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Women of Reproductive Age with Endometriosis are Not Osteopenic 1
FERTILITY AND STERILITYt VOL. 69, NO. 5, MAY 1998 Copyright ©1998 American Society for Reproductive Medicine Published by Elsevier Science Inc. Printed on acid-free paper in U.S.A.
Women of reproductive age with endometriosis are not osteopenic Uwe Ulrich, M.D.,*†‡ Robert Murano, M.S.,† Michael A. Skinner, B.S.,§ Helen Yin, M.S.,§ and Charles H. Chesnut III, M.D.† University of Washington, Seattle, Washington; Zeneca Pharmaceuticals Inc., Wilmington, Delaware
Objective: To determine whether women of reproductive age with endometriosis are osteopenic and whether bone density decreases with higher stages of endometriosis. Design: A multicenter cross-sectional study was performed. Setting: Thirty-nine gynecological clinics in the United States, Canada, and Puerto Rico. Patient(s): Two hundred forty-one women of reproductive age with laparoscopically proved endometriosis. Intervention(s): Diagnostic laparoscopy, bone densitometry. Main Outcome Measure(s): Endometriosis stages according to the criteria of the American Society for Reproductive Medicine, lumbar spine bone mineral density (L2–L4) as measured by dual-energy x-ray absorptiometry. Result(s): The mean lumbar spine bone mineral density, as well as the distribution of bone mineral density, of the women with endometriosis was similar to that of a normal population. There were no significant differences between endometriosis stage groups I–IV regarding bone mineral density as well as body weight, body mass index, and height. Received June 3, 1997; revised and accepted November 25, 1997. Supported by grant Ul 142/ 1-1 (U.U.) from the German Research Foundation, Bonn, Germany. Presented in part at the 13th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Edinburgh, United Kingdom, June 22–25, 1997. * Department of Obstetrics and Gynecology, University of Washington. † Osteoporosis Research Group, University of Washington Medical Center. ‡ Reprint requests and present address: Uwe Ulrich, M.D., Department of Obstetrics and Gynaecology, University of Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany (FAX: 49-228287-5795). § Zeneca Pharmaceuticals Inc. 0015-0282/98/$19.00 PII S0015-0282(98)00037-5
Conclusion(s): Women of reproductive age with endometriosis are not osteopenic. More advanced stages of endometriosis are not associated with a decrease in lumbar spine bone mineral density. (Fertil Sterilt 1998;69:821–5. ©1998 by American Society for Reproductive Medicine.) Key Words: Endometriosis, bone mineral density, dual-energy x-ray absorptiometry, osteopenia, osteoporosis
Previous findings concerning bone mineral density in women of reproductive age with endometriosis have been conflicting (1). Although some investigators (2) have suggested that peripheral bone mass is decreased in women with endometriosis, others (3– 6) found normal spine and hip bone mineral values in this condition compared with controls (Table 1). According to one theory, endometriosis is assumed to be based on a general immune dysfunction. Hence, various connective tissues, including collagen-containing tissues such as bone, may be affected by the disease per se (1, 7, 8). Furthermore, at present, state-of-the-art therapy for endometriosis involves the relatively long-term application of gonadotropinreleasing hormone analogues (GnRH-a). This treatment, when given without bone-sparing add-back therapy, has been shown to cause a rapid increase in bone resorption with decrease in bone mineral density (9) and perhaps results in microarchitectural deterioration of cancel-
lous bone that may never be reversed completely (10, 11). It is, therefore, of utmost clinical importance to investigate whether endometriosis per se is associated with low bone density if such treatment is to be considered. This study investigated whether women of reproductive age with endometriosis have reduced lumbar spine bone mineral density and whether bone mineral density decreases with more advanced stages of the disease. We report data obtained from a large cohort of patients with endometriosis.
MATERIALS AND METHODS Subjects Two hundred forty-one premenopausal women aged 30.35 6 6.31 years (range, 18 – 47) with laparoscopically proved endometriosis were studied. The patients were recruited for a prospective, randomized, controlled multicenter trial comparing 3.6 mg goserelin (Zoladex, Zeneca Inc., ICI 821
TABLE 1 Previous reports concerning endometriosis and bone mass. Year (reference)
No. of patients/no. of controls studied
Comite et al.
1989 (2)
41/35
QCT/distal radius
Lane et al. Lane et al. Rico et al.
1991 (3) 1991 (4) 1993 (6)
85/52 100 28/33
Dochi et al.
