Naturally occurring androgen excess cows are present in dairy and beef herds and have similar characteristics to women with PCOS.

Beef cows with excess androstenedione (A4; High A4) in follicular fluid (FF) and secreted by the ovarian cortex have been reported from the University of Nebraska-Lincoln physiology herd displaying characteristics reminiscent of polycystic ovary syndrome (PCOS). Thus, we hypothesized that naturally occurring High A4 cows were present in other dairy and beef herds. Fourteen Jordan (Amman, Jordon) dairy heifers and 16 U.S. Meat Animal Research Center beef heifers were classified by FF (High A4: A4 > 40 ng/mL and Control: A4 < 20 ng/mL) and/or cortex culture media (High A4 > 1 ng/mL/d or Control < 1 ng/mL/d). High A4 dairy heifers (n = 6) had greater A4 concentrations (7.6-fold) in FF and (98-fold) greater in ovarian cortex culture media with greater numbers of primordial and fewer later-stage follicles than Controls (n = 8) even after 7 d of culture. Also, the ovarian cortex had greater staining for Picro Sirius red in High A4 dairy heifers compared with Controls indicating increased fibrosis. Thecal cells from High A4 dairy heifers had greater STAR, LHCGR, CYP17A, CD68, and PECAM mRNA expression with increased mRNA abundance of CYP17A1 and CD68 in the ovarian cortex cultures compared with Control dairy heifers. Similarly, cortex culture media from High A4 beef heifers (n = 10) had increased A4 (290-fold; P ≤ 0.001), testosterone (1,427-fold; P ≤ 0.001), and progesterone (9-fold; P ≤ 0.01) compared with Control heifers with increased primordial follicles and decreased later-stage follicles even after 7 d of culture, indicating abnormal follicular development. High A4 ovarian cortex cultures from beef heifers also had increased fibrosis markers and greater expression of PECAM (P = 0.01) with a tendency for increased vascular endothelial cadherin compared with Controls (n = 6). These two trials support our hypothesis that naturally occurring androgen excess cows are present in other dairy and beef herds. The ability to identify these females that have excess A4 ovarian microenvironments may allow for their use in understanding factors causing abnormal follicle development linked to androgen excess and inflammation.

Androgen steroid hormones, normally present in the male, but produced in excess in the female, can result in inflammation and dysfunction of tissues, which, in turn, can lead to ovulatory dysfunction. We have previously identified females with naturally occurring excess androgen in our research herd. In the current paper, we have also identified two other cow populations (one dairy and one beef) that have similar excess androgen production. This suggests that these excess androgen females occur naturally and may be used as models to study androgen excess situations that contribute to subfertility.

VEGFA165 can rescue excess steroid secretion, inflammatory markers, and follicle arrest in the ovarian cortex of High A4 cows†.

A population of cows with excess androstenedione (A4; High A4) in follicular fluid, with follicular arrest, granulosa cell dysfunction, and a 17% reduction in calving rate was previously identified. We hypothesized that excess A4 in the ovarian microenvironment caused the follicular arrest in High A4 cows and that vascular endothelial growth factor A would rescue the High A4 phenotype. In trial 1, prior to culture, High A4 ovarian cortex (n = 9) had greater numbers of early stage follicles (primordial) and fewer later-stage follicles compared to controls (n = 11). Culture for 7 days did not relieve this follicular arrest; instead, High A4 ovarian cortex had increased indicators of inflammation, anti-Mullerian hormone, and A4 secretion compared to controls. In trial 2, we tested if vascular endothelial growth factor A isoforms could rescue the High A4 phenotype. High A4 (n = 5) and control (n = 5) ovarian cortex was cultured with (1) PBS, (2) VEGFA165 (50 ng/mL), (3) VEGFA165B (50 ng/mL), or (4) VEGFA165 + VEGFA165B (50 ng/mL each) for 7 days. Follicular progression increased with VEGFA165 in High A4 cows with greater early primary, primary, and secondary follicles than controls. Similar to trial 1, High A4 ovarian cortex secreted greater concentrations of A4 and other steroids and had greater indicators of inflammation compared to controls. However, VEGFA165 rescued steroidogenesis, oxidative stress, and fibrosis. The VEGFA165 and VEGFA165b both reduced IL-13, INFα, and INFß secretion in High A4 cows to control levels. Thus, VEGFA165 may be a potential therapeutic to restore the ovarian steroidogenic microenvironment and may promote folliculogenesis.