PMID- 33522579
OWN - NLM
STAT- MEDLINE
DCOM- 20211020
LR  - 20211020
IS  - 1945-7170 (Electronic)
IS  - 0013-7227 (Linking)
VI  - 162
IP  - 5
DP  - 2021 May 1
TI  - Neurokinin 3 Receptor Antagonism Ameliorates Key Metabolic Features in a 
      Hyperandrogenic PCOS Mouse Model.
LID - bqab020 [pii]
LID - 10.1210/endocr/bqab020 [doi]
AB  - Polycystic ovary syndrome (PCOS) is a prevalent endocrine condition characterized 
      by a range of endocrine, reproductive, and metabolic abnormalities. At present, 
      management of women with PCOS is suboptimal as treatment is only symptomatic. 
      Clinical and experimental advances in our understanding of PCOS etiology support 
      a pivotal role for androgen neuroendocrine actions in PCOS pathogenesis. 
      Hyperandrogenism is a key PCOS trait and androgen actions play a role in 
      regulating the kisspeptin-/neurokinin B-/dynorphin (KNDy) system. This study 
      aimed to investigate if targeted antagonism of neurokinin B signaling through the 
      neurokinin 3 receptor (NK3R) would reverse PCOS traits in a dihydrotestosterone 
      (DHT)-induced mouse model of PCOS. After 3 months, DHT exposure induced key 
      reproductive PCOS traits of cycle irregularity and ovulatory dysfunction, and 
      PCOS-like metabolic traits including increased body weight; white and brown fat 
      pad weights; fasting serum triglyceride and glucose levels, and blood glucose 
      incremental area under the curve. Treatment with a NK3R antagonist (MLE4901) did 
      not impact the observed reproductive defects. In contrast, following NK3R 
      antagonist treatment, PCOS-like females displayed decreased total body weight, 
      adiposity, and adipocyte hypertrophy, but increased respiratory exchange ratio, 
      suggesting NK3R antagonism altered the metabolic status of the PCOS-like females. 
      NK3R antagonism did not improve circulating serum triglyceride or fasted glucose 
      levels. Collectively, these findings demonstrate that NK3R antagonism may be 
      beneficial in the treatment of adverse metabolic features associated with PCOS 
      and support neuroendocrine targeting in the development of novel therapeutic 
      strategies for PCOS.
CI  - (c) The Author(s) 2021. Published by Oxford University Press on behalf of the 
      Endocrine Society. All rights reserved. For permissions, please e-mail: 
      journals.permissions@oup.com.
FAU - Sucquart, Irene E
AU  - Sucquart IE
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Nagarkar, Ruchi
AU  - Nagarkar R
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Edwards, Melissa C
AU  - Edwards MC
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Rodriguez Paris, Valentina
AU  - Rodriguez Paris V
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Aflatounian, Ali
AU  - Aflatounian A
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Bertoldo, Michael J
AU  - Bertoldo MJ
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Campbell, Rebecca E
AU  - Campbell RE
AD  - Centre of Neuroendocrinology and Department of Physiology, School of Biomedical 
      Sciences, University of Otago, Dunedin 9054, New Zealand.
FAU - Gilchrist, Robert B
AU  - Gilchrist RB
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
FAU - Begg, Denovan P
AU  - Begg DP
AD  - Department of Behavioural Neuroscience, School of Psychology, University of New 
      South Wales, Sydney, NSW 2052, Australia.
FAU - Handelsman, David J
AU  - Handelsman DJ
AD  - Andrology Laboratory, ANZAC Research Institute, University of Sydney, Concord 
      Hospital, NSW 2139, Australia.
FAU - Padmanabhan, Vasantha
AU  - Padmanabhan V
AD  - Department of Pediatrics, University of Michigan, Ann Arbor, MI 48109, USA.
FAU - Anderson, Richard A
AU  - Anderson RA
AD  - Medical Research Council Centre for Reproductive Health, University of Edinburgh, 
      Edinburgh EH16 4TJ, UK.
FAU - Walters, Kirsty A
AU  - Walters KA
AD  - Fertility and Research Centre, School of Women's & Children's Health, University 
      of New South Wales, Sydney, NSW 2052, Australia.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Endocrinology
JT  - Endocrinology
JID - 0375040
RN  - 0 (Androgens)
RN  - 0 (Blood Glucose)
RN  - 0 (Lectins)
RN  - 0 (MLEC protein, human)
RN  - 0 (Membrane Proteins)
RN  - 0 (Receptors, Neurokinin-3)
RN  - 0 (Triglycerides)
RN  - 08J2K08A3Y (Dihydrotestosterone)
SB  - IM
MH  - Androgens/blood
MH  - Animals
MH  - Blood Glucose/metabolism
MH  - Dihydrotestosterone/adverse effects
MH  - Disease Models, Animal
MH  - Female
MH  - Humans
MH  - Hyperandrogenism/genetics/metabolism
MH  - Lectins/*administration & dosage
MH  - Membrane Proteins/*administration & dosage
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Polycystic Ovary Syndrome/chemically induced/*drug therapy/genetics/metabolism
MH  - Receptors, Neurokinin-3/*antagonists & inhibitors/genetics/metabolism
MH  - Triglycerides/blood
OTO - NOTNLM
OT  - animal model
OT  - hyperandrogenism
OT  - neuroendocrine
OT  - polycystic ovary syndrome (PCOS)
EDAT- 2021/02/02 06:00
MHDA- 2021/10/21 06:00
CRDT- 2021/02/01 08:45
PHST- 2020/12/03 00:00 [received]
PHST- 2021/02/02 06:00 [pubmed]
PHST- 2021/10/21 06:00 [medline]
PHST- 2021/02/01 08:45 [entrez]
AID - 6125280 [pii]
AID - 10.1210/endocr/bqab020 [doi]
PST - ppublish
SO  - Endocrinology. 2021 May 1;162(5):bqab020. doi: 10.1210/endocr/bqab020.