1994 (5)
48/48
Dual-energy Dual-energy Dual-energy legs, total Dual-energy
Author
Densitometry used/ skeletal site measured
x-ray x-ray x-ray body x-ray
Finding
densitometry/spine densitometry/spine densitometry/head, arms, trunk,
Both cortical and trabecular bone mass reduced in patients compared with controls No difference in bone mineral density Normal bone mineral density in patients No difference in bone mineral content
densitometry/hip, spine, total body
No difference in bone mineral density
Pharmaceuticals Group, Wilmington, DE) with or without hormone add-back therapy for the treatment of endometriosis. This trial was conducted at 39 clinical sites in North America, including the United States, Canada, and Puerto Rico. Data of this prospective study will be reported later. Local institutional review board approval was obtained at each site, and written informed consent was obtained from each volunteer before the study.
eters, respectively. To ensure comparability of the data, cross-calibration with the same Hologic spine phantom was performed on all machines. Genant et al. (13) showed that the ratio of patient bone mineral density measured on Lunar and Hologic machines was approximately 2.4% smaller than the ratio of the Hologic phantom measurement on the two machines. A much smaller difference was measured for Norland and Hologic. These factors were incorporated with the spine phantom cross-calibration data to generate a conversion factor for each individual machine.
At the time of laparoscopy, the stage of the disease was classified according to the criteria of the American Society for Reproductive Medicine (12). All patients had regular menstrual cycles, i.e., 21– 40 days, and all exhibited symptoms attributable to their endometriosis (i.e., pelvic pain, dyspareunia, and/or dysmenorrhea). Patients with a history of GnRH-a treatment were excluded from the analysis because this may have affected bone density. Patient characteristics are displayed in Table 2.
Bone mass data are expressed as both absolute bone densities in g/cm2 and z scores; the bone density of a particular patient was compared with the mean lumbar spine bone mineral density of a healthy, age-matched control group according to the Hologic database. Z scores were calculated as the number of standard deviations above or below the age-matched mean of the Hologic reference database.
Bone Densitometry Lumbar spine bone mineral density at vertebrae 2– 4 was measured by dual-energy x-ray absorptiometry using Hologic (Waltham, MA, n 5 91), Norland (Fort Atkinson, WI, n 5 6), or Lunar (Madison, WI, n 5 144) bone densitom-
For the Hologic lumbar spine reference database, 605 white women were studied at the University of California at San Diego; most of these women were volunteers, and .90% were recruited from the San Diego area. In addition,
TABLE 2 Characteristics of 241 women of reproductive age with laparoscopically proved endometriosis. Endometriosis stage I (n 5 85)
Parameter Age (y) Weight (kg) Height (cm) BMI (kg/m2) Bone mineral density (g/cm2)† Bone mineral density z score (number of SDs)
II (n 5 71)
III (n 5 50)
IV (n 5 35)
29.00 6 6.26 66.09 6 14.21 164.53 6 6.27 24.45 6 5.31 1.082 6 0.122
29.93 6 6.53 60.53 6 10.61 162.76 6 7.32 22.88 6 3.99 1.063 6 0.099
30.72 6 5.72 65.46 6 14.35 164.85 6 6.62 24.05 6 4.79 1.096 6 0.124
33.94 6 5.53 65.82 6 16.93 161.94 6 6.72 24.92 6 5.04 1.092 6 0.112
0.120 6 1.108
20.054 6 0.894
0.229 6 1.133
0.214 6 1.008
P value* 0.001 NS NS NS NS NS
Note: Values are means 6 SD. NS 5 not significant. * Calculated by analysis of variance. † Lumbar spine vertebrae 2– 4, measured by dual-energy x-ray absorptiometry.
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Vol. 69, No. 5, May 1998
FIGURE 1 Mean (6SD) lumbar spine bone mineral density (L2–L4) in women of reproductive age with endometriosis stages I–IV.
the spine database contains 218 observations of children aged 1–19 years. These data came from the Children’s Hospital, Columbus, Ohio. Subjects with renal or hepatic disease, hyperparathyroidism, hyperthyroidism, amenorrhea (in young women), hyperprolactinemia, oophorectomy before age 50, hypogonadism, rheumatoid arthritis, ankylosing spondylitis, Paget’s disease, cancer, malabsorption, and diabetes were excluded. Subjects treated with steroids, anticonvulsants, fluorides, diuretics, and estrogens also were removed, as were subjects with vertebral compression or fracture, laminectomy, severe osteophytes, or scoliosis. Outliers more than 63 SD from the age-matched mean for the population were removed on a statistical basis (14, 15). Bone mineral density recalculations after proper calibration, as well as bone densitometry quality assurance, were performed by the University of Washington Osteoporosis Research Group, Seattle, Washington.
Statistical Analysis Lumbar spine bone mineral density, body weight and height, and body mass index (BMI, as calculated by body weight/body height2) were compared between endometriosis stage groups I–IV with the use of analysis of variance (ANOVA) with Fisher’s protected least significant difference being performed as post hoc testing. Bone mineral density z scores of the whole study cohort were compared with zero by the two-tailed, one-sample t-test. The probability that a mean difference of 2% in bone mineral density between endometriosis stage groups could be detected is FERTILITY & STERILITYt
about 25% (statistical power 5 0.25) for the given sample size. However, we would be able to detect the smallest difference (approximately 1.7%) from zero 80% of the time (i.e., with a statistical power of 0.8) with the one-sample t-test. Data are presented as means 6 SD. A P value of ,0.05 was considered statistically significant. Calculations were performed with the Microsoft Excel version 4.0 and StatView version 4.0 software packages for Macintosh.
