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Obstetrics & Gynecology:
doi: 10.1097/AOG.0b013e3181809e25
Original Research

Endometrial Effects of Tibolone in Elderly, Osteoporotic Women

Ettinger, Bruce MD1; Kenemans, Peter MD2; Johnson, Susan R. MD, MS3; Mol-Arts, Mirjam MD4; Van Os, Steve MD4; Seifert, Wilfried PhD4; Verweij, Pierre J.M. PhD4; Cummings, Steven R. MD1

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Author Information

From the 1University of California, San Francisco, San Francisco, California; 2Department of Obstetrics and Gynaecology, Free University Medical Center, Amsterdam, the Netherlands; 3Departments of Obstetrics and Gynecology and of Epidemiology, Roy J. and Lucille A. Carver College of Medicine and College of Public Health, University of Iowa, Iowa City, Iowa; and 4Organon, NV, part of Schering-Plough, Oss, the Netherlands.

Supported by Organon International (Oss, the Netherlands)—provided for research purposes only. Organon also donated the study drugs.

The authors thank the coordinating centers: University of California, San Francisco, CA, and NV Organon, Oss, the Netherlands. The authors also thank those who performed the pathologic assessment of endometrial biopsy specimens: Alex Ferenczy, MD (Los Angeles County and University of Southern California Medical Center, Los Angeles, CA), Carlos Felix, MD (McGill University, Ontario, Canada), and Richard Zaino, MD (Hershey Medical Center, Hershey, PA).

Corresponding author: Bruce Ettinger, MD, 156 Lombard Street #13, San Francisco, CA 94111; e-mail: doc.ettinger@gmail.com.

Financial Disclosure Dr. Ettinger has received consulting fees from Eli Lily (Indianapolis, IN), Barr Pharmaceuticals (Montvale, NJ), GlaxoSmithKline (Philadelphia, PA), Organon (Roseland, NJ), Proctor & Gamble (Cincinnati, OH), and Roche (Basel, Switzerland). Dr. Kenemans has received consulting fees from Wyeth-Ayerst (Madison, NJ), Organon, Proctor & Gamble, Servier (Neuilly-Sur-Seine, France), and honoraria From Solvay (Marietta, GA), Théramex (Monaco, France), and Pfizer. Dr. Cummings has received support and consultation fees from Eli Lilly, Pfizer, and Organon, He receives royalties on a patent for ultra–low-dose estrogen marketed as Menostar by Berlex (Montvale, NJ). Dr. Johnson has received grant support from Wyeth-Ayerst and Organon, and honoraria from Eli Lilly, Wyeth-Ayerst, Procter & Gamble, and Pfizer. Drs. Mol-Arts, Verweij, Seifert, and Van Os were employees of Organon during the conduct of this study.

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Abstract

OBJECTIVE: To investigate endometrial effects of tibolone administered to postmenopausal women for 3 years.

METHODS: Postmenopausal women (N=3,519) aged 60–85 years (mean 68 years) with a uterus and with osteoporosis were randomly assigned to receive tibolone orally, 1.25 mg per day, or identical placebo. We evaluated effects on endometrial thickness in all women, and examined endometrial histology in 635 participants considered to be at increased risk for abnormalities (with unexpected vaginal bleeding or endometrial thickness more than 4 mm).

RESULTS: During the first year of study, mean endometrial thickness increased 1 mm in women receiving tibolone (P<.001), but no further increases were noted during the next 2 years. Diagnostic biopsies among 499 women receiving tibolone and 136 who were receiving placebo showed cumulative incidences of endometrial hyperplasia less than 1%. Among the 15% of women whose biopsy showed an endometrial polyp (similar rate in tibolone and placebo), those receiving tibolone were more than twice as likely to show hyperplasia within the polyp. A marginal increase in grade 1 endometrioid adenocarcinoma (P=.06 compared with placebo) was found among women receiving tibolone. Prevalences of vaginal bleeding during the study were 10.8% in the tibolone group and 2.8% in the placebo group (P<.001).

CONCLUSION: Tibolone treatment during 3 years minimally increased endometrial thickness, hyperplastic polyps, endometrial carcinoma, and vaginal bleeding.

