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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e3181f386bb
Original Research

Endometrial Safety of Ultra-Low-Dose Estradiol Vaginal Tablets

Simon, James MD; Nachtigall, Lila MD; Ulrich, Lian G. MD; Eugster-Hausmann, Michaela MD; Gut, Robert MD, PhD

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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: jsimon@jamesasimonmd.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.

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Abstract

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

The decline in endogenous estrogen levels after menopause can cause vasomotor symptoms, osteoporosis, and urogenital atrophy symptoms, which negatively affect the general well-being and quality of life of postmenopausal women.1 Unlike vasomotor symptoms, which often last for a period of time and eventually subside, urogenital atrophy symptoms tend to worsen over time.1,2 Individuals with urogenital atrophy have symptoms including vaginal dryness, vaginal and vulvar irritation, vaginal soreness, pain and burning during urination (dysuria), increased vaginal discharge, vaginal odor, vaginal infections, recurrent urinary tract infections, pain associated with sexual activity (dyspareunia), and vaginal bleeding associated with sexual activity.2–6 It is estimated that up to 75% of postmenopausal women experience vaginal dryness related to vaginal atrophy.7

Because of the concerns of potential adverse effects associated with long-term systemic use of exogenous estrogen, vaginally delivered estrogen with limited systemic absorption has emerged as the preferred method to treat vaginal atrophy symptoms. Numerous studies have confirmed that locally delivered estrogen is effective in relieving the symptoms and is also well-tolerated.7

The purpose of the current analysis is to evaluate the incidence rate of endometrial hyperplasia and carcinoma in the pooled study population from two studies (VAG-2195 and VAG-1748) using the identical ultra-low-dose vaginal estradiol (E2) and having the identical duration of treatment (1 year). This approach resulted in a large number of individuals with endometrial biopsy data for evaluation of the effect (if any) of the 10-microgram vaginal E2 tablet on the incidence rate of hyperplasia and carcinoma over the course of 1 year of treatment.

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MATERIALS AND METHODS

Studies VAG-2195 and VAG-1748 were approved by Independent Ethics Committee or Institutional Review Board before trial initiation, and individuals gave informed consent. The first study (VAG-2195) enrolled individuals from 45 sites in the United States and four sites in Canada during 2005 to 2007. This study was a double-blind, randomized, parallel group, placebo-controlled, multicenter trial of 52 weeks to evaluate the efficacy and safety of 10-microgram E2 for treatment of vaginal atrophy. A total of 309 individuals were randomized two-to-one to 10-microgram E2 (n=205) or placebo (n=104 randomized, n=103 exposed), respectively. The randomization and blinding methods for VAG-2195 study were described previously.8 The second study enrolled individuals from 40 sites in Czech Republic, Denmark, Finland, France, Hungary, Norway, and Sweden during 2007 to 2008. This study was an open-label multicenter study in which all individuals were to receive 10-microgram E2 treatment for 52 weeks. Treatment regimen for both studies were identical: 10-microgram E2 tablet or placebo (VAG-2195) inserted vaginally once daily during the first 2 weeks of treatment and then twice weekly for the remaining 50 weeks. Endometrial biopsies were performed and samples were histologically analyzed at baseline and at the end of the trial by the same laboratory for the evaluation of endometrial hyperplasia and carcinoma rate. The study populations from both trials were pooled to generate a combined 10-microgram E2-treated population of 541 individuals. Please see Box 1 for patient inclusion and exclusion criteria.

Box 1
Box 1
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The primary safety end point was the endometrial hyperplasia and carcinoma rate in the pooled population from studies VAG-2195 and VAG-1748 after 12 months of treatment. Endometrial biopsy samples were assessed at the beginning and end of the study. Individuals with endometrial hyperplasia and cancer at screening were excluded from the study (in trial VAG-1748 individuals with polyps were also excluded). Assessment of endometrial biopsy samples was made according to predefined and generally accepted histological criteria3,10 by two independent pathologists blinded to treatment assignment. In cases of disagreement between the two pathologists, a third blinded examiner was to be called on, and the most severe diagnosis was to be reported as the final diagnosis.3,10 Endometrial biopsies as well as transvaginal ultrasound assessments were used for evaluation of the endometrium. Transvaginal ultrasound examination preceded all endometrial biopsies.