RESULTS The mean lumbar spine bone mineral density, as well as the distribution of bone mineral density, of the 241 women with endometriosis was similar to that of a normal, agematched population according to the Hologic database (mean [6SD] bone mineral density 1.081 6 0.115 g/cm2, mean [6SD] z score 0.105 6 1.040, not statistically significant from zero). In addition, the bone mineral density values between endometriosis groups I–IV were not statistically significant (Fig. 1). There were also no statistically significant differences between endometriosis stage groups regarding body height and body mass index (Table 2). Patients with stage IV disease were older than the patients in any other group, but there were no other differences between groups I–III. However, the bone mass of patients with stage IV disease was not lower. There was a trend toward a smaller body weight in women with endometriosis stage II, although this trend did not reach statistical significance (P 5 0.06). 823
DISCUSSION In this group of 241 premenopausal women with endometriosis, lumbar spine bone mineral density was normal for patient age. The distribution of bone mineral density in the whole cohort was similar to that of the normal population. In addition, there was no relationship between endometriosis stage and bone mineral density, i.e., bone mineral density did not decrease with more advanced stages of the disease. However, our statistical probability that a mean difference in bone mineral density of 2% between endometriosis stage groups was detectable was 25%; in other words, one cannot rule out the possibility that with a larger number of subjects measured a statistically significant difference between groups could have been detected. The lumbar spine was chosen as the skeletal site to be measured in this study because the mainly trabecular bone structure of the spine is more likely to show slight changes in bone mineral density compared with sites containing predominantly cortical bone. Previously, Comite et al. (2) suggested that values for both cortical and trabecular wrist bone mass as assessed by quantitative computed tomography are significantly reduced in patients with endometriosis compared with controls. Measuring spinal (3, 4, 5) and femoral (5) bone density, and total body bone mineral content (6) by dual-energy x-ray absorptiometry did not confirm these data. Lane et al. (4) discussed a potential selection bias in the report of Comite et al. (2) because the data were obtained from only one geographical area, whereas in their own studies, the samples were taken at eight (3) and nine (4) investigational sites in the United States and Canada, respectively. Given this consideration, the data in the present study should be representative in terms of demography because they were obtained from 39 sites throughout North America. In addition, in the one study that found reduced bone mineral density in patients with endometriosis (2), both cortical and trabecular forearm bone density values were measured by quantitative computed tomography, whereas in the other investigations cited, as well as in the present study, bone mineral density was measured by dual-energy x-ray absorptiometry at sites containing predominantly trabecular bone (3–5). Hence, in these latter studies (3–5), the investigators actually may have been more likely to detect existing differences in bone mineral density because of the greater sensitivity of a trabecular site, such as the lumbar spine, to potential skeletal changes (Table 1). There are several findings that have prompted clinical investigators to study bone mineral density in patients with endometriosis. First, current understanding of the pathogenesis of endometriosis is focusing more and more on immune phenomena involved in this disease (1, 2, 7, 8). For instance, endometrial implants may contain immunoreactive transforming growth factor-alpha as well as epidermal growth factor (16). In addition, endometriosis lesions have been 824
Ulrich et al.
Endometriosis and bone mass
shown to be a source of interleukin-1 (1), which may stimulate bone resorption both in vitro and in vivo (17). Both transforming growth factor-alpha and epidermal growth factor also may stimulate osteoclastic bone resorption (17). Moreover, infertile women with endometriosis exhibit higher circulating interleukin levels compared with controls (18). Because macrophage activity is enhanced in endometriotic tissue, abnormal immune response may result (1). Therefore, these and other paracrine and immune phenomena, potentially, could be linked to bone remodeling and subsequent net bone loss (1). Finally, besides occurring in the pelvic peritoneum and in reproductive organs, endometriosis lesions have been found in almost all regions of the body (1), providing further evidence that endometriosis may be a general rather than an exclusively local disorder, although the principal manifestations of the disease are in the gynecological area. Second, anovulation and endometriosis have been suggested to coexist occasionally, at least in infertile patients (19). Because anovulation has been associated with spinal bone loss (20), bone mineral density may be reduced in such patients presenting with both endometriosis and anovulation. Third, besides surgery, endometriosis currently is treated most frequently with GnRH-a therapy. This therapy rapidly and dramatically increases bone resorption as shown by the assessment of specific markers of bone resorption, namely, N-telopeptides of collagen type I degradation (9). This effect on bone remodeling due to GnRH-a therapy may cause detrimental and perhaps irreversible effects on both bone mass and microarchitecture (10). Whether bone mineral density