CLINICAL TRIAL REGISTRATION: ClinicalTrials.org, www.clinicaltrials.org, NCT00519857

LEVEL OF EVIDENCE: I

For many years, tibolone has been widely used throughout the world for alleviation of climacteric complaints and to prevent bone loss.1 Long-Term Intervention on Fracture with Tibolone (LIFT), a recently completed study of tibolone's efficacy in reducing the risk of osteoporotic fracture showed mixed benefits and risks; on one hand, there were reduced risks of spine and nonspine fractures and a reduced risk of breast cancer, but on the other hand, an increased risk of stroke and a trend (P=.06) toward an increased risk of endometrial cancer.2

The biochemistry and mechanisms of action of this drug's several active metabolites in various tissues are complex and not fully understood; various estrogenic, androgenic, and progestogenic actions have been shown.3,4 Among women mean age 52 years, these metabolites seemed to have a balanced effect on the endometrium, similar to the effects of estrogen continuously combined with progestogen.5,6 The population of women in LIFT was considerably older and were enrolled because they had either vertebral fractures or low bone mineral density; we now report on tibolone's effect on endometrial thickness, endometrial histology, and vaginal bleeding during the LIFT trial. The objective of this study was to investigate endometrial effects of tibolone administered to postmenopausal women for 3 years.

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MATERIALS AND METHODS

Details of the design and methods have been published.2 Long-Term Intervention on Fractures with Tibolone was conducted at 80 clinical centers in 21 countries. Participants were women with vertebral fracture or low bone mineral density aged 60 to 85 years who were at least 5 years beyond menopause. Women included in this report are those who began the study with an intact uterus. Women were excluded if they had unexplained uterine bleeding; ultrasonographic endometrial double wall thickness more than 4 mm; abnormal mammogram suggestive of breast cancer; a history of metabolic bone disease; previous use of bone-active medication; hormone use within 3 months before study; or other conditions that may be related to increased adverse effects of tibolone. The institutional review boards at each site approved the study protocol, and informed consent was obtained from all study participants.

By means of a centralized, interactive, telephone response voice system, participants at each clinical center were assigned to tibolone orally, 1.25 mg, or placebo in a 1:1 ratio in randomly permuted blocks of four with allocation concealed. Enrollment took place between July 2001 and June 2003. Participants, investigators, and outcome assessors were blinded to treatment assignment.

At screening (baseline), transvaginal ultrasonography was performed to measure endometrial double wall thickness; thickness more than 4 mm was reason for exclusion. The protocol called for a Pipelle (Prodimen, Neuilly-en-Thelle, France) suction curette endometrial biopsy in those participants considered at risk for endometrial abnormalities defined as follows: vaginal bleeding (persistent [more than 7 days] and severe [more than two pads or tampons/day] during the first 3 months, or persistent bleeding or spotting during the first 6 months, or frequent bleeding or spotting after 6 months) or double endometrial thickness image on ultrasound exceeding 4 mm during treatment. Endometrial samples were evaluated by two independent, treatment-blinded pathologists with expertise in endometrial histology; a standard system of diagnosis was used.7 If the two initial diagnoses did not agree on normal compared with abnormal histology, a third pathologist adjudicated the case. Adjudication was required for 6 of 972 (0.6%) specimens.

Outcome measures of this gynecologic evaluation study included endometrial thickness (measured annually) and probability of vaginal bleeding (assessed at biannual visits). Outcomes were assessed during exposure to study drug and for a 30-day period after its discontinuation (“in-treatment analysis”). Because vaginal bleeding was captured only through adverse event reporting, its accurate severity and duration were not assessed.

Endometrial histology was classified as insufficient for diagnosis or by the following categories, in order of clinical importance: “atrophic,” “inactive,” “proliferative,” “progestatational,” “hyperplasia,” or “adenocarcinoma.” Participants receiving more than one histologic diagnosis at follow-up visits were included in the most clinically important category.

Relative risks and their 95% confidence intervals were calculated using the normal approximation. Incidences of endometrial thickness more than 4 mm and more then 6 mm were analyzed. In asymptomatic women, the latter is a level considered by many experts to indicate need for further investigations such as endometrial biopsy.8 Times to “event” were censored at last study medication intake plus 30 days. Tibolone to placebo relative hazards and their 95% confidence intervals were obtained from a Cox proportional hazards model for time to first documented endometrial thickness more than 4 mm (respectively, 6 mm) with a single covariate for treatment. Additionally, a Cox model was fitted with the following covariates: age younger than 70 years, time since menopause more than 15 years, body mass index more than 28 kg/m2, smoking at study entry, and baseline endometrial thickness more then 2 mm.

