Constant Estrus: Role of Rostral Hypothalamic Monoamines in Development of Reproductive Dysfunction in Aging Rats*

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Abstract
This study investigates whether constant estrus (CE) induced pharmacologically might serve as a model for analyzing the reproductive dysfunction that occurs with advancing age in female rats. Antimetabolites of catecholamines [αmethyl-p-tyrosine (AMT) and diethyldithiocarbamate (DDC)] and of serotonin [p-chlorophenylalanine (PCPA)] were administered via indwelling cannulae to the rostral suprachiasmatic nucleus region (SNR) of young adult rats during diestrus 2. Subsequent changes in vaginal cycling, ovarian and uterine morphologies, hypothalamic monoamine concentrations, and serum gonadotropins were measured, and the values were compared with those from aged CE rats. Although each drug treatment induced prolonged vaginal cornification, the resulting CE showed qualitative differences. PCPA was the most effective drug in mimicking the condition of old CE rats. AMT and DDC usually produced irregular cycles rather than CE, but in approximately 50% of the treated animals this initial period of irregularity was followed by prolonged vaginal estrus. Drug treatment at control sites was ineffective in producing CE, confirming that SNR is a brain area critically involved in this syndrome. Ovaries from aged and PCPA-treated rats were polyfollicular and lacked corpora lutea, and those from AMT- or DDC-treated rats contained both unovulated follicles and corpora lutea. Uteri from AMT- or DDC-treated rats, but not those from PCPAtreated and aged rats, were ballooned and of the proestrous type due to retention of excessive luminal fluid. Basal serum LH values for controls, PCPA-treated, and aged CE rats were similar and significantly higher than those for AMT- or DDC-treated rats. FSH values were elevated above control values in all experimental groups. Serotonin (5-HT) and, to a lesser extent, norepinephrine (NE) levels in the hypothalamus were reduced in PCPA-treated rats, while NE levels alone were depressed after AMT or DDC treatment. Dopamine levels were unchanged from control values in all drug treatment groups. All monoamines were significantly reduced in aged CE rats when compared to those in young estrous females; however, the relative concentrations of 5-HT, NE, and dopamine resembled those in PCPA-treated rats. Drug-induced decrements in hypothalamic 5-HT, associated with a moderate reduction in NE levels but not a reduction of NE alone, produce in young cycling rats a CE syndrome similar to that occurring spontaneously in aged animals. In light of the great number of 5-HT terminals in the suprachiasmatic nucleus and the ascribed role of this nucleus in generating gonadotropic rhythms, we speculate that abnormal 5-HT metabolism in the SNR with advancing age may result in a loss of timing and activation of phasic LH release, thereby resulting in CE.