recovers completely after the cessation of GnRH-a therapy is still being debated, and it may take more than 6 months after cessation of treatment before the bone mass deficit is reversed (11, 21). However the question remains whether bone mineral density recovery in terms of bone quantity (as assessed by dual-energy x-ray absorptiometry) truly reflects the reversibility of microarchitectural changes, and thus both bone quantity and bone quality, as shown in studies using morphometry (10). Given these considerations, it is of great clinical importance to assess whether endometriosis per se is associated with reduced bone mass because GnRH-a therapy superimposed on low bone mineral density could place a patient at a particularly high risk for clinically significant bone mass loss and, potentially, later osteoporosis. We are well aware of a potential limitation of the present study, namely, the lack of a control group recruited at the sites where the study was performed. That is why we compared the bone mineral density of each patient with the Hologic reference database, thus providing z scores. An ideal control group for patients with endometriosis would consist of regularly menstruating women of reproductive age in whom endometriosis was laparoscopically excluded. In the Vol. 69, No. 5, May 1998
third and fourth decade of life, many women may be affected by endometriosis, with prevalences reported to range between 1% and 50%, depending on study population, setting, and design (1, 8, 22). In addition, the disease may go unrecognized in many affected women because of the absence of clinical symptoms. The Hologic bone mineral density reference database provides a reasonable representation of the normal population, and we believe that the use of this database as a control group for our study cohort is appropriate (14, 15). Two recent European studies have shown that there is a good agreement of the spinal bone densities in premenopausal women with the reference ranges provided by dual-energy x-ray absorptiometry equipment (23, 24). In fact, in one report from the United Kingdom, the investigators questioned the need for local reference ranges for lumbar spine bone mineral density (23). Finally, if numerous investigational sites using different dual-energy x-ray absorpiometry equipment are involved in a multicenter study, proper calibration of the dual-energy x-ray absorpiometry scanners and comparison of the data obtained from different machines under the control of a designated center must be performed (13, 25). In summary, we found that lumbar spine bone mineral density was normal for age in a cohort of 241 premenopausal women with laparoscopically proved endometriosis. More advanced stages of the disease were not associated with a decrease in lumbar spine bone mineral density. Based on both previous investigations (3– 6) and the present findings, the possibility that endometriosis per se is associated with osteopenia seems unlikely.
3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13.
14. 15. 16.
17. 18.
19. 20. 21. Acknowledgments: The authors thank Michael Soules, M.D. (University of Washington, Seattle, Washington), for his critical comments on the manuscript and the clinical investigators at the 39 study sites. They also are indebted to Peter Steiger, Ph.D., and Thomas Kelly, Senior Scientist (Hologic Inc., Waltham, Massachusetts), for kindly providing information regarding the Hologic Reference Database.
22. 23. 24.
References 1. DeCherney AH, Dawood MY, Chesnut CH III. Endometriosis therapy: what impact on bone mass? Contemp Obstet Gynecol 1993;38:62–74. 2. Comite F, Delman M, Hutchinson-Williams K, DeCherney AH, Jensen
FERTILITY & STERILITYt
25.
P. Reduced bone mass in reproductive-aged women with endometriosis. J Clin Endocrinol Metab 1989;69:837– 42. Lane N, Baptista J, Snow-Harter C. Bone mineral density of the lumbar spine in endometriosis subjects compared to an age-similar control population. J Clin Endocrinol Metab 1991;72:510 – 4. Lane N, Baptista J, Orwoll E. Bone mineral density of the lumbar spine in women with endometriosis. Fertil Steril 1991;55:537– 42. Dochi T, Lees B, Sidhu M, Stevenson JC. Bone density and endometriosis. Fertil Steril 1994;61:175–7. Rico H, Revilla M, Arnanz F, Villa LF, Perera S, Arribas I. Total and regional bone mass values and biochemical markers of bone remodelling in endometriosis. Obstet Gynecol 1993;81:272–5. Dmowski WP, Braun D, Gebel H. Endometriosis: genetic and immunologic aspects. Prog Clin Biol Res 1990;323:99 –122. Gleicher N. Immune dysfunction—a potential target for treatment in endometriosis. Br J Obstet Gynaecol 1995;102(12 Suppl):4 –7. Marshall LA, Cain DF, Dmowski WP, Chesnut CH III. Urinary Ntelopeptides to monitor bone resorption while on GnRH agonist therapy. Obstet Gynecol 1996;87:350 – 4. Compston JE, Yamaguchi K, Croucher PI, Garrahan NJ, Lindsay PC, Shaw RW. The effects of gonadotrophin-releasing hormone agonists on iliac crest cancellous bone structure in women with endometriosis. Bone 1995;16:261–7. Taga M, Minaguchi H. Reduction of bone mineral density by gonadotropin-releasing hormone agonist, nafarelin, is not completely reversible at 6 months after the cessation of administration. Acta Obstet Gynecol Scand 1996;75:162–5. American Fertility Society. Revised American Fertility Society classification of endometriosis: 1985. Fertil Steril 1985;43:351–2. Genant HK, Grampp S, Glu¨er CS, Faulkner KG, Jergas M, Engelke K, et al. Universal standardization for dual x-ray absorptiometry: patient and phantom cross-calibration results. J Bone Miner Res 1994;9:1503– 14. Kelly T. Bone mineral reference database for American men and women. J Bone Miner Res 1990;5(2 Suppl):S249. Hologic QDR 4500 Operator’s