Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study

Nanette Santoro, Amanda Allshouse, Genevieve Neal-Perry, Lubna Pal, Rogerio A. Lobo, Frederick Naftolin, Dennis M. Black, Eliot A. Brinton, Matthew J. Budoff, Marcelle I. Cedars, Maritza M. Dowling, Mary Dunn, Carey E. Gleason, Howard N. Hodis, Barbara Isaac, Maureen Magnani, Jo Ann E Manson, Virginia M Miller, Hugh S. Taylor, Whitney WhartonErin Wolff, Viola Zepeda, Mitchell M. Harman

Research output: Contribution to journalArticle

17 Citations (Scopus)

Abstract

OBJECTIVE:: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS:: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45?mg (n?=?230) or transdermal estradiol (t-E2) 50?μg (n?=?225; both with micronized progesterone 200?mg for 12 d each mo), or placebos (PBOs; n?=?275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS:: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P?<?0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P?=?0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P?=?0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS:: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

Original languageEnglish (US)
JournalMenopause
DOIs
StateAccepted/In press - Oct 24 2016

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Conjugated (USP) Estrogens
Progesterone
Estradiol
Estrogens
Placebos
Sleep Initiation and Maintenance Disorders
Hormones
Hot Flashes
Sweat
Therapeutics
Body Mass Index

ASJC Scopus subject areas

  • Obstetrics and Gynecology

Cite this

Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo : the Kronos Early Estrogen Prevention Study. / Santoro, Nanette; Allshouse, Amanda; Neal-Perry, Genevieve; Pal, Lubna; Lobo, Rogerio A.; Naftolin, Frederick; Black, Dennis M.; Brinton, Eliot A.; Budoff, Matthew J.; Cedars, Marcelle I.; Dowling, Maritza M.; Dunn, Mary; Gleason, Carey E.; Hodis, Howard N.; Isaac, Barbara; Magnani, Maureen; Manson, Jo Ann E; Miller, Virginia M; Taylor, Hugh S.; Wharton, Whitney; Wolff, Erin; Zepeda, Viola; Harman, Mitchell M.

In: Menopause, 24.10.2016.

Research output: Contribution to journalArticle

Santoro, N, Allshouse, A, Neal-Perry, G, Pal, L, Lobo, RA, Naftolin, F, Black, DM, Brinton, EA, Budoff, MJ, Cedars, MI, Dowling, MM, Dunn, M, Gleason, CE, Hodis, HN, Isaac, B, Magnani, M, Manson, JAE, Miller, VM, Taylor, HS, Wharton, W, Wolff, E, Zepeda, V & Harman, MM 2016, 'Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo: the Kronos Early Estrogen Prevention Study', Menopause. https://doi.org/10.1097/GME.0000000000000756
Santoro, Nanette ; Allshouse, Amanda ; Neal-Perry, Genevieve ; Pal, Lubna ; Lobo, Rogerio A. ; Naftolin, Frederick ; Black, Dennis M. ; Brinton, Eliot A. ; Budoff, Matthew J. ; Cedars, Marcelle I. ; Dowling, Maritza M. ; Dunn, Mary ; Gleason, Carey E. ; Hodis, Howard N. ; Isaac, Barbara ; Magnani, Maureen ; Manson, Jo Ann E ; Miller, Virginia M ; Taylor, Hugh S. ; Wharton, Whitney ; Wolff, Erin ; Zepeda, Viola ; Harman, Mitchell M. / Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo : the Kronos Early Estrogen Prevention Study. In: Menopause. 2016.
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abstract = "OBJECTIVE:: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS:: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45?mg (n?=?230) or transdermal estradiol (t-E2) 50?μg (n?=?225; both with micronized progesterone 200?mg for 12 d each mo), or placebos (PBOs; n?=?275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS:: Moderate to severe hot flashes (from 44{\%} at baseline to 28.3{\%} for PBO, 7.4{\%} for t-E2, and 4.2{\%} for o-CEE) and night sweats (from 35{\%} at baseline to 19{\%} for PBO, 5.3{\%} for t-E2, and 4.7{\%} for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P?<?0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P?=?0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P?=?0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS:: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.",
author = "Nanette Santoro and Amanda Allshouse and Genevieve Neal-Perry and Lubna Pal and Lobo, {Rogerio A.} and Frederick Naftolin and Black, {Dennis M.} and Brinton, {Eliot A.} and Budoff, {Matthew J.} and Cedars, {Marcelle I.} and Dowling, {Maritza M.} and Mary Dunn and Gleason, {Carey E.} and Hodis, {Howard N.} and Barbara Isaac and Maureen Magnani and Manson, {Jo Ann E} and Miller, {Virginia M} and Taylor, {Hugh S.} and Whitney Wharton and Erin Wolff and Viola Zepeda and Harman, {Mitchell M.}",
year = "2016",
month = "10",
day = "24",
doi = "10.1097/GME.0000000000000756",
language = "English (US)",
journal = "Menopause",
issn = "1072-3714",
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TY - JOUR

