Aviva Y Cohn 1 2 3, Leilah K Grant 3 4 5, Margo D Nathan 2, Aleta Wiley 2 3, Mathena Abramson 2 3, Jessica A Harder 2, Sybil Crawford 6, Elizabeth B Klerman 3 4 5 7, Frank A J L Scheer 4 5, Ursula B Kaiser 1, Shadab A Rahman 4 5, Hadine Joffe 2 3
J Clin Endocrinol Metab. 2023 May 19;dgad285.
doi: 10.1210/clinem/dgad285.
Abstract
Context: Perturbations to the hypothalamic-pituitary-adrenal (HPA) axis have been hypothesized to increase post-menopausal cardiometabolic risk. Although sleep disturbance, a known risk factor for cardiometabolic disease, is prevalent during the menopause transition, it is unknown whether menopause-related sleep disturbance and estradiol decline disturb the HPA axis.
Objective: We examined the impact of experimental fragmentation of sleep and suppression of estradiol as a model of menopause on cortisol levels in healthy young women.
Design: Twenty-two women completed a 5-night inpatient study during the mid-to-late follicular phase (estrogenized). A subset (n=14) repeated the protocol after gonadotropin-releasing hormone agonist-induced estradiol suppression. Each inpatient study included two unfragmented sleep nights followed by three experimental sleep fragmentation nights.
Setting: Academic medical center.
Participants: Premenopausal women.
Intervention: Sleep fragmentation and pharmacological hypoestrogenism.
Main outcome measures: Serum bedtime cortisol levels and cortisol awakening response (CAR).
Results: Bedtime cortisol increased 27% (p=0.03) and CAR decreased 57% (p=0.01) following sleep fragmentation compared to unfragmented sleep. Polysomnographic-derived wake after sleep-onset (WASO) was positively associated with bedtime cortisol levels (p=0.047) and negatively associated with CAR (p<0.01). Bedtime cortisol levels were 22% lower in the hypo-estrogenized state compared to the estrogenized state (p=0.02), while CAR was similar in both estradiol conditions (p=0.38).
Conclusions: Both estradiol suppression and modifiable menopause-related sleep fragmentation independently perturb HPA axis activity. Sleep fragmentation, commonly seen in menopausal women, may disrupt the HPA axis, which in turn may lead to adverse health effects as women age.