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Progestogen use in women approaching the menopause and breast cancer risk
Maturitas 62 (2009) 338–342
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Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Progestogen use in women approaching the menopause and breast cancer risk Carlo Campagnoli ∗ , Simona Ambroggio, Maria Rosa Lotano, Clementina Peris S.C. Ginecologia Endocrinologica Ospedale Ostetrico Ginecologico, ASO OIRM-S.Anna, Torino, Corso Spezia 60, Italy
a r t i c l e
i n f o
Article history: Received 6 August 2008 Received in revised form 7 October 2008 Accepted 15 October 2008 Keywords: Progestogens Menopausal transition Hormone therapy Breast cancer
a b s t r a c t Objective: Progestogens, particularly synthetic progestins, are widely used to contrast the clinical consequences of the relative hyperestrogenism that characterizes the years preceding the menopause. As a large body of data on postmenopausal hormone therapy (HT) demonstrates that the addition of synthetic progestins to estrogen increases the breast cancer risk compared to estrogen alone, it is important to evaluate if the use of progestogens in premenopausal years is associated with the risk of breast cancer. Methods: Main literature data on the association with breast cancer risk of progestogens, either used alone in premenopausal years or added to estrogen in postmenopausal HT, were reviewed. Results: Available data suggest that long-term current use of progestogens in premenopausal women after the age of 40 years can increase the risk of breast cancer. Consistently with the data on postmenopausal HT, the risk increase is higher for lobular cancer than for ductal cancer. Conclusions: The most important and widely accepted indications to the use of progestogens in the years preceding the menopause are anovulatory menstrual disorders, for which a limited period of treatment is generally sufficient. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of increased breast cancer risk and clinical benefits have to be weighed. Anyway, as micronized progesterone and dydrogesterone, at least when they were used in postmenopausal HT, seem to have, according to a large observational study, a safer risk profile on the breast, the preferential use of these preparations could be suggested. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progestogen-only medications in women approaching the menopause and breast cancer risk: epidemiological findings . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusive remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Progesterone has a role in mammary gland development. In mice, it contributes to the growth and differentiation of the Terminal Ductal Lobular Units (TDLU), promoting lobulo-alveolar development, whereas estradiol stimulates ductal elongation. In humans, the role of progesterone is less clear: it is assumed that progesterone has a similar role and stimulates TDLU formation and
∗ Corresponding author at: Sant’Anna Gynecological Hospital, Endocrinological Gynecology, Corso Spezia 60, 10126 Turin, Italy. Tel.: +39 0113134605; fax: +39 0113134798. E-mail address: [email protected] (C. Campagnoli). 0378-5122/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.10.017
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expansion during puberty and pregnancy. It is noteworthy that this unit is the site from which many epithelial hyperplasia and carcinoma arise [1]. However, whether progesterone and/or synthetic progestins have a role in promoting breast cancer is a highly controversial topic. Natural progesterone can act on breast tissue in various ways: by interacting with two nuclear receptors (PR-A and PR-B) that can have different influence on the proliferative responses of breast tissue [2,3]; by influencing autocrine/paracrine factors (e.g. growth factors) [4]; by acting through metabolites that bind to specific membrane receptors and that could have opposite effects on cell proliferation and adhesion [5]; and by influencing the activity of the enzymes involved in the formation and transformation of estrogens in breast tissue [6]. This complexity of effects
C. Campagnoli et al. / Maturitas 62 (2009) 338–342
contributes to explain the fact that, while the proliferative activity of estrogens is well established, the in vitro studies on progesterone activity give contrasting results, even if an antiproliferative effect seems to prevail, due to the antiestrogenic action, favoured, for instance, by the inhibition of estrogen receptor activation [7]. Overall in vivo data suggest that natural progesterone does not have detrimental effects on breast tissue (as reviewed; [8]), consistently with epidemiological findings showing that high levels of endogenous progesterone do not increase [9] or may even reduce [10,11] breast cancer risk in premenopausal women. Moreover, the risk of breast cancer does not appear increased when natural micronized progesterone is added to estrogen in hormone therapy (HT) for postmenopausal women [12,13]. By contrast, most of the studies showed that the addition of synthetic progestins to estrogen in HT significantly increases breast cancer risk compared to estrogen alone [8,12,14]. The increase of the risk refers to both ductal and lobular cancer, but it is particularly elevated for the latter, id est, the histological subtype originating from the functional unit whose development is stimulated by progesterone [13–17]. Progestogens, particularly synthetic progestins, are widely used to contrast the relative hyperestrogenism that characterizes the years preceding the menopause, the so called “menopausal transition” [18,19]. An accepted indication to the cyclical use of progestogens are menstrual irregularities, particularly anovulatory metrorrhagia [20–22] and meno-metrorrhagia associated with miomas [23]. Progestins are also used in the treatment of endometriosis-related complaints [23] or for contraception, particularly as injectable depot medroxyprogesterone acetate (DMPA) or levonorgestrel-releasing intrauterine system (LNG-IUS) [24]. Further indications could be fibrocystic mastopathy, that occurs mainly between the ages of 35 and 50 years [25], and cyclical mastalgia [26,27]. Progestogens to contrast breast problems in premenopausal women are widely prescribed in France [28–30]. This practice was supported by the results of a cohort study of premenopausal women with benign breast disease, in which the long-term use of 19-nortestosterone derivatives was found to be significantly associated with a lower risk of breast cancer [31]. However, a recent large cohort study from France showed an increased breast cancer risk with long-term use of progestogens in premenopausal years [32]. 2. Progestogen-only medications in women approaching the menopause and breast cancer risk: epidemiological findings A comprehensive review on the breast cancer risk associated with the use of progestin-only contraceptives has been recently published by a joint Committee of two Canadian Societies [33]. Some of the “summary statements” were that in general population: (1) use of DMPA does not increase the risk of breast cancer; (2) although not as well-studied as the combined contraceptive pill, progestin-only pills do not appear to increase the risk of breast cancer; (3) the limited data available suggest that LNG-IUS does not seem to increase the risk [33]. The main findings on the breast cancer risk associated with the cyclical use of progestogens to contrast the consequences of the relative hyperestrogenism come from France. This is not surprising, as cyclical progestogens were used in a high percentage of French women, 36%, according to a recent study on 2254 pre- or perimenopausal women aged 45 years or older [30]. Another French study showed that the main indications of progestogen use were functional disorders of perimenopause (57%) and breast problems (47%) [29]. The association of premenopausal progestogen use with breast cancer risk was first studied in a cohort of 1150 French women,
