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Raul Riquelme, Freddy Ruz, Artur Mayerhofer and Hernán E Lara

An increase in the sympathetic tone in the rat ovary induces a polycystic ovary (PCOS-like) phenotype. No information exists about its impact on fertility. In contrast, increased follicular development and improved fertility in rats were found after pharmacological inhibition of acetylcholinesterase, which increased intraovarian acetylcholine (ACh). Now, we studied the impact of sympathetic stress, followed by a recovery period without stress, on the cholinergic and noradrenergic systems of the rat ovary and on fertility. To activate ovarian sympathetic nerves, female Sprague–Dawley rats were exposed to cold stress (4°C/3 h day for 28 days; first period), followed by a 28-day period without cold stress (second period). No changes in estrous cyclicity during the first period was found. At the end of this period, ovarian levels of NA and ACh were increased. Morphometric analysis showed lower numbers of secondary and antral follicles, enhanced follicular atresia and fewer corpora lutea. Plasma progesterone was lower and testosterone was higher than that in controls. At end of the second period, ovarian ACh levels had returned to control levels, but NA levels remained elevated. The second period was also characterized by the presence of cystic follicles in the ovary, by elevated plasma testosterone and estradiol levels, while progesterone levels were decreased. Estrous cyclicity and ovulation during that period were irregular and fertility decreased. Thus, cold stress initially activated both ovarian noradrenergic and cholinergic system. After stress, the ovary did not fully recover and activation of the noradrenergic system persisted and correlated with cystic ovarian morphology and decreased fertility.

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Daniela Fernandois, Gonzalo Cruz, Eun Kyung Na, Hernán E Lara and Alfonso H Paredes

Previous work has demonstrated that the increase in the activity of sympathetic nerves, which occurs during the subfertility period in female rats, causes an increase in follicular cyst development and impairs follicular development. In addition, the increase in ovarian sympathetic activity of aged rats correlates with an increased expression of kisspeptin (KISS1) in the ovary. This increase in KISS1 could participate in the decrease in follicular development that occurs during the subfertility period. We aimed to determine whether the blockade of ovarian sympathetic tone prevents the increase in KISS1 expression during reproductive aging and improves follicular development. We performed 2 experiments in rats: (1) an in vivo blockade of beta-adrenergic receptor with propranolol (5.0 mg/kg) and (2) an ovarian surgical denervation to modulate the sympathetic system at these ages. We measured Kisspeptin and follicle-stimulating hormone receptor (FSHR) mRNA and protein levels by qRT-PCR and western blot and counted primordial, primary and secondary follicles at 8, 10 and 12 months of age. The results showed that ovarian KISS1 decreased but FSHR increased after both propranolol administration and the surgical denervation in rats of 8, 10 and 12 months of age. An increase in FSHR was related to an increase in the number of smaller secondary follicles and a decreased number of primordial follicles at 8, 10 and 12 months of age. These results suggest that intraovarian KISS1 is regulated by sympathetic nerves via a beta-adrenergic receptor and participates locally in ovarian follicular development in reproductive aging.

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Miguel del Campo, Néstor Lagos and Hernán Lara

A high sympathetic tone is observed in the development and maintenance of the polycystic ovary (PCO) phenotype in rats. Neosaxitoxin (NeoSTX) specifically blocks neuronal voltage-dependent Na+ channels, and we studied the capacity of NeoSTX administered into the ovary to block sympathetic nerves and PCO phenotype that is induced by estradiol valerate (EV). The toxin was administered with a minipump inserted into the bursal cavity using two protocols: (1) the same day as EV administration and (2) 30 days after EV to block the final step of cyst development and maintenance of the condition. We studied the estrous cycling activity, follicular morphology, steroid plasma levels, and norepinephrine concentration. NeoSTX administered together with EV decreased NA intraovarian levels that were induced by EV, increased the number of corpora lutea, decreased the number of follicular cyst found after EV administration, and decreased the previously increased testosterone plasma levels induced by the PCO phenotype. Estrous cycling activity also recovered. NeoSTX applied after 30 days of EV administration showed near recovery of ovary function, suggesting that there is a specific window in which follicular development could be protected from cystic development. In addition, plasma testosterone levels decreased while those of progesterone increased. Our data strongly suggest that chronic inhibition of sympathetic nerves by a locally applied long-lasting toxin is a new tool to manage the polycystic phenotype in the rat and could be applied to other mammals depending on sympathetic nerve activity.