Probability of vaginal bleeding (defined as an adverse event with a Medical Dictionary for Regulatory Activities preferred term contained in a prespecified set of terms) were analyzed similar to categorized endometrial thickness. All analyses were performed using SAS 9 (SAS Institute Inc., Cary, NC).

Based on prior studies, the expected cumulative 3-year endometrial hyperplasia incidence in the placebo group was 1%. Using 3,479 participants followed with ultrasonography, we had more than 99% power to detect a 2% difference between placebo and tibolone treatment (P=.05, one-tailed test). Using a much more conservative scenario in which only the 635 women who were biopsied are considered, we have more than 80% power to detect a 4.5% difference between placebo (1%) and tibolone (5.5%).

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RESULTS

A detailed description of participants in the LIFT trial has been published.2 Of the 4,506 subjects who took at least one dose of study drug, there were 3,519 with a uterus (1,746 in the tibolone group and 1,773 in the placebo group). Included are six from each group whose baseline endometrial thickness exceeded 4 mm. Among the 12 subjects whose baseline endometrial thickness exceeded 4 mm, seven were continued in the study. Their 1-year follow-up thickness ranged from 2.0–6.9 mm in the tibolone group (n=4) and from 2.8–3.0 mm in the placebo group (n=3).

Treatment groups did not differ in demographics or gynecologic history at baseline (Table 1). About two thirds were aged 70 years or older, 25% had body mass index 28 or more, and approximately one in five had taken postmenopausal hormone therapy in the past.

Table 1
Table 1
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In January 2006, the LIFT Data Safety Monitoring Board recommended stopping the trial because the tibolone group had an increased risk of stroke, and the primary aim of the trial, a decreased risk of vertebral fracture, had been demonstrated. Median treatment duration was 34 months. In the tibolone group, 561 (32.1%) of the women continued to receive study medication for at least 3 years, whereas 633 (35.7%) continued to receive the placebo pills for 3 years. A complete listing of adverse events is published in the primary LIFT Study article.2 In this endometrial substudy, study drug was discontinued in 333 (19.1%) patients in the tibolone group and in 240 (13.5%) patients in the placebo group because of adverse events (P<.001). Vaginal bleeding was indicated as reason for discontinuation in 55 (3.2%) women receiving tibolone and 15 (0.8%) among those on placebo. During the study, 18 (1.0%) women in the tibolone and 15 (0.8%) in the placebo group underwent hysterectomies.2 The most common reason was uterine prolapse (five in each group), followed by endometrial abnormalities (five tibolone; one placebo), and cervical abnormalities (two in each group).

Mean endometrial thickness at baseline was similar between tibolone and placebo groups (Table 1). During treatment, mean thickness was stable among women receiving placebo but increased approximately 1 mm in the first year of tibolone treatment, (P<.001) thereafter remaining in the range of 2.8–3.2 mm (P<.001 for group differences at all annual assessments). At one year, endometrial thickness more than 4 mm was observed in 533 (19.7%) women receiving tibolone and 168 (4.6%) in the placebo group. At subsequent annual assessments, these prevalences remained approximately the same. Based on all time points, the probabilities of endometrial thickness more then 4 mm were 33.3% and 9.9% for tibolone and placebo groups, respectively (relative hazards [RH] 4.74, 95% confidence interval [CI] 3.92–5.75). The probabilities of endometrial thickness exceeding 6 mm during study were 17.0% and 3.4% (RH 7.24, 95%CI 5.20–10.07). Among those women on tibolone whose endometrial thickness exceeded 6 mm after 1 year, who remained on treatment and had follow-up measurements at 2 and 3 years, endometrial thickness in 21.7% remained more than 6 mm, decreased to 4–6 mm in 20.3%, and decreased to less than 4 mm in 58.0%. On the other hand, 6.6% of women receiving tibolone whose endometrial thickness was less than 4 mm at 1 year developed thickness more than 6 mm in subsequent years; this contrasted with 1.1% of such women on placebo.

Based on endometrial thickness results, biopsy was indicated in 533 women receiving tibolone and 168 women receiving placebo. Of these 701 participants, 415 (78%) and 100 (60%) underwent biopsy in tibolone and placebo groups, respectively. Based on vaginal bleeding reports among women with normal endometrial thickness measurements, an additional 84 women receiving tibolone and 36 receiving placebo underwent biopsy. As a result, one or more biopsies were performed in 499 women in the tibolone group and 136 among women in the placebo group (relative risk 3.72, 95% CI 3.12–4.45).