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80% aged >35 years at first visit, with benign breast disease, who were followed-up for 10 years [31]. In this cohort the overall progestogen use and the duration of use were not found to be associated with breast cancer risk. When progestogens were classified in two categories (19-nortestosterone derivatives vs. other progestogens), 19-nortestosterone derivatives at high doses were found to be significantly associated with a lower breast cancer risk (relative risk (RR): 0.48; 95% confidence interval (CI): 0.25–0.90). These results did not seem to support the hypothesis that progestogens increase breast cancer risk. They suggested instead that high doses of progestogens endowed with strong antigonadotropic activity might have a beneficial effect on the risk of breast cancer in premenopausal women, possibly because they cause a decrease in estradiol levels [34]. In the same cohort study of women with benign breast disease, no association between breast cancer risk and the use of percutaneous progesterone (topically applied on the breast) was observed [35]. The main problem of this cohort study of 1150 women is the limited number of breast cancer (n = 44) observed during the 10 years follow-up period. Different findings were obtained by another study from France, based on the E3N cohort, which includes approximately 100,000 teachers followed up with periodic questionnaires. The association between progestogen-only intake prior to menopause and after the age of 40 years and breast cancer risk was recently studied in approximately 70,000 women of this large cohort [32]. Overall, ever use of progestogens before menopause was not significantly associated with risk. However, a significant increase in risk associated with the duration of use was found. Among current users of progestogens, use longer than 4.5 years was significantly associated with risk (RR: 1.44; 95% CI: 1.03–2.00), but not use shorter than 4.5 years. After discontinuation, and whatever the duration, the risk were close to unity [32]. The data of E3N cohort were furtherly evaluated to assess the risk of breast cancers defined by their histology [F. Clavel-Chapelon, personal communication; 36]. An increased risk of lobular carcinoma associated with premenopausal use of progestogens among both current and past users (Hazard Ratio (HR): 1.51; 95% CI: 1.02–2.24 and HR: 1.38; 95% CI: 1.08–1.75, respectively) was found. Regarding ductal carcinoma, only current use of progestogens for more than 4.5 years was significantly associated with increased risk (HR: 1.49; 95% CI: 1.00–2.22), while current use for less than 4.5 years and past use were not associated with increased risk [36]. Patterns of risk did not show marked differences with the use of different synthetic progestins, either antigonadotropic (chlormadinone acetate, cyproterone acetate, ethynodiol, lynestrenol, medroxyprogesterone acetate (MPA), nomegestrol acetate, norethisterone acetate, promegestone) or not (demegestone, dydrogesterone, medrogestone), and also of micronized progesterone [32]. This latter finding diverges from the result of the study of postmenopausal women of the same cohort suggesting that, contrarily to most of the synthetic progestin, the use of micronized progesterone in the menopausal HT is not associated with an increase in breast cancer risk [12,13]. 3. Discussion The most relevant data on the association of breast cancer risk with progestogens come from studies on the use of these preparations as a part of menopausal HT. According to a comprehensive review published in 2005 [14], evidence from either randomized controlled trials (RCTs) or observational studies indicated that breast cancer risk was increased with estrogen plus progestin more than with estrogen alone. The risk was lower in RCTs than in observational studies (Table 1). As suggested by two recent reports based on the Women’s Health Initiative (WHI) trials and the large WHI
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Table 1 Average estimates of breast cancer risk with hormone use. Unopposed estrogen User cases Randomized controlled trials Adherent women Epidemiological studies Current use Ever use
Estrogen plus progestin RR (95% CI)
User cases
RR (95% CI)
103
0.79 (0.61–1.02)
248
1.24 (1.03–1.50) 1.49 (1.13–1.96)
2862 4193
1.18 (1.01–1.38) 1.08 (0.97–1.20)
3455 4193
1.70 (1.36–2.13) 1.31 (1.12–1.53)
Derived from Ref. [14].
observational study [37,38], the reason of this discrepancy could be that in RCTs a large part of the women began the therapy many years post-menopause, whilst most women in the observational studies began at menopause or within few years of menopause. Most observational studies showed that estrogen plus progestin use was more strongly related to risk of lobular cancer and/or ductal-lobular cancer than to risk of ductal cancer, and that the increased risk diminished after discontinuing hormones and normalized within 5 years [14], independently of histological type [15–17]. The greater part of findings on the consequences of the progestin addition to estrogen in menopausal HT, to which we referred above, came from US, UK or Scandinavian Countries [4,8], where MPA or 19-nortestosterone derivatives were mainly used [8]. No difference, regarding breast cancer risk, was found between these preparations in the Million Women Study [39]. Further informations are given by recent studies from Germany and France, where a wide range of synthetic progestins, and also micronized progesterone, are used in menopausal HT. A population-based case-control study from Germany revealed a higher risk for 19-nortestosterone derivatives than for progesterone derivatives or 17-hydroxyprogesterone derivatives grouped together, but only when they were used in continuous combined regimen [40]. More detailed informations on the single progestogens come from two studies based on the French E3N cohort [12,13]. In this cohort of approximately 80,000 postmenopausal teachers, the first study found that, compared to the use of estrogen alone, the addition of micronized progesterone or of the retroprogesterone dydrogesterone did not increase