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Obstetrics & Gynecology 2000;96:373-379
© 2000 by The American College of Obstetricians and Gynecologists
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ORIGINAL RESEARCH

Norethindrone Acetate and Estradiol-Induced Endometrial Hyperplasia

ROBERT J. KURMAN, MD, JUAN CARLOS FÉLIX, MD, DAVID F. ARCHER, MD, NAYAN NANAVATI, MSC, JOAN-CARLES ARCE, MD and DEAN L. MOYER, MD

From the Departments of Gynecology and Obstetrics and Pathology, The Johns Hopkins Hospital, Baltimore, Maryland; Department of Pathology, Women’s and Children Hospital at University of Southern California, Los Angeles, California; Clinical Research Center, Eastern Virginia Medical School, Norfolk, Virginia; Novo Nordisk Pharmaceuticals Inc., Princeton, New Jersey; and Department of Pathology, Women’s and Children Hospital at University of Southern California, Los Angeles, California.

Address reprint requests to: Robert J. Kurman, MD Departments of Gynecology and Obstetrics and Pathology The Johns Hopkins Hospital 600 North Wolfe Street, Room 709 Baltimore, MD 21287


   Abstract
Top
Abstract
Materials and Methods
 Results
 Discussion
 References
 
Objective: To identify the lowest effective continuous dose of norethindrone acetate that significantly reduces 12-month incidence of endometrial hyperplasia associated with unopposed 17ß-estradiol (E2), 1 mg.

Methods: In a double-masked, randomized, multicenter study, 1176 healthy postmenopausal women 45 years of age or older without evidence of endometrial abnormalities were given 12 months of treatment with unopposed E2, 1 mg, or continuous-combined regimens of E2, 1 mg, and norethindrone acetate, 0.1 mg, 0.25 mg, or 0.5 mg. Endometrial histology was evaluated at the end of the treatment period.

Results: Continuous-combined E2-norethindrone acetate regimens significantly reduced 12-month incidence of endometrial hyperplasia compared with unopposed E2 1 mg (P < .001). Endometrial hyperplasia occurred in 14.6% of women treated with unopposed E2 1 mg, whereas in all continuous-combined groups, the rate decreased to less than 1%. Among patients who received E2-norethindrone acetate 0.1 mg, incidence was 0.8%; among those who received 0.25 mg and 0.5 mg, it was 0.4%.

Conclusion: Continuous norethindrone acetate at doses as low as 0.1 mg combined with E2 1 mg effectively negated risk for endometrial hyperplasia associated with unopposed E2 1 mg, at least for the first year of therapy.

Many epidemiologic studies have indicated that unopposed estrogen in women with intact uteri is associated with dose-dependent increased risk for endometrial cancer.1–7 Although addition of a progestogen reduces the risk, the extent of reduction, appropriate dose of progestogen, type of progestogen, and mode of administration (ie, continuous versus cyclic) are not clear.5–9

Until recently, doses of progestogen for endometrial protection were derived empirically rather than from large-scale dose-ranging clinical trials. Few studies had adequate designs and sufficient samples to establish minimal doses of progestogen adequate for endometrial protection.10,11 The lowest possible dose of progestogen that can ensure endometrial safety should be proposed because there is limited evidence of any other benefit to adding it. The effect of progestogens on breast cancer risk and modification of potential cardioprotective effects associated with estrogen use are currently unknown.12,13 Reducing the dose of progestogen to that which adequately opposes the endometrial stimulation of the specific dose of estrogen and minimizes unexpected bleeding is clinically justifiable.

Endometrial hyperplasia is an abnormal proliferative response to estrogenic stimulation that is prevented by adequate doses of progestogen. Reduction of incidence of endometrial hyperplasia associated with estrogen therapy can be evaluated in clinical trials of relatively short duration, ie, 12 months,10 and provides a clinically relevant endpoint for establishing endometrial safety because some forms of endometrial hyperplasia are believed to be precursors of endometrial adenocarcinoma.14

Many reports exist on the effects of medroxyprogesterone acetate, but data on regimens with norethindrone acetate as the progestogen are fewer.15,16 Norethindrone acetate, a C19-nortestosterone derivative, is a potent progestational agent that produces marked atrophic changes in endometrium compared with other derivatives of progesterone.17,18 The doses of norethindrone acetate that provide protection against endometrial stimulation of E2 1 mg, a dose frequently used in clinical practice for vasomotor symptom relief and prevention of bone loss in postmenopausal women, have not been established and are investigated in this study.