T1 - Longitudinal changes in menopausal symptoms comparing women randomized to low-dose oral conjugated estrogens or transdermal estradiol plus micronized progesterone versus placebo

T2 - the Kronos Early Estrogen Prevention Study

AU - Santoro, Nanette

AU - Allshouse, Amanda

AU - Neal-Perry, Genevieve

AU - Pal, Lubna

AU - Lobo, Rogerio A.

AU - Naftolin, Frederick

AU - Black, Dennis M.

AU - Brinton, Eliot A.

AU - Budoff, Matthew J.

AU - Cedars, Marcelle I.

AU - Dowling, Maritza M.

AU - Dunn, Mary

AU - Gleason, Carey E.

AU - Hodis, Howard N.

AU - Isaac, Barbara

AU - Magnani, Maureen

AU - Manson, Jo Ann E

AU - Miller, Virginia M

AU - Taylor, Hugh S.

AU - Wharton, Whitney

AU - Wolff, Erin

AU - Zepeda, Viola

AU - Harman, Mitchell M.

PY - 2016/10/24

Y1 - 2016/10/24

N2 - OBJECTIVE:: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS:: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45?mg (n?=?230) or transdermal estradiol (t-E2) 50?μg (n?=?225; both with micronized progesterone 200?mg for 12 d each mo), or placebos (PBOs; n?=?275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS:: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P?<?0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P?=?0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P?=?0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS:: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

AB - OBJECTIVE:: The objective of the present study was to compare the efficacy of two forms of menopausal hormone therapy in alleviating vasomotor symptoms, insomnia, and irritability in early postmenopausal women during 4 years. METHODS:: A total of 727 women, aged 42 to 58, within 3 years of their final menstrual period, were randomized to receive oral conjugated estrogens (o-CEE) 0.45?mg (n?=?230) or transdermal estradiol (t-E2) 50?μg (n?=?225; both with micronized progesterone 200?mg for 12 d each mo), or placebos (PBOs; n?=?275). Menopausal symptoms were recorded at screening and at 6, 12, 24, 36, and 48 months postrandomization. Differences in proportions of women with symptoms at baseline and at each follow-up time point were compared by treatment arm using exact χ tests in an intent-to-treat analysis. Differences in treatment effect by race/ethnicity and body mass index were tested using generalized linear mixed effects modeling. RESULTS:: Moderate to severe hot flashes (from 44% at baseline to 28.3% for PBO, 7.4% for t-E2, and 4.2% for o-CEE) and night sweats (from 35% at baseline to 19% for PBO, 5.3% for t-E2, and 4.7% for o-CEE) were reduced significantly by 6 months in women randomized to either active hormone compared with PBO (P?<?0.001 for both symptoms), with no significant differences between the active treatment arms. Insomnia and irritability decreased from baseline to 6 months postrandomization in all groups. There was an intermittent reduction in insomnia in both active treatment arms versus PBO, with o-CEE being more effective than PBO at 36 and 48 months (P?=?0.002 and 0.05) and t-E2 being more effective than PBO at 48 months (P?=?0.004). Neither hormone treatment significantly affected irritability compared with PBO. Symptom relief for active treatment versus PBO was not significantly modified by body mass index or race/ethnicity. CONCLUSIONS:: Recently postmenopausal women had similar and substantial reductions in hot flashes and night sweats with lower-than-conventional doses of oral or transdermal estrogen. These reductions were sustained during 4 years. Insomnia was intermittently reduced compared with PBO for both hormone regimens.

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