CLIMACTERIC 2015;18:448–452
Invited Editorial
Should we abstain from treating women with endometriosis using menopausal hormone therapy, for fear of an increased ovarian cancer risk? Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
S. Rozenberg, C. Antoine, J. Vandromme and M. Fastrez Department of Obstetrics and Gynecology, CHU Saint-Pierre, Université Libre de Bruxelles, Vrije Universiteit Brussel, Brussels, Belgium Key words: ENDOMETRIOSIS, MENOPAUSAL HORMONE THERAPY, RISK, OVARIAN CANCER
ABSTRACT Women suffering from endometriosis often have an early menopause, resulting in severe menopausal symptoms and an increased risk of osteoporosis. They are therefore candidates for menopausal hormone therapy (MHT). Unfortunately, MHT may increase the risk of endometriosis recurrence. Moreover, endometriosis patients are at increased risk of ovarian cancer, which may be further enhanced by MHT use. It is unknown, however, whether MHT more frequently increases type I (low-grade serous tumors), which seem to be increased when endometriosis is present, or type II (the more aggressive high-grade serous) tumors. We propose the following decision-making algorithm for endometriosis patients considering MHT. Those who have been treated with bilateral salpingo-oophorectomy, and in whom there is no residual endometriotic disease, can probably be treated using MHT without risk of endometriosis recurrence or fear of ovarian cancer. For women with significant, residual endometriosis lesions, the benefit may outweigh the risks, when menopause is reached before the age of 45 years or when severe symptoms are present.
The Collaborative Group on Epidemiological Studies of Ovarian Cancer recently reported that the use of menopausal hormone therapy (MHT) for 5–10 years, from around the age of 50 years, is associated with approximately one extra ovarian cancer per 1000–2000 women1. The increased risk was observed globally for invasive ovarian cancers, for serous and endometrioid tumors but not for mucinous or clear-cell tumors (Table 1). The question arises as to whether women who have additional risks of ovarian cancer, such as a past history of endometriosis, have an even higher ovarian cancer risk when using MHT. Indeed, endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer2. It remains controversial as to whether endometriosis per se reduces the ovarian reserve3 or whether it is brought on by endometriosis surgery4,5. Many of these women (about 12% according to some studies) will be treated surgically by a total hysterectomy
and a bilateral salpingo-oophorectomy, sometimes at an early age, leading to severe menopausal symptoms and an increased osteoporosis risk6–8. In view of these findings, should these women use MHT? What associated, increased risk will these women encounter, using MHT? Theoretically, there are two types of these women. The first type may encounter an increased risk of endometriosis recurrence. Actually, this may also occur with no MHT, and may be due to the residual steroid secretion of estrogens and androgens by the postmenopausal ovaries, since a high recurrence rate (62%) has been reported in advanced stages of endometriosis, when the ovaries were preserved8,9. Ovarian preservation has been reported to carry a six-fold risk of recurrent pain and eight-fold risk of reoperation9. The recurrence of endometriosis symptoms and pelvic pain seems to be directly correlated to the surgical precision and removal
Correspondence: Professor S. Rozenberg, Department of Obstetrics and Gynecology, St Peter University Hospital, Hoog Str 322, 1000 Brussels, Belgium; E-mail: [email protected] INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1041905
Received 26-03-2015 Revised 01-04-2015 Accepted 14-04-2015
Endometriosis, menopausal hormone therapy and ovarian cancer risk
Rozenberg et al.
