Endometrial safety of ultra-low-dose estradiol vaginal tablets.
OBJECTIVE
To evaluate the endometrial hyperplasia and carcinoma rate after 52-week treatment with ultra-low-dose 10-microgram 17β-estradiol vaginal tablets in postmenopausal women with vaginal atrophy.


METHODS
Endometrial biopsy data from individuals using active treatment (n=205) in a randomized, double-blind, placebo-controlled trial were pooled with the data from an open-label endometrial safety trial (n=336). Patients received 10-microgram estradiol vaginal tablets for 52 weeks. All endometrial biopsy samples were histologically analyzed at baseline and at end of trial by the same laboratory in both trials.


RESULTS
A total of 541 women using estradiol were included in the combined analysis of endometrial safety. A total of 456 women completed the trials, and 443 women had a biopsy performed at week 52: 85.6% were categorized as "atrophic endometrium," 12.6% had nonevaluable biopsy samples, 1.1% had polyps, and 0.2% were categorized as "weakly proliferative." One case of complex hyperplasia without atypia was reported in an individual exposed to trial drug for only 9 days. One woman's biopsy sample demonstrated endometrioid adenocarcinoma, grade 2, but the lack of an evaluable screening biopsy sample makes it uncertain whether the carcinoma was preexisting. In total, two events of hyperplasia and carcinoma were reported in 386 evaluable biopsy samples (incidence rate 0.52% per year).


CONCLUSIONS
The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women is 0% to 1%. The results of this pooled analysis therefore support the endometrial safety of unopposed ultra-low-dose vaginal estrogen. There was no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram estradiol vaginal tablets for 1 year under study conditions.


BACKGROUND
ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748).


METHODS
II.
Simon
James
J
From Women's Health & Research Consultants, Washington, DC; New York University School of Medicine, New York, New York; Copenhagen University Hospital Rigshospitalet, Department of Gynecology and Obstetrics, Copenhagen, Denmark; Novo Nordisk FemCare AG, Zurich, Switzerland; Novo Nordisk, Princeton, New Jersey.
Nachtigall
Lila
L
Ulrich
Lian G
LG
Eugster-Hausmann
Michaela
M
Gut
Robert
R
D001284:Atrophy; D004311:Double-Blind Method; D004714:Endometrial Hyperplasia / Q000139:chemically induced / Q000453:epidemiology*; D016889:Endometrial Neoplasms / Q000139:chemically induced / Q000453:epidemiology*; D004958:Estradiol / Q000008:administration & dosage* / Q000009:adverse effects; D004967:Estrogens / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D006801:Humans; D008875:Middle Aged; D018579:Patient Selection; D014621:Vagina / Q000473:pathology; D014622:Vaginal Creams, Foams, and Jellies
D004967:Estrogens; D014622:Vaginal Creams, Foams, and Jellies; D004958:Estradiol