Our primary objective was to determine the lowest continuous dose of norethindrone acetate combined with E2 1 mg that effectively reduces the incidence of endometrial hyperplasia compared with unopposed E2 1 mg. The bleeding profile associated with each treatment in this study was reported elsewhere.16


   Materials and Methods
Top
Abstract
 Materials and Methods
Results
 Discussion
 References
 
A double-masked, randomized, parallel, controlled study was conducted in 40 centers in the United States and was approved by the appropriate Institutional Review Boards at each institution. Volunteer participants signed informed consent forms and were considered eligible if they were healthy women 45 years or older with an intact uterus, were minimum 12 months postmenopause, and had serum E2 levels up to 25 pg/mL. Women were ineligible if they had been treated with estrogen in the previous 12 weeks or with estrogen-progestogen combinations in the previous 8 weeks; had known, suspected, or history of hormone-dependent tumors or cancers; had known or suspected endometrial hyperplasia at study entry biopsy (or, when endometrial biopsy could not be done, had an endometrial thickness greater than 4 mm measured by transvaginal ultrasonography); had vaginal bleeding of unknown cause; were more than 30% above ideal body weight; had known deep-vein thrombosis, active thrombophlebitis, thromboembolic disorder, cerebro-vascular accident, or history of these conditions; had myocardial infarction or ischemic heart disease in the previous 6 months; had treated or untreated systolic blood pressure (BP) greater than 160 mmHg or diastolic BP greater than 100 mmHg; had presence of any endocrine disorder except controlled thyroid disease; were known alcohol or drug abusers; or had a known smoking habit of one pack of cigarettes or more per day. During the study, women were not allowed to use glucocorticoids (except topical preparations), any other estrogen or progestogen products, or any drug known to influence estrogen metabolism.

The randomization code was generated using a block size of eight to ensure equal distribution of treatment groups across study sites. At each site, women were assigned to the lowest available randomization number. Women were randomized equally to receive unopposed E2 1 mg, continuous-combined E2 1 mg and norethindrone acetate 0.1 mg, continuous-combined E2 1 mg and norethindrone acetate 0.25 mg, or continuous-combined E2 1 mg and norethindrone acetate 0.5 mg (Activelle, Novo Nordisk A/S, Bagsvaerd, Denmark). Study drugs were in tablet form and were manufactured, supplied, and packaged identically by Novo Nordisk. Women were instructed to take a single tablet orally once daily, preferably at bedtime for 12 months (12 cycles of 28 days).

The sample-size calculation assumed that incidence of endometrial hyperplasia would be no more than 1% in the continuous-combined groups and 7% in the unopposed E2. On the basis of those assumptions, approximately 250 women per group would have provided 80% power to detect a statistical difference (at the .05 level) between treatment groups, assuming a dropout rate of about 25%; therefore, a minimum of 1000 postmenopausal women were required for this study.

Endometrial biopsies were done at screening visits and the end of the study (after 12 months’ treatment or at the time of withdrawal in case of premature discontinuation). Investigators were instructed to use a Pipelle de Cornier suction curette (Prodimed, Neuillyen-Thelle, France) or similar device for endometrial sampling. Endometrial samples were immediately placed in 10% formalin solution for processing into paraffin blocks (Novamed Laboratory, Thousand Oaks, CA). Sections were stained with hematoxylineosin for independent histopathologic evaluation by pathologists who were blinded to treatment allocation and to each other’s results.

Before the study, three pathologists met to discuss histologic definitions and criteria for diagnosis. Endometrial hyperplasias were classified according to criteria proposed by the International Society of Gynecological Pathologists and the World Health Organization, which take into account the degree of glandular complexity and crowding and the presence of cytologic atypia. Thus, hyperplasia is divided into simple hyperplasia with or without atypia, and complex hyperplasia with or without atypia. Disordered proliferative phase was defined as a glandular abnormality similar to simple hyperplasia but focal in distribution. Insufficient tissue for histopathologic diagnosis and diagnoses of atrophy, proliferative, and secretory endometrium were considered normal.