Based on European Medicines Agency guidelines, biopsies yielding insufficient tissue for diagnosis and endometrial thickness less than 5 mm on ultrasonography were categorized as “atrophic endometrium.”10 In this study, a more stringent cut-off value of less than 4 mm was used instead of 5 mm, consistent with the inclusion criteria.

Other safety end points included vital signs, laboratory tests, physical and gynecological examinations, Pap cervical test, transvaginal ultrasound examination, local tolerability, mammogram, and quantization of adverse events. These results have been previously published;9 therefore, they will not be discussed in this article.

The background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women with or without currently marketed combined hormone therapy products is reported to be 0% to 1%.3 Data from pooled analysis of clinical trials using several recently marketed estrogen and progestin combinations showed that the incidence of hyperplasia or more serious adverse endometrial outcomes was approximately 0.26% during the first year of treatment.10 Given the background incidence rate of hyperplasia and carcinoma in the general population with or without recently marketed combinations, it would require a sample size of 300 women treated for 1 year to prove within 80% statistical power that there was no difference in the hyperplasia and carcinoma rate between the ultra-low-dose 10-microgram E2 vaginal tablet and the background rate.

Endometrial biopsy results and endometrial thickness for the completers (week 52) and the intent-to-treat population (week 52 last observation carried forward) are summarized. A last-observation-carried-forward approach was used for data imputation at the end of study. P values for the difference in endometrial thickness change from baseline between the placebo and E2 10-microgram groups were calculated from analysis of covariance with treatment effect and baseline values as a covariate included in the model.

The endometrial hyperplasia and carcinoma rate in the pooled population from studies VAG-2195 and VAG-1748 at the end of 12-month treatment was calculated based on all enrolled individuals who received at least one dose of study medication and had an evaluable endometrial biopsy result at 12 months of therapy. Based on the European Medicines Agency guideline and study protocol, the following categories were included in the analysis: evaluable endometrial biopsies at 1 year; biopsy samples with “insufficient” tissue for diagnosis and endometrial thickness less than 4 mm (categorized as “atrophic” endometrium), and biopsy samples with diagnosis of hyperplasia or carcinoma performed during the study, whatever the duration of the treatment.

Nonevaluable biopsy samples according to the European Medicines Agency guidelines10 and study protocol were results with a final diagnosis of “no tissue” or “insufficient tissue for diagnosis” and endometrial thickness 4 mm or more, as well as biopsies performed before minimal treatment duration (1 year), except for biopsy samples showing hyperplasia or carcinoma.

For the demonstration of endometrial safety of a new hormone therapy product, the U.S. Food and Drug Administration (FDA) requires the hyperplasia and carcinoma rate to be less than 1% after 1 year of treatment, with an upper bound of the one-sided 95% CI for that rate being 4% or less, whereas the European Medicines Agency requires that the upper bound of a two-sided 95% CI of the observed frequency of endometrial events should not exceed 2%. Both the one-sided 95% CI and the two-sided 95% CI of the hyperplasia and carcinoma rate were calculated to fulfill the regulatory requirements.

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RESULTS

Baseline characteristics are presented in Table 1. The total number of individuals exposed to 10-microgram E2 in the combined study population was 541, and 456 (84.3%) completed the studies. The overall completion rate was higher in the 10-microgram E2 group (84.3%) as compared with the placebo group (68.0%, P<.001; Table 2). Among the 85 individuals who discontinued prematurely in the 10-microgram E2 group, 29 individuals (34.1%) discontinued because of adverse events, 31 (36.5%) individuals discontinued because of “other” reasons (such as lost to follow-up or withdrawal of informed consent), 13 individuals (15.3%) discontinued because of noncompliance with the protocol, and only 12 individuals (14.1%) withdrew because of ineffective therapy. In the placebo group, the drop-out rate attributable to ineffective therapy was higher (33.3%) as compared with the E2 group (14.1%), which contributed to the overall higher drop-out rate in the placebo group (Table 2).