Table 1 Overall, and by histological type, ovarian cancer risk increase or reduction associated respectively with endometriosis, contraception and menopausal hormone therapy (MHT)
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Endometriosisa Histological type
OR
95% CI
Invasive cancer Serous low-grade (type I) high-grade (type II) Endometrioid Mucinous Clear-cell
1.46
1.31–1.63
2.11 1.13 2.04 1.02 3.05
1.39–3.20 0.97–1.32 1.67–2.48 0.69–1.50 2.43–3.84
Contraception: % reduction in risk per 5/10 years use, by ovarian tumor histology (SE)b,d Significant reduction 20.5 % (SE 1.9%)b Significant reduction 22.1% (SE 2.9%)b Type I, HR 0.54 (95% CI 0.31–0.94)d Type II, HR 0.71 (95% CI 0.51–0.97)d Significant reduction 27.1% (SE 4.8%) No protection 6.7% (SE 5.8%) Significant reduction 21.3% (SE 7.3%)
MHT: RR compared to never-users, adjusted for age at menopause, hysterectomy, oral contraceptive use, and parityc RR
95% CI
1.43 1.40
1.31–1.56 1.31–1.49
1.28 0.80 0.80
1.13–1.45 0.63–0.93 0.65–0.98
RR, relative risk; OR, odds ratio; 95% CI, 95% confidence interval; SE, Standard estimates Adapted from reference 22; b, per 5 years, adapted from reference 19; c, adapted from reference 1; d, per 10 years, adapted from reference 17
a,
of peritoneal and deeply infiltrating disease, suggesting that surgical efforts should always aim completely to eliminate the endometriotic lesions in order to keep the risk of recurrence as low as possible8,9. But is this risk further increased when using MHT? It may be so. One must admit that data are scarce. The Cochrane Database review published by Al Kadri and colleagues10 reported only two trials assessing the risk of recurrence using MHT after surgical menopause. The first study conducted by Matorras and colleagues11 estimated this risk in 115 women receiving MHT and 57 who were not. They observed no recurrence among untreated women as compared to a 3.5% rate in MHT-treated ones11. In their experience, the risk of recurrence was related to the incomplete surgery11. In a much smaller trial (n 21), Fedele and colleagues12 compared the effect of transdermal estradiol (E2) 50 mg, administered twice weekly associated with cyclic medroxyprogesterone acetate 10 mg daily for 12 days per month as compared to tibolone 2.5 mg administered orally once a day in a continuous regimen. After 12 months, four patients out of ten in the E2 group and one out of 11 in the tibolone group experienced moderate pelvic pain, but in many patients surgery had not been complete and residual endometriosis was common12. The authors of the Cochrane review10 concluded that MHT for women with endometriosis in post-surgical menopause could result in pain and disease recurrence but also that the evidence in literature is not strong enough to recommend depriving severely symptomatic patients of this treatment. Although the study conducted by Fedele and colleagues12 lacked statistical power to detect a significant difference, many authors suggest administering continuous, combined MHT regimens in endometriosis patients, especially when no surgery or incomplete surgery was performed. The second type of women are those patients suffering from endometriosis who may also be at increased risk of malignant transformation of residual disease foci. The lifetime risk of ovarian cancer varies between 0.47% in Japan and 1.8% in the US13. Eighty to ninety percent are of
Climacteric
epithelial origin. Of these, 50–60% are categorized as serous, 8–10% as mucinous, and 10–15% either as endometrioid or clear-cell13. It has been hypothesized that many ovarian cancers have an extra-ovarian origin14–17. Serous ovarian carcinomas, the most common histologic subtype, may indeed come from serous tubal intraepithelial carcinoma developed in the fimbriae of the Fallopian tubes. It is commonly hypothesized that repeated retrograde menstruation may expose the Fallopian tubes to iron-induced oxidative stress, resulting from hemolysis of erythrocytes by pelvic macrophages (the incessant menstruation hypothesis)18. Mucinous tumors may originate in the colonic mucosa or endocervical epithelium, and clear cell and endometrioid tumors may be linked to endometriosis and display characteristics of endometrial tissue14–17. These findings were first observed after prophylactic salpingo-oophorectomies in patients carrying BRCA-1 and -2 mutations. As a consequence, risk-reducing surgery for patients with such mutations currently includes complete removal of the ovaries and Fallopian tubes. Furthermore, it may be logical to perform a salpingectomy only, at the time of hysterectomy for benign indications in young women17. On the other hand, continuing ovulation and damage to the ovaries, and therefore increasing the number of mutations, have long been viewed as risk factors for ovarian cancer, while parity or hormonal contraception, limiting the number of ovulation periods, have repeatedly been found to be protective19 (Table 1). There are only limited data about the protective effect of oral contraceptives in endometriosis patients. Modugno and colleagues20 pooled information on the self-reported history of endometriosis from four population-based, case-controlled studies of incidents of epithelial ovarian cancer, comprising 2098 cases and 2953 control subjects. The use of oral contraceptives for more than 10 years was associated with about 80% reduction in risk among women with endometriosis20.