Screening endometrial slides were centrally evaluated by a single pathologist (D.M.) to rule out abnormal histologies, which included disordered proliferative phase or hyperplasia. End-of-study endometrial slides were centrally evaluated independently by two pathologists (D.M. and J.C.F.) who were blinded to each other’s diagnoses and to treatment allocations. If both pathologists agreed that an endometrial sample was normal, no further evaluation was done. If a sample was considered abnormal by either pathologist, the slide was evaluated by a third pathologist (R.J.K.) to adjudicate the final histopathologic diagnosis. When all three pathologists found a slide to be abnormal, the diagnosis with the worst prognosis (ie, highest likelihood for progression to carcinoma) was the final one. The worst expected prognoses, in decreasing order of severity, were complex hyperplasia with atypia, simple hyperplasia with atypia, complex hyperplasia without atypia, simple hyperplasia without atypia, and disordered proliferative phase.

Incidence of normal and abnormal endometrium and of each abnormal histologic diagnosis were calculated for each treatment group by using the number of women with a specific diagnosis divided by the number of women with endometrial biopsies at the end of the study within that group. Pairwise comparisons based on the Fisher exact test were done to compare incidence rates of endometrial hyperplasia at the end of the study between the unopposed E2 group and each of the continuous-combined groups. Incidences of normal and abnormal endometrium and of each abnormal histologic diagnosis also were calculated for women older than 65 years. The distribution of endometrial hyperplasia according to time since menopause and treatment group also was tabulated.

Agreement between the two reviewing pathologists on normality versus abnormality was evaluated by using {kappa} statistics. Pairwise comparisons between treatment groups in number of women who withdrew from the study were analyzed by using the Fisher exact test. A significance level of .05 was applied for analyses. Statistical analyses were done by using SAS software, version 6.09 (SAS Institute Inc., Cary, NC).


   Results
Top
Abstract
 Materials and Methods
 Results
Discussion
 References
 
We included 1176 postmenopausal women with intact uterus; of these 89% (1043) were enrolled on the basis of a normal endometrium on screening biopsy and 11% (133) were enrolled on the basis of endometrial thickness 4 mm or less on screening transvaginal ultrasonography. The main demographic characteristics of the study population and information on participant disposition are shown in Table 1Go. Treatment groups were homogeneous with respect to the main demographic characteristics. A significantly (P < .05) higher discontinuation rate was observed in the unopposed E2 group compared with the other groups.


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  		Table 1. Disposition and Demographic Characteristics of Participants at Study Entry
 
Of the 1176 randomized women, 925 completed 12 months of treatment and 988 had endometrial histologic evaluations at the end of the study. All endometrial samples were evaluated independently by two pathologists, except for eight slides (all categorized as normal by the first pathologist) that were lost or broken in transit between the pathologists. The {kappa} value between the two initial reviewing pathologists was 0.36 (95% confidence interval 0.23, 0.48).

Distribution of endometrial normality and abnormality and incidence and type of endometrial hyperplasia at the end of the study is shown in Table 2Go. In the four treatment groups, approximately 5%–10% of endometrial samples were interpreted by the pathologists as having insufficient tissue for diagnosis and were included in the normal category. No endometrial carcinomas were found on end-of-study biopsies. Thirty-six endometrial hyperplasias were found in the unopposed E2 group. In the continuous-combined groups, two endometrial hyperplasias were diagnosed in the E2-norethindrone acetate 0.1 mg group, and one each in the E2-norethindrone acetate 0.25 mg and 0.5 mg groups. In the unopposed E2 group, incidence of hyperplasia at the end of the trial was 14.6%, whereas it was less than 1% in the continuous-combined groups: 0.8% (two of 249) in the E2-norethindrone acetate 0.1 mg group, 0.4% (one of 251) in the E2-norethindrone acetate 0.25 mg group, and 0.4% (one of 241) in the E2-norethindrone acetate 0.5 mg group. That difference was a statistically significant (P < .001) reduction in the incidence of endometrial hyperplasia for the continuous-combined groups compared with the unopposed E2 group. Incidence of disordered proliferative phase was also significantly (P < .001) higher in the unopposed E2 group than in the continuous-combined groups: 8.5% in the unopposed E2 group, 0.4% in the E2-norethindrone acetate 0.1 mg group, and 0% in both the E2-norethindrone acetate 0.25 mg and 0.5 mg groups (Table 2Go).