Table 1
Table 1
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Table 2
Table 2
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Endometrial biopsy results obtained at screening are presented in Table 3. At baseline, 537 individuals in the 10-microgram E2 treatment group had endometrial biopsy performed, among which 500 individuals' biopsy results (93.1%) were in the “atrophic” or “inactive” category, which represents the expected endometrial status in the study population of postmenopausal women undergoing investigation. This included 169 individuals (31.5%) with tissue insufficient for diagnosis and all of them had endometrial thickness less than 4 mm, 273 (50.8%) individuals with atrophic endometrium and 58 (10.8%) individuals with inactive endometrium. In addition, 23 individuals' biopsy results (4.3%) revealed “no tissue” (these biopsies were supposed to have been repeated or the participant had withdrawn from study, but one such individual with a “no tissue” biopsy result at screening was enrolled without a repeat biopsy, ie, no baseline status, and later had endometrial cancer diagnosed); nine individuals (1.7%) were found to have endometrial polyps, three individuals (0.6%) were in the “other” category at screening (two individuals had a biopsy report of “endometritis with mixed inflammatory pattern” and completed the study, one participant had “atypical epithelial proliferation” and withdrew because of violation of inclusion and exclusion criteria), and two (0.4%) individuals' biopsy samples showed “weakly proliferative” endometrium.

Table 3
Table 3
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At week 52, a total of 443 individuals had an endometrial biopsy performed (Table 3). Among the 443 biopsy results, 379 (85.6%) were in the categories of tissue insufficient for diagnosis, atrophic, or inactive endometrium. This included 121 individuals (27.3%) who had “tissue insufficient for diagnosis and endometrial thickness less than 4 mm, and therefore would be categorized atrophic, 193 individuals (43.6%) who had atrophic endometrium, and 65 individuals (14.7%) who had inactive endometrium. Fifty-six biopsy samples were not evaluable according to the underlying criteria: 51 (11.5%) individuals' biopsy samples revealed no tissue and five individuals' biopsy samples (1.1%) had tissue insufficient for diagnosis but endometrial thickness 4 mm or more (none of the individuals' endometrial thickness was considered to be clinically significantly increased). Five individuals (1.1%) were found to have polyps, one participant's biopsy sample (0.2%) was weakly proliferative endometrium, and one participant (0.2%) was found to have adenomyosis (other category).

One patient from study VAG-2195, a 62-year-old woman treated with trial drug for 324 days, had endometrioid adenocarcinoma, grade 2, stage 1B (approximately one third of myometrial invasion, diagnosis made in 2006). For this participant, because screening biopsy revealed “no tissue” but was not repeated, it is uncertain if the carcinoma was preexisting at baseline. The patient had a previous history of using a systemic unopposed estrogen and methyltestosterone combination for approximately 2 years for hot flushes.

One case of complex hyperplasia without atypia was diagnosed in a participant (from study VAG-2195) who discontinued the study prematurely after only 9 days of trial drug exposure. According to the European Medicines Agency guideline, biopsies with diagnosis of hyperplasia or carcinoma performed during the study regardless of the duration of the treatment should be included; therefore, this case was included in the analysis. When the last-observation-carried-forward approach was used in the intention-to-treat population (week 52 last observation carried forward), the results were similar to those of week 52 (Table 3).

In the combined E2 group with a total number of 386 evaluable biopsy samples at 12 months, one case of endometrial hyperplasia and one case of endometrioid carcinoma were reported, resulting in an incidence rate of hyperplasia and carcinoma of 0.52% per year. The one-sided 95% CI for the E2 treatment group was [0–1.62%], with the upper bound of the one-sided 95% CI result remaining less than 4% as required by the FDA. The two-sided 95% CI was [0.06%–1.86%], with the upper bound of the two-sided 95% CI result being less than 2% as required by the European Medicines Agency (Table 4). Regardless of the method of calculation, these findings meet the requirements from both regulatory authorities (FDA and European Medicines Agency) for endometrial safety.

Table 4
Table 4
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Endometrial thickness (double layer) was measured by transvaginal ultrasonography in a standard fashion during the course of these trials. In the placebo group, mean endometrial thickness was 2.20 mm at baseline and remained unchanged after 52 weeks of observation; in the 10-microgram E2 group, it was 2.14 mm at baseline and also remained unchanged at the end of the study, indicating no changes in either group (P>.05; Table 5). Results of the intention-to-treat population (week 52 last observation carried forward) are similar to those of the completers (week 52).

