Cows with Follicular Fluid Androgen Excess Exhibit Anovulation and Have Altered Circulating Sex Hormone Binding Globulin, Gonadotropin Secretion and Plasma and Follicular Fluid Composition

Our laboratory identified a group of cows with excess intrafollicular concentrations of androstenedione (A4; >30 fold), reduced calving rates, and theca gene expression profiles similar to women with Polycystic Ovary Syndrome (PCOS). Based on these previous studies, we hypothesized that High A4 cows (n=6) have altered endocrine and metabolic profiles with irregular reproductive cycles compared to Low A4 controls (n=5). To test this hypothesis, cows were 1) synchronized to a more natural estrous cycle (one injection of Prostaglandin F 2 alpha (PG) and ablation of follicles greater than 7 mm (FA) on the same day) without ultrasound; 2) a more intensively manipulated estrous cycle (multiple injections of PG and FA); 3) stimulated with a low dose of FSH overtime and ovariectomized; to measure endocrine, follicular and lipid parameters during these three different cycles and at ovariectomy. Hormone data was analyzed using the MIXED procedure of SAS with day, group, and interaction as the fixed effects in a repeated measures model. Random Forest algorithm was used to select the top three lipids which were then compared between groups through unpaired t-test. Plasma sex hormone binding globulin (SHBG) and nonesterified fatty acids (NEFA) concentrations were reduced in High A4 cows during the natural and manipulated cycle vs Low A4 cows. Intensive manipulation of estrous cycles resulted in reduced SHBG in Low A4 cows compared to a natural cycle. Also, High A4 cows ovulated without behavioral estrus or displayed estrus without ovulation. Furthermore, at day 10 serum LH and FSH concentrations (P = 0.02), (P < 0.0001) were reduced in High A4 cows. Lipidomic analysis identified reduced hydroperoxy, phosphatidylcholine and lyso-phosphatidylethanolamine whereas phosphatidylglycerol was increased in blood plasma of High A4 compared to Low A4 cows. At ovariectomy after FSH stimulation there were fewer granulosa cells per mL of follicular fluid (P = 0.007) and dipalmitoylphosphatidylcholine (DPPC) was greater while monoacylglycerol was lower in High A4 vs Low A4 cows. Phosphatidylethanolamine and sphingomyelin were both reduced in follicular fluid of High A4 cows. Thus overall, High A4 cows had reduced gonadotropin secretion, NEFA, SHBG, and altered lipids during a non-FSH-stimulated cycle. High A4 cows had an impaired ability to respond to FSH stimulation resulting in reduced granulosa cell numbers and altered lipids. These altered metabolic factors may influence gonadotropin hormone secretion resulting in altered reproductive cycles and reduced calving rate in these High A4 cows.

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