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  		Table 2. Endometrial Histology at the End of the Study
 
Simple hyperplasia without atypia was the most frequent type of endometrial hyperplasia in the unopposed E2 group; it accounted for 30 of the 36 cases. Of the other six hyperplasias, four were complex hyperplasias without atypia and two were complex hyperplasias with atypia. One case each of complex hyperplasia with atypia occurred in the E2-norethindrone acetate 0.1 mg and 0.25 mg groups. The one case of endometrial hyperplasia in the E2-norethindrone acetate 0.5 mg group was simple hyperplasia without atypia.

As shown in Table 3Go, the distribution of endometrial hyperplasias according to time since menopause did not suggest increased risk in women who were less than 3 years beyond last menses compared with those women who were 3 years or more beyond last menses. All eight hyperplasias in women who were less than 3 years beyond last menses were in the unopposed E2 group, and all except one were simple hyperplasias without atypia (the other was complex hyperplasia without atypia).


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  		Table 3. Distribution of Endometrial Hyperplasia According to Time Since Menopause
 
Subpopulation analysis of end-of-study endometrial biopsy results among women older than 65 years are shown in Table 4Go and are in line with those of the overall population. No endometrial abnormalities were found in the continuous-combined groups, whereas 19.0% and 14.3% of elderly women in the unopposed E2 group had endometrial hyperplasia and disordered proliferative phase, respectively. Endometrial hyperplasias in the elderly women were simple hyperplasias without atypia.


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  		Table 4. Endometrial Histology in Women Older Than 65 Years
 

   Discussion
Top
Abstract
 Materials and Methods
 Results
 Discussion
References
 
A placebo group was not included in this trial, but data from other large prospective studies suggested an annual incidence of endometrial abnormalities in non-treated postmenopausal women of approximately 1%.11 Therefore, the frequency of endometrial abnormalities associated with the combinations of E2 and low doses of norethindrone acetate in this study is low and within those seen in the background population.

Although a previous report suggested that endometrial growth and response to a 1-mg dose of micronized E2 was similar to that observed with 0.625 mg of conjugated equine estrogens,19 endometrial histopathology associated with those different estrogens has never been compared adequately in the same study, according to a MEDLINE search from 1980 to April 2000 using the terms "estrogen," "histology," "biopsy," and "endometrium." The approximate 15% incidence rate of endometrial hyperplasia that we observed with unopposed E2 seems to be lower than the rate of 22% reported for 0.625 mg of conjugated estrogens in a study with similar design and duration.10 However, definitions, adjudication procedures, and observer (pathologist)-related differences might account for small differences in incidence rates between studies; thus, across-study comparisons cannot be made directly. Nevertheless, the relevant conclusions from the available studies are that therapy with unopposed estrogen increases frequency of endometrial hyperplasia, even after a relatively short time. The addition of low doses of progestogen blunts the increased occurrence of hyperplasia, yielding an incidence similar to that in the background (untreated) population.

Endometrial hyperplasia comprises a heterogeneous group of abnormal proliferations with different rates of progression to endometrial carcinoma.14 Cytologic atypia, and to a lesser extent glandular complexity, appears to increase the likelihood of progression to carcinoma.20,21 In our study, simple hyperplasia without atypia was the most frequent abnormality. The number of atypical hyperplasias was very low, even in the unopposed E2 group. Our findings are similar to those reported in another large prospective 12-month study.10 Increasing treatment duration to 3 years increased incidence of hyperplasia with glandular complexity and atypia associated with unopposed estrogen, but not with continuous-combined estrogen-progestogen.11 Therefore, it would be unlikely that the number of architectural abnormalities and cytological atypia found after 12 months of treatment in the continuous-combined groups would have increased if the study had been prolonged. Another frequent histopathologic diagnosis in the unopposed E2 group was disordered proliferative phase, which is generally considered to be the most minimal endometrial response to estrogen stimulation detectable by conventional light microscopy and is unlikely to have great potential of progression to endometrial carcinoma.14

