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Neuro-pharmacological reinstatement of ovulation and associated neurobiology in a macaque model of functional hypothalamic amenorrhoea

Abstract STUDY QUESTION What is the underlying neuropathology in a cynomolgus macaque model of functional hypothalamic amenorrhoea (FHA) and can it be normalized to restore ovulation? SUMMARY ANSWER Anovulatory monkeys exhibited increased hypothalamic norepinephrine (NE), kisspeptin and gonadotropin...

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Published in:Human reproduction (Oxford) 2021-01, Vol.36 (1), p.175-188
Main Authors: Bethea, Cynthia L, Cameron, Judy L
Format: Article
Language:English
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Summary:Abstract STUDY QUESTION What is the underlying neuropathology in a cynomolgus macaque model of functional hypothalamic amenorrhoea (FHA) and can it be normalized to restore ovulation? SUMMARY ANSWER Anovulatory monkeys exhibited increased hypothalamic norepinephrine (NE), kisspeptin and gonadotropin-releasing hormone (GnRH) in the early follicular phase, but administration of the NE reuptake inhibitor (NRI), reboxetine (REB), restored ovulation during stress and normalized NE, kisspeptin and GnRH. WHAT IS KNOWN ALREADY Female cynomolgus macaques, like women, show individual reproductive sensitivity to modest psychosocial and metabolic stress. During stress, resilient females ovulate through two menstrual cycles whereas stress-sensitive (SS) macaques immediately cease ovulation. On Day 5 of a non-stressed menstrual cycle, resilient macaques have less NE synthesizing enzyme [dopamine β-hydroxylase (DBH)], kisspeptin and GnRH innervation of the medial basal hypothalamus but more endogenous serotonin than SS macaques. Stress increased DBH/NE, kisspeptin and GnRH but did not alter serotonin. STUDY DESIGN, SIZE, DURATION In a longitudinal design, 27 adult (7–13 years) female cynomolgus macaques (Macaca fascicularis) with three different levels of sensitivity to stress were monitored with daily vaginal swabs and frequent serum progesterone (P) measurements. Three 90-day experimental periods called ‘Cycle Sets’ were monitored. A Cycle Set consisted of one ovulatory menstrual cycle without stress, and two cycles, or 60 days, with modest stress. Each Cycle Set was followed by a rest period. During a Cycle Set, individuals were either untreated (placebo) or administered escitalopram (CIT) or REB. Ultimately, half of each sensitivity group was euthanized during stress with CIT or REB treatment and the hypothalamus was obtained. Neurobiological endpoints were compared between CIT and REB treatment groups in stress resilient and SS monkeys. PARTICIPANTS/MATERIALS, SETTING, METHODS The monkeys were housed at the University of Pittsburgh primate facility for the duration of the experiments. Upon euthanasia, their brains and serum samples were shipped to the Oregon National Primate Research Center. The hypothalamus was examined with immunohistochemistry for the expression of DBH (a marker for NE axons), kisspeptin and GnRH. P was measured in the serum samples by radioimmunoassay. MAIN RESULTS AND THE ROLE OF CHANCE Daily administration of REB restored ovulation in 9 of 10
ISSN:0268-1161
1460-2350
DOI:10.1093/humrep/deaa296