Daily exams when a follicle was ≥ 30 mm in diameter

Materials and Methods Blood samples collected Once per week for progesterone analysis Once daily for 10 days for luteinizing hormone (LH) Investigators were blinded to treatment No knowledge of teasing behavior, ultrasound exam results or hormone analyses

Results: Behavior All saline (placebo) treated mares expressed normal estrus All medroxyprogesterone treated mares expressed normal estrus None of the altrenogest treated mares showed behavioral estrus Treatment Group Duration of Estrus Saline 8 ± 2 days MPA 7 ± 1 days Altrenogest 0 days ___________________

Results: Behavior Yellow = estrus Green = diestrus

Results: Ovarian Follicular Development All saline treated mares developed large follicles, normal uterine edema and ovulated All MPA treated mares developed large follicles, normal uterine edema and ovulated None of the altrenogest treated mares developed large follicles, or edema and none ovulated during the treatment period ___________________

Results: Progesterone Concentrations ___________________ Blue = Saline Pink = MPA Green = Altrenogest

Results: Luteinizing Hormone All saline treated mares exhibited an increase in luteinizing hormone (LH) associated with estrus All MPA treated mares exhibited an increase in LH associated with estrus None of the altrenogest treated mares exhibited an increase in LH; none of the mares were in estrus ___________________

Results: Serum LH Concentrations Blue = Saline Pink = MPA Green = Altrenogest

Conclusion A loading dose of 1,600 mg MPA followed by once per week doses of 400 mg of MPA for 6 weeks: Did not suppress behavioral estrus Did not inhibit follicular development Did not prevent ovulation Did not block the increase in LH associated with estrus There was no difference in efficacy between MPA treatment and a saline placebo

Conclusion Altrenogest treatment resulted in suppression of behavioral estrus, prevented formation of large follicles, and suppressed secretion of luteinizing hormone No mares treated with altrenogest ovulated during the treatment period

Hypothesis for lack of efficacy of MPA: Final Conclusion Medroxyprogesterone had no apparent biological activity relative to alteration of behavioral estrus or follicular development or modulation of pituitary LH secretion Hypothesis for lack of efficacy of MPA: It is theorized that MPA, a synthetic progestin, does not bind to the equine progesterone receptor