Manual. Waltham, MA: Hologic Inc., 1995. Simms JS, Chegini N, Williams RS, Rossi AM, Dunn WA. Identification of epidermal growth factor, transforming growth factor-alpha, and epidermal growth factor receptor in surgically induced endometriosis in rats. Obstet Gynecol 1991;78:850 –7. Rodman GD. Role of cytokines in the regulation of bone resorption. Calcif Tissue Int 1993;53(1 Suppl):94 – 8. Koumantakis E, Matalliotakis I, Neonaki M, Froudarakis, Georgoulias V. Soluble serum interleukin-2 receptor, interleukin-6 and interleukin-1a in patients with endometriosis and in controls. Arch Gynecol Obstet 1994;255:107–12. Soules MR, Malinak LR, Bury R, Poindexter A. Endometriosis and anovulation: a coexisting problem in the infertile female. Am J Obstet Gynecol 1976;125:412–5. Prior JC, Vigna YM, Schechter MT, Burgess AE. Spinal bone loss and ovulatory disturbances. N Engl J Med 1990;323:1221–7. Paoletti AM, Serra GG, Cagnacci A, Vacca AMB, Guerriero S, Solla E, et al. Spontaneous reversibility of bone loss induced by gonadotropinreleasing hormone analog treatment. Fertil Steril 1996;65:707–10. Wheeler JM. Epidemiology and prevalence of endometriosis. Infertil Reprod Med Clin North Am 1992;3(3):545–59. Ryan PJ, Spector TP, Blake GM, Doyle DV, Fogelman I. A comparison of reference bone mineral density measurements derived from two sources: referred and population based. Br J Radiol 1993;66:1138 – 41. Lehmann R, Wapniarz M, Randerath O, Kvasnicka HM, John W, Reincke M, et al. Dual-energy X-ray absorptiometry at the lumbar spine in German men and women: a cross-sectional study. Calcif Tissue Int 1995;56:350 – 4. Rencken ML, Murano R, Drinkwater BL, Chesnut CH III. In vitro comparability of dual-energy X-ray absorptiometry bone densitometers. Calcif Tissue Int 1991;48:245– 8.
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Women of reproductive age with endometriosis are not osteopenic Uwe Ulrich, M.D.,*†‡ Robert Murano, M.S.,† Michael A. Skinner, B.S.,§ Helen Yin, M.S.,§ and Charles H. Chesnut III, M.D.† University of Washington, Seattle, Washington; Zeneca Pharmaceuticals Inc., Wilmington, Delaware
Objective: To determine whether women of reproductive age with endometriosis are osteopenic and whether bone density decreases with higher stages of endometriosis. Design: A multicenter cross-sectional study was performed. Setting: Thirty-nine gynecological clinics in the United States, Canada, and Puerto Rico. Patient(s): Two hundred forty-one women of reproductive age with laparoscopically proved endometriosis. Intervention(s): Diagnostic laparoscopy, bone densitometry. Main Outcome Measure(s): Endometriosis stages according to the criteria of the American Society for Reproductive Medicine, lumbar spine bone mineral density (L2–L4) as measured by dual-energy x-ray absorptiometry. Result(s): The mean lumbar spine bone mineral density, as well as the distribution of bone mineral density, of the women with endometriosis was similar to that of a normal population. There were no significant differences between endometriosis stage groups I–IV regarding bone mineral density as well as body weight, body mass index, and height. Received June 3, 1997; revised and accepted November 25, 1997. Supported by grant Ul 142/ 1-1 (U.U.) from the German Research Foundation, Bonn, Germany. Presented in part at the 13th Annual Meeting of the European Society of Human Reproduction and Embryology (ESHRE), Edinburgh, United Kingdom, June 22–25, 1997. * Department of Obstetrics and Gynecology, University of Washington. † Osteoporosis Research Group, University of Washington Medical Center. ‡ Reprint requests and present address: Uwe Ulrich, M.D., Department of Obstetrics and Gynaecology, University of Bonn, Sigmund Freud Strasse 25, 53105 Bonn, Germany (FAX: 49-228287-5795). § Zeneca Pharmaceuticals Inc. 0015-0282/98/$19.00 PII S0015-0282(98)00037-5
Conclusion(s): Women of reproductive age with endometriosis are not osteopenic. More advanced stages of endometriosis are not associated with a decrease in lumbar spine bone mineral density. (Fertil Sterilt 1998;69:821–5. ©1998 by American Society for Reproductive Medicine.) Key Words: Endometriosis, bone mineral density, dual-energy x-ray absorptiometry, osteopenia, osteoporosis
Previous findings concerning bone mineral density in women of reproductive age with endometriosis have been conflicting (1). Although some investigators (2) have suggested that peripheral bone mass is decreased in women with endometriosis, others (3– 6) found normal spine and hip bone mineral values in this condition compared with controls (Table 1). According to one theory, endometriosis is assumed to be based on a general immune dysfunction. Hence, various connective tissues, including collagen-containing tissues such as bone, may be affected by the disease per se (1, 7, 8). Furthermore, at present, state-of-the-art therapy for endometriosis involves the relatively long-term application of gonadotropinreleasing hormone analogues (GnRH-a). This treatment, when given without bone-sparing add-back therapy, has been shown to cause a rapid increase in bone resorption with decrease in bone mineral density (9) and perhaps results in microarchitectural deterioration of cancel-
lous bone that may never be reversed completely (10, 11). It is, therefore, of utmost clinical importance to investigate whether endometriosis per se is associated with low bone density if such treatment is to be considered. This study investigated whether women of reproductive age with endometriosis have reduced lumbar spine bone mineral density and whether bone mineral density decreases with more advanced stages of the disease. We report data obtained from a large cohort of patients with endometriosis.
