Lipoic Acid Supplementation in the Ovariectomized Ewe
Mottet, Rachel Susan
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Inadequate concentrations of progesterone during gestation can result in impaired embryonic growth and losses. These losses may be attributed to an overactive mechanism of progesterone catabolism or improper luteal function, which results in low concentration of progesterone. Progesterone catabolism occurs to the greatest extent by the liver, which holds a vast supply of cytochrome P450 enzymes and aldo-keto reductases that are involved in steroid inactivation. Insulin is a hormone produced by the pancreas that is involved in glucose uptake and metabolism. Progesterone catabolism is decreased in the presence of elevated insulin levels. Lipoic acid is a naturally occurring antioxidant and multienzyme cofactor which has been shown to increase insulin sensitivity and enhance glucose uptake in a number of species. The objectives of the current experiments were to 1) determine if administering a racemic mixture of lipoic acid by gavage at a dose of 32 mg/kg BW would increase peripheral progesterone concentrations, decrease progesterone clearance rates, or modulate cytochrome P450 2C (CYP2C), cytochrome P450 3A (CYP3A), or aldo-keto reductase 1 C (AKRIC) hepatic enzyme activity, and 2) determine if dosing lipoic acid directly into the rumen at 32 mg/kg BW or 64 mg/kg BW would increase progesterone in the blood, decrease progesterone clearance rates, or modulate insulin. In the first trial, Katahdin cross ovariectomized ewes were randomly assigned to a control or a lipoic acid treatment group. In this experiment, a controlled internal drug release (CIDR) device was inserted in all ewes and serum samples were collected daily for five days to determine progesterone. Liver biopsies were performed on day 10 to measure CYP2C, CYP3A, and AKRI C activity. Following liver biopsies, CIDRs were removed and an intensive blood sampling was performed to measure progesterone decay from peripheral circulation. We found that while lipoic acid does not have an effect on peripheral progesterone concentrations or hepatic enzyme activity, lipoic acid supplemented ewes have decreased progesterone clearance rates compared to control ewes. In the second trial, ovariectomized Katahdin cross ewes were randomly assigned to a control, low lipoic acid (32 mg/kg BW), or a high lipoic acid (64 mg/kg BW) treatment group. A CIDR was inserted in all ewes and blood samples were taken daily for 4 days. Following CIDR removal on day 11, an intensive blood sampling was performed to measure progesterone decay from peripheral circulation. One week following CIDR removal, ewes underwent an intravenous glucose tolerance test. It was found that lipoic acid supplementation did not affect progesterone concentrations, progesterone clearance, or insulin area under the curve. There was a treatment effect such that high lipoic acid dosed ewes had higher area under the curve for glucose when compared to control and low lipoic acid dosed ewes. Although no differences in progesterone concentrations were seen in the second trial, we speculate that the administration method rather than the efficacy of lipoic acid may account for the lack of differences observed. This theory is based on evidence from our first trial that oral lipoic acid supplementation did in fact reduce progesterone catabolism, as well as published data demonstrating that ruminally dosed lipoic acid is less effective than the equivalent oral dose.