κ Agonists as a novel therapy for menopausal hot flashes

Abstract

Objective Postmenopausal hot flash etiology is poorly understood, making it difficult to develop and target ideal therapies. A network of hypothalamic estrogen-sensitive neurons producing Kisspeptin, Neurokinin B, and Dynorphin (KNDy neurons), located adjacent to the thermoregulatory center, regulate pulsatile secretion of GnRH and LH. Dynorphin may inhibit this system by binding kappa opioid receptors within the vicinity of KNDy neurons. We hypothesize that hot flashes are reduced by KNDy neuron manipulation. Methods A double-blind, cross-over, placebo-controlled pilot study evaluated the effect of a kappa agonist (KA).Hot flash frequency was the primary outcome. Twelve healthy postmenopausal women with moderate-severe hot flashes, ages 48-60 years, were randomized. Eight women with sufficient baseline hot flashes for statistical analysis completed all 3 interventions: placebo, standard Pentazocine/Naloxone (50/0.5 mg) or low-dose Pentazocine/Naloxone (25/0.25 mg). In an inpatient research setting, each participant received the 3 interventions, in randomized order, on 3 separate days. On each day, an intravenous catheter was inserted for luteinizing hormone (LH) blood sampling, and skin conductance and Holter monitors were placed. Subjective hot flash frequency and severity were recorded. Results Mean hot flash frequency 2-7 hours following therapy initiation was lower than that for placebo (KA standard-dose: 4.75 ± 0.67; KA low-dose: 4.50 ± 0.57; and placebo: 5.94 ± 0.78 hot flashes/5 hours; p =0.025). Hot flash intensity did not vary between interventions. LH pulsatility mirrored objective hot flashes in some, but not all women. Conclusions This pilot suggests that kappa agonists may affect menopausal vasomotor symptoms.

Neurokinin 3 Receptor Antagonism Reveals Roles for Neurokinin B in the Regulation of Gonadotropin Secretion and Hot Flashes in Postmenopausal Women

“…The reduction in frequency of LH pulses with the NK3R antagonist observed here in the group of women with flash symptoms suggests the mechanism of flashes to be tied to the hypothalamic control of pulsatile GnRH secretion. This is consistent with studies showing a synchronisation of LH pulses with hot flashes in women [20][21][22]. Although these data support the involvement of NKB in vasomotor symptoms, it is possible that separate pathways exist, those that mediate hot flashes and those that are associated with pulsatile GnRH/LH secretion, with both involving NKB regulation.…”

“…Manipulation of high LH/GnRH pulsatility in postmenopausal women may open new paradigms in the management of menopausal hot flashes, since functional links between pathways driving GnRH pulsatility and vasomotor symptoms have been proposed [20]. Synchronisation of LH pulses with hot flashes in women has been demonstrated [21,22], and administration of exogenous NKB induced hot flash-like symptoms in healthy premenopausal women [23]. Using a selective NK3R antagonist, the role of NKB in the regulation of the hypergonadotropic state in menopausal women and its interaction with kisspeptin was therefore investigated.…”

Menopausal hot flashes: The role of magnesium and select endocrine factors

“…Continuous transdermal nitroglycerin is a new experimental treatment for hot flashes that works by tolerance-induced suppression of nitric oxidemediated vasodilation [48]. Treatments that target the KNDy system are also currently being studied [49,50]. Some women are unable to use hormone therapy as treatment due to contraindications to exogenous estrogen, such as those with a history of breast cancer, therefore it is important to study other possible treatments for hot flashes [51].…”

Pathophysiology of hot flashes with focus on neurohormonal regulation (a review)

“…Кроме того, при аблации KNDyнейронов крысы лучше поддерживали внутреннюю температуру тела [3,25]. Известно, что KNDy-нейроны соседствуют со структурами, отвечающими за регуляцию температуры тела [3,[35][36][37], в том числе со срединным преоптическим ядром, важным компонентом термосенсорного пути защиты от перегрева. Таким образом, связи KNDy-нейронов как с преоптическими структурами, отвечающими на терморегуляцию, так и с ГнРГ-нейронами объясняют временну´ю связь между приливами и пульсами секреции ЛГ у женщин в постменопаузе.…”