Approximately 20% of biopsies were inadequate for histologic categorization. The majority of adequate biopsies indicated atrophy (96.1% and 89.0% among women receiving placebo and tibolone, respectively). Among adequate biopsies, benign proliferative or progestational changes were observed in 9.6% of those receiving tibolone compared 3.0% of the placebo group.

Table 2 summarizes the clinical details of the four cases of endometrial cancer and the three cases of endometrial hyperplasia. As previously reported,2 endometrial cancer was found in four women assigned to tibolone and none in the placebo group (P<.06); none of these four women reported vaginal bleeding, but all four showed substantial on-treatment increases in endometrial thickness (4.0, 5.0, 6.1, and 6.9 mm). None had received prior hormone therapy or had a history of diabetes, and only one was obese. The histologic type was endometrioid adenocarcinoma, and all were well-differentiated, minimally invasive cancers. Endometrial hyperplasia was found in two women taking tibolone and one woman taking placebo; the hyperplasia was atypical in one woman in each group. In these women, risk factors for endometrial hyperplasia were again minimal. The in-treatment incidences of endometrial hyperplasia and endometrial cancer among women assigned to tibolone were each less than 1 per 1,000 woman-years and these did not differ statistically significantly from rates in the placebo group. Endometrial polyps were found in 15% of biopsies in both tibolone and placebo groups; whereas one of 21 (4.8%) polyps from placebo subjects was hyperplastic (with atypia), nine of 75 (12.0%) polyps from tibolone-treated women were considered hyperplastic (three with atypia). Two of the hyperplastic polyp cases (both with atypia) were diagnosed within 6 weeks of starting therapy; one of these women showed evidence of a polyp on her screening vaginal ultrasonogram.

Table 2
Table 2
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Cumulative vaginal bleeding probability increased over the first 2 years and then leveled off (Fig. 1). The probabilities of vaginal bleeding during the first year of the study were 6.8% and 1.5% for tibolone compared with placebo groups. During the entire follow-up, the probabilities of vaginal bleeding were 10.8% in the tibolone group and 2.8% in the placebo group (Kaplan-Meier estimates; RH 4.63, 95% CI 3.25–6.60).

Fig. 1
Fig. 1
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Among several potential confounding variables, only baseline thickness was statistically significantly associated with likelihood of thickened (more than 6 mm) endometrium (Table 3), whereas smoking and obesity tended to mitigate against the development of increased thickness. Among these potential confounders, smoking showed a statistically significant inverse association with likelihood of vaginal bleeding, and surprisingly, greater baseline endometrial thickness was inversely associated with bleeding events (Table 4).

Table 3
Table 3
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Table 4
Table 4
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DISCUSSION

In this study in elderly osteoporotic (mean age 68 years) women, an average of 3 years of treatment with tibolone did not increase the rate of endometrial hyperplasia. Compared with placebo, tibolone treatment resulted in a fivefold greater risk of developing endometrial thickness more than 6 mm, a level, in the absence of bleeding, that usually mandates further investigation.8 Additionally, vaginal bleeding occurred three to four times more often among women receiving tibolone. The combined effects of these two factors yielded a greater than fourfold higher biopsy rate among women receiving tibolone. Biopsy was unlikely to show endometrial hyperplasia in either group, but women receiving tibolone showed a more than twofold higher likelihood of hyperplastic polyps. In a 36-month, open, prospective clinical trial of 485 postmenopausal women, endometrial polyps were found to be more than three times as common among women receiving tibolone compared with those on hormone therapy (HT); however, all polyps among those receiving tibolone were classified as atrophic or functional.9

Previously, Cummings et al2 reported a statistically nonsignificant increase in endometrial cancer among women receiving tibolone in the LIFT study; we now describe in more detail that these cancers were well-differentiated and of the type usually associated with hormone therapy.10 Furthermore, cancer diagnosis early in treatment suggests growth stimulus rather than tumor induction.

In many ways, endometrial effects of tibolone seem quite similar to continuous combined HT; in clinical trials, there is a small but definite increase in mean endometrial thickness during the first year,5,6 most treated women show endometrial atrophy,5,6 there are issues with vaginal bleeding initially that diminish with time,5,6 and there is no observed increase in risks of hyperplasia5,6,11–13 or of endometrial cancer.5,6,11–13 However, in the Million Women observational study, a nearly twofold increased risk of endometrial cancer was reported for women receiving tibolone, whereas no such increases were observed among women receiving continuous combined HT.14 A United Kingdom primary care database study suggests two possible explanations for this apparent increase.15 First, compared with women receiving continuous combined HT, women receiving tibolone were more likely to have taken long-term unopposed estrogen therapy before initiating the treatment of interest. Second, they were also more likely to have had prior uterine procedures, which could be considered a risk factor for subsequent endometrial neoplasms.

