Post on 05-Feb-2018
Advances in Our Understanding of the Etiology of Hot Flushes
Naomi E. RanceUniversity of Arizona College of Medicine
ER
Ovary
GnRH
Estrogen LH
FSH
Menopause and the human hypothalamus
Pituitary
HypothalamusHOT FLUSH
Neuronal hypertrophy in the infundibular (arcuate) nucleus of postmenopausal women
Premenopausal Postmenopausal
•These neurons express estrogen receptor α
Rance et al., JCEM, 1990
Premenopausal Postmenopausal
Hypertrophy and increased NKB gene expression in the infundibular (arcuate) nucleus of postmenopausal
women
Rance and Young, Endocrinology, 1991
•Severe congenital deficiency in LH and FSH
•Low circulating sex steroids
•Failure of puberty
•Infertility
Topaloglu et al., Nature Genetics, March 2009
Neurokinin B is essential for human reproduction
Mutations in the gene encoding NKB or its receptor (NK3R) results in hypogonadotrophic hypogonadism:
Menopause and the human hypothalamus
KNDy neurons
Rance, Peptides, 2009
Core Temperature
The Hot Flush
• Caused by estrogen withdrawal • Consists of activation of heat defense mechanisms• Results in a drop in core temperature
Freedman Am. J. Hum. Biol. 2001
Skin Temperature
Minutes Minutes
Degr
ees o
C
Degr
ees o
C
Each arrow indicates the onset of a flush episode
Casper et al, Science 1979
Hot flushes are linked to pulsatile LH secretion!
LH (m
lU/m
l)
Hours
Studying the mechanism of flushes from a basic science perspective
A hot flush is characterized by the episodic activation of heat dissipation effectors.
The brain pathways controlling heat-defense in the rat are known. (Nakamura and Morrison, PNAS, 2010)
Estrogen affects thermoregulation in the rat.(Dacks & Rance, Endocrinology 2010, Williams et al., Endocrinology 2010)
Estrogen modulates the neural circuitry controlling heat-dissipation effectors in the rat.
(Dacks et al., Endocrinology 2011)
Do KNDy neurons play a role in thermoregulation?
•
Estradiol reduces tail skin temperature in the rat
Tail skin temperature during the dark phase
Williams et al., Endocrinology, 2010
A thermosensory pathway regulating heat-defense
Nakamura and Morrison, PNAS, 2010
KNDy neurons project to the MnPO
MnPO neurons express NK3 receptors!
Krajewski et al., Neuroscience 2010, Dacks et al., Endocrinology 2011
Activation of NK3R neurons in the MnPO decreases core temperature.
Dacks et al., Endocrinology 2011
Drop in body temperature
What happens if we selectively destroy KNDy neurons?
Mittelman-Smith et al., PNAS, 2012
Selective ablation of KNDy neurons using NK3-SAP
KNDy neurons (NKB)
Control NK3-SAP
NK3-SAP
Mittelman-Smith et al., Endocrinology. 2012
Control NK3-SAP
NPY neurons
Effects of OVX and estradiol replacement on serum LH in control rats
Control
Mittelman-Smith et al., Endocrinology. 2012
Effects of OVX and estradiol replacement on serum LH in control and KNDy-ablated rats
Control
NK3-SAP
Mittelman-Smith et al., Endocrinology. 2012
Ablation of KNDy neurons in the rat reduces tail skin temperature
Evidence that KNDy neurons facilitate cutaneous vasodilatation, a cardinal sign of a hot flash!
Mittelman-Smith et al. PNAS, 2012
Evidence that KNDy neurons facilitate tail skin vasodilation
Mittelman-Smith et al. PNAS, 2012
Modulation of body temperature and LH secretion by hypothalamic KNDy neurons
Mittelman-Smith et al. PNAS, 2012
Modulation of body temperature and LH secretion by hypothalamic KNDy neurons: A novel hypothesis on the
mechanism of flushes
Hot Flush
Rance et al., Frontiers in Neuroendocrinology, 2013
Acknowledgements
Monica ChawlaTy AbelSteve DanzerAdonna RometoTatiana Sandoval-GuzmanPenny DacksMelinda Mittelman-SmithHemalini WilliamsMarina Cholanian
Sally KrajewskiMichelle BurkeMiranda Anderson
National Institutes on Aging, Arizona Biomedical Research Center, Evelyn McNight Brain Institute, Undergraduate Biology Research Program
Committee on Neuroscience, Neuroscience and Physiological Sciences IDPs
Research TechniciansGraduate Students
CollaboratorsNathaniel McMullenW. Scott Young,IIIMary Lou VoytkoAndrej Romanovsky
NKBI