449
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Endometriosis, menopausal hormone therapy and ovarian cancer risk Experimental data reported that some ovarian cancer cells share a number of estrogen-regulated pathways with other hormone-dependent cancers such as breast and endometrial cancer18. Steroids and estrogens in particular may promote tumor growth at the cellular level through a receptor-dependent effect, by binding to the nuclear estrogen receptor-alpha and promoting gene transcription of proto-oncogenes, or by binding to membrane-bound G-protein and activating a second messenger or through an independent effect by enhancing reactive metabolites via cytochrome P450 enzymes (CYPs), causing DNA mutations in various genes in Fallopian tube cells. Particularly metabolites such as catechol metabolites and 4-hydroxy E2/E1 (4-OHE2/E1) have been shown to have carcinogenic effects18. It has been hypothesized that ovarian carcinogenesis may occur in two distinct pathways. Type I tumors (predominantly low-grade, serous histologic subtype) may develop from precursor lesions such as borderline tumors or endometriosis, may be associated with KRAS, BRAF or PTEN mutations and have low chromosomal instability, whereas type II tumors (predominantly high-grade serous histologic subtype) are aggressive neoplasms which harbor TP53 mutations and exhibit high chromosomal instability2,21. The study by the Collaborative Group on Epidemiological Studies of Ovarian Cancer1 did not specify whether the ovarian cancer risk was more often associated with type I (low grade serous) or type II (high grade serous tumors) (Table 2). There are many arguments for considering endometriosis as a premalignant condition. The subject was recently reviewed using a metaanalysis13. Ovarian endometrial cysts often have a monoclonal origin; the prevalence of endometriosis is increased in ovarian cancer patients (ranging from as low as 3.4% to as high as 52.6%) and, inversely, the prevalence of ovarian cancer is increased in endometriosis patients, ranging between 2.0 and 17.0%13. The correlation between endometriosis and ovarian cancer is highly dependent on which histological type is being investigated, with clear-cell and
Rozenberg et al. endometrioid subtypes showing the strongest correlation13,22 (Table 1). Merritt and colleagues23 reported that having a history of endometriosis almost doubled the risk for a type I tumor. On the other hand, some studies have reported a reduced risk of ovarian cancer among women with endometriosis, once these women had undergone radical, surgical extirpation of endometriosis implantations or even unilateral oophorectomy24. Few studies have actually evaluated whether MHT increases the risk of ovarian cancer in endometriosis patients. In a small retrospective case–control study, Zanetta and colleagues25 were unable to observe a significantly higher risk for the development of ovarian cancer with prolonged use of unopposed estrogens or with higher body mass index. Only when obesity and the use of unopposed estrogens were considered together did the difference become statistically significant. The authors concluded, nevertheless, that hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis25. Finally, considering the scarcity of data, one may suggest that the decision whether to prescribe MHT has to be weighed taking into account the patient’s age and the impact of early menopause on her quality of life. Few scientific societies have issued guidelines but those which have (such as EMAS or ESHRE) recommend hormone therapy for women with a premature or early menopause prescribed until the average age of natural menopause and it should also be considered for older women with severe climacteric symptoms6,26. Although the data are limited, as mentioned earlier, these guidelines suggest administering either continuous combined estrogen–progestogen therapies or tibolone in women with or without a history of hysterectomy in order to reduce the risk of endometriosis-related pain recurrence6,26. In Figure 1, we propose a decision-making algorithm for endometriosis patients who are nearing menopause and considering MHT. Women who have been treated with bilateral
Table 2 Type of epithelial ovarian cancer, hypothesized origin, and characteristics. Adapted from Mungenast and Thalhammer, 2014 Grade of carcinoma High-grade serous Low-grade serous
Endometrial Clear-cell Mucinous
450
Type/probable origin
Clinical course
Type II tumors/serous tubal intraepithelial carcinoma Type I tumors/borderline tumors of ovary or from papillary tubal hyperplasia
Advanced stage, somber prognosis Often low-stage
Atypical endometriosis, uterus Atypical endometriosis, uterus Colonic mucosa or endocervical epithelium, or mucinous borderline tumor
Often low-stage Often low-stage Low-stage
Involved mutations TP53 mutations Rarely have TP53 mutations; rather phosphatase and tensin homolog (PTEN), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) CTNNB1, PTEN, ARID1A ARID1A KRAS, HER2
Climacteric
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Endometriosis, menopausal hormone therapy and ovarian cancer risk
Rozenberg et al.
