Independent Contributions of Nocturnal Hot Flashes and Sleep Disturbance to Depression in Estrogen-Deprived Women.
Women are at increased risk for mood disturbance during the menopause transition. Hot flashes (HFs), sleep disruption, and fluctuating estradiol levels correlate with menopause-associated depression but co-occur, making cause and effect relationships difficult to disentangle.



Using a GnRH agonist (GnRHa) experimental model, we investigated whether depressive symptoms are associated with HFs and/or are explained by concomitant sleep fragmentation in the absence of estradiol fluctuation.



Depressive symptoms, objective polysomnographic sleep parameters, subjective sleep quality, serum estradiol, and HFs were assessed before and 4 weeks after open-label depot GnRHa (leuprolide 3.75-mg) administration.



Academic medical center.



Twenty-nine healthy nondepressed premenopausal volunteers (mean age, 27.3 years).



Serum estradiol was rapidly and uniformly suppressed. HFs developed in 69% of the subjects. On univariate analysis, worsening of mood was predicted by increases in time in light sleep (stage N1), number of transitions to wake, non-REM arousals, subjective sleep quality, and reductions in perceived sleep efficiency (all P < .045), as well as the number of nighttime (P = .006), but not daytime (P = .28), HFs reported. In adjusted models, the number of nighttime HFs reported, increases in non-REM arousals, time in stage N1, transitions to wake, and reduced sleep quality remained significant predictors of mood deterioration (P ≤ .05).



Depressive symptoms emerged after estradiol withdrawal in association with objectively and subjectively measured sleep disturbance and the number of nighttime, but not daytime, HFs reported. Results suggest that sleep disruption and perceived nighttime HFs both contribute to vulnerability to menopause-associated depressive symptoms in hypoestrogenic women.
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Hadine
H
Joffe
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Sybil L
SL
Crawford
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Marlene P
MP
Freeman
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
David P
DP
White
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Matt T
MT
Bianchi
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Semmie
S
Kim
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Nicole
N
Economou
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Julie
J
Camuso
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Janet E
JE
Hall
Department of Psychiatry (H.J., S.K., J.C.), Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Department of Psychosocial Oncology and Palliative Care (H.J.), Dana Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts 02215; Department of Psychiatry (H.J., M.P.F., N.E., L.S.C.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; Department of Medicine (S.L.C.), Division of Preventive and Behavioral Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01655; Division of Sleep Medicine (D.P.W.), Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115; Sleep Division, Department of Neurology (M.T.B.), and Reproductive Endocrine Unit, Department of Medicine (J.E.H.), Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114; and National Institute of Environmental Health Sciences (J.E.H.), National Institutes of Health, Research Triangle Park, North Carolina 27709.
Lee S
LS
Cohen
D000293:Adolescent; D000328:Adult; D003863:Depression / Q000139:chemically induced / Q000378:metabolism*; D004958:Estradiol / Q000097:blood / Q000378:metabolism*; D005300:Fertility Agents, Female / Q000008:administration & dosage / Q000494:pharmacology; D007987:Gonadotropin-Releasing Hormone / Q000819:agonists* / Q000494:pharmacology; D064368:Healthy Volunteers; D019584:Hot Flashes / Q000139:chemically induced / Q000378:metabolism*; D006801:Humans; D016729:Leuprolide / Q000008:administration & dosage / Q000494:pharmacology; D008593:Menopause / Q000378:metabolism; D008875:Middle Aged; D012893:Sleep Wake Disorders / Q000139:chemically induced / Q000378:metabolism*; D055815:Young Adult
D005300:Fertility Agents, Female; D007987:Gonadotropin-Releasing Hormone; D004958:Estradiol; D016729:Leuprolide
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