Long-Term Neonatal Estrogen Exposure Causes Irreversible Inhibition of LH Pulses by Suppressing Arcuate Kisspeptin Expression via Estrogen Receptors α and β in Female Rodents

Apr 4, 2017Endocrinology

Long-term estrogen exposure in newborn female rodents permanently reduces hormone pulses by lowering key hormone signals through estrogen receptors

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Abstract

Long-term exposure to supraphysiological doses of estrogen during the neonatal period leads to irreversible reproductive dysfunction in female rats.

Neonatal estrogen exposure causes persistent vaginal diestrus in female rats.
This exposure results in a significant reduction of Kiss1/kisspeptin expression in the arcuate nucleus of the brain.
Pulsatile luteinizing hormone (LH) release is profoundly suppressed even after ovariectomy in adulthood.
A single injection of estrogen at day 5 postpartum leads to normal LH pulse patterns and estrous cycles post-ovariectomy.
The reduction in LH release is likely due to a deficiency of ARC kisspeptin neurons caused by neonatal estrogen exposure.
Both estrogen receptors ERα and ERβ are involved in the suppression of Kiss1 expression in this context.

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Exposure to estrogen during the developmental period causes reproductive dysfunction in mammals, because the developing brain is highly sensitive to estrogens. In the present study, we report that long-term exposure to supraphysiological doses of estrogen during the neonatal critical period causes irreversible suppression of Kiss1/kisspeptin expression in the arcuate nucleus (ARC) via estrogen receptor-alpha (ERα) and ERβ, resulting in reproductive dysfunction in female rats. Daily estradiol-benzoate (EB) administration from days 0 to 10 postpartum caused persistent vaginal diestrus in female rats. The female rats showed profound suppression of pulsatile luteinizing hormone (LH) release and ARC Kiss1/kisspeptin expression even after ovariectomy at adulthood. In contrast, female rats treated with a single EB injection at day 5 postpartum exhibited persistent vaginal estrus and showed comparable LH pulses and numbers of ARC Kiss1-expressing cells to vehicle-treated controls after ovariectomy at adulthood. Because the LH secretory response to exogenous kisspeptin was spared in female rats with neonatal long-term estrogen exposure, the LH pulse suppression was most probably due to ARC kisspeptin deficiency. Furthermore, neonatal estrogen might act through both ERα and ERβ, because EB exposure significantly reduced the number of ARC Kiss1-expressing cells in wild-type mice but not in ERα or ERβ knockout mice. Taken together, long-term exposure to supraphysiological doses of estrogen in the developing brain might cause defects in ARC kisspeptin neurons via ERα and ERβ, resulting in inhibition of pulsatile LH release and lack of estrous cyclicity.

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Long-Term Neonatal Estrogen Exposure Causes Irreversible Inhibition of LH Pulses by Suppressing Arcuate Kisspeptin Expression via Estrogen Receptors α and β in Female Rodents

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