title: Clinical effects of the fetal estrogen estetrol in a multiple-rising-dose study in postmenopausal women.
abstract: OBJECTIVE
  Estetrol (E4) is a natural fetal estrogen. The safety of increasing doses of E4 and its preliminary effects on the vagina, endometrium and menopausal vasomotor symptoms were investigated.
  
  
  METHODS
  This was a partly randomized, open-label, multiple-rising-dose study in 49 postmenopausal women. Subjects with an intact uterus were randomized to receive either 2mg E4 or 2mg estradiol-valerate (E2V) for 28days. Subsequent dose-escalation groups (non-randomized) were: 10mg E4 (intact uterus and ≥35 hot flushes/week); and 20mg and 40mg E4 (hysterectomized subjects).
  
  
  METHODS
  Adverse events (AEs) and vaginal cytology were evaluated in all treatment groups; hot flushes/sweating and endometrial proliferation were analyzed with 2 and 10mg E4 and 2mg E2V.
  
  
  RESULTS
  Estetrol appeared to be safe, without serious drug-related AEs. In all the groups there was a clear shift from parabasal to superficial vaginal cells, indicating an estrogenic effect and a potential for the treatment of vulvovaginal atrophy. The endometrial thickness remained stable in the 2mg E4 group and increased with E2V and 10mg E4. A decrease in the mean number of hot flushes and sweating was seen with 2 and 10mg E4 and 2mg E2V.
  
  
  CONCLUSIONS
  Estetrol in a dose range of 2-40mg per day improved vaginal cytology and vasomotor symptoms in postmenopausal women. Endometrial proliferation occurred with the 10mg dose. Estetrol seems a safe and suitable candidate to develop further for hormone therapy.
authors.affiliation: Pantarhei Bioscience BV, Zeist, The Netherlands. Electronic address: hcb@pantarheibio.com.
authors.forename: Herjan J T
authors.initials: HJ
authors.lastname: Coelingh Bennink
authors.affiliation: Pantarhei Bioscience BV, Zeist, The Netherlands.
authors.forename: Carole
authors.initials: C
authors.lastname: Verhoeven
authors.affiliation: Pantarhei Bioscience BV, Zeist, The Netherlands.
authors.forename: Yvette
authors.initials: Y
authors.lastname: Zimmerman
authors.affiliation: Pantarhei Bioscience BV, Zeist, The Netherlands.
authors.forename: Monique
authors.initials: M
authors.lastname: Visser
authors.affiliation: University of Liège, Liège, Belgium.
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Foidart
authors.affiliation: Department of Women's and Children's Health, Karolinska Institutet and Karolinska University Hospital, Stockholm, Sweden.
authors.forename: Kristina
authors.initials: K
authors.lastname: Gemzell-Danielsson
mesh_terms: D000368:Aged; D004305:Dose-Response Relationship, Drug; D004717:Endometrium / Q000187:drug effects*; D004953:Estetrol / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D005260:Female; D019584:Hot Flashes / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D017698:Postmenopause; D016896:Treatment Outcome; D014623:Vaginal Diseases / Q000188:drug therapy* / Q000473:pathology
chemical_list: D004953:Estetrol
keywords: Endometrium; Estetrol; Estrogen; Hormone therapy; Vasomotor symptoms; Vulvovaginal atrophy