It is not known whether the endometrium is more sensitive in women close to menopause than in older women. Information is limited on endometrial response to estrogen or estrogen-progestogen therapy in elderly women. Increased incidence among younger postmenopausal women would indicate a higher endometrial response or an added effect of the exogenous estrogen over endogenous E2 production. In our study, the frequency of endometrial hyperplasia in the unopposed E2 group was not higher among women closer to menopause. Continuous-combined hormone replacement regimens have been used primarily in clinical practice in women who are a few years past menopause because of concerns about the risk for unexpected bleeding and about endometrial safety in women closer to menopause. No firm conclusions can be made about the continuous-combined groups because few hyperplasias were reported. Our data do not suggest that women closer to menopause have a higher risk for endometrial hyperplasia during estrogen or estrogen-progestogen therapy. Findings in women older than 65 years agreed with those in the overall population, suggesting that endometrium in elderly women responds to unopposed estrogenic stimulation as effectively as endometrium in younger women and that addition of low-dose progestogen also effectively blocks that stimulation.

One limitation of our study is that overweight and obese women were included at a rate similar to that reported for the US background population,22 but severely obese women (BMI 35 kg/m2 or more) were not studied; therefore, our results should not be generalized to that population. In addition, we found a moderate level of concordance ({kappa} = 0.36) between the initial two pathologists; thus, despite agreement on the histologic criteria before the start of the trial, this value emphasizes the subjective nature of the evaluation and highlights the importance of having several evaluators in this type of study. A higher level of concordance would have been preferred; however, to help attenuate the effects of this {kappa} value, we included a third arbiter pathologist who adjudicated all discrepancies.

Continuous-combined regimens appear to provide adequate endometrial protection, but the bleeding profile associated with each of these regimens differs markedly. The combination of E2-norethindrone acetate 0.5 mg produced the lowest incidence of bleeding.16 In clinical practice, treatment with continuous-combined regimens is meant to achieve or maintain amenorrhea; thus, consideration should be given to the dose of progestogen in terms of endometrial protection and of bleeding profile.


   Footnotes
 
The authors thank the other members of The Endometrium Study Group who participated in the study: A. L. Abt, A. B. Aven, T. Baird, E. Barrett-Connor, R. K. Bath, M. Bauder, S. Berkowitz, B. Chenault, Y. Choi, L. Cohen, R. Cole, M. H. Davidson, K. Davis, M. H. Dorin, M. V. Farmer, S. Funk, R. Graham, M. Greenwald, W. Heine, R. Jacobson, J. Johnson, I. Kerber, T. Lefton, J. P. Lenihan, D. McCluskey, M. McDermott, H. G. McQuarrie, H. Medina, M. Noel, M. Notelovitz, G. D. Parker, M. Rein, M. Reynolds, J. Rice, P. Ripley, G. Schade, F. Schaerf, S. Sharmahd, L. Speroff, C. Stunkel, C. Sweet, I. Weisberg, S. R. Weiss, R. Wilson, and C. Wysham. They also thank W.-C. Huang of Novo Nordisk Pharmaceuticals, Princeton, New Jersey, for statistical support.

Supported by Novo Nordisk Pharmaceuticals Inc., Princeton, New Jersey.

Financial Disclosure

This research was supported by payments for pathology studies to the respective institutions from Novo Nordisk Pharmaceuticals, Princeton, New Jersey, who markets estradiol norethindrone acetate. Joan-Carles Arce is an employee of, Nayan Nanavati is a former employee of, and David F. Archer is a paid consultant to Novo Nordisk. None of the authors holds stock in the company.

PII S0029-7844(00)00944-3

Received January 7, 2000. Received in revised form April 3, 2000. Accepted April 20, 2000.


   References
Top
Abstract
 Materials and Methods
 Results
 Discussion
 References
 
1. Smith DC, Prentice R, Thompson DC, Herrman WL. Association of exogenous estrogen and endometrial carcinoma. N Engl J Med 1975;293:1164–7.[Abstract]

2. Ziel HK, Finkle WD. Increased risk of endometrial carcinoma among users of conjugated estrogens. N Engl J Med 1975;293:1167–70.[Abstract]

3. Shapiro S, Kelly JP, Rosenberg L, Kaufman DW, Hlmrich SP, Rosenshein NB, et al. Risk of localized and widespread endometrial cancer in relation to recent and discontinued use of conjugated estrogens. N Engl J Med 1985;313:969–72.[Abstract]

4. Paganini-Hill A, Ross RK, Henderson BE. Endometrial cancer and patterns of use of oestrogen replacement therapy: A cohort study. Br J Cancer 1989;59:445–7.[Medline]

5. Pike MC, Peters RK, Cozen W, Probst-Hensch NM, Felix JC, Wan PC, et al. Estrogen-progestin replacement therapy and endometrial cancer. J Natl Cancer Inst 1997;89:1110–6.[Abstract/Free Full Text]

6. Beresford SA, Weiss NS, Voigt LF, McKnight B. Risk of endometrial cancer in relation to use of oestrogen combined with cyclic progestagen therapy in postmenopausal women. Lancet 1997;349: 258–61.[Medline]

7. Weiderpass E, Adami HO, Baron JA, Magnusson C, Bergström R, Lindgren A, et al. Risk of endometrial cancer following estrogen replacement with and without progestins. J Natl Cancer Inst 1999;91:1131–7.[Abstract/Free Full Text]

8. Paterson MEL, Wade-Evans T, Sturdee D, Thom MT, Studd JW. Endometrial disease after treatment with oestrogens and progestogens in the climacteric. BMJ 1980;1:822–4.

9. Voigt LF, Weiss NJ, Chu J, Daling JR, McKnight B, van Belle G. Progestogen supplementation of exogenous estrogens and risk of endometrial cancer. Lancet 1991;338:274–7.[Medline]

10. Woodruff JD, Pickar JH. Incidence of endometrial hyperplasia in postmenopausal women taking conjugated estrogens (Premarin) with medroxyprogesterone acetate or conjugated estrogens alone. Am J Obstet Gynecol 1994;170:1213–23.[Medline]

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

12. Colditz GA, Hankinson SE, Hunter DJ, Willett WG, Manson JE, Stampfer MJ, et al. The use of estrogen and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995; 332:1589–93.[Abstract/Free Full Text]

13. Hulley S, Grady D, Bush T, Furberg C, Herrington D, Riggs B, et al. Randomized trial of estrogen plus progestin for secondary prevention of cardiac heart disease in postmenopausal women. JAMA 1998;280:605–13.[Abstract/Free Full Text]

14. Kurman RJ, Norris HJ. Endometrial hyperplasia and related cellular changes. In: RJ Kurman, ed. Blaustein’s pathology of the female genital tract. 4th ed. New York: Springer-Verlag, 1994:411–37.

15. Speroff L, Rowan J, Symons J, Genant H, Wilborn W. The comparative effect on bone density, endometrium, and lipids of continuous hormones as replacement therapy (CHART Study). JAMA 1996;276:1397–403.[Abstract]

16. Archer DF, Dorin MH, Heine W, Nanavati N, Arce JC. Uterine bleeding in postmenopausal women on continuous therapy with estradiol and norethindrone acetate. Obstet Gynecol 1999;94:323–9.[Abstract/Free Full Text]

17. King RJ, Whitehead MI. Assessment of the potency of orally administered progestins in women. Fertil Steril 1986;46:1062–6.[Medline]

18. Dallenbach-Hellweg G. Exogenous (iatrogenic) changes of the endometrium. In: Dallenbach-Hellweg G, ed. Histopathology of the endometrium. 4th ed. Berlin, Germany: Springer-Verlag, 1987: 158–200.

19. Ettinger B, Bainton L, Upmalis DH, Citron JT, VanGessel A. Comparison of endometrial growth produced by unopposed conjugated estrogens or by micronized estradiol in postmenopausal women. Am J Obstet Gynecol 1997;176:112–7.[Medline]

20. Kurman RJ, Kaminski PF, Norris HJ. The behaviour of endometrial hyperplasia: A long term study of "untreated" hyperplasia in 170 patients. Cancer 1985;56:403–12.[Medline]

21. Ferenczy A, Gelfand M. The biological significance of cytological atypia in progestogen-treated endometrial hyperplasia. Am J Obstet Gynecol 1989;160:126–31.[Medline]

22. Must A, Spadano J, Coakley AE, Colditz G, Dietz W. The disease burden associated with overweight and obesity. JAMA 1999;282: 1523–9.[Abstract/Free Full Text]





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