MATERIALS AND METHODS Subjects Two hundred forty-one premenopausal women aged 30.35 6 6.31 years (range, 18 – 47) with laparoscopically proved endometriosis were studied. The patients were recruited for a prospective, randomized, controlled multicenter trial comparing 3.6 mg goserelin (Zoladex, Zeneca Inc., ICI 821
TABLE 1 Previous reports concerning endometriosis and bone mass. Year (reference)
No. of patients/no. of controls studied
Comite et al.
1989 (2)
41/35
QCT/distal radius
Lane et al. Lane et al. Rico et al.
1991 (3) 1991 (4) 1993 (6)
85/52 100 28/33
Dochi et al.
1994 (5)
48/48
Dual-energy Dual-energy Dual-energy legs, total Dual-energy
Author
Densitometry used/ skeletal site measured
x-ray x-ray x-ray body x-ray
Finding
densitometry/spine densitometry/spine densitometry/head, arms, trunk,
Both cortical and trabecular bone mass reduced in patients compared with controls No difference in bone mineral density Normal bone mineral density in patients No difference in bone mineral content
densitometry/hip, spine, total body
No difference in bone mineral density
Pharmaceuticals Group, Wilmington, DE) with or without hormone add-back therapy for the treatment of endometriosis. This trial was conducted at 39 clinical sites in North America, including the United States, Canada, and Puerto Rico. Data of this prospective study will be reported later. Local institutional review board approval was obtained at each site, and written informed consent was obtained from each volunteer before the study.
eters, respectively. To ensure comparability of the data, cross-calibration with the same Hologic spine phantom was performed on all machines. Genant et al. (13) showed that the ratio of patient bone mineral density measured on Lunar and Hologic machines was approximately 2.4% smaller than the ratio of the Hologic phantom measurement on the two machines. A much smaller difference was measured for Norland and Hologic. These factors were incorporated with the spine phantom cross-calibration data to generate a conversion factor for each individual machine.
At the time of laparoscopy, the stage of the disease was classified according to the criteria of the American Society for Reproductive Medicine (12). All patients had regular menstrual cycles, i.e., 21– 40 days, and all exhibited symptoms attributable to their endometriosis (i.e., pelvic pain, dyspareunia, and/or dysmenorrhea). Patients with a history of GnRH-a treatment were excluded from the analysis because this may have affected bone density. Patient characteristics are displayed in Table 2.
Bone mass data are expressed as both absolute bone densities in g/cm2 and z scores; the bone density of a particular patient was compared with the mean lumbar spine bone mineral density of a healthy, age-matched control group according to the Hologic database. Z scores were calculated as the number of standard deviations above or below the age-matched mean of the Hologic reference database.
Bone Densitometry Lumbar spine bone mineral density at vertebrae 2– 4 was measured by dual-energy x-ray absorptiometry using Hologic (Waltham, MA, n 5 91), Norland (Fort Atkinson, WI, n 5 6), or Lunar (Madison, WI, n 5 144) bone densitom-
For the Hologic lumbar spine reference database, 605 white women were studied at the University of California at San Diego; most of these women were volunteers, and .90% were recruited from the San Diego area. In addition,
TABLE 2 Characteristics of 241 women of reproductive age with laparoscopically proved endometriosis. Endometriosis stage I (n 5 85)
Parameter Age (y) Weight (kg) Height (cm) BMI (kg/m2) Bone mineral density (g/cm2)† Bone mineral density z score (number of SDs)
II (n 5 71)
III (n 5 50)
IV (n 5 35)
29.00 6 6.26 66.09 6 14.21 164.53 6 6.27 24.45 6 5.31 1.082 6 0.122
29.93 6 6.53 60.53 6 10.61 162.76 6 7.32 22.88 6 3.99 1.063 6 0.099
30.72 6 5.72 65.46 6 14.35 164.85 6 6.62 24.05 6 4.79 1.096 6 0.124
33.94 6 5.53 65.82 6 16.93 161.94 6 6.72 24.92 6 5.04 1.092 6 0.112
0.120 6 1.108
20.054 6 0.894
0.229 6 1.133
0.214 6 1.008
P value* 0.001 NS NS NS NS NS
Note: Values are means 6 SD. NS 5 not significant. * Calculated by analysis of variance. † Lumbar spine vertebrae 2– 4, measured by dual-energy x-ray absorptiometry.