Figure 1 Algorithm: Menopausal hormone therapy (MHT) in endometriosis patients after the menopause. This algorithm is not evidence-based but an expert opinion
salpingo-oophorectomy, and in whom there is no residual endometriotic disease, can probably be treated using MHT without fear of ovarian cancer. For those who reached menopause before the age of 45 years, the benefit may outweigh the risks. For women with significant, residual endometriosis lesions (such as endometriomas or other deep infiltrating lesions), the risk–benefit balance will depend on the severity of the symptoms. Those who begin menopause at an early age or suffer from severe symptoms should also be considered for MHT (Figure 1). This algorithm is not evidence-based, but an expert opinion, since there is an important lack of data. Future studies should answer the remaining, unanswered questions:
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• Is MHT more frequently associated with type I (low-grade serous) or type II (high-grade serous) tumors? • Is there an additional risk in endometriosis patients when using MHT?
• Is it is worthwhile to monitor endometriosis patients with residual disease using tumor markers such as CA 125, HE4 and/or ultrasound (Figure 1)? Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
451
Endometriosis, menopausal hormone therapy and ovarian cancer risk
Rozenberg et al.
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References 1. Collaborative Group on Epidemiological Studies of Ovarian Cancer. Menopausal hormone use and ovarian cancer risk: individual participant meta-analysis of 52 epidemiological studies. Lancet 2015 Feb 12. pii: S0140-6736(14)61687-1. doi: 10.1016/S0140-6736(14)61687-1. Epub ahead of print 2. Vercellini P, Viganò P, Somigliana E, Fedele L. Endometriosis: pathogenesis and treatment. Nat Rev Endocrinol 2014;10: 261–75 3. Muzii L, Di Tucci C, Di Feliciantonio M, Marchetti C, Perniola G, Panici PB. The effect of surgery for endometrioma on ovarian reserve evaluated by antral follicle count: a systematic review and meta-analysis. Hum Reprod 2014;29:2190–8 4. Iwase A, Nakamura T, Nakahara T, Goto M, Kikkawa F. Assessment of ovarian reserve using anti-Müllerian hormone levels in benign gynecologic conditions and surgical interventions: a systematic narrative review. Reprod Biol Endocrinol 2014;12:125 5. Ferrero S, Scala C, Racca A, et al. Second surgery for recurrent unilateral endometriomas and impact on ovarian reserve: a casecontrol study. Fertil Steril 2015 Feb 11. pii: S0015-0282(15) 00079-5. Epub ahead of print 6. Moen MH, Rees M, Brincat M, et al.; European Menopause and Andropause Society. EMAS position statement: Managing the menopause in women with a past history of endometriosis. Maturitas 2010;67:94–7 7. Rozenberg S, Vandromme J, Antoine C. Postmenopausal hormone therapy: risks and benefits. Nat Rev Endocrinol 2013;9:216–27 8. Rizk B, Fischer AS, Lotfy HA, et al. Recurrence of endometriosis after hysterectomy. Facts Views Vis Obgyn 2014;6:219–27 9. Namnoum AB, Hickman TN, Goodman SB, Gehlbach DL, Rock JA. Incidence of symptom recurrence after hysterectomy for endometriosis. Fertil Steril 1995;64:898–902 10. Al Kadri H, Hassan S, Al-Fozan HM, Hajeer A. Hormone therapy for endometriosis and surgical menopause. Cochrane Database Syst Rev 2009;(1):CD005997. doi: 10.1002/14651858. CD005997.pub2 11. Matorras R, Elorriaga MA, Pijoan JI, Ramón O, Rodríguez-Escudero FJ. Recurrence of endometriosis in women with bilateral adnexectomy (with or without total hysterectomy) who received hormone replacement therapy. Fertil Steril 2002;77:303–8 12. Fedele L, Bianchi S, Raffaelli R, Zanconato G. Comparison of transdermal estradiol and tibolone for the treatment of oophorectomized women with deep residual endometriosis. Maturitas 1999;32:189–93 13. Heidemann LN, Hartwell D, Heidemann CH, Jochumsen KM. The relation between endometriosis and ovarian cancer – a review. Acta Obstet Gynecol Scand 2014;93:20–31