significantly breast cancer risk, contrarily to other synthetic progestins – chlormadinone acetate, cyproterone acetate, medrogestone, MPA, nomegestrol acetate, norethisterone acetate, promegestone – each significantly associated with a risk increase. The RRs were 1.29 (95% CI: 1.02–1.65) with unopposed estrogen (mainly transdermal estradiol), 1.00 (95% CI: 0.83–1.22) with the addition of micronized progesterone, 1.16 (95% CI: 0.94–1.43) with the addition of dydrogesterone, and 1.69 (95% CI: 1.50–1.91) with the addition of the other synthetic progestins [12]. The second study based on the E3N cohort examined whether the associations of the different types of HTs with breast cancer risk vary across different types of carcinoma [13]. In this study, ever-use of estrogen plus micronized progesterone was not significantly associated with the risk of both ductal and lobular cancers, though a trend of increased risk of lobular carcinoma with increasing duration of use was found; estrogen plus dydrogesterone use were not associated with the risk of ductal cancer and associated with increase of risk of lobular cancer (RR 1.7; 95% CI: 1.1–2.6); on the contrary, use of estrogen plus other synthetic progestins was significantly associated with increased risk of both ductal carcinoma (RR 1.6; 95% CI: 1.3–1.8) and lobular (and ductal-lobular) carcinoma (RR 2.0; 95% CI: 1.5–2.7) [13]. The suggestion, coming from the French studies [12,13], that the addition to estrogen of micronized progesterone or dydrogesterone may have a safer risk profile is consistent with the in vivo data suggesting that natural progesterone does not have detrimental effects on breast tissue (as reviewed, [8]), and with epidemiological find-
ings showing that high levels of endogenous progesterone do not increase [9], or may even reduce [10,11], breast cancer risk in premenopausal women. The activities of dydrogesterone are similar to those of natural progesterone [41], so it is not surprising that it also could have a safer risk profile on the breast than the other synthetic progestins. Micronized progesterone administered in addition to estradiol did not result, compared to estradiol alone, in significantly greater proliferation in lobular and ductal breast epithelium in postmenopausal macaques, contrarily to what was found with the addition of MPA to estradiol [7]. It is not clear how synthetic progestins increase proliferation of breast epithelium and the risk of breast cancer. MPA and 19-nortestosterone derivatives (to the use of which large part of the data on menopausal HT and breast cancer risk refers) have androgenic activities that can increase breast cancer risk via their negative influence on metabolic risk factors [42,43] or via the disruption of androgen receptor signalling [44]. However, in France, from which detailed informations on the use of different progestins come, androgenic progestins were used in only a minority of women [12], while the most used synthetic progestins in menopausal HT were non-androgenic (progesterone derivatives or 19-norprogesterone derivatives) or even antiandrogenic (cyproterone acetate). It is possible that different mechanisms are involved for different progestins. A general explanation could be that – depending on molecular structure, pharmacokinetics and biological potency – some progestins differ from progesterone in interactions with the two isoform of the PR [3,45], and with other members of the nuclear receptor superfamily [2,38,46], leading to non-physiological or over-physiological effects on breast tissue. Particularly relevant could be the fact that, at the currently used doses, the biological potency and the half-life times of oral progesterone, and to a lesser extent of dydrogesterone, are remarkably lower than potency and half-life times of the other synthetic progestins (Tables 2 and 3) [2,46,47]. Both synthetic progestins added to estrogen in menopausal HT [15–17] and progestogens used alone in premenopausal women [F. Clavel-Chapelon, personal communication; 36] are more markedly related to risk of lobular than ductal cancer. This could find a biological plausibility in studies suggesting that progesterone stimulates lobular-alveolar unit [1]. However, women of less of 40 years, in spite of endogenous progesterone, show, respect to older women, a percentage of lobular cancer significantly lower than the percentage of ductal cancer, the great majority of lobular cancer being diagnosed in older women even in Countries where Table 2 Potencies of different oral progestogens. Progestin
Therapeutic dose
Levonorgestrel Norethisterone Medroxyprogesterone acetate Dydrogesterone Progesterone
0.15–0.5 mg 1 mg 2.5–10 mg 20 mg 100–300 mg
Derived from Ref. [46].
Potency 2–6.7 1 0.1–0.4 0.05 0.0033–0.01
C. Campagnoli et al. / Maturitas 62 (2009) 338–342 Table 3 Pharmacokinetic differences between oral progestins: progesterone derivatives and 19-norprogesterone derivatives. Preparation Dydrogesterone Medroxyprogesterone acetate Medrogestone Nomegestrol acetate Chlormadinone acetate Cyproterone acetate
Storage in fat tissue +
++ ++
Half life (t1/2 ) (h) 14–17 15–30 35 30–50 40–80 50–60
Derived from Refs. [2,47].
hormone therapies are less frequently used [48]. Estrogen plus progestin HT is associated with significant elevation in lobular cancer risk even after a brief period of use (odds ratios 4.2; 95% CI: 1.8–9.8, for 3–4.9 years of use) [17]. It is possible that estrogen plus progestin stimulate the growth of foci of lobular carcinoma that would remain undetectable in the absence of HT exposure [17]. The possibility that progestins exert non-physiological or over-physiological effects cannot be discharged. Progestogen-only therapy before menopause seems to be associated with an increased risk of lobular cancer even in past users (HR: 1.38; 95% CI: 1.08–1.75) [36]. On the contrary, studies on the progestins in menopausal HT consistently did not find a risk increase in past users, independently of histological type [15,17]. This discrepancy could be due to differences in estrogen level and/or activity between women in premenopausal years and women on menopausal HT. Oral estrogens can have some relevant peculiarities (as reviewed; [42]) and the widely used conjugated equine estrogens, particularly when initiated some years after onset of menopause [38], tend to decrease the risk of breast cancer [49], and specifically the risk of ductal carcinoma without increasing the risk of lobular carcinoma [17]. Regarding transdermal estradiol administered by patches or percutaneous gel, the current therapeutic doses lead to estradiol levels of 30–90 pg/ml [2], while mean estradiol level during the perimenopausal transition is higher (approximately 130 pg/ml) [18]. Indeed, estrogen level do not begin to decline until less than a year before menopause and women experiencing perimenopausal transition actually have higher overall estrogen levels, a fact that is explained by an increased ovarian response to the increase of FSH [18,50]. Moreover, some data suggest that serum level of estradiol could be even higher in cases in which progestogens are indicated, for instance perimenopausal meno-metrorrhagia [51]. The safer risk profile of progesterone and dydrogesterone respect to other synthetic progestins, as showed in the studies on menopausal HT [12,13], did not emerge in the studies on progestogen use in premenopausal years [32,36]. This could be partially due to limited number of cases in the subgroups of women treated with the different progestogens. However, the differences in estrogen activity between premenopausal women and postmenopausal women treated with transdermal estradiol or oral estrogen (see above), might contribute to explain this discrepancy. 