Although baseline endometrial biopsies were not performed in LIFT, the increases in endometrial thickness and vaginal bleeding observed in these elderly women with osteoporosis suggest that tibolone may have stimulatory effects on the endometrium that are not fully counteracted by the progestogenic effects of its delta-4 isomer.16 The effect of tibolone in younger women, ages 45–65 years without osteoporosis, was studied in the Tibolone Histology of the Endometrium and Breast Endpoints Study trial,5 which compared two tibolone dosages (2.5 mg and 1.25 mg) to 0.625 mg conjugated estrogens combined with 2.5 mg medroxyprogesterone acetate (continuous combined HT). In that study, over 2 years of follow-up, 80–88% of 2,634 participants showed an atrophic endometrium, there were comparable (0.5 mm) increases in mean endometrial thickness across treatment groups, and no cases of endometrial cancer. Endometrial hyperplasia was not found in women receiving tibolone, and was found in only two (0.2%) of those receiving continuous combined HT. In a similar study of endometrial safety, women aged 45–79 years received either tibolone 2.5 mg daily or continuous combined HT for 3 years.6 Mean endometrial thickness increased similarly in both groups (1.5 mm for tibolone, 0.7mm for continuous combined HT) during the first year and subsequently showed no further increase. Among 233 women on active therapy, no endometrial hyperplasia was found and one endometrial cancer was found in each treatment group. Vaginal bleeding, assessed by daily diaries, occurred in 66% of women on continuous combined HT, 48% of women receiving tibolone, and 23% of the placebo group.

Vaginal bleeding is a major factor adversely affecting a woman's adherence to long-term hormone therapy.17 During our study, bleeding data were not acquired by diaries, but rather through adverse event reporting. The former method is far more sensitive to bleeding, and thus our study's data may underrepresent the true incidence of troublesome vaginal bleeding. However, vaginal bleeding was rarely reported as a reason for discontinuing tibolone in our study.

Our study has the advantages of being a large randomized trial with excellent follow-up and participant adherence to assigned regimens. More than 90% of participants in our study had one or more transvaginal ultrasound evaluations during follow-up; however, only a minority (one quarter) underwent endometrial biopsy—yet these were the women most likely to show endometrial abnormalities due to increased ultrasonographic thickness or bleeding.

Our cohort was too small and follow-up too short to exclude the possibility of a change in incidence of endometrial cancer. The risks of endometrial hyperplasia and endometrial cancer among women taking exogenous unopposed estrogen is duration-dependent.10,12 Estimates are that within a few years nearly one half of women exposed to unopposed estrogen will develop hyperplasia,12 but many years are required for simple hyperplasia to progress to complex-atypical endometrial hyperplasia and ultimately to adenocarcinoma.18 Our finding of no increase in incidence of hyperplasia suggests that tibolone does not cause this type of progression. Furthermore, our finding of more hyperplastic polyps among women on tibolone suggests a different mechanism for possible neoplastic conversion.

Over 3 years, the endometrial cancer rate among those receiving tibolone (full LIFT tibolone cohort, with and without a uterus) was 0.7 in 1,000 patient years; this rate is similar to the annual rate of 0.9 in 1,000 for white females aged 65 years and older reported in the United States by Surveillance, Epidemiology, and End Results.19 However, women participating in LIFT were screened with ultrasonography at baseline and thus might be expected to have a lower rate of endometrial cancer than the general population.

Monitoring endometrial thickness for women taking tibolone is not cost-effective, because about one in six women on tibolone show levels more than 6 mm, yet only one in 85 such women were found to have endometrial cancer. Vaginal bleeding was also a poor indicator of endometrial cancer in women taking tibolone; bleeding occurred in about one in 10 women on tibolone, yet none of the four women with endometrial cancer in our study reported vaginal bleeding. Although we did not identify a high rate of endometrial pathology among women who had bleeding during the study, we recommend that unexpected bleeding among women using tibolone be evaluated with either biopsy or transvaginal ultrasonography consistent with the standard protocol for evaluating postmenopausal bleeding.

