Pharmacodynamics of clomiphene citrate in cyclic mares

Clomiphene citrate (CC), a selective estrogen receptor modulator (SERM), is an orally administered reproductive drug that improved follicular recruitment and development primarily in human but also in bovine, ovine, and lagomorph species. Experimental data from mare after CC administration are slim; however, a 40 year-old, anecdotal case report describes some success after use of CC in 3 anestrous mares. We hypothesized that administration of CC in mare would result in an increased number of ovarian follicles. Objectives were to quantify AMH, LH, and FSH serum concentrations, to characterize endometrial edema, and changes in follicular dynamics between treated and control mares. Light-breed mares (n = 12) of 6 - 18 years were utilized from mid-July to early August.

Mares (n = 6) had oral treatment of CC (500 mg) once daily for 5 consecutive days and control mares (n = 6) had oral placebo. Blood samples for AMH concentrations were collected on days 1, 3, 6, and 9. Blood samples for FSH and LH concentrations were collected prior to first dose of drug and then once daily through treatment period. Transrectal ultrasonography and follicle mapping were performed in both treated and control mares. Statistical analyses were done using two-way repeated measures ANOVA, with p ≤ 0.05. Administration of CC did not induce changes in follicle numbers (p > 0.05). Plasma AMH concentrations did not differ between experimental groups; however, mean concentrations relative to time were different (p = 0.009). There were no differences for plasma FSH or LH concentrations, however, daily mean plasma LH varied (p < 0.001) with time within experimental groups. Endometrial edema scores were higher (p = 0.041) in mares treated with CC than in control mares, after allowing for time effect. In conclusion, daily administration of CC for 5 consecutive days did not affect follicle numbers or elicit substantial endocrine response. In humans, efficacy of CC treatment in correcting ovulatory dysfunction derives from its blocking effect on hypothalamic estrogen receptors. That, in turn, causes a significant release of FSH and LH. In contrast, in the present study, CC treatment had substantial estrogenic effects in uterus by inducing endometrial edema. Thus, it remains to be elucidated whether CC in mare has ability to modulate FSH and LH secretion. Pharmacokinetics analyses of blood samples are pending, and could provide a basis for revised protocols for CC administration.

Keywords: Equine, LH, FSH, AMH, estrogen, follicle dynamics

This manuscript was originally published in the journal Clinical Theriogenology Vol 12(3) Sept 2020.  Clinical Theriogenology is the official journal of the Society for Theriogenology (SFT) and the American College of Theriogenologists (ACT).  This content has been reproduced on the IVIS website with the explicit permission of the SFT/ACT.