Context Hyperprolactinemia suppresses GnRH-induced LH pulses. The hypothalamic neuropeptide kisspeptin potently stimulates the secretion of GnRH. The effects of exogenous kisspeptin administration on GnRH pulse generation in the setting of hyperprolactinemia have not previously been explored. Objective To examine the effects of kisspeptin on GnRH secretion, as reflected by LH secretion, in women with hyperprolactinemia. Participants Women with hyperprolactinemia. Intervention Women with hyperprolactinemia (n=11) participated in two, 12-hour visits. Prior to study visits, subjects underwent washout of dopamine agonist and/or combined oral contraceptive. Frequent blood sampling was performed (one sample was collected every 10 minutes). Visit 1 involved no intervention, in order to examine baseline LH pulsatility. During Visit 2, kisspeptin 112-121 (0.24 nmol/kg) was administered every 1 hour, for 10 hours. At hour 11, one IV bolus of GnRH (75 ng/kg) was administered. Results Repetitive IV bolus (IVB) kisspeptin administration increased the total number of LH pulses in the setting of hyperprolactinemia. The inter-pulse interval declined during the same time frames. LH pulse amplitude did not change, but the mean LH rose. In 6 participants with progesterone levels suggestive of an anovulatory state, mean LH, and estradiol levels increased significantly at Visit 2. In the entire cohort, FSH and PRL levels did not change significantly across the two visits. 73% of subjects exhibited an LH pulse within 30 minutes of first kisspeptin dose. Conclusions Kisspeptin is capable of stimulating hypothalamic GnRH-induced LH pulses in the setting of hyperprolactinemia.
Consolidated memories can be returned to a labile state upon reactivation. The re-stabilization of reactivated memories, or reconsolidation, can allow for change in previously established memories. Given the role of sleep in the initial consolidation of memories, sleep may be important for reconsolidation as well. However, effects of sleep on reconsolidation and specific aspects of sleep that may contribute are unclear. Here, participants learned 30 picture-location pairs. After overnight sleep, initial consolidation was tested. Following either one day (Experiment 1) or one week (Experiment 2), participants were tested again to reactivate their memory and then learned 30 novel picture-location pairs. Control groups (Experiment 1) received no reactivation prior to new learning. Twelve hours later, after daytime wakefulness or overnight sleep, participants completed a final memory test. Sleep participants underwent polysomnography between reactivation and final tests. In Experiment 1, reactivation led to preservation of memory compared to no reactivation. Sleep was associated with less post-reactivation memory decline than waking, with memory preservation positively related to time spent in non-rapid-eye movement sleep. In Experiment 2, sleep was associated with greater post-reactivation memory improvement than waking, with improvement positively related to sigma activity. These results suggest sleep enhances reconsolidation-based strengthening of episodic memories.
Knockout mice for the kisspeptin receptor, Kiss1r, (Kiss1r−/−) and its ligand kisspeptin, Kiss1, (Kiss1−/−) replicate the phenotype of isolated hypogonadotropic hypogonadism (IHH) associated with variants of these genes in humans. A recent report suggests that kisspeptin may be involved in human fetal adrenocortical development and function. Herein, we characterized the adrenal function and morphology in Kiss1−/− mice that do not go through normal puberty. Two fetal markers were expressed in eosinophilic cells potentially derived from the X-zone that should disappear at puberty in male mice, and during the first pregnancy in female animals. Although the hypercorticosteronism observed in Kiss1−/− females corrected overtime, hyperaldosteronism persisted at 14 months, and correlated with overexpression of Star. To determine if KISS1 and KISS1R genes are involved in the development of primary aldosteronism (PA) and hypercortisolism (Cushing syndrome-CS) in humans, we sequenced these 2 genes in 65 patients with PA and/or CS. Interestingly, a patient with CS presented with a germline KISS1 variant (p.H90D, rs201073751). We also found three rare variants in the KISS1R gene in three patients with PA: p.C95W (rs141767649), p.A189T (rs73507527) and p.R229R (rs115335009). The two missense variants have been previously associated with IHH. Our findings suggest that KISS1 may play a role in adrenal function in mice and possibly adrenocortical steroid hormone secretion in humans, beyond its recently described role in human fetal adrenocortical development.
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