In this study, 3 years of treatment with tibolone did not increase the rate of endometrial hyperplasia, but substantially increased the probabilities of excessively thick endometrium, of hyperplastic endometrial polyps, and of vaginal bleeding. Tibolone has been shown to relieve menopausal symptoms20 and to reduce both spine and nonspine fracture risks,2 and it may also reduce the risks of breast and colon cancers2; however, caution must be shown when prescribing to the elderly because of the increase in stroke associated with its use.2 The endometrial cancer risk with tibolone is marginal in terms of statistical significance, and the tumors seem well-differentiated and minimally invasive. Overall, tibolone's potential risk for causing serious endometrial abnormalities was small during an average follow-up of 3 years, and its apparent lack of estrogenic-type endometrial stimulation is reassuring.

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REFERENCES

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5. Archer DF, Hendrix S, Gallagher JC, Rymer J, Skouby S, Ferenczy A, et al. Endometrial effects of tibolone. J Clin Endocrinol Metab 2007;92:911–8.

6. Langer RD, Landgren BM, Rymer J, Helmond FA, OPAL Investigators. Effects of tibolone and continuous combined conjugated estrogen/medroxyprogesterone acetate on the endometrium and vaginal bleeding: results of the OPAL Study. Am J Obstet Gynecol 2006;195:1320–7.

7. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In: Kurman RJ, editor. Blaustein's pathology of the female genital tract. 4th ed. New York (NY): Springer-Verlag; 1994. p. 411–38.

8. Smith-Bindman R, Kerlikowske K, Feldstein VA, Subak L, Scheidler J, Segal M, et al. Endovaginal ultrasound to exclude endometrial cancer and other endometrial abnormalities. JAMA 1998;280:1510–7.

9. Perez-Medina T, Bajo-Arenas J, Haya J, Sanfrutos L, Iniesta S, Bueno B, et al. Tibolone and risk of endometrial polyps: a prospective, comparative study of hormone therapy. Menopause 2003;10:534–7.

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11. Pickar JH, Yeh IT, Wheeler JE, Cunnane MF, Speroff L. Endometrial effects of lower doses of conjugated equine estrogens and medroxyprogesterone acetate: two-year substudy results. Fertil Steril 2003;80:1234–40.

12. Effects of hormone replacement therapy on endometrial histology in postmenopausal women. The Postmenopausal Estrogen/ Progestin Interventions (PEPI) Trial. The Writing Group for the PEPI Trial. JAMA 1996;275:370–5.

13. Anderson GL, Judd HL, Kaunitz AM, Barad DH, Beresford SA, Pettinger M, et al. Effects of estrogen plus progestin on gynecologic cancers and associated diagnostic procedures: the Women's Health Initiative randomized trial. JAMA 2003;290:1739–48.

14. Beral V, Bull D, Reeves G, Million Women Study Collaborators. Endometrial cancer and hormone-replacement therapy in the Million Women Study. Lancet 2005;365:1543–51.

15. Wierik EJ, Hendricks PT, Boerstoel-Streefland M. Clinical background of women prescribed tibolone or combined estrogen + progestogen therapies: a UK MediPlus study. Climacteric 2004;7:197–209.

16. Kloosterboer HJ, Schoonen WG, Deckers GH, Klijn JG. Effects of progestagens and Org OD14 in in vitro and in vivo tumor models. J Steroid Biochem Mol Biol 1994;49:311–8.

17. Ettinger B, Pressman A, Silver P. Effect of age on reasons for initiation and discontinuation of hormone replacement therapy [published erratum appears in Menopause 2000;7:135]. Menopause 1999;6:282–9.

18. Kurman RJ, Kaminski PF, Norris HJ. The behavior of endometrial hyperplasia. A long-term study of “untreated” hyperplasia in 170 patients. Cancer 1985;56:403–12.

19. Ries LA, Melbert D, Krapcho M, Mariotto A, Miller BA, Feuer EJ, et al, editors. Contents of the SEER Cancer Statistics Review, 1975-2004. Bethesda (MD): National Cancer Institute; 2006. Available at: http://seer.cancer.gov/csr/1975_2004/results_merged/sect_07_corpus_uteri.pdf. Based on November 2006 SEER data submission, posted to the SEER web site, 2007. Retrieved January 10, 2008.

20. Landgren MB, Helmond FA, Engelen S. Tibolone relieves climacteric symptoms in highly symptomatic women with at least seven hot flushes and sweats per day. Maturitas 2005;50:222–30.

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