Neuroendocrine mechanisms underlying social inhibition of puberty are not well understood. Here, we use a model exhibiting the most profound case of pubertal suppression among mammals to explore a role for RFamide-related peptide-3 [RFRP-3; mammalian ortholog to gonadotropin-inhibitory hormone (GnIH)] in neuroendocrine control of reproductive development. Naked mole rats (NMRs) live in sizable colonies where breeding is monopolized by two to four dominant animals, and no other members exhibit signs of puberty throughout their lives unless they are removed from the colony. Because of its inhibitory action on the reproductive axis in other vertebrates, we investigated the role of RFRP-3 in social reproductive suppression in NMRs. We report that RFRP-3 immunofluorescence expression patterns and RFRP-3/GnRH cross-talk are largely conserved in the NMR brain, with the exception of the unique presence of RFRP-3 cell bodies in the arcuate nucleus (Arc). Immunofluorescence comparisons revealed that central expression of RFRP-3 is altered by reproductive status, with RFRP-3 immunoreactivity enhanced in the paraventricular nucleus, dorsomedial nucleus, and Arc of reproductively quiescent NMRs. We further observed that exogenous RFRP-3 suppresses gonadal steroidogenesis and mating behavior in NMRs given the opportunity to undergo puberty. Together, our findings establish a role for RFRP-3 in preserving reproductive immaturity, and challenge the view that stimulatory peptides are the ultimate gatekeepers of puberty.eusocial | GnIH | naked mole rat | puberty | RFRP-3

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Summary We assessed the validity of the Edmonton Symptom Assessment System (ESAS‐r) in kidney transplant recipients (KTR). A cross‐sectional sample of 252 KTR was recruited. Individual ESAS‐r symptom scores and symptom domain scores were evaluated. Internal consistency, convergent validity, and construct validity were assessed with Cronbach’s α, Spearman’s rank correlations, and a priori‐defined risk group comparisons. Mean (SD) age was 51 (16), 58% were male, and 58% Caucasian. ESAS‐r Physical, Emotional, and Global Symptom Scores demonstrated good internal consistency (α > 0.8 for all). ESAS‐r Physical and Global Symptom Scores strongly correlated with PHQ‐9 scores (0.72, 95% CI: 0.64–0.78 and 0.74, 95% CI: 0.67–0.80). For a priori‐defined risk groups, individual ESAS‐r symptom score differed between groups with lower versus higher eGFR [pain: 1 (0–3) vs. 0 (0–2), delta = 0.18; tiredness: 3 (1–5) vs. 1.5 (0–4), delta = 0.21] and lower versus higher hemoglobin [tiredness: 3 (1–6) vs. 2 (0–4), delta = 0.27]. ESAS‐r Global and Physical Symptom Scores differed between groups with lower versus higher hemoglobin [13 (6–29) vs. 6.5 (0–18.5), delta = 0.3, and 9 (2–19) vs. 4 (0–13), delta = 0.24] and lower versus higher eGFR [11 (4–20) vs. 6.5 (2–13), delta = 0.21, and 7 (2–16) vs. 3 (0–9), delta = 0.26]. These data support reliability and construct validity of ESAS‐r in KTR. Future studies should explore its clinical utility for symptom assessment among KTR.

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