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14. Piek JM, van Diest PJ, Zweemer RP, et al. Dysplastic changes in prophylactically removed Fallopian tubes of women predisposed to developing ovarian cancer. J Pathol 2001;195:451–6 15. Leeper K, Garcia R, Swisher E, Goff B, Greer B, Paley P Pathologic findings in prophylactic oophorectomy specimens in high-risk women. Gynecol Oncol 2002;87:52–6 16. Piek JM, Verheijen RH, Kenemans P, Massuger LF, Bulten H, van Diest PJ. BRCA1/2-related ovarian cancers are of tubal origin: a hypothesis. Gynecol Oncol 2003;90:491 17. Fortner RT, Ose J, Merritt MA, et al. Reproductive and hormonerelated risk factors for epithelial ovarian cancer by histologic pathways, invasiveness, and histologic subtypes: Results from the EPIC cohort. Int J Cancer 2015 Feb 5. doi: 10.1002/ijc.29471. Epub ahead of print 18. Mungenast F, Thalhammer T. Estrogen biosynthesis and action in ovarian cancer. Front Endocrinol (Lausanne) 2014;5:192 19. Beral V, Doll R, Hermon C, Peto R, Reeves G. Ovarian cancer and oral contraceptives: collaborative reanalysis of data from 45 epidemiological studies including 23,257 women with ovarian cancer and 87,303 controls. Lancet 2008;371:303–14 20. Modugno F, Ness RB, Allen GO, Schildkraut JM, Davis FG, Goodman MT. Oral contraceptive use, reproductive history, and risk of epithelial ovarian cancer in women with and without endometriosis. Am J Obstet Gynecol 2004;191:733–40 21. Shih IeM, Kurman RJ. Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. Am J Pathol 2004;164:1511–18 22. Pearce CL, Templeman C, Rossing MA, et al.; Ovarian Cancer Association Consortium. Association between endometriosis and risk of histological subtypes of ovarian cancer: a pooled analysis of case-control studies. Lancet Oncol 2012;13:385–94 23. Merritt MA, De Pari M, Vitonis AF, Titus LJ, Cramer DW, Terry KL. Reproductive characteristics in relation to ovarian cancer risk by histologic pathways. Hum Reprod 2013;28: 1406–17 24. Melin AS, Lundholm C, Malki N, Swahn ML, Sparèn P, Bergqvist A. Hormonal and surgical treatments for endometriosis and risk of epithelial ovarian cancer. Acta Obstet Gynecol Scand 2013;92:546–54 25. Zanetta GM, Webb MJ, Li H, Keeney GL. Hyperestrogenism: a relevant risk factor for the development of cancer from endometriosis. Gynecol Oncol 2000;79:18–22 26. Dunselman GA, Vermeulen N, Becker C, et al.; European Society of Human Reproduction and Embryology. ESHRE guideline: management of women with endometriosis. Hum Reprod 2014;29:400–12
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Invited Editorial
Should we abstain from treating women with endometriosis using menopausal hormone therapy, for fear of an increased ovarian cancer risk? Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
S. Rozenberg, C. Antoine, J. Vandromme and M. Fastrez Department of Obstetrics and Gynecology, CHU Saint-Pierre, Université Libre de Bruxelles, Vrije Universiteit Brussel, Brussels, Belgium Key words: ENDOMETRIOSIS, MENOPAUSAL HORMONE THERAPY, RISK, OVARIAN CANCER
ABSTRACT Women suffering from endometriosis often have an early menopause, resulting in severe menopausal symptoms and an increased risk of osteoporosis. They are therefore candidates for menopausal hormone therapy (MHT). Unfortunately, MHT may increase the risk of endometriosis recurrence. Moreover, endometriosis patients are at increased risk of ovarian cancer, which may be further enhanced by MHT use. It is unknown, however, whether MHT more frequently increases type I (low-grade serous tumors), which seem to be increased when endometriosis is present, or type II (the more aggressive high-grade serous) tumors. We propose the following decision-making algorithm for endometriosis patients considering MHT. Those who have been treated with bilateral salpingo-oophorectomy, and in whom there is no residual endometriotic disease, can probably be treated using MHT without risk of endometriosis recurrence or fear of ovarian cancer. For women with significant, residual endometriosis lesions, the benefit may outweigh the risks, when menopause is reached before the age of 45 years or when severe symptoms are present.
