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Differential Effects of Menopausal Hormone Formulations on Plasma Orexin A levels in Women of the Kronos Early Estrogen Prevention Study

Orexin A (OxA) is a hypothalamic neuropeptide involved in regulation of feeding behavior, metabolism, sleep‐wakefulness and emotion. Plasma levels of this peptide increase with age in both men and women. However, little is known about changes in circulating OxA levels during age‐associated, sex‐ specific hormonal changes, such as menopause, or the effect of menopausal hormone therapy (MHT) on OxA levels. No studies have assessed changes of OxA levels after discontinuation of MHT. The objective of this study was to assess plasma OxA during and three years after cessation of either oral conjugated equine estrogen (o‐CEE, n = 17), transdermal 17β‐estradiol (t‐E2; n= 20), or placebo pills and patches (n = 22) in healthy recently menopausal women (> 6 months < 3 years from their menses) who participated in the Kronos Early Estrogen Prevention Study. The plasma OxA was measured by enzyme‐linked immune absorbent assay prior to randomization to treatment (Baseline) and at 12 months, 24 months, 36 months, 48 months after randomization and at 36 months after cessation of study MHT. Data are presented as median with 25th and 75th percentile. Baseline plasma levels of OxA did not differ among groups (o‐CEE: 3.02 (2.2–4.4) ng/mL, t‐E2=4.09 (3.6–4.5) ng/mL, Placebo= 3.15 (2.5–6.2) ng/mL. During MHT treatment, women randomized to o‐CEE had higher OxA levels when compared to their baseline values at 24, 36 and 48 months of exposure (4.4 ng/mL (2.5–6.3), 4.1 ng/mL(2.5–7.3), 4.2 ng/mL(3.1–6.5), respectively). Changes of OxA levels in the t‐E2 and placebo groups were variable and did not show a consistent trend over the MHT treatment period. Three years after cessation of MHT, only the o‐CEE group showed significantly higher Ox A levels than during the treatment phase of the trial (treatment 3 year discontinuation median – 48 month treatment median =1.369 ng/mL). Our study suggests that the formulation of MHT, in particular o‐CEE (contain metabolites of estrogen) increases plasma OxA. This is the first study to assess Ox A levels for a period of more than 6 months under MHT and after years of discontinuation. If plasma levels of OxA reflect those in the brain, these results may explain in part the beneficial effects of o‐CEE on mood and other menopausal symptoms in women of KEEPS. An increase in OxA driven by o‐CEE could be a mechanism by which MHT helps women regulate energy metabolism and emotional behavior responses.