Table 5
Table 5
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DISCUSSION

Endometrial hyperplasia is a potentially precancerous proliferation of the endometrium. Endometrial cancer is one of the most common gynecologic cancers in the United States, with an estimated incidence of 42,160 new cases in 2009.11 A recently published Cochrane Review of hormone therapy in postmenopausal women indicates that in women with an intact uterus, systematically administered unopposed estrogen is associated with increased risk of endometrial hyperplasia at all dose levels.12 This is supported by the North American Menopause Society's 2010 position statement stating that “Unopposed systemic estrogen therapy in postmenopausal women with an intact uterus is associated with increased endometrial cancer risk related to the estrogen therapy dose and duration of use. Standard-dose therapy (0.625 mg/d conjugated estrogen (CE) or the equivalent), when used for more than 3 years, is associated with up to a fivefold increased risk of endometrial cancer; if used for 10 years, the risk increases up to 10-fold. This increased risk persists for several years after estrogen therapy discontinuation.”12 For local estrogen therapy, the available evidence is limited with respect to large-scale studies and especially long-term follow-up; thus, there are still ongoing discussions about the need for endometrial surveillance in asymptomatic women and whether the addition of a progestogen is required when using local estrogen therapy. Based on the currently available evidence, the North American Menopause Society's 2007 position statement on local vaginal estrogen concluded that progestogen is generally not indicated when low-dose estrogen is administered locally for vaginal atrophy.7

Since the initial publication of the Women's Health Initiative estrogen plus progestin study results,14 health authorities and medical associations are recommending the lowest effective dose of hormone therapy be utilized for the shortest time consistent with therapeutic goals.13,15–17 Even before those recommendations, the development of a new formulation of the marketed 25-microgram E2 vaginal tablet, containing an ultra-low-dose 10-microgram E2, was initiated by Novo Nordisk.18 The efficacy and safety of this 10-microgram E2 vaginal tablet has been investigated in the randomized, double-blind, placebo-controlled trial (VAG-2195).8 A second study (VAG-1748) was undertaken specifically to evaluate endometrial safety by endometrial biopsy after 12 months of treatment with the ultra-low-dose 10-microgram E2 tablet in a larger number of individuals.19 The endometrial safety results from these two studies were pooled in the current analysis to meet the highly specific requirements from the regulatory authorities (both FDA and European Medicines Agency) for the demonstration of endometrial safety of newly developed medicinal products for the treatment of postmenopausal symptoms.3,10 One case of endometrial hyperplasia without atypia and one case of endometrioid adenocarcinoma were identified in the pooled analysis of 541 individuals who underwent 1 year treatment with 10-microgram E2 vaginal tablets. Among these individuals, 386 had evaluable biopsy results at 1 year. Because the participant with complex hyperplasia without atypia only received 9 days of study drug, this event is not to be considered study drug related. The adenocarcinoma event reported in this study was associated with the absence of an adequate baseline endometrial biopsy. It is therefore not possible to know with certainty whether this endometrial pathology was present at baseline. It remains unlikely that 11 months of exposure to the ultra-low-dose 10-microgram vaginal E2 tablet (total exposure 1.14 mg) used in this study would have a causal relationship with the development of endometrial cancer. Additionally, this study participant had a previous history of unopposed estrogen and methyltestosterone combination therapy for approximately 2 years in the 1990s for vasomotor symptoms (hot flushes and night sweats), and such therapy is associated with endometrioid adenocarcinoma that is both dose- and duration-dependent.12 The elevated risk of endometrial hyperplasia and adenocarcinoma associated with unopposed estrogen therapy remains significantly elevated for more than 10 years after cessation of therapy.19,20

The reported background incidence rate of endometrial hyperplasia and carcinoma in postmenopausal women with or without currently marketed combined hormone therapy products is 0% to 1%.3 Reed et al21 reported that the incidence rate of total hyperplasia (including simple, complex, and atypical) peaks in women 50 to 54 years of age at 386 cases per 100,000 persons per year. The incidence rate of 0.52% per year for endometrial hyperplasia or cancer, calculated out of the 386 evaluable patients and biopsy samples in the current analysis, meets the requirements of regulatory authorities to demonstrate endometrial safety for newly developed hormone therapy products and supports that there is no increased risk of endometrial hyperplasia and carcinoma in postmenopausal women undergoing treatment with 10-microgram E2 vaginal tablets for 1 year.

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REFERENCES

1.Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. Menopause 2010;17:194–203.