The Collaborative Group on Epidemiological Studies of Ovarian Cancer recently reported that the use of menopausal hormone therapy (MHT) for 5–10 years, from around the age of 50 years, is associated with approximately one extra ovarian cancer per 1000–2000 women1. The increased risk was observed globally for invasive ovarian cancers, for serous and endometrioid tumors but not for mucinous or clear-cell tumors (Table 1). The question arises as to whether women who have additional risks of ovarian cancer, such as a past history of endometriosis, have an even higher ovarian cancer risk when using MHT. Indeed, endometriosis is associated with a 50% increase in the risk of epithelial ovarian cancer2. It remains controversial as to whether endometriosis per se reduces the ovarian reserve3 or whether it is brought on by endometriosis surgery4,5. Many of these women (about 12% according to some studies) will be treated surgically by a total hysterectomy
and a bilateral salpingo-oophorectomy, sometimes at an early age, leading to severe menopausal symptoms and an increased osteoporosis risk6–8. In view of these findings, should these women use MHT? What associated, increased risk will these women encounter, using MHT? Theoretically, there are two types of these women. The first type may encounter an increased risk of endometriosis recurrence. Actually, this may also occur with no MHT, and may be due to the residual steroid secretion of estrogens and androgens by the postmenopausal ovaries, since a high recurrence rate (62%) has been reported in advanced stages of endometriosis, when the ovaries were preserved8,9. Ovarian preservation has been reported to carry a six-fold risk of recurrent pain and eight-fold risk of reoperation9. The recurrence of endometriosis symptoms and pelvic pain seems to be directly correlated to the surgical precision and removal
Correspondence: Professor S. Rozenberg, Department of Obstetrics and Gynecology, St Peter University Hospital, Hoog Str 322, 1000 Brussels, Belgium; E-mail: [email protected] INVITED EDITORIAL © 2015 International Menopause Society DOI: 10.3109/13697137.2015.1041905
Received 26-03-2015 Revised 01-04-2015 Accepted 14-04-2015
Endometriosis, menopausal hormone therapy and ovarian cancer risk
Rozenberg et al.
Table 1 Overall, and by histological type, ovarian cancer risk increase or reduction associated respectively with endometriosis, contraception and menopausal hormone therapy (MHT)
Climacteric Downloaded from informahealthcare.com by University of Otago on 07/27/15 For personal use only.
Endometriosisa Histological type
OR
95% CI
Invasive cancer Serous low-grade (type I) high-grade (type II) Endometrioid Mucinous Clear-cell
1.46
1.31–1.63
2.11 1.13 2.04 1.02 3.05
1.39–3.20 0.97–1.32 1.67–2.48 0.69–1.50 2.43–3.84
Contraception: % reduction in risk per 5/10 years use, by ovarian tumor histology (SE)b,d Significant reduction 20.5 % (SE 1.9%)b Significant reduction 22.1% (SE 2.9%)b Type I, HR 0.54 (95% CI 0.31–0.94)d Type II, HR 0.71 (95% CI 0.51–0.97)d Significant reduction 27.1% (SE 4.8%) No protection 6.7% (SE 5.8%) Significant reduction 21.3% (SE 7.3%)
MHT: RR compared to never-users, adjusted for age at menopause, hysterectomy, oral contraceptive use, and parityc RR
95% CI
1.43 1.40
1.31–1.56 1.31–1.49
1.28 0.80 0.80
1.13–1.45 0.63–0.93 0.65–0.98
RR, relative risk; OR, odds ratio; 95% CI, 95% confidence interval; SE, Standard estimates Adapted from reference 22; b, per 5 years, adapted from reference 19; c, adapted from reference 1; d, per 10 years, adapted from reference 17
a,
of peritoneal and deeply infiltrating disease, suggesting that surgical efforts should always aim completely to eliminate the endometriotic lesions in order to keep the risk of recurrence as low as possible8,9. But is this risk further increased when using MHT? It may be so. One must admit that data are scarce. The Cochrane Database review published by Al Kadri and colleagues10 reported only two trials assessing the risk of recurrence using MHT after surgical menopause. The first study conducted by Matorras and colleagues11 estimated this risk in 115 women receiving MHT and 57 who were not. They observed no recurrence among untreated women as compared to a 3.5% rate in MHT-treated ones11. In their experience, the risk of recurrence was related to the incomplete surgery11. In a much smaller trial (n 21), Fedele and colleagues12 compared the effect of transdermal estradiol (E2) 50 mg, administered twice weekly associated with cyclic medroxyprogesterone acetate 10 mg daily for 12 days per month as compared to tibolone 2.5 mg administered orally once a day in a continuous regimen. After 12 months, four patients out of ten in the E2 group and one out of 11 in the tibolone group experienced moderate pelvic pain, but in many patients surgery had not been complete and residual endometriosis