Limbic Seizures Alter Reproductive Function in the Female Rat

Abstract

Summary:Purpose: Reproductive dysfunction and endocrine disorders are common among women with temporal lobe epilepsy. This study used the kindled rat model to test the hypothesis that limbic seizures directly contribute to reproductive dysfunction.Methods: Kindling electrodes were implanted in the basolatera1 amygdala in adult female rats. Females were kindled by either brief, daily, suprathreshold stimulations with a bipolar electrode or sham-kindled (controls). Electrographic and behavioral seizures were monitored. Estrous cycles also were monitored with daily vaginal smears.Results: Seizures arrested ovarian cyclicity in all (n = 42) kindled animals, the rats exhibiting persistent vaginal cornification (PVC). In these animals PVC was associated with high serum estradiol, increased pituitary weight, and polyfollicular ovaries consisting of many cystic follicles, as well as follicles in various stages of growth and atresia. In 93% of females, this effect occurred after the development of stage 5 motor seizures, when focal seizures had secondarily generalized. In contrast, only five (21%) of 24 sham-kindled controls exhibited PVC. A single injection of progesterone (P4) temporarily restored cyclicity in five (18%) of 28 kindled females exhibiting PVC. In contrast, P, administration restored cyclicity in all five shamkindled controls that had spontaneously stopped cycling. P, treatment to kindled females in PVC resulted in a different endocrine profile than that in non-P4-treated, kindled rats in PVC. P4-treated rats had high serum estradiol, testosterone, and prolactin levels; they showed an increase in pituitary weight; and their ovaries contained numerous corpora lutea and cystic follicles surrounded by markedly overdeveloped thecal cell layers.Conclusions: Seizures initiated in the amygdala result in impairment of the hypothalamic-pituitary axis, resulting in loss of ovarian cyclicity.

MANAGEMENT OF ENDOCRINE DISEASE: Secondary polycystic ovary syndrome: theoretical and practical aspects

“…This may explain the finding of an increased LH pulse, high levels of LH or an altered LH-to-FSH ratio that has been repeatedly observed in untreated epileptic women with regular menses, which supports the concept that the disease by itself may contribute to neuroendocrine and reproductive abnormalities (86). Further evidence from preclinical studies shows that the induction of temporolimbic seizures in animals was able to cause changes in reproductive hormone levels and also supports the potential combination of both neuroendocrine and ovarian disruption in the regulation of the hypothalamic pituitary axis as well as in the steroidogenetic theca pathways (87,88). The negative impact of VPA may, therefore, be additional to the intrinsic neuroendocrine alterations of the different pattern of epilepsy, as described above, due to the specific mechanisms by which VPA may disrupt both neuroendocrine circuits and the ovarian theca cell function, leading in turn to the development of PCOS.…”

Changes in hippocampal function of ovariectomized rats after sequential low doses of estradiol to simulate the preovulatory estrogen surge

“…Vaginal cytology was examined as previously described (Edwards et al, 1999;Scharfman et al, 2003). In brief, 2-3 month old animals were examined daily between 10:00 a.m. and 12:00 p.m., using a 30 lL sample from the vaginal cavity to evaluate the relative abundance of leukocytes, epithelial cells, or cornified epithelial cells.…”

The Anticonvulsant Effects of Progesterone and 5α‐dihydroprogesterone on Amygdala‐kindled Seizures in Rats

“…It is important to note that amygdala kindling suppresses cycling in female rats, stopping the cycle in persistent estrus (12). Thus variations in endogenous hormones need not be considered when working with kindled rats.…”

“…The phase of the estrous cycle was recorded as previously described by Edwards et al (12). Smears were taken for 6 consecutive days after stability testing, and the phase of the estrous cycle was noted for each day.…”