FRI008 Impact Of Sleep Fragmentation And Estradiol Suppression On Leptin, Ghrelin, Satiety And Hunger In Women: An Experimental Menopause Model To Understand Menopause-related Body Fat Gain
Authors: Rahman Shadab A , Grant Leilah K , Cohn Aviva , Nathan Margo Diana , Harder Jessica , Gonsalvez Irene , Scheer Frank A J L , Klerman Elizabeth B , Crawford Sybil , Luo Tianyu , Menezes Ellexa , Roy Ancella , Joseph Anna , Wiley Aleta , Kaiser Ursula B , Joffe Hadine 
Published: October 2023

Disclosure: S.A. Rahman: Consulting Fee; Self; Sultan & Knight Limited, Bambu Vault LLC, Lucidity Lighting Inc. Grant Recipient; Self; Seoul Semiconductor Co. Ltd, Biological Innovation and Optimization Systems, LLC, Merck & Co, Inc, Pfizer Inc, Vanda Pharmaceuticals Inc, Lighting Science Group. Speaker; Self; Starry Skies Lake Superior, University of Minnesota Medical School, PennWell Corp, and Seoul Semiconductor Co. Ltd. Stock Owner; Self; Melcort Inc. L.K. Grant: None. A. Cohn: None. M.D. Nathan: None. J. Harder: Consulting Fee; Self; Atman Health; O’Rourke & Hawk, LLP. Grant Recipient; Self; Brigham and Women’s Hospital; President and Fellows of Harvard College. Owner/Co-Owner; Self; Jessica Harder, MD. Stock Owner; Self; Atman Health. Other; Self; Centerfield Media Holding Company. I. Gonsalvez: None. F.A. Scheer: Consulting Fee; Self; University of Alabama at Birmingham. Other; Self; Board of Directors for the Sleep Research Society. E.B. Klerman: Consulting Fee; Self; Circadian Therapeutics, The National Sleep Foundation, Sanofi-Genzynel. Other; Self; Travel support from the Sleep Research Society. S. Crawford: None. T. Luo: None. E. Menezes: None. A. Roy: None. A. Joseph: None. A. Wiley: None. U.B. Kaiser: None. H. Joffe: Consulting Fee; Self; Bayer, Hello Therapeutics. Grant Recipient; Self; National Institutes of Health, Merck, Pfizer.

Body fat increases during the menopause transition. In addition to menopause-related estradiol (E2) decline, sleep fragmentation (wake episodes interrupting sleep) due to hot flashes, without a reduction in total sleep time, is common. We examined whether E2 decline and sleep fragmentation decrease the satiety hormone, leptin, increase the orexigenic hormone, ghrelin, and their behavioral correlates satiety and hunger, which would promote positive energy balance and body fat gain. We studied 38 healthy premenopausal female volunteers (mean age [±SD] 29.7±6.7 years) in a 5-night inpatient study under eucaloric conditions, once in the mid-to-late follicular phase (high-E2) and again after gonadotropin-releasing hormone agonist-induced E2-suppression (hypo-E2) in a subset (n=27). Each inpatient study involved 2 nights of unfragmented sleep followed by 3 nights of experimentally induced sleep fragmentation to achieve ∼1hr of wake after sleep-onset without reducing total sleep time. Serum for leptin and acetylated ghrelin assays and self-reported satiety and hunger via visual analog scales were collected fasting ∼1hr after waking each morning. Values were normalized relative to each individual’s baseline (high-E2, unfragmented sleep) and then compared between conditions using generalized linear mixed models. Mean (±SD) levels of leptin and ghrelin at baseline were 38.5±21.2 ng/mL and 640.9±362.0 pg/mL, respectively. Compared to the high-E2 state, omnibus analysis of E2 suppression during both unfragmented and fragmented sleep showed significant reduction from the high-E2 to hypo-E2 state in satiety-promoting leptin levels (least squares mean % of baseline [±SE]: 101.0±1.1% vs. 90.0±3.0%, p=0.001), but unchanged self-rated satiety (109.3±7.8% vs. 102.6±15.6%, p=0.58). E2 suppression also did not change hunger-promoting ghrelin levels (101.0±3.1% vs. 97.0±1.4%, p=0.13) or self-rated hunger (103.3±6.6% vs. 133.2±30.5%, p=0.28). Omnibus analysis of sleep fragmentation during both high-E2 and hypo-E2 states showed that, relative to unfragmented sleep, leptin levels were unchanged (94.0±1.5% vs. 96.7±2.5%, p=0.22), but self-rated satiety was significantly lower (113.1±11.0% vs. 99.2±11.9%, p=0.048) after sleep fragmentation. There was a trend towards the lowest satiety in the hypo-E2 sleep fragmented state (interaction p=0.052). Sleep fragmentation did not change ghrelin levels (100.7±1.8% vs. 97.3±2.7%, p=0.13) or self-rated hunger (103.0±6.2% vs. 133.6±30.0%, p=0.25). These results demonstrate significant adverse changes in leptin and satiety in women induced, respectively, by E2 suppression and sleep fragmentation, independent of aging. Findings support likely independent contributions of E2 decline and sleep fragmentation during the menopause transition toward positive energy balance and body fat gain. Funding: NIH R01AG053838 (PI: H Joffe).

Presentation: Friday, June 16, 2023