was common12. The authors of the Cochrane review10 concluded that MHT for women with endometriosis in post-surgical menopause could result in pain and disease recurrence but also that the evidence in literature is not strong enough to recommend depriving severely symptomatic patients of this treatment. Although the study conducted by Fedele and colleagues12 lacked statistical power to detect a significant difference, many authors suggest administering continuous, combined MHT regimens in endometriosis patients, especially when no surgery or incomplete surgery was performed. The second type of women are those patients suffering from endometriosis who may also be at increased risk of malignant transformation of residual disease foci. The lifetime risk of ovarian cancer varies between 0.47% in Japan and 1.8% in the US13. Eighty to ninety percent are of
Climacteric
epithelial origin. Of these, 50–60% are categorized as serous, 8–10% as mucinous, and 10–15% either as endometrioid or clear-cell13. It has been hypothesized that many ovarian cancers have an extra-ovarian origin14–17. Serous ovarian carcinomas, the most common histologic subtype, may indeed come from serous tubal intraepithelial carcinoma developed in the fimbriae of the Fallopian tubes. It is commonly hypothesized that repeated retrograde menstruation may expose the Fallopian tubes to iron-induced oxidative stress, resulting from hemolysis of erythrocytes by pelvic macrophages (the incessant menstruation hypothesis)18. Mucinous tumors may originate in the colonic mucosa or endocervical epithelium, and clear cell and endometrioid tumors may be linked to endometriosis and display characteristics of endometrial tissue14–17. These findings were first observed after prophylactic salpingo-oophorectomies in patients carrying BRCA-1 and -2 mutations. As a consequence, risk-reducing surgery for patients with such mutations currently includes complete removal of the ovaries and Fallopian tubes. Furthermore, it may be logical to perform a salpingectomy only, at the time of hysterectomy for benign indications in young women17. On the other hand, continuing ovulation and damage to the ovaries, and therefore increasing the number of mutations, have long been viewed as risk factors for ovarian cancer, while parity or hormonal contraception, limiting the number of ovulation periods, have repeatedly been found to be protective19 (Table 1). There are only limited data about the protective effect of oral contraceptives in endometriosis patients. Modugno and colleagues20 pooled information on the self-reported history of endometriosis from four population-based, case-controlled studies of incidents of epithelial ovarian cancer, comprising 2098 cases and 2953 control subjects. The use of oral contraceptives for more than 10 years was associated with about 80% reduction in risk among women with endometriosis20.
449
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Endometriosis, menopausal hormone therapy and ovarian cancer risk Experimental data reported that some ovarian cancer cells share a number of estrogen-regulated pathways with other hormone-dependent cancers such as breast and endometrial cancer18. Steroids and estrogens in particular may promote tumor growth at the cellular level through a receptor-dependent effect, by binding to the nuclear estrogen receptor-alpha and promoting gene transcription of proto-oncogenes, or by binding to membrane-bound G-protein and activating a second messenger or through an independent effect by enhancing reactive metabolites via cytochrome P450 enzymes (CYPs), causing DNA mutations in various genes in Fallopian tube cells. Particularly metabolites such as catechol metabolites and 4-hydroxy E2/E1 (4-OHE2/E1) have been shown to have carcinogenic effects18. It has been hypothesized that ovarian carcinogenesis may occur in two distinct pathways. Type I tumors (predominantly low-grade, serous histologic subtype) may develop from precursor lesions such as borderline tumors or endometriosis, may be associated with KRAS, BRAF or PTEN mutations and have low chromosomal instability, whereas type II tumors (predominantly high-grade serous histologic subtype) are aggressive neoplasms which harbor TP53 mutations and exhibit high chromosomal instability2,21. The study by the Collaborative Group on Epidemiological Studies of Ovarian Cancer1 did not specify whether the ovarian cancer risk was more often associated with type I (low grade serous) or type II (high grade serous tumors) (Table 2). There are many arguments for considering endometriosis as a premalignant condition. The subject was recently reviewed using a metaanalysis13. Ovarian endometrial cysts often have a monoclonal origin; the prevalence of endometriosis is increased in ovarian cancer patients (ranging from as low as 3.4% to as high as 52.6%) and, inversely, the prevalence of ovarian cancer is increased in endometriosis patients, ranging between 2.0 and 17.0%13. The correlation between endometriosis and ovarian cancer is highly dependent on which histological type is being investigated, with clear-cell and