4. Conclusive remarks Anovulatory metrorrhagia and meno-metrorrhagia associated with miomas are the most important and widely accepted indication to the use of progestogen alone in the years preceding the menopause [20–23]. The mean duration of perimenopausal transition, when anovulation becomes prevalent, is 5.0 years, with a range of 2–8 years [18]. Generally, use of progestogens for menstrual irregularities is limited either in number of days for treatment cycle (10–15 days) or in number of treatment cycles, 12 or less according to a French report [29]. Available data suggest that, in
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premenopausal women of more than 40 years, overall breast cancer risk increases for progestogen use longer than 4.5 years but not for use shorter than 4.5 years [32]. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of an increased breast cancer risk and clinical benefits have to be weighed. Anyway, as natural progesterone and dydrogesterone, at least when they were used in postmenopausal HT [12,13], seem to have a safer risk profile on the breast, the preferential use of these preparations could be suggested. Conflict of interest Prof. Campagnoli received support as speaker in congress and meetings or as participant in study groups from (in alphabetic order) Effik, Eli Lilly, Novo-Nordisk, Organon, Rottapharm, Schering, Solvay, Wyeth. References [1] Clarke RB. Ovarian steroids and the human breast: regulation of stem cells and cell proliferation. Maturitas 2006;54:327–34. [2] Kuhl H. Pharmacology of estrogens and progestins: influence of different routes of administration. Climacteric 2005;8(S1):S3–63. [3] Leo JCL, Lin VCN. The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner. Int J Cancer 2008;122:230–43. [4] Seeger H, Mueck AO. Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experimental vs. clinical data. J Steroid Biochem Mol Biol 2008;109:11–5. [5] Wiebe JP. Progesterone metabolites in breast cancer. Endocr Relat Cancer 2006;13:717–38. [6] Pasqualini JR. Progestins and breast cancer. Gynecol Endocrinol 2007; 23(S1):32–41. [7] Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat 2007;101:125–34. [8] Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005;96:95–108. [9] Eliassen AH, Missmer SA, Tworoger SS, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 2006;98:1406–15. [10] Micheli A, Muti P, Secreto G, et al. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer 2004;112:312–8. [11] Kaaks R, Berrino F, Key T, et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2005;97:755–65. [12] Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11. [13] Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol 2008;26:1260–8. [14] Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormone treatment. Hum Reprod Update 2005;11:545–60. [15] Reeves GK, Beral V, Green J, Gathani T, Bull D. Hormonal therapy for menopause and breast cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 2006;7:910–8. [16] Biglia N, Mariani L, Sgro L, Mininanni P, Moggio G, Sismondi P. Increased incidence of lobular breast cancer in women treated with hormone replacement therapy: implications for diagnosis, surgical and medical treatment. Endocr Relat Cancer 2007;14:549–67. [17] Li CI, Malone KE, Porter KE, et al. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev 2008;17:43–50. [18] Speroff L. The perimenopausal transition. Ann NY Acad Sci 2000;900:375–92. [19] Practice Committee of the American Society for Reproductive Medicine. The menopausal transition. Fertil Steril 2006;86(S5):S253–6. [20] Jain A, Santoro N. Endocrine mechanisms and management for abnormal bleeding due to perimenopausal changes. Clin Obstet Gynecol 2005;48:295–331. [21] Duckitt K. Medical management of perimenopausal menorrhagia: an evidencebased approach. Menopause Int 2007;13:14–8. [22] Hickey M, Higham J, Fraser IS. The Cochrane Database of Systemic ReviewsProgestogens versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation. Cochrane Libr 2008;2.
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[38] Prentice RL, Chlebowski RT, Stefanick ML, et al. Conjugated equine estrogens and breast cancer risk in the Women’s Health Initiative clinical trial and observational study. Am J Epidemiol 2008;167:1407–15. [39] Beral V, Million Women Study Collaborators. Breast cancer and hormonereplacement therapy in the Million Women Study. Lancet 2003;362: 419–27. [40] Flesch-Janys D, Slanger T, Mutschelknauss E, et al. Risk of different histological types of postmenopausal breast cancer by type and regimen of menopausal hormone therapy. Int J Cancer 2008;123:933–41. [41] Schindler AE, Campagnoli C, Druckmann R, et al. Classification and pharmacology of progestins. Maturitas 2003;46:S7–16. [42] Campagnoli C, Abbà C, Ambroggio S, Lotano MR, Peris C. Differential effects of various progestogens on metabolic risk factors for breast cancer. Gynecol Endocrinol 2007;23(S1):22–31. [43] Campagnoli C, Pasanisi P, Peris C, Berrino F. Insulin-like Growth Factor-I and breast cancer: epidemiological and clinical data. In: Pasqualini JR, editor. Breast cancer: prognosis, treatment and prevention. 2nd ed. New York: Informa Healthcare; 2008. p. 323–42. [44] Birrell SN, Butler LM, Harris JM, Buchanan G, Tilley WD. Disruption of androgen receptor signaling by sinthetic progestins may increase risk of developing breast cancer. FASEB J 2007;21:2285–93. [45] Gompel A, Courtin A. Progesterone receptors isoforms and human breast cancer. In: Pasqualini JR, editor. Breast cancer: prognosis, treatment and prevention. 2nd ed. New York: Informa Healthcare; 2008. p. 113–22. [46] Stanczyk FZ. All progestins are not created equal. Steroids 2003;68: 879–90. [47] Stanczyk FZ. Pharmacokinetics and potency of progestins used for hormone replacement therapy and contraception. Rev Endocr Metab Disorders 2002;3:211–4. [48] Mersin H, Yildirim E, Gulben K, Berberoglu U. Is invasive lobular carcinoma different from invasive ductal carcinoma? EJSO 2003;29:390–5. [49] Stefanick ML, Anderson GL, Margolis KL, et al. Effects of conjugated equine estrogens on breast cancer and mammography screening in postmenopausal women with hysterectomy. JAMA 2006;295:1647–57. [50] Prior JC. Ovarian aging and the perimenopausal transition: the paradox of endogenous ovarian hyperstimulation. Endocrine 2005;26:297–300. [51] Moen MH, Kahn H, Bjerve KS, Halvorsen TB. Menometrorrhagia in the perimenopause is associated with increased serum estradiol. Maturitas 2004;47:151–5.
