Endometriosis and Its Treatment with Danazol Or Lupron in Relation to Ovarian Cancer

5142 Vol. 9, 5142–5144, November 1, 2003 Clinical Cancer Research

Featured Article Endometriosis and Its Treatment with Danazol or Lupron in Relation to Ovarian Cancer

Carrie M. Cottreau, Roberta B. Ness,1 ing androgens, have been hypothesized to have potentially mu- Francesmary Modugno, Glenn O. Allen, and tagenic effects on the ovarian epithelium (1). To test whether Marc T. Goodman exogenous androgens may be associated with ovarian cancer, we examined the effects of medications used for endometriosis, University of Pittsburgh Graduate School of Public Health, which have opposing effects on androgens. Danazol (17-␣- Pittsburgh, Pennsylvania [C. M. C., R. B. N., F. M., G. O. A.]; University of Pittsburgh Cancer Institute, Pittsburgh, Pennsylvania ethinltestosterone) is a synthetic androgen that binds to andro- [F. M., G. O. A.]; and Cancer Research Center, University of Hawaii, gen receptors and sex hormone-binding globulin resulting in a Honolulu, Hawaii [M. T. G.] 3-fold increase in free testosterone (2). Leuprolide (lupron) and nafarelin (Synarel) are gonadotropin-releasing hormone ana- logues, which, with repeated doses, suppress the secretion of Abstract follicle-stimulating hormone and luteinizing hormone, causing a Purpose: It has been hypothesized that circulating an- hormonal milieu similar to that seen during menopause (3). drogens may be involved in the development of ovarian Each medication is prescribed for symptomatic treatment of cancer. The androgenic medication, danazol, and the anti- endometriosis, although all have other therapeutic uses. Because androgenic medications, leuprolide and nafarelin, are com- danazol and luprolide/nafarelin have opposing effects on andro- monly used in the treatment of endometriosis. We assessed gen levels, we hypothesized that they would differentially im- the associations between the use of these medications and pact ovarian cancer risk. ovarian cancer. Experimental Design: We pooled information on self- reported use of danazol and leuprolide/nafarelin from two Materials and Methods population-based case-control studies of incident ovarian We pooled data on danazol and lupron/nafarelin use from cancer, comprising 1373 cases and 1980 controls. Odds ratios two ovarian cancer case-control studies. The characteristics of for the association between danazol and ovarian cancer, and these studies have been described elsewhere (4). Briefly, both leuprolide/nafarelin and ovarian cancer were adjusted for age, studies used a population-based, case-control design to study parity, oral contraceptive use, and family history of ovarian epithelial ovarian cancer. One study was conducted in Eastern cancer. These analyses were repeated among the 120 cases and Pennsylvania (5). It recruited women ages 20–69 from 39 124 controls who reported having had endometriosis. hospitals in the region and ascertained controls, frequency were at a significantly matched to cases by age, and area of residence, by random digit (19 ؍ Results: Danazol users (n elevated 3.2 fold (95% confidence interval, 1.2–8.5) risk of dialing or Healthcare Finance Administration files. A total of developing ovarian cancer, whereas leuprolide/nafarelin users 767 cases (88% of eligible subjects) and 1367 controls (72% of were not at significantly elevated risk (odds ratio, 1.0; eligible subjects) were enrolled. The other study was conducted (23 ؍ n) 95% confidence interval, 0.4–2.4). Similar results were ob- in Hawaii/Los Angeles (6). It recruited women ages 18–87 tained among the subset of women with endometriosis. from any of the major hospital centers on the island of Oahu. Conclusions: Danazol, but not leuprolide/nafarelin, in- Controls, frequency matched to cases by age, race, and location, creased the risk of ovarian cancer. This supports the hy- were identified from within a state-wide population registry or pothesis that androgen excess may be associated with the Healthcare Finance Administration files. A total of 606 cases development of ovarian cancer. (65% of eligible subjects) and 613 controls (72% of eligible subjects) were enrolled. A total of 1373 cases and 1980 controls Introduction was enrolled in the combined analysis. Both studies carried out standardized in-person interviews Ovarian cancer is the leading cause of death from gyneco- using modified versions of a single questionnaire. This ques- logic cancer, yet its etiology is unknown. Sex hormones, includ- tionnaire based recall for reproduction events on a life calendar with important events during a woman’s life used to enhance her memory for date-related information. Danazol use and lupron/ nafarelin use were captured as follows. In one study (5) subjects Received 5/8/03; revised 7/14/03; accepted 7/29/03. were specifically asked if they had ever used danazol or lupron/ The costs of publication of this article were defrayed in part by the nafarelin, and the duration of use of each. In the other study (6), payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to subjects were simply asked to identify any hormonal drug use. indicate this fact. Information was available on potentially important con- This work was supported in part by National Cancer Institute Grants founding variables related to ovarian cancer risk such as age R01CA61095, R01-CA-58598, N01-CN-67001, and K07-CA80668- (continuous), gravidity (continuous), oral contraceptive use (du- 01A1. 1 To whom requests for reprints should be addressed, at University of ration), and family history of ovarian cancer (categorical). Pittsburgh, 130 DeSoto Street, 517 Parran Hall, Pittsburgh, PA 15261. Women were categorized as having endometriosis if they had Phone: (412) 624-3045; Fax: (412) 624-1056; E-mail: [email protected]. been informed by a doctor or other health professional that they Downloaded from clincancerres.aacrjournals.org on September 26, 2021. © 2003 American Association for Cancer Research. Clinical Cancer Research 5143

Table 1 Characteristics of subjects according to danazol and GnRH-a use Drug usea No use Danazol use Lupron/nafarelin use

Characteristics n ϭ 3316 n ϭ 19 n ϭ 23 Mean Age (SD) 51.8 (13.0) 46.2 (10.2) 39.9 (6.6)b Mean gravidity (SD) 2.7 (2.1) 1.8 (1.5)c 1.4 (1.7)b Family history of ovarian cancer 79 (2.4) 0 (0.0) 0 (0.0) Education (%) Ͻhigh school 361 (10.9) 0 (0.0) 0 (0.0)b High school 994 (30.0) 4 (21.1) 4 (17.4) Ͼhigh school 1961 (59.1) 15 (78.9) 19 (82.6) Oral contraceptive used (%) Never 1376 (41.5) 5 (26.3) 2 (8.7)b Ͻ12 months 527 (15.9) 4 (21.1) 3 (13.0) 12–60 months 781 (23.6) 7 (36.8) 12 (52.2) Ͼ60 months 618 (18.6) 3 (15.8) 6 (26.1) Missing 14 (0.4) 0 0 Diagnosed with endometriosise 214 (6.5) 18 (94.7)c 17 (73.9)b a 5 individuals used danazol and lupron. b P Ͻ 0.05 for the comparison of leuprolide/nafarelin users versus use of neither set of medications. c P Ͻ 0.05 for the comparison of danazol users versus use of neither set of medications. d 14 subjects missing duration of oral contraceptive use information. e 6 subjects that did not use either danazol or leuprolide/nafarelin have an unknown diagnosis of endometriosis.

had endometriosis or infertility from endometriosis. Subjects lupron, women who used danazol had fewer pregnancies (P Ͻ were also categorized as having endometriosis if they reported 0.05). As expected, women who used danazol or luprolide/nafare- taking medications to treat endometriosis. One hundred and lin were much more likely to have been diagnosed with endometri- twenty cases and 124 controls reported having had endometriosis. osis (P Ͻ 0.001). Women who used luprolide/nafarelin were To test the appropriateness of pooling the data estimates younger (P Ͻ 0.001), more educated (P ϭ 0.05), less gravid (P Ͻ from the two studies, we calculated a ␹2 statistic for heteroge- 0.005), and more likely to use oral contraceptives (P ϭ 0.001) than neity. In none of the analyses did we find statistically significant women who used neither danazol or luprolide/nafarelin. heterogeneity between two studies. After adjusting for age, gravidity, oral contraceptive use, 2 Pooled ORs, with corresponding 95% CIs were calculated and family history of ovarian cancer, women who used dana- as the primary measure of effect size. Because both studies used zol had over three times the risk for ovarian cancer compared frequency rather than individual matching and matched on the with users of neither danazol nor lupron/nafarelin (adjusted basis of broad criteria, such as age within 5–10-year intervals, OR for users, 3.2; 95% CI, 1.2– 8.5; Table 2). Luprolide/ we used unconditional logistic regression models to adjust for nafarelin was not associated with ovarian cancer risk (adjust- any additional effects of potential confounding variables. In- ed OR, 1.0; 95% CI, 0.4–2.4). The odds of ovarian cancer cluded in the models were age and gravidity as continuous associated with danazol use of 1–3 months duration as com- variables, and oral contraceptive use and family history of pared with nonuse was 1.6 (95% CI, 0.3– 8.3) and for Ն4 ovarian cancer as dichotomous (yes/no) variables. months duration was 4.7 (95% CI, 1.3–17.3). In contrast, the Because both danazol and lupron are prescribed primarily odds of ovarian cancer with luprolide/nafarelin use of 1–3 for the treatment of endometriosis, which is in itself a risk factor months duration was 0.4 (95% CI, 0.1–1.9) and for Ն4 for ovarian cancer, we repeated our multivariable analyses in- months duration was 1.8 (95% CI, 0.6–5.6). Five women cluding only women with a history of endometriosis. Among used both danazol and luprolide. When we excluded these women with endometriosis, we also examined the effect of other women from the analyses, the OR for danazol (adjusted OR, treatments on ovarian cancer risk. Only data from one of the 3.4; 95% CI, 1.0–10.8) and the OR for luprolide/nafarelin studies (5) was available for this last analysis. changed little (adjusted OR, 0.7; 95% CI, 0.3–2.0). Restricting the adjusted analyses to include only women Results diagnosed with endometriosis, danazol use was still associated The proportion of women reporting danazol or luprolide/ with an increased risk of ovarian cancer (OR, 2.9; 95% CI, nafarelin use was low, with only 19 women reporting danazol 1.0–8.5), whereas the association between luprolide/nafarelin use and only 23 reporting luprolide/nafarelin use (Table 1). use and ovarian cancer remained nonsignificant (OR, 1.4; 95% Compared with women who had never used either danazol or CI, 0.5–4.1). Other treatments for endometriosis including oral contraceptive use (OR, 0.5; 95% CI, 0.3–0.9), hysterectomy (OR, 0.6; 95% CI, 0.3–1.2), and infertility drug use (OR, 1.2; 95% CI, 0.6–2.4), were not significantly related to elevated 2 The abbreviations used are: OR, odds ratio; CI, confidence interval. ovarian cancer risk among women with endometriosis.

Table 2 ORs and 95% CIs of ovarian cancer risk in relation to danazol and lupron use Crude OR Adjusted OR Medication Cases Controls (95% CI) (95% CI)a All women Danazol Neither medication 1354 1962 Yes 13 6 3.1 (1.2–8.3) 3.2 (1.2–8.5) Lupron or nafarelin Neither medication 1354 1962 Yes 9 14 0.9 (0.4–2.2) 1.0 (0.4–2.4) Women with endometriosis Danazol Neither medication 101 113 Yes 13 5 2.9 (1.0–8.5) 2.9 (1.0–8.5) Lupron or nafarelin Neither medication 101 113 Yes 9 8 1.3 (0.6–4.4) 1.4 (0.5–4.1) a Adjusted for age and gravidity as continuous variables and oral contraceptive use, and family history of ovarian cancer use as dichotomous variables.

Discussion our findings be replicated. Less clear is any concern about the In this pooled analysis, danazol was an independent risk factor use of exogenous androgens in women without endometriosis. for ovarian cancer. The occurrence of ovarian cancer was 3.2 times Female body builders sometimes take androgens to increase higher among women who used danazol compared with women muscle mass. Increasingly, postmenopausal women are also who used neither drug. The association between danazol use and taking androgenic drugs for this same purpose as well as to ovarian cancer persisted among a subset of women with endometri- enhance libido. Additional study of the long-term effects of osis. Luprolide and nafarelin, on the other hand, were not signifi- exogenous androgen use in women is essential. cantly related to ovarian cancer risk. Indeed, none of the other treatments for endometriosis (oral contraceptives, hysterectomy, References infertility drug use, surgical treatment, and other hormone use) 1. Risch, H. A. Hormonal etiology of epithelial ovarian cancer, with a significantly elevated ovarian cancer risk. hypothesis concerning the role of androgens and progesterone. J. Natl. Our findings support the hypothesis that circulating andro- Cancer Inst., 90: 1774–1786, 1998. gen levels may be involved in the development of ovarian 2. Olive, D. L., and Pritts, E. A. Treatment of endometriosis. N. Engl. cancer. Androgens have been shown to stimulate the growth of J. Med., 345: 266–275, 2001. ovarian epithelial cells in vivo, leading to ovarian neoplasm (7). 3. Moghissi, K. S. Medical treatment of endometriosis. Clin. Obstet. Most ovarian cancer tumors express androgen receptors, and Gynecol., 42: 620–630, 1999. ovarian cancer cell growth is inhibited in vitro by antiandrogens 4. Ness, R. B., Cramer, D. W., Goodman, M. T., Kjaer, S. K., Mallin, K., Mosgaard, B. J., Purdie, D. M., Risch, H. A., Vergona, R., and Wu, (8, 9). Furthermore, in a prospective study, women who devel- A. Infertility, fertility drugs and ovarian cancer: a pooled analysis of oped ovarian cancer had 50% higher levels of circulating an- case-control studies. Am. J. Epidemiol., 155: 217–224, 2002. drogens than women who did not develop the disease (10). 5. Ness, R. B., Grisso, J. A., Klapper, J., Schlesselman, J. J., Silberz- Although we considered the possibility that women who weig, S., Vergona, R., Morgan, M., Wheeler, J. E., and the SHARE used danazol had more severe endometriosis compared with Study Group. Risk of ovarian cancer in relation to estrogen and proges- tin dose and use characteristics of oral contraceptives. Am. J. Epide- lupron users, we know of no evidence to this effect. Danazol miol., 152: 233–241, 2000. was developed in the 1970s and quickly become the most 6. Goodman, M. T., McDuffie, K., Kolonel, L. N., Terada, K., Donlon, common treatment for endometriosis. Lupron was approved by T. A., Wilkens, L. R., Guo, C., and LeMarchand, L. Case-control study the Food and Drug Administration for use in the treatment of of ovarian cancer and polymorphisms in genes involved in catecho- endometriosis in 1990. Both danazol and lupron are equally lestrogen formation and metabolism. Cancer Epidemiol. Biomark. Prev., effective; however, because of the androgenic side effects of 10: 209–216, 2001. danazol, lupron is now the preferred medication (3). 7. Silva, E. G., Tornos, C., Fritsche, H. A., El-Nagger, A., Gray, K., Ordonez, N. G., Luna, M., and Gershenson, D. The induction of benign Selection and information biases were minimized in this epithelial neoplasms of the ovaries in guinea pigs by testosterone stim- pooled analysis by the population-based study design, large ulation: a potent animal model. Mod. Pathol., 10: 879–883, 1997. sample size, structured interviews, and detailed data collection 8. Chadha, S., Rao, B. R., Slotman, B. J., van Vroonhoven, C. C. J., and on danazol and lupron use. However, the study was limited by van der Kwast, T. H. An immunohistochemical evaluation of androgen and the few women using danazol or lupron and by the derivation of progesterone receptors in ovarian tumors. Hum. Pathol., 24: 90–95, 1993. data on medication use from self-reports. 9. Slotman, B. J., and Rao, B. R. Response to inhibition of androgen action of human ovarian cancer cell in vitro. Cancer Lett., 45: 312–320, 1989. Despite these limitations, our data suggest that danazol use 10. Helzlsouer, K. J., Alberg, A. J., Gordon, G. B., Longscope, C., increases the risk of ovarian cancer among women with endo- Bush, T. L., Hoffman, S. C., and Comstock, G. W. Serum gonadotropins metriosis. This potential for risk may moderate enthusiasm for and steroids hormones and the development of ovarian cancer. JAMA, the use of danazol in treating endometriosis, particularly should 271: 1926–1930, 1995.

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Carrie M. Cottreau, Roberta B. Ness, Francesmary Modugno, et al.

Clin Cancer Res 2003;9:5142-5144.

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