Contraceptive hormones -ethinyl estradiol and levonorgestrel- cognitive effect and noradrenergic alterations
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The advent of fertility control by contraceptive hormones swept into the mid-twentieth century altering women’s lives more than anticipated. The pharmacological mechanism of action of these potent hormones was known but not correlated to central nervous system targets with downstream consequences. Over fifty years, few studies questioned altered cognitive processing in this modified endocrinological state. Using a rat model, this dissertation uncovers different cognitive abilities that present with chronic contraceptive treatment. Our focus was the locus coeruleus, an area of the brain ascribed to attention, and its noradrenergic projection areas—hippocampus and prefrontal cortex, all sexually dimorphic. Rats, receiving three weeks of daily ethinyl estradiol 10µg or 30µg and levonorgestrel 20µg or 60µg were tested in learning and anxiety tasks relevant to the norepinephrine system. The lower doses proved to be ovulation suppressive, and the higher doses were chosen for dose-dependent observations. In the elevated-plus maze and shock-probe defensive burying, anxiolytic-like behavior was noted in the low dose groups. In the learning tests, dose-dependent effects of drug treatments were manifest, with the low dose showing an impairment and the high dose an enhancement compared to the natural low hormone state of the rat. In-situ hybridization was performed for locus coeruleus tyrosine hydroxylase, the rate-limiting enzyme for the production of norepinephrine, and hippocampal brain-derived neurotrophic hormone, a neurotrophin. Both were reduced in the low dose drug-treated groups, and, when combined with behavioral results, suggested an altered noradrenergic tone. Duplicating the experiment, with the low and high dose of ethinyl estradiol only, the novel object recognition testing again showed enhanced learning in the higher dose ethinyl estradiol treated rats. Consistent with this behavior, the ethinyl estradiol 30µg treated rats’ tissue norepinephrine level was significantly greater than both the control and the ethinyl estradiol 10µg group, in the prefrontal cortex—an area necessary for recent memory retrieval. These distinct dose-dependent actions of ethinyl estradiol on learning/memory and norepinephrine levels suggest a threshold to the minimal dose of ethinyl estradiol used in contraceptive hormone regimens. These findings could have significant consequences for the 10.6 million women using contraceptive hormones in the United States.