Contents lists available at ScienceDirect
Maturitas journal homepage: www.elsevier.com/locate/maturitas
Review
Progestogen use in women approaching the menopause and breast cancer risk Carlo Campagnoli ∗ , Simona Ambroggio, Maria Rosa Lotano, Clementina Peris S.C. Ginecologia Endocrinologica Ospedale Ostetrico Ginecologico, ASO OIRM-S.Anna, Torino, Corso Spezia 60, Italy
a r t i c l e
i n f o
Article history: Received 6 August 2008 Received in revised form 7 October 2008 Accepted 15 October 2008 Keywords: Progestogens Menopausal transition Hormone therapy Breast cancer
a b s t r a c t Objective: Progestogens, particularly synthetic progestins, are widely used to contrast the clinical consequences of the relative hyperestrogenism that characterizes the years preceding the menopause. As a large body of data on postmenopausal hormone therapy (HT) demonstrates that the addition of synthetic progestins to estrogen increases the breast cancer risk compared to estrogen alone, it is important to evaluate if the use of progestogens in premenopausal years is associated with the risk of breast cancer. Methods: Main literature data on the association with breast cancer risk of progestogens, either used alone in premenopausal years or added to estrogen in postmenopausal HT, were reviewed. Results: Available data suggest that long-term current use of progestogens in premenopausal women after the age of 40 years can increase the risk of breast cancer. Consistently with the data on postmenopausal HT, the risk increase is higher for lobular cancer than for ductal cancer. Conclusions: The most important and widely accepted indications to the use of progestogens in the years preceding the menopause are anovulatory menstrual disorders, for which a limited period of treatment is generally sufficient. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of increased breast cancer risk and clinical benefits have to be weighed. Anyway, as micronized progesterone and dydrogesterone, at least when they were used in postmenopausal HT, seem to have, according to a large observational study, a safer risk profile on the breast, the preferential use of these preparations could be suggested. © 2008 Elsevier Ireland Ltd. All rights reserved.
Contents 1. 2. 3. 4.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Progestogen-only medications in women approaching the menopause and breast cancer risk: epidemiological findings . . . . . . . . . . . . . . . . . . . . . . Discussion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusive remarks . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conflict of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction Progesterone has a role in mammary gland development. In mice, it contributes to the growth and differentiation of the Terminal Ductal Lobular Units (TDLU), promoting lobulo-alveolar development, whereas estradiol stimulates ductal elongation. In humans, the role of progesterone is less clear: it is assumed that progesterone has a similar role and stimulates TDLU formation and
∗ Corresponding author at: Sant’Anna Gynecological Hospital, Endocrinological Gynecology, Corso Spezia 60, 10126 Turin, Italy. Tel.: +39 0113134605; fax: +39 0113134798. E-mail address: [email protected] (C. Campagnoli). 0378-5122/$ – see front matter © 2008 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.maturitas.2008.10.017
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expansion during puberty and pregnancy. It is noteworthy that this unit is the site from which many epithelial hyperplasia and carcinoma arise [1]. However, whether progesterone and/or synthetic progestins have a role in promoting breast cancer is a highly controversial topic. Natural progesterone can act on breast tissue in various ways: by interacting with two nuclear receptors (PR-A and PR-B) that can have different influence on the proliferative responses of breast tissue [2,3]; by influencing autocrine/paracrine factors (e.g. growth factors) [4]; by acting through metabolites that bind to specific membrane receptors and that could have opposite effects on cell proliferation and adhesion [5]; and by influencing the activity of the enzymes involved in the formation and transformation of estrogens in breast tissue [6]. This complexity of effects
C. Campagnoli et al. / Maturitas 62 (2009) 338–342
contributes to explain the fact that, while the proliferative activity of estrogens is well established, the in vitro studies on progesterone activity give contrasting results, even if an antiproliferative effect seems to prevail, due to the antiestrogenic action, favoured, for instance, by the inhibition of estrogen receptor activation [7]. Overall in vivo data suggest that natural progesterone does not have detrimental effects on breast tissue (as reviewed; [8]), consistently with epidemiological findings showing that high levels of endogenous progesterone do not increase [9] or may even reduce [10,11] breast cancer risk in premenopausal women. Moreover, the risk of breast cancer does not appear increased when natural micronized progesterone is added to estrogen in hormone therapy (HT) for postmenopausal women [12,13]. By contrast, most of the studies showed that the addition of synthetic progestins to estrogen in HT significantly increases breast cancer risk compared to estrogen alone [8,12,14]. The increase of the risk refers to both ductal and lobular cancer, but it is particularly elevated for the latter, id est, the histological subtype originating from the functional unit whose development is stimulated by progesterone [13–17]. Progestogens, particularly synthetic progestins, are widely used to contrast the relative hyperestrogenism that characterizes the years preceding the menopause, the so called “menopausal transition” [18,19]. An accepted indication to the cyclical use of progestogens are menstrual irregularities, particularly anovulatory metrorrhagia [20–22] and meno-metrorrhagia associated with miomas [23]. Progestins are also used in the treatment of endometriosis-related complaints [23] or for contraception, particularly as injectable depot medroxyprogesterone acetate (DMPA) or levonorgestrel-releasing intrauterine system (LNG-IUS) [24]. Further indications could be fibrocystic mastopathy, that occurs mainly between the ages of 35 and 50 years [25], and cyclical mastalgia [26,27]. Progestogens to contrast breast problems in premenopausal women are widely prescribed in France [28–30]. This practice was supported by the results of a cohort study of premenopausal women with benign breast disease, in which the long-term use of 19-nortestosterone derivatives was found to be significantly associated with a lower risk of breast cancer [31]. However, a recent large cohort study from France showed an increased breast cancer risk with long-term use of progestogens in premenopausal years [32]. 