title: Vaginal estradiol use and the risk for cardiovascular mortality.
abstract: OBJECTIVE
  Does the use of post-menopausal vaginal estradiol (VE) affect the mortality risk for coronary heart disease (CHD) and stroke.
  
  
  CONCLUSIONS
  The use of VE reduces the risk for cardiovascular mortality.
  
  
  BACKGROUND
  A growing number of women use VE for post-menopausal genitourinary symptoms. Although this therapy is intended to have only local effects, estrogen is absorbed into the blood circulation and thus VE use may also have systemic effects.
  
  
  METHODS
  We studied a nationwide cohort in Finland 1994-2009 during which post-menopausal women (n = 195 756) initiated the use of VE (age [mean ± SD] 65.7 ± 10.9 years). Follow-up data gathered 1.4 million women-years and we assessed the mortality risk due to CHD (n= 9656) or stroke (n = 4294).
  
  
  METHODS
  The mortality risk in VE users was compared with that in the age-matched background population (standardized mortality ratio; [SMR]; 95% confidence interval) and related to various durations of exposure to VE (1 to ≤3, >3 to ≤5, >5 to ≤10 and >10 years).
  
  
  RESULTS
  The use of VE was accompanied by decreases in the risk for CHD and stroke death. The risk reduction for CHD death was highest for >3 to ≤5 years exposure (SMR 0.64; 0.57-0.70) and for stroke for >5 to ≤10 years exposure (SMR 0.64; 0.57-0.72). The risk reductions for both CHD and stroke mortality were detected in all age groups with the highest risk reduction being in women aged 50-59 years (SMR 0.43; 0.19-0.88 and SMR 0.21; 0.06-0.58, respectively).
  
  
  CONCLUSIONS
  Our series lack a placebo arm and thus, may harbor a healthy woman bias. Moreover, data on clinical variables such as weight, smoking, blood pressure and family background were unobtainable for this study. Women using both VE and systemic hormone therapy (HT) were included in the comparator background population. This should not cause any significant error because the proportion of women using VE or other HT was modest (<10% in age-matched population) and because the use of systemic HT also reduces death risks in the same population. Our data cannot be directly applied for local regimens containing conjugated equine estrogens, because they are absorbed differently and may show effects that differ from those of estradiol.
  
  
  CONCLUSIONS
  In 1000 women using VE for up to 10 years, a maximum of 24 fewer CHD deaths and 18 fewer stroke deaths is likely to occur.
  
  
  BACKGROUND
  This work was supported by unrestricted grants from the Päivikki and Sakari Sohlberg Foundation, the Emil Aaltonen Foundation, the Finnish Medical Foundation, Finska Läkaresällskapet, the Orion Farmos Research Foundation, the Paavo Nurmi Foundation and a special governmental grant for health sciences research. The funding sources had no role in the study design, data handling or manuscript preparation. EPID Research is a company that performs financially supported studies for several pharmaceutical companies. Dr Korhonen, Dr Hoti and MSc Vattulainen, employed by Epid Research, report financial activities from several other pharmaceutical companies outside the submitted work. Dr Mikkola has been a speaker and/or received consulting fees from Mylan and Novo Nordisk. Dr Tuomikoski has been a speaker and/or received consulting fees from Orion and Mylan. The remaining authors report no conflict of interest.
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki University, PO Box 140, 00029 HUS Helsinki, Finland Folkhälsan Research Center, Helsinki, Finland tomi.mikkola@hus.fi.
authors.forename: Tomi S
authors.initials: TS
authors.lastname: Mikkola
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki University, PO Box 140, 00029 HUS Helsinki, Finland Folkhälsan Research Center, Helsinki, Finland.
authors.forename: Pauliina
authors.initials: P
authors.lastname: Tuomikoski
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki University, PO Box 140, 00029 HUS Helsinki, Finland Folkhälsan Research Center, Helsinki, Finland.
authors.forename: Heli
authors.initials: H
authors.lastname: Lyytinen
authors.affiliation: EPID Research Oy, Metsänneidonkuja 12, 02130 Espoo, Finland.
authors.forename: Pasi
authors.initials: P
authors.lastname: Korhonen
authors.affiliation: EPID Research Oy, Metsänneidonkuja 12, 02130 Espoo, Finland.
authors.forename: Fabian
authors.initials: F
authors.lastname: Hoti
authors.affiliation: EPID Research Oy, Metsänneidonkuja 12, 02130 Espoo, Finland.
authors.forename: Pia
authors.initials: P
authors.lastname: Vattulainen
authors.affiliation: National Institute for Health and Welfare, PO Box 30, 00271 Helsinki, Finland.
authors.forename: Mika
authors.initials: M
authors.lastname: Gissler
authors.affiliation: Department of Obstetrics and Gynecology, Helsinki University Central Hospital, Helsinki University, PO Box 140, 00029 HUS Helsinki, Finland Folkhälsan Research Center, Helsinki, Finland.
authors.forename: Olavi
authors.initials: O
authors.lastname: Ylikorkala
mesh_terms: D000368:Aged; D002317:Cardiovascular Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D015331:Cohort Studies; D003327:Coronary Disease / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D003692:Delayed-Action Preparations / Q000008:administration & dosage / Q000627:therapeutic use; D011307:Drug Prescriptions; D004958:Estradiol / Q000008:administration & dosage / Q000627:therapeutic use*; D004967:Estrogens / Q000008:administration & dosage / Q000627:therapeutic use*; D005260:Female; D052776:Female Urogenital Diseases / Q000188:drug therapy*; D005387:Finland / Q000453:epidemiology; D005500:Follow-Up Studies; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D012042:Registries; D012307:Risk Factors; D020521:Stroke / Q000453:epidemiology / Q000401:mortality / Q000517:prevention & control*; D014622:Vaginal Creams, Foams, and Jellies
chemical_list: D002317:Cardiovascular Agents; D003692:Delayed-Action Preparations; D004967:Estrogens; D014622:Vaginal Creams, Foams, and Jellies; D004958:Estradiol
keywords: cardiovascular death; coronary heart disease; estrogen; myocardial infarction; stroke; topical vaginal estrogen