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).
CONCLUSION: 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.
CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov, www.clinicaltrials.gov, NCT00108849 (VAG-2195) and NCT00431132 (VAG 1748).
LEVEL OF EVIDENCE: II
There is no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram E2 vaginal tablets for 1 year.
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.
For a list of principal investigators and institutional review boards for the studies discussed in this article, see Appendix 1 and Appendix 2 online at http://links.lww.com/AOG/A199 and http://links.lww.com/AOG/A200.
Supported by Novo Nordisk A/S, Bagsvaerd, Denmark. Anjun Cao from Novo Nordisk (Princeton, NJ) served as the statistician on this project. Dongmei Zhang from Novo Nordisk (Princeton, NJ) provided medical writing and editorial support.
The authors thank the principal investigators who participated in the conduct of these two trials.
Corresponding author: James Simon, MD, CCD, NCMP, FACOG, Women's Health & Research Consultants, 1850 M Street, NW; Suite 450, Washington, DC 20036; e-mail: email@example.com.
Financial Disclosure Dr. Simon serves as a consultant for Allergan, Alliance for Better Bone Health, Amgen, Ascend Therapeutics, Azur Pharma, Bayer, BioSante, Boehringer Ingelheim, Concert Pharmaceuticals, Corcept Therapeutics, Depomed, Fabre-Kramer, GlaxoSmithKline, Graceway Pharmaceuticals, KV Pharmaceutical, Lipocine, Meditrina Pharmaceuticals, Merck, Merrion Pharmaceuticals, Nanma/Tripharma/Trinity, NDA Partners, Novo Nordisk, Novogyne, Pear Tree Pharmaceuticals, QuatRx Pharmaceuticals, Roche, Schering-Plough, Sciele, Solvay, Teva, Ther-Rx, Warner Chilcott, and Wyeth. He has received grants from BioSante, Boehringer Ingelheim, FemmePharma, GlaxoSmithKline, Nanma/Tripharma/Trinity, Novartis, Procter and Gamble, QuatRx Pharmaceuticals, and Teva. Dr. Simon also serves on speakers' bureaus for Amgen, Ascend, Bayer, Boehringer Ingelheim, GlaxoSmithKline, KV, Merck, Novartis, Novo Nordisk, Novogyne, Sciele, Teva, Ther-Rx, Warner Chilcott, and Wyeth. Dr. Lila Nachtigall serves as a member of the advisory board for Novo Nordisk and Upsher Smith, and a member of the speakers' bureau for Upsher Smith, Wyeth, Novo Nordisk, and Novartis. Dr. Lian G. Ulrich has received speaker's fees from Novo Nordisk and from Organon Schering Plough (now merged with Merck & Co). Dr. Michaela Eugster-Hausmann and Dr. Robert Gut are employees of Novo Nordisk.