2. Progestogen-only medications in women approaching the menopause and breast cancer risk: epidemiological findings A comprehensive review on the breast cancer risk associated with the use of progestin-only contraceptives has been recently published by a joint Committee of two Canadian Societies [33]. Some of the “summary statements” were that in general population: (1) use of DMPA does not increase the risk of breast cancer; (2) although not as well-studied as the combined contraceptive pill, progestin-only pills do not appear to increase the risk of breast cancer; (3) the limited data available suggest that LNG-IUS does not seem to increase the risk [33]. The main findings on the breast cancer risk associated with the cyclical use of progestogens to contrast the consequences of the relative hyperestrogenism come from France. This is not surprising, as cyclical progestogens were used in a high percentage of French women, 36%, according to a recent study on 2254 pre- or perimenopausal women aged 45 years or older [30]. Another French study showed that the main indications of progestogen use were functional disorders of perimenopause (57%) and breast problems (47%) [29]. The association of premenopausal progestogen use with breast cancer risk was first studied in a cohort of 1150 French women,
339
80% aged >35 years at first visit, with benign breast disease, who were followed-up for 10 years [31]. In this cohort the overall progestogen use and the duration of use were not found to be associated with breast cancer risk. When progestogens were classified in two categories (19-nortestosterone derivatives vs. other progestogens), 19-nortestosterone derivatives at high doses were found to be significantly associated with a lower breast cancer risk (relative risk (RR): 0.48; 95% confidence interval (CI): 0.25–0.90). These results did not seem to support the hypothesis that progestogens increase breast cancer risk. They suggested instead that high doses of progestogens endowed with strong antigonadotropic activity might have a beneficial effect on the risk of breast cancer in premenopausal women, possibly because they cause a decrease in estradiol levels [34]. In the same cohort study of women with benign breast disease, no association between breast cancer risk and the use of percutaneous progesterone (topically applied on the breast) was observed [35]. The main problem of this cohort study of 1150 women is the limited number of breast cancer (n = 44) observed during the 10 years follow-up period. Different findings were obtained by another study from France, based on the E3N cohort, which includes approximately 100,000 teachers followed up with periodic questionnaires. The association between progestogen-only intake prior to menopause and after the age of 40 years and breast cancer risk was recently studied in approximately 70,000 women of this large cohort [32]. Overall, ever use of progestogens before menopause was not significantly associated with risk. However, a significant increase in risk associated with the duration of use was found. Among current users of progestogens, use longer than 4.5 years was significantly associated with risk (RR: 1.44; 95% CI: 1.03–2.00), but not use shorter than 4.5 years. After discontinuation, and whatever the duration, the risk were close to unity [32]. The data of E3N cohort were furtherly evaluated to assess the risk of breast cancers defined by their histology [F. Clavel-Chapelon, personal communication; 36]. An increased risk of lobular carcinoma associated with premenopausal use of progestogens among both current and past users (Hazard Ratio (HR): 1.51; 95% CI: 1.02–2.24 and HR: 1.38; 95% CI: 1.08–1.75, respectively) was found. Regarding ductal carcinoma, only current use of progestogens for more than 4.5 years was significantly associated with increased risk (HR: 1.49; 95% CI: 1.00–2.22), while current use for less than 4.5 years and past use were not associated with increased risk [36]. Patterns of risk did not show marked differences with the use of different synthetic progestins, either antigonadotropic (chlormadinone acetate, cyproterone acetate, ethynodiol, lynestrenol, medroxyprogesterone acetate (MPA), nomegestrol acetate, norethisterone acetate, promegestone) or not (demegestone, dydrogesterone, medrogestone), and also of micronized progesterone [32]. This latter finding diverges from the result of the study of postmenopausal women of the same cohort suggesting that, contrarily to most of the synthetic progestin, the use of micronized progesterone in the menopausal HT is not associated with an increase in breast cancer risk [12,13]. 3. Discussion The most relevant data on the association of breast cancer risk with progestogens come from studies on the use of these preparations as a part of menopausal HT. According to a comprehensive review published in 2005 [14], evidence from either randomized controlled trials (RCTs) or observational studies indicated that breast cancer risk was increased with estrogen plus progestin more than with estrogen alone. The risk was lower in RCTs than in observational studies (Table 1). As suggested by two recent reports based on the Women’s Health Initiative (WHI) trials and the large WHI
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Table 1 Average estimates of breast cancer risk with hormone use. Unopposed estrogen User cases Randomized controlled trials Adherent women Epidemiological studies Current use Ever use
Estrogen plus progestin RR (95% CI)
User cases
RR (95% CI)
103
0.79 (0.61–1.02)
248
1.24 (1.03–1.50) 1.49 (1.13–1.96)
2862 4193
1.18 (1.01–1.38) 1.08 (0.97–1.20)
3455 4193
1.70 (1.36–2.13) 1.31 (1.12–1.53)
Derived from Ref. [14].