2.Bachmann GA, Nevadunsky NS. Diagnosis and treatment of atrophic vaginitis. Am Fam Physician 2000;61:3090–6.

3.U.S. Department of Health and Human Services Food and Drug Administration Center for Drug Evaluation and Research. Guidance for industry: estrogen and estrogen/progestin drug products to treat vasomotor symptoms and vulvar and vaginal atrophy symptoms—recommendations for clinical evaluation. Washington, DC: U.S. Department of Health and Human Services; 2003.

4.Archer DF. Efficacy and tolerability of local estrogen therapy for urogenital atrophy. Menopause Epub ahead of print 2010 July 13.

5.Beard MK. Atrophic vaginitis. Can it be prevented as well as treated? Postgrad Med 1992;91:257–60.

6.Pandit L, Ouslander JG. Postmenopausal vaginal atrophy and atrophic vaginitis. Am J Med Sci 1997;314:228–31.

7.The role of local vaginal estrogen for treatment of vaginal atrophy in postmenopausal women: 2007 position statement of The North American Menopause Society. Menopause 2007;14(3 Pt 1):355–69.

8.Simon J, Nachtigall L, Gut R, Lang E, Archer DF, Utian W. Effective treatment of vaginal atrophy with an ultra-low-dose estradiol vaginal tablet. Obstet Gynecol 2008;112:1053–60.

9.Ulrich LS, Naessen T, Elia D, Goldstein JA, Eugster-Hausmann M, VAG-1748 Trial Investigators. Endometrial safety of ultra-low-dose Vagifem 10 microg in postmenopausal women with vaginal atrophy. Climacteric 2010;13:228–37.

10.Committee for Medical Products for Human Use (CHMP). Guideline on clinical investigation of medical products for hormone replacement therapy of oestrogen deficiency symptoms in postmenopausal women. London (UK): European Medicines Agency; 2005.

11.American Cancer Society. Cancer facts and figures 2009. Atlanta (GA): American Cancer Society; 2009.

12.Furness S, Roberts H, Marjoribanks J, Lethaby A, Hickey M, Farquhar C. Hormone therapy in postmenopausal women and risk of endometrial hyperplasia. The Cochrane Database of Systematic Reviews 2009, Issue 2. Art. No.: CD000402. DOI: 10.1002/14651858.CD000402.pub3.

13.Utian WH, Bachmann GA, Cahill EB, Gallagher JC, Grodstein F, Heiman JR, et al. Estrogen and progestogen use in postmenopausal women: 2010 position statement of The North American Menopause Society. Menopause 2010;17:242–55.

14.Rossouw JE, Anderson GL, Prentice RL, LaCroix AZ, Kooperberg C, Stefanick ML, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results from the Women's Health Initiative randomized controlled trial. JAMA 2002;288:321–33.

15.Cobin RH, Futterweit W, Ginzburg SB, Goodman NF, Kleerekoper M, Licata AA, et al. American Association of Clinical Endocrinologists medical guidelines for clinical practice for the diagnosis and treatment of menopause. Endocrinol Pract 2006;12:315–37.

16.Gompel A, Rozenberg S, Barlow DH, EMAS Board Members. The EMAS 2008 update on clinical recommendations on postmenopausal hormone replacement therapy. Maturitas 2008;61:227–32.

17.Board of International Menopause Society, Pines A, Sturdee DW, Birkhauser MH, Schneider HP, Gambacciani M, Panay N. IMS updated recommendations on postmenopausal hormone therapy. Climacteric 2007;10:181–94.

18.Bachmann G, Lobo RA, Gut R, Nachtigall L, Notelovitz M. Efficacy of low-dose estradiol vaginal tablets in the treatment of atrophic vaginitis: a randomized controlled trial. Obstet Gynecol 2008;111:67–76.

19.Green PK, Weiss NS, McKnight B, Voigt LF, Beresford SA. Risk of endometrial cancer following cessation of menopausal hormone use (Washington, United States). Cancer Causes Control 1996;7:575–80.

20.Sturdee DW. Endometrial cancer and HRT. Rev Gynaecol Pract 2005;5:51–6.

21.Reed SD, Newton KM, Clinton WL, Epplein M, Garcia R, Allison K, et al. Incidence of endometrial hyperplasia. Am J Obstet Gynecol 2009;200:678–6.

Figure. No caption available.


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