Age-related LH surge dysfunction correlates with reduced responsiveness of hypothalamic anteroventral periventricular nucleus kisspeptin neurons to estradiol positive feedback in middle-aged rats

Abstract

Female reproductive aging in rats is characterized by reduced gonadotropin releasing hormone (GnRH) neuronal activation under estradiol positive feedback conditions and a delayed and attenuated luteinizing hormone (LH) surge. The newly identified excitatory neuropeptide kisspeptin is proposed to be a critical mediator of the pubertal transition and the ovarian steroid-induced LH surge. We previously showed that estradiol induces less kisspeptin mRNA expression in the anterior hypothalamus [anatomical location of anteroventral periventricular nucleus (AVPV)] in middle-aged than in young rats and intrahypothalamic infusion of kisspeptin restores LH surge amplitude in middle-aged females. Thus, reduced kisspeptin neurotransmission may contribute to age-related LH surge abnormalities. This study tested the hypothesis that middle-aged females will also exhibit reduced numbers of kisspeptin immunopositive neurons in the AVPV under estradiol positive feedback conditions. Using immunohistochemistry, we demonstrate that middle-aged females primed with ovarian steroids have fewer AVPV kisspeptin immunopositive neurons than young females. Age did not affect kisspeptin mRNA expression in the pituitary, numbers of kisspeptin immunopositive neurons in the arcuate nucleus, or estradiol-dependent reductions in kisspeptin mRNA expression in the posterior hypothalamus (containing the arcuate nucleus). These data strongly suggest that age-related LH surge dysfunction results, in part, from a reduced sensitivity of AVPV kisspeptin neurons to estradiol and hence decreased availability of AVPV kisspeptin neurons to activate GnRH neurons under positive feedback conditions.

Prior attenuation of KiSS1/GPR54 signaling in the anteroventral periventricular nucleus is a trigger for the delayed effect induced by neonatal exposure to 17alpha-ethynylestradiol in female rats

“…Recently, moreover, not only the alteration in the LH surge, but also attenuation of KiSS1/GPR54 signaling in the hypothalamus of middle-aged rats have been reported in several articles [28,29,41], suggesting depression of kisspeptin neuron might be a trigger for age-related LH surge dysfunction and reproductive aging [28]. In the present study, we confirmed the similar serial dysfunction of the kisspeptin neuron and LH surge in young adult animals neonatally exposed to EE.…”

“…Since no abnormalities in ovarian follicles were detected in these animals, disruption of the HPG axis, especially of the luteinizing hormone (LH) surge and hypothalamic KiSS1/GPR54 signaling are predicted. In fact, there are a few reports that show a significant decrease in KiSS1 mRNA expression and kisspeptinimmunoreactivity in the hypothalamic kisspeptin neurons in middle-aged rats [28,29] and in animals neonatally exposed to various estrogenic compounds [30][31][32]. However, the selected dose in these reports are extremely high, and sufficient to cause the "masculinization" of the female brain; therefore, the contribution of kisspeptin to the occurrence of delayed effects induced by low-dose neonatal exposure to estrogenic compounds remains unclear.…”

Ovarian kisspeptin expression is related to age and to monocyte chemoattractant protein-1

“…Interestingly, cumulus and mural GCs have been shown to reflect the characteristics of the oocyte thus providing a noninvasive means to assess oocyte quality [35]. Our current findings suggest that in an infertile population, agerelated upregulation in kiss1r expression may alter kisspeptin sensitivity in human cumulus GCs indicating a possible agerelated physiologic role, similar to that observed in the hypothalamus [7,8], for the kisspeptin system in human follicular dynamics. These findings were supported by current data from mice where old mice had significantly higher kiss1 and kiss1r in their ovaries compared to younger reproductive-aged mice.…”

“…We and others have documented that reproductive aging is characterized by reduced hypothalamic kiss1 expression [7,8]. On the other hand, women with diminished ovarian reserve have a significant increase in ovarian sympathetic nerve fibers [9] whose stimulation with β-adrenergic agonist induces ovarian kiss1 expression [4].…”

Differential effects of aging on estrogen negative and positive feedback

“…3, 6, and 39), a diminished diurnal rhythm of suprachiasmatic nucleus input (17), and reduced responsiveness to kisspeptin (18). However, there is considerable evidence that estrogen positive feedback in women is mediated primarily at the pituitary, with hypothalamic GnRH secretion playing only a permissive role (14,15,21).…”