observational study [37,38], the reason of this discrepancy could be that in RCTs a large part of the women began the therapy many years post-menopause, whilst most women in the observational studies began at menopause or within few years of menopause. Most observational studies showed that estrogen plus progestin use was more strongly related to risk of lobular cancer and/or ductal-lobular cancer than to risk of ductal cancer, and that the increased risk diminished after discontinuing hormones and normalized within 5 years [14], independently of histological type [15–17]. The greater part of findings on the consequences of the progestin addition to estrogen in menopausal HT, to which we referred above, came from US, UK or Scandinavian Countries [4,8], where MPA or 19-nortestosterone derivatives were mainly used [8]. No difference, regarding breast cancer risk, was found between these preparations in the Million Women Study [39]. Further informations are given by recent studies from Germany and France, where a wide range of synthetic progestins, and also micronized progesterone, are used in menopausal HT. A population-based case-control study from Germany revealed a higher risk for 19-nortestosterone derivatives than for progesterone derivatives or 17-hydroxyprogesterone derivatives grouped together, but only when they were used in continuous combined regimen [40]. More detailed informations on the single progestogens come from two studies based on the French E3N cohort [12,13]. In this cohort of approximately 80,000 postmenopausal teachers, the first study found that, compared to the use of estrogen alone, the addition of micronized progesterone or of the retroprogesterone dydrogesterone did not increase significantly breast cancer risk, contrarily to other synthetic progestins – chlormadinone acetate, cyproterone acetate, medrogestone, MPA, nomegestrol acetate, norethisterone acetate, promegestone – each significantly associated with a risk increase. The RRs were 1.29 (95% CI: 1.02–1.65) with unopposed estrogen (mainly transdermal estradiol), 1.00 (95% CI: 0.83–1.22) with the addition of micronized progesterone, 1.16 (95% CI: 0.94–1.43) with the addition of dydrogesterone, and 1.69 (95% CI: 1.50–1.91) with the addition of the other synthetic progestins [12]. The second study based on the E3N cohort examined whether the associations of the different types of HTs with breast cancer risk vary across different types of carcinoma [13]. In this study, ever-use of estrogen plus micronized progesterone was not significantly associated with the risk of both ductal and lobular cancers, though a trend of increased risk of lobular carcinoma with increasing duration of use was found; estrogen plus dydrogesterone use were not associated with the risk of ductal cancer and associated with increase of risk of lobular cancer (RR 1.7; 95% CI: 1.1–2.6); on the contrary, use of estrogen plus other synthetic progestins was significantly associated with increased risk of both ductal carcinoma (RR 1.6; 95% CI: 1.3–1.8) and lobular (and ductal-lobular) carcinoma (RR 2.0; 95% CI: 1.5–2.7) [13]. The suggestion, coming from the French studies [12,13], that the addition to estrogen of micronized progesterone or dydrogesterone may have a safer risk profile is consistent with the in vivo data suggesting that natural progesterone does not have detrimental effects on breast tissue (as reviewed, [8]), and with epidemiological find-
ings showing that high levels of endogenous progesterone do not increase [9], or may even reduce [10,11], breast cancer risk in premenopausal women. The activities of dydrogesterone are similar to those of natural progesterone [41], so it is not surprising that it also could have a safer risk profile on the breast than the other synthetic progestins. Micronized progesterone administered in addition to estradiol did not result, compared to estradiol alone, in significantly greater proliferation in lobular and ductal breast epithelium in postmenopausal macaques, contrarily to what was found with the addition of MPA to estradiol [7]. It is not clear how synthetic progestins increase proliferation of breast epithelium and the risk of breast cancer. MPA and 19-nortestosterone derivatives (to the use of which large part of the data on menopausal HT and breast cancer risk refers) have androgenic activities that can increase breast cancer risk via their negative influence on metabolic risk factors [42,43] or via the disruption of androgen receptor signalling [44]. However, in France, from which detailed informations on the use of different progestins come, androgenic progestins were used in only a minority of women [12], while the most used synthetic progestins in menopausal HT were non-androgenic (progesterone derivatives or 19-norprogesterone derivatives) or even antiandrogenic (cyproterone acetate). It is possible that different mechanisms are involved for different progestins. A general explanation could be that – depending on molecular structure, pharmacokinetics and biological potency – some progestins differ from progesterone in interactions with the two isoform of the PR [3,45], and with other members of the nuclear receptor superfamily [2,38,46], leading to non-physiological or over-physiological effects on breast tissue. Particularly relevant could be the fact that, at the currently used doses, the biological potency and the half-life times of oral progesterone, and to a lesser extent of dydrogesterone, are remarkably lower than potency and half-life times of the other synthetic progestins (Tables 2 and 3) [2,46,47]. Both synthetic progestins added to estrogen in menopausal HT [15–17] and progestogens used alone in premenopausal women [F. Clavel-Chapelon, personal communication; 36] are more markedly related to risk of lobular than ductal cancer. This could find a biological plausibility in studies suggesting that progesterone stimulates lobular-alveolar unit [1]. However, women of less of 40 years, in spite of endogenous progesterone, show, respect to older women, a percentage of lobular cancer significantly lower than the percentage of ductal cancer, the great majority of lobular cancer being diagnosed in older women even in Countries where Table 2 Potencies of different oral progestogens. Progestin
Therapeutic dose
Levonorgestrel Norethisterone Medroxyprogesterone acetate Dydrogesterone Progesterone
0.15–0.5 mg 1 mg 2.5–10 mg 20 mg 100–300 mg
Derived from Ref. [46].
Potency 2–6.7 1 0.1–0.4 0.05 0.0033–0.01
C. Campagnoli et al. / Maturitas 62 (2009) 338–342 Table 3 Pharmacokinetic differences between oral progestins: progesterone derivatives and 19-norprogesterone derivatives. Preparation Dydrogesterone Medroxyprogesterone acetate Medrogestone Nomegestrol acetate Chlormadinone acetate Cyproterone acetate
Storage in fat tissue +
++ ++
Half life (t1/2 ) (h) 14–17 15–30 35 30–50 40–80 50–60
Derived from Refs. [2,47].