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FIGURE 1 Mean (6SD) lumbar spine bone mineral density (L2–L4) in women of reproductive age with endometriosis stages I–IV.
the spine database contains 218 observations of children aged 1–19 years. These data came from the Children’s Hospital, Columbus, Ohio. Subjects with renal or hepatic disease, hyperparathyroidism, hyperthyroidism, amenorrhea (in young women), hyperprolactinemia, oophorectomy before age 50, hypogonadism, rheumatoid arthritis, ankylosing spondylitis, Paget’s disease, cancer, malabsorption, and diabetes were excluded. Subjects treated with steroids, anticonvulsants, fluorides, diuretics, and estrogens also were removed, as were subjects with vertebral compression or fracture, laminectomy, severe osteophytes, or scoliosis. Outliers more than 63 SD from the age-matched mean for the population were removed on a statistical basis (14, 15). Bone mineral density recalculations after proper calibration, as well as bone densitometry quality assurance, were performed by the University of Washington Osteoporosis Research Group, Seattle, Washington.
Statistical Analysis Lumbar spine bone mineral density, body weight and height, and body mass index (BMI, as calculated by body weight/body height2) were compared between endometriosis stage groups I–IV with the use of analysis of variance (ANOVA) with Fisher’s protected least significant difference being performed as post hoc testing. Bone mineral density z scores of the whole study cohort were compared with zero by the two-tailed, one-sample t-test. The probability that a mean difference of 2% in bone mineral density between endometriosis stage groups could be detected is FERTILITY & STERILITYt
about 25% (statistical power 5 0.25) for the given sample size. However, we would be able to detect the smallest difference (approximately 1.7%) from zero 80% of the time (i.e., with a statistical power of 0.8) with the one-sample t-test. Data are presented as means 6 SD. A P value of ,0.05 was considered statistically significant. Calculations were performed with the Microsoft Excel version 4.0 and StatView version 4.0 software packages for Macintosh.
RESULTS The mean lumbar spine bone mineral density, as well as the distribution of bone mineral density, of the 241 women with endometriosis was similar to that of a normal, agematched population according to the Hologic database (mean [6SD] bone mineral density 1.081 6 0.115 g/cm2, mean [6SD] z score 0.105 6 1.040, not statistically significant from zero). In addition, the bone mineral density values between endometriosis groups I–IV were not statistically significant (Fig. 1). There were also no statistically significant differences between endometriosis stage groups regarding body height and body mass index (Table 2). Patients with stage IV disease were older than the patients in any other group, but there were no other differences between groups I–III. However, the bone mass of patients with stage IV disease was not lower. There was a trend toward a smaller body weight in women with endometriosis stage II, although this trend did not reach statistical significance (P 5 0.06). 823
DISCUSSION In this group of 241 premenopausal women with endometriosis, lumbar spine bone mineral density was normal for patient age. The distribution of bone mineral density in the whole cohort was similar to that of the normal population. In addition, there was no relationship between endometriosis stage and bone mineral density, i.e., bone mineral density did not decrease with more advanced stages of the disease. However, our statistical probability that a mean difference in bone mineral density of 2% between endometriosis stage groups was detectable was 25%; in other words, one cannot rule out the possibility that with a larger number of subjects measured a statistically significant difference between groups could have been detected. The lumbar spine was chosen as the skeletal site to be measured in this study because the mainly trabecular bone structure of the spine is more likely to show slight changes in bone mineral density compared with sites containing predominantly cortical bone. Previously, Comite et al. (2) suggested that values for both cortical and trabecular wrist bone mass as assessed by quantitative computed tomography are significantly reduced in patients with endometriosis compared with controls. Measuring spinal (3, 4, 5) and femoral (5) bone density, and total body bone mineral content (6) by dual-energy x-ray absorptiometry did not confirm these data. Lane et al. (4) discussed a potential selection bias in the report of Comite et al. (2) because the data were obtained from only one geographical area, whereas in their own studies, the samples were taken at eight (3) and nine (4) investigational sites in the United States and Canada, respectively. Given this consideration, the data in the present study should be representative in terms of demography because they were obtained from 39 sites throughout North America. In addition, in the one study that found reduced bone mineral density in patients with endometriosis (2), both cortical and trabecular forearm bone density values were measured by quantitative computed tomography, whereas in the other investigations cited, as well as in the present study, bone mineral density was measured by dual-energy x-ray absorptiometry at sites containing predominantly trabecular bone (3–5). Hence, in these latter studies (3–5), the investigators actually may have been more likely to detect existing differences in bone mineral density because of the greater sensitivity of a trabecular site, such as the lumbar spine, to potential skeletal changes (Table 1). There are several findings that have prompted clinical investigators to study bone mineral density in patients with endometriosis. First, current understanding of the pathogenesis of endometriosis is focusing more and more on immune phenomena involved in this disease (1, 2, 7, 8). For instance, endometrial implants may contain immunoreactive transforming growth factor-alpha as well as epidermal growth factor (16). In addition, endometriosis lesions have been 824
Ulrich et al.
Endometriosis and bone mass
shown to be a source of interleukin-1 (1), which may stimulate bone resorption both in vitro and in vivo (17). Both transforming growth factor-alpha and epidermal growth factor also may stimulate osteoclastic bone resorption (17). Moreover, infertile women with endometriosis exhibit higher circulating interleukin levels compared with controls (18). Because macrophage activity is enhanced in endometriotic tissue, abnormal immune response may result (1). Therefore, these and other paracrine and immune phenomena, potentially, could be linked to bone remodeling and subsequent net bone loss (1). Finally, besides occurring in the pelvic peritoneum and in reproductive organs, endometriosis lesions have been found in almost all regions of the body (1), providing further evidence that endometriosis may be a general rather than an exclusively local disorder, although the principal manifestations of the disease are in the gynecological area. Second, anovulation and endometriosis have been suggested to coexist occasionally, at least in infertile patients (19). Because anovulation has been associated with spinal bone loss (20), bone mineral density may be reduced in such patients presenting with both endometriosis and anovulation. Third, besides surgery, endometriosis currently is treated most frequently with GnRH-a therapy. This therapy rapidly and dramatically increases bone resorption as shown by the assessment of specific markers of bone resorption, namely, N-telopeptides of collagen type I degradation (9). This effect on bone remodeling due to GnRH-a therapy may cause detrimental and perhaps irreversible effects on both bone mass and microarchitecture (10). Whether bone mineral density recovers completely after the cessation of GnRH-a therapy is still being debated, and it may take more than 6 months after cessation of treatment before the bone mass deficit is reversed (11, 21). However the question remains whether bone mineral density recovery in terms of bone quantity (as assessed by dual-energy x-ray absorptiometry) truly reflects the reversibility of microarchitectural changes, and thus both bone quantity and bone quality, as shown in studies using morphometry (10). Given these considerations, it is of great clinical importance to assess whether endometriosis per se is associated with reduced bone mass because GnRH-a therapy superimposed on low bone mineral density could place a patient at a particularly high risk for clinically significant bone mass loss and, potentially, later osteoporosis. We are well aware of a potential limitation of the present study, namely, the lack of a control group recruited at the sites where the study was performed. That is why we compared the bone mineral density of each patient with the Hologic reference database, thus providing z scores. An ideal control group for patients with endometriosis would consist of regularly menstruating women of reproductive age in whom endometriosis was laparoscopically excluded. In the Vol. 69, No. 5, May 1998
third and fourth decade of life, many women may be affected by endometriosis, with prevalences reported to range between 1% and 50%, depending on study population, setting, and design (1, 8, 22). In addition, the disease may go unrecognized in many affected women because of the absence of clinical symptoms. The Hologic bone mineral density reference database provides a reasonable representation of the normal population, and we believe that the use of this database as a control group for our study cohort is appropriate (14, 15). Two recent European studies have shown that there is a good agreement of the spinal bone densities in premenopausal women with the reference ranges provided by dual-energy x-ray absorptiometry equipment (23, 24). In fact, in one report from the United Kingdom, the investigators questioned the need for local reference ranges for lumbar spine bone mineral density (23). Finally, if numerous investigational sites using different dual-energy x-ray absorpiometry equipment are involved in a multicenter study, proper calibration of the dual-energy x-ray absorpiometry scanners and comparison of the data obtained from different machines under the control of a designated center must be performed (13, 25). In summary, we found that lumbar spine bone mineral density was normal for age in a cohort of 241 premenopausal women with laparoscopically proved endometriosis. More advanced stages of the disease were not associated with a decrease in lumbar spine bone mineral density. Based on both previous investigations (3– 6) and the present findings, the possibility that endometriosis per se is associated with osteopenia seems unlikely.
3. 4. 5. 6. 7. 8. 9. 10.
11.
12. 13.
14. 15. 16.
17. 18.
19. 20. 21. Acknowledgments: The authors thank Michael Soules, M.D. (University of Washington, Seattle, Washington), for his critical comments on the manuscript and the clinical investigators at the 39 study sites. They also are indebted to Peter Steiger, Ph.D., and Thomas Kelly, Senior Scientist (Hologic Inc., Waltham, Massachusetts), for kindly providing information regarding the Hologic Reference Database.
22. 23. 24.
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