Rozenberg et al. endometrioid subtypes showing the strongest correlation13,22 (Table 1). Merritt and colleagues23 reported that having a history of endometriosis almost doubled the risk for a type I tumor. On the other hand, some studies have reported a reduced risk of ovarian cancer among women with endometriosis, once these women had undergone radical, surgical extirpation of endometriosis implantations or even unilateral oophorectomy24. Few studies have actually evaluated whether MHT increases the risk of ovarian cancer in endometriosis patients. In a small retrospective case–control study, Zanetta and colleagues25 were unable to observe a significantly higher risk for the development of ovarian cancer with prolonged use of unopposed estrogens or with higher body mass index. Only when obesity and the use of unopposed estrogens were considered together did the difference become statistically significant. The authors concluded, nevertheless, that hyperestrogenism, either endogenous or exogenous, is a significant risk factor for the development of cancer from endometriosis25. Finally, considering the scarcity of data, one may suggest that the decision whether to prescribe MHT has to be weighed taking into account the patient’s age and the impact of early menopause on her quality of life. Few scientific societies have issued guidelines but those which have (such as EMAS or ESHRE) recommend hormone therapy for women with a premature or early menopause prescribed until the average age of natural menopause and it should also be considered for older women with severe climacteric symptoms6,26. Although the data are limited, as mentioned earlier, these guidelines suggest administering either continuous combined estrogen–progestogen therapies or tibolone in women with or without a history of hysterectomy in order to reduce the risk of endometriosis-related pain recurrence6,26. In Figure 1, we propose a decision-making algorithm for endometriosis patients who are nearing menopause and considering MHT. Women who have been treated with bilateral
Table 2 Type of epithelial ovarian cancer, hypothesized origin, and characteristics. Adapted from Mungenast and Thalhammer, 2014 Grade of carcinoma High-grade serous Low-grade serous
Endometrial Clear-cell Mucinous
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Type/probable origin
Clinical course
Type II tumors/serous tubal intraepithelial carcinoma Type I tumors/borderline tumors of ovary or from papillary tubal hyperplasia
Advanced stage, somber prognosis Often low-stage
Atypical endometriosis, uterus Atypical endometriosis, uterus Colonic mucosa or endocervical epithelium, or mucinous borderline tumor
Often low-stage Often low-stage Low-stage
Involved mutations TP53 mutations Rarely have TP53 mutations; rather phosphatase and tensin homolog (PTEN), v-Ki-ras2 Kirsten rat sarcoma viral oncogene homology (KRAS), and v-raf murine sarcoma viral oncogene homolog B1 (BRAF) CTNNB1, PTEN, ARID1A ARID1A KRAS, HER2
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Endometriosis, menopausal hormone therapy and ovarian cancer risk
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Figure 1 Algorithm: Menopausal hormone therapy (MHT) in endometriosis patients after the menopause. This algorithm is not evidence-based but an expert opinion
salpingo-oophorectomy, and in whom there is no residual endometriotic disease, can probably be treated using MHT without fear of ovarian cancer. For those who reached menopause before the age of 45 years, the benefit may outweigh the risks. For women with significant, residual endometriosis lesions (such as endometriomas or other deep infiltrating lesions), the risk–benefit balance will depend on the severity of the symptoms. Those who begin menopause at an early age or suffer from severe symptoms should also be considered for MHT (Figure 1). This algorithm is not evidence-based, but an expert opinion, since there is an important lack of data. Future studies should answer the remaining, unanswered questions:
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• Is MHT more frequently associated with type I (low-grade serous) or type II (high-grade serous) tumors? • Is there an additional risk in endometriosis patients when using MHT?
• Is it is worthwhile to monitor endometriosis patients with residual disease using tumor markers such as CA 125, HE4 and/or ultrasound (Figure 1)? Conflict of interest The authors report no confl ict of interest. The authors alone are responsible for the content and writing of this paper. Source of funding
Nil.
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