hormone therapies are less frequently used [48]. Estrogen plus progestin HT is associated with significant elevation in lobular cancer risk even after a brief period of use (odds ratios 4.2; 95% CI: 1.8–9.8, for 3–4.9 years of use) [17]. It is possible that estrogen plus progestin stimulate the growth of foci of lobular carcinoma that would remain undetectable in the absence of HT exposure [17]. The possibility that progestins exert non-physiological or over-physiological effects cannot be discharged. Progestogen-only therapy before menopause seems to be associated with an increased risk of lobular cancer even in past users (HR: 1.38; 95% CI: 1.08–1.75) [36]. On the contrary, studies on the progestins in menopausal HT consistently did not find a risk increase in past users, independently of histological type [15,17]. This discrepancy could be due to differences in estrogen level and/or activity between women in premenopausal years and women on menopausal HT. Oral estrogens can have some relevant peculiarities (as reviewed; [42]) and the widely used conjugated equine estrogens, particularly when initiated some years after onset of menopause [38], tend to decrease the risk of breast cancer [49], and specifically the risk of ductal carcinoma without increasing the risk of lobular carcinoma [17]. Regarding transdermal estradiol administered by patches or percutaneous gel, the current therapeutic doses lead to estradiol levels of 30–90 pg/ml [2], while mean estradiol level during the perimenopausal transition is higher (approximately 130 pg/ml) [18]. Indeed, estrogen level do not begin to decline until less than a year before menopause and women experiencing perimenopausal transition actually have higher overall estrogen levels, a fact that is explained by an increased ovarian response to the increase of FSH [18,50]. Moreover, some data suggest that serum level of estradiol could be even higher in cases in which progestogens are indicated, for instance perimenopausal meno-metrorrhagia [51]. The safer risk profile of progesterone and dydrogesterone respect to other synthetic progestins, as showed in the studies on menopausal HT [12,13], did not emerge in the studies on progestogen use in premenopausal years [32,36]. This could be partially due to limited number of cases in the subgroups of women treated with the different progestogens. However, the differences in estrogen activity between premenopausal women and postmenopausal women treated with transdermal estradiol or oral estrogen (see above), might contribute to explain this discrepancy. 4. Conclusive remarks Anovulatory metrorrhagia and meno-metrorrhagia associated with miomas are the most important and widely accepted indication to the use of progestogen alone in the years preceding the menopause [20–23]. The mean duration of perimenopausal transition, when anovulation becomes prevalent, is 5.0 years, with a range of 2–8 years [18]. Generally, use of progestogens for menstrual irregularities is limited either in number of days for treatment cycle (10–15 days) or in number of treatment cycles, 12 or less according to a French report [29]. Available data suggest that, in
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premenopausal women of more than 40 years, overall breast cancer risk increases for progestogen use longer than 4.5 years but not for use shorter than 4.5 years [32]. Awaiting for further data, when using progestogens for longer periods to treat other problems (endometriosis, cyclical mastalgia, etc.), the possibility of an increased breast cancer risk and clinical benefits have to be weighed. Anyway, as natural progesterone and dydrogesterone, at least when they were used in postmenopausal HT [12,13], seem to have a safer risk profile on the breast, the preferential use of these preparations could be suggested. Conflict of interest Prof. Campagnoli received support as speaker in congress and meetings or as participant in study groups from (in alphabetic order) Effik, Eli Lilly, Novo-Nordisk, Organon, Rottapharm, Schering, Solvay, Wyeth. References [1] Clarke RB. Ovarian steroids and the human breast: regulation of stem cells and cell proliferation. Maturitas 2006;54:327–34. [2] Kuhl H. Pharmacology of estrogens and progestins: influence of different routes of administration. Climacteric 2005;8(S1):S3–63. [3] Leo JCL, Lin VCN. The activities of progesterone receptor isoform A and B are differentially modulated by their ligands in a gene-selective manner. Int J Cancer 2008;122:230–43. [4] Seeger H, Mueck AO. Are the progestins responsible for breast cancer risk during hormone therapy in the postmenopause? Experimental vs. clinical data. J Steroid Biochem Mol Biol 2008;109:11–5. [5] Wiebe JP. Progesterone metabolites in breast cancer. Endocr Relat Cancer 2006;13:717–38. [6] Pasqualini JR. Progestins and breast cancer. Gynecol Endocrinol 2007; 23(S1):32–41. [7] Wood CE, Register TC, Lees CJ, Chen H, Kimrey S, Cline JM. Effects of estradiol with micronized progesterone or medroxyprogesterone acetate on risk markers for breast cancer in postmenopausal monkeys. Breast Cancer Res Treat 2007;101:125–34. [8] Campagnoli C, Clavel-Chapelon F, Kaaks R, Peris C, Berrino F. Progestins and progesterone in hormone replacement therapy and the risk of breast cancer. J Steroid Biochem Mol Biol 2005;96:95–108. [9] Eliassen AH, Missmer SA, Tworoger SS, et al. Endogenous steroid hormone concentrations and risk of breast cancer among premenopausal women. J Natl Cancer Inst 2006;98:1406–15. [10] Micheli A, Muti P, Secreto G, et al. Endogenous sex hormones and subsequent breast cancer in premenopausal women. Int J Cancer 2004;112:312–8. [11] Kaaks R, Berrino F, Key T, et al. Serum sex steroids in premenopausal women and breast cancer risk within the European Prospective Investigation into Cancer and Nutrition (EPIC). J Natl Cancer Inst 2005;97:755–65. [12] Fournier A, Berrino F, Clavel-Chapelon F. Unequal risks for breast cancer associated with different hormone replacement therapies: results from the E3N cohort study. Breast Cancer Res Treat 2008;107:103–11. [13] Fournier A, Fabre A, Mesrine S, Boutron-Ruault MC, Berrino F, Clavel-Chapelon F. Use of different postmenopausal hormone therapies and risk of histology- and hormone receptor-defined invasive breast cancer. J Clin Oncol 2008;26:1260–8. [14] Collins JA, Blake JM, Crosignani PG. Breast cancer risk with postmenopausal hormone treatment. Hum Reprod Update 2005;11:545–60. [15] Reeves GK, Beral V, Green J, Gathani T, Bull D. Hormonal therapy for menopause and breast cancer risk by histological type: a cohort study and meta-analysis. Lancet Oncol 2006;7:910–8. [16] Biglia N, Mariani L, Sgro L, Mininanni P, Moggio G, Sismondi P. Increased incidence of lobular breast cancer in women treated with hormone replacement therapy: implications for diagnosis, surgical and medical treatment. Endocr Relat Cancer 2007;14:549–67. [17] Li CI, Malone KE, Porter KE, et al. Relationship between menopausal hormone therapy and risk of ductal, lobular, and ductal-lobular breast carcinomas. Cancer Epidemiol Biomarkers Prev 2008;17:43–50. [18] Speroff L. The perimenopausal transition. Ann NY Acad Sci 2000;900:375–92. [19] Practice Committee of the American Society for Reproductive Medicine. The menopausal transition. Fertil Steril 2006;86(S5):S253–6. [20] Jain A, Santoro N. Endocrine mechanisms and management for abnormal bleeding due to perimenopausal changes. Clin Obstet Gynecol 2005;48:295–331. [21] Duckitt K. Medical management of perimenopausal menorrhagia: an evidencebased approach. Menopause Int 2007;13:14–8. [22] Hickey M, Higham J, Fraser IS. The Cochrane Database of Systemic ReviewsProgestogens versus oestrogens and progestogens for irregular uterine bleeding associated with